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Venkatesh V, Frishman WH, Aronow WS. Coarctation of the Aorta: Review of Current Literature. Cardiol Rev 2025:00045415-990000000-00468. [PMID: 40249172 DOI: 10.1097/crd.0000000000000936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/19/2025]
Abstract
Coarctation of the aorta (CoA) is a cardiovascular anomaly characterized by focal narrowing of the aorta, typically occurring near the insertion of the ductus arteriosus in the descending aorta. CoA is most commonly a congenital heart defect, usually coexisting with other cardiac congenital defects, however, rarely can be acquired in high inflammatory states. Precise pathogenesis is unknown; however, it is hypothesized that CoA is due to altered intrauterine blood flow leading to underdevelopment of the aortic arch, along with involvement of excessive ductal tissue into the wall of the aorta. Clinical manifestation varies based on age of presentation but the most common finding in adult patients is early onset hypertension with decreased blood supply to the lower extremities. There is a variety of both invasive and noninvasive diagnostic modalities to confirm the presence of CoA. Management options include prompt invasive correction with balloon angioplasty, percutaneous stent placement, or surgery. Patients with CoA require long-term follow-up but generally have favorable outcomes with timely diagnosis.
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Affiliation(s)
- Vishnu Venkatesh
- From the Departments of Cardiology and Medicine, Westchester Medical Center and New York Medical College, Valhalla, NY
| | | | - Wilbert S Aronow
- From the Departments of Cardiology and Medicine, Westchester Medical Center and New York Medical College, Valhalla, NY
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2
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Melik I, Brackett DG, Sanders SP, Carreon CK. Anomalous Origin of the Right Coronary Artery From Pulmonary Trunk in a Hypoplastic Left Heart Syndrome With 15q11.2 BP1-BP2 Microdeletion: A Novel Association. Pediatr Dev Pathol 2025; 28:133-136. [PMID: 39690518 DOI: 10.1177/10935266241304856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2024]
Abstract
A 15q11.2 (BP1-BP2) deletion was detected in a 4-day-old boy who had hypoplastic left heart syndrome (HLHS) diagnosed prenatally by echocardiography. Postmortem examination revealed an anomalous origin of the right coronary artery from the pulmonary trunk (ARCAPT). This genetic defect is known to cause syndromic presentations and believed to participate in cardiovascular defects but to the best of our knowledge no HLHS with ARCAPT was reported to have this genetic defect before. This case presents a novel association and suggests involvement of the 15q11.2 deletion in a syndromic presentation. Further studies are necessary to explore this genetic link and its clinical implications.
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Affiliation(s)
- Ibrahim Melik
- The Cardiac Registry, Departments of Cardiology, Pathology, and Cardiac Surgery, Boston Children's Hospital, Boston, MA, USA
- Tanta University, Tanta, Egypt
| | - Diane G Brackett
- Department of Pathology, Massachusetts General Hospital and Cambridge Health Alliance, Boston, MA, USA
- Department of Pathology, Harvard Medical School, Boston, MA, USA
| | - Stephen P Sanders
- The Cardiac Registry, Departments of Cardiology, Pathology, and Cardiac Surgery, Boston Children's Hospital, Boston, MA, USA
- Department of Pediatrics, Harvard Medical School, Boston, MA, USA
| | - Chrystalle Katte Carreon
- The Cardiac Registry, Departments of Cardiology, Pathology, and Cardiac Surgery, Boston Children's Hospital, Boston, MA, USA
- Department of Pathology, Harvard Medical School, Boston, MA, USA
- Department of Pathology, Boston Children's Hospital, Boston, MA, USA
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3
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Diaz-Gil D, Silva-Gomez N, Morton SU, Seidman JG, Seidman CE, Zurakowski D, Staffa SJ, Marx GR, Emani SM, Del Nido PJ, Friehs I. Predictive modeling of endocardial fibroelastosis recurrence in patients with congenital heart disease. J Thorac Cardiovasc Surg 2025; 169:366-374. [PMID: 39208926 DOI: 10.1016/j.jtcvs.2024.08.036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Revised: 08/14/2024] [Accepted: 08/15/2024] [Indexed: 09/04/2024]
Abstract
BACKGROUND Endocardial fibroelastosis (EFE) is a major effector in the maldevelopment of the heart in patients with congenital heart disease. Despite successful surgical removal, EFE can redevelop, but the underlying cause of EFE recurrence remains unknown. This study aimed to identify hemodynamic predictors and genetic links to epithelial/endothelial-to-mesenchymal transition (EMT/EndMT) alterations for preoperative risk assessment. METHODS We assessed the impact of preoperative hemodynamic parameters on EFE recurrence in a cohort of 92 patients with congenital heart disease who underwent left ventricular (LV) EFE resection between January 2010 and March 2021. Additionally, whole-exome sequencing in 18 patients was used to identify rare variants (minor allele frequency <10-5) in high-expression heart (HHE) genes related to cardiac EMT/EndMT and congenital heart disease. RESULTS EFE recurred in 55.4% of patients, within a median of 2.2 years postsurgery. Multivariable analysis revealed specific hemodynamic parameters (mitral valve inflow and area, LV filling pressure, and aortic valve gradient and diameter) as predictors, forming a predictive model with an area under the receiver operating characteristic curve of 0.782. Furthermore, 89% of the patients exhibited damaging variants in HHE genes, with 38% linked to cardiac EMT/EndMT Gene Ontology processes and 22% associated with known congenital heart disease genes. Notably, HHE genes associated with cardiac EMT/EndMT were significantly associated with faster EFE recurrence in a multivariate analysis (hazard ratio, 3.56; 95% confidence interval, 1.24-10.17; P = .018). CONCLUSIONS These findings established a predictive scoring system using preoperative hemodynamic parameters for EFE recurrence risk assessment. Alterations in HHE genes, particularly those linked to cardiac EMT/EndMT, exacerbate the risk of recurrence.
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Affiliation(s)
- Daniel Diaz-Gil
- Department of Cardiac Surgery, Boston Children's Hospital, Boston, Mass; Department of Pediatrics, Boston Children's Hospital, Boston, Mass; Department of Pediatrics, Harvard Medical School, Boston, Mass; Department of Pediatrics, Boston University Chobanian & Avedisian School of Medicine, Boston, Mass; Department of Pediatric Heart Medicine and Adults with Congenital Heart Disease, University Heart and Vascular Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | - Sarah U Morton
- Department of Pediatrics, Boston Children's Hospital, Boston, Mass; Department of Pediatrics, Harvard Medical School, Boston, Mass; Division of Newborn Medicine, Department of Medicine, Boston Children's Hospital, Boston, Mass
| | | | - Christine E Seidman
- Department of Genetics, Harvard Medical School, Boston, Mass; Cardiovascular Division, Brigham and Women's Hospital, Boston, Mass; Department of Medicine, Harvard Medical School, Boston, Mass; Howard Hughes Medical Institute, Chevy Chase, Md
| | - David Zurakowski
- Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Boston, Mass; Department of Anesthesia, Harvard Medical School, Boston, Mass
| | - Steven J Staffa
- Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Boston, Mass
| | - Gerald R Marx
- Department of Pediatrics, Harvard Medical School, Boston, Mass; Department of Cardiology, Boston Children's Hospital, Boston, Mass
| | - Sitaram M Emani
- Department of Cardiac Surgery, Boston Children's Hospital, Boston, Mass; Department of Surgery, Harvard Medical School, Boston, Mass
| | - Pedro J Del Nido
- Department of Cardiac Surgery, Boston Children's Hospital, Boston, Mass; Department of Surgery, Harvard Medical School, Boston, Mass
| | - Ingeborg Friehs
- Department of Cardiac Surgery, Boston Children's Hospital, Boston, Mass; Department of Surgery, Harvard Medical School, Boston, Mass.
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4
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Gabriel GC, Yagi H, Tan T, Bais A, Glennon BJ, Stapleton MC, Huang L, Reynolds WT, Shaffer MG, Ganapathiraju M, Simon D, Panigrahy A, Wu YL, Lo CW. Mitotic block and epigenetic repression underlie neurodevelopmental defects and neurobehavioral deficits in congenital heart disease. Nat Commun 2025; 16:469. [PMID: 39774941 PMCID: PMC11707140 DOI: 10.1038/s41467-024-55741-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Accepted: 12/24/2024] [Indexed: 01/11/2025] Open
Abstract
Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease associated with microcephaly and poor neurodevelopmental outcomes. Here we show that the Ohia HLHS mouse model, with mutations in Sap130, a chromatin modifier, and Pcdha9, a cell adhesion protein, also exhibits microcephaly associated with mitotic block and increased apoptosis leading to impaired cortical neurogenesis. Transcriptome profiling, DNA methylation, and Sap130 ChIPseq analyses all demonstrate dysregulation of genes associated with autism and cognitive impairment. This includes perturbation of REST transcriptional regulation of neurogenesis, disruption of CREB signaling regulating synaptic plasticity, and defects in neurovascular coupling mediating cerebral blood flow. Adult mice harboring either the Pcdha9 mutation, which show normal brain anatomy, or forebrain-specific Sap130 deletion via Emx1-Cre, which show microcephaly, both demonstrate learning and memory deficits and autism-like behavior. These findings provide mechanistic insights indicating the adverse neurodevelopment in HLHS may involve cell autonomous/nonautonomous defects and epigenetic dysregulation.
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Affiliation(s)
- George C Gabriel
- Department of Pediatrics and Department of Developmental Biology, University of Pittsburgh, Pittsburgh, USA
| | - Hisato Yagi
- Department of Pediatrics and Department of Developmental Biology, University of Pittsburgh, Pittsburgh, USA
| | - Tuantuan Tan
- Department of Pediatrics and Department of Developmental Biology, University of Pittsburgh, Pittsburgh, USA
| | - Abha Bais
- Department of Pediatrics and Department of Developmental Biology, University of Pittsburgh, Pittsburgh, USA
| | - Benjamin J Glennon
- Department of Pediatrics and Department of Developmental Biology, University of Pittsburgh, Pittsburgh, USA
| | - Margaret C Stapleton
- Department of Pediatrics and Department of Developmental Biology, University of Pittsburgh, Pittsburgh, USA
| | - Lihua Huang
- Chinese University of Hong Kong, Hong Kong, China
| | - William T Reynolds
- Department of Pediatrics and Department of Developmental Biology, University of Pittsburgh, Pittsburgh, USA
| | - Marla G Shaffer
- Department of Pediatrics and Department of Developmental Biology, University of Pittsburgh, Pittsburgh, USA
| | | | - Dennis Simon
- Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, USA
| | - Ashok Panigrahy
- Department of Radiology, University of Pittsburgh, Pittsburgh, USA
| | - Yijen L Wu
- Department of Pediatrics and Department of Developmental Biology, University of Pittsburgh, Pittsburgh, USA
| | - Cecilia W Lo
- Department of Pediatrics and Department of Developmental Biology, University of Pittsburgh, Pittsburgh, USA.
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Nappi F. In-Depth Genomic Analysis: The New Challenge in Congenital Heart Disease. Int J Mol Sci 2024; 25:1734. [PMID: 38339013 PMCID: PMC10855915 DOI: 10.3390/ijms25031734] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Revised: 01/25/2024] [Accepted: 01/27/2024] [Indexed: 02/12/2024] Open
Abstract
The use of next-generation sequencing has provided new insights into the causes and mechanisms of congenital heart disease (CHD). Examinations of the whole exome sequence have detected detrimental gene variations modifying single or contiguous nucleotides, which are characterised as pathogenic based on statistical assessments of families and correlations with congenital heart disease, elevated expression during heart development, and reductions in harmful protein-coding mutations in the general population. Patients with CHD and extracardiac abnormalities are enriched for gene classes meeting these criteria, supporting a common set of pathways in the organogenesis of CHDs. Single-cell transcriptomics data have revealed the expression of genes associated with CHD in specific cell types, and emerging evidence suggests that genetic mutations disrupt multicellular genes essential for cardiogenesis. Metrics and units are being tracked in whole-genome sequencing studies.
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Affiliation(s)
- Francesco Nappi
- Department of Cardiac Surgery, Centre Cardiologique du Nord, 93200 Saint-Denis, France
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6
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Yagi H, Xu X, Gabriel GC, Lo C. Molecular Pathways and Animal Models of Hypoplastic Left Heart Syndrome. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1441:947-961. [PMID: 38884763 DOI: 10.1007/978-3-031-44087-8_61] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/18/2024]
Abstract
Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease (CHD) with underdevelopment of left-sided heart structures. While previously uniformly fatal, surgical advances now provide highly effective palliation that allows most HLHS patients to survive their critical CHD. Nevertheless, there remains high morbidity and mortality with high risk of heart failure. As hemodynamic compromise from restricted aortic blood flow has been suggested to underlie the poor LV growth, this suggests the possibility of prenatal fetal intervention to recover LV growth. As such interventions have yielded ambiguous results, the optimization of therapy will require more mechanistic insights into the developmental etiology for HLHS. Clinical studies have shown high heritability for HLHS, with an oligogenic etiology indicated in conjunction with genetic heterogeneity. This is corroborated with the recent recovery of mutant mice with HLHS. With availability-induced pluripotent stem cell (iPSC)-derived cardiomyocytes from HLHS mice and patients, new insights have emerged into the cellular and molecular etiology for the LV hypoplasia in HLHS. Cell proliferation defects were observed in conjunction with metaphase arrest and the disturbance of Hippo-YAP signaling. The left-sided restriction of the ventricular hypoplasia may result from epigenetic perturbation of pathways regulating left-right patterning. These findings suggest new avenues for fetal interventions with therapies using existing drugs that target the Hippo-YAP pathway and/or modulate epigenetic regulation.
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Affiliation(s)
- Hisato Yagi
- Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Xinxiu Xu
- Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - George C Gabriel
- Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Cecilia Lo
- Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
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7
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Pfitzer C, Schmitt KRL, Benson WD. Human Genetics of Hypoplastic Left Heart Syndrome. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1441:937-945. [PMID: 38884762 DOI: 10.1007/978-3-031-44087-8_60] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/18/2024]
Abstract
Hypoplastic left heart syndrome (HLHS) is a severe congenital cardiovascular malformation characterized by hypoplasia of the left ventricle, aorta, and other structures on the left side of the heart. The pathologic definition includes atresia or stenosis of both the aortic and mitral valves. Despite considerable progress in clinical and surgical management of HLHS, mortality and morbidity remain concerns. One barrier to progress in HLHS management is poor understanding of its cause. Several lines of evidence point to genetic origins of HLHS. First, some HLHS cases have been associated with cytogenetic abnormalities (e.g., Turner syndrome). Second, studies of family clustering of HLHS and related cardiovascular malformations have determined HLHS is heritable. Third, genomic regions that encode genes influencing the inheritance of HLHS have been identified. Taken together, these diverse studies provide strong evidence for genetic origins of HLHS and related cardiac phenotypes. However, using simple Mendelian inheritance models, identification of single genetic variants that "cause" HLHS has remained elusive, and in most cases, the genetic cause remains unknown. These results suggest that HLHS inheritance is complex rather than simple. The implication of this conclusion is that researchers must move beyond the expectation that a single disease-causing variant can be found. Utilization of complex models to analyze high-throughput genetic data requires careful consideration of study design.
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Affiliation(s)
- Constanze Pfitzer
- Department of Congenital Heart Disease/Paediatric Cardiology, German Heart Center Berlin, Berlin, Germany
| | - Katharina R L Schmitt
- Department of Congenital Heart Disease/Paediatric Cardiology, German Heart Center Berlin, Berlin, Germany
| | - Woodrow D Benson
- Department of Pediatrics, Herma Heart Center, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee, WI, USA.
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Blue EE, White JJ, Dush MK, Gordon WW, Wyatt BH, White P, Marvin CT, Helle E, Ojala T, Priest JR, Jenkins MM, Almli LM, Reefhuis J, Pangilinan F, Brody LC, McBride KL, Garg V, Shaw GM, Romitti PA, Nembhard WN, Browne ML, Werler MM, Kay DM, National Birth Defects Prevention Study, University of Washington Center for Mendelian Genomics, Mital S, Chong JX, Nascone-Yoder NM, Bamshad MJ. Rare variants in CAPN2 increase risk for isolated hypoplastic left heart syndrome. HGG ADVANCES 2023; 4:100232. [PMID: 37663545 PMCID: PMC10474499 DOI: 10.1016/j.xhgg.2023.100232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Accepted: 08/07/2023] [Indexed: 09/05/2023] Open
Abstract
Hypoplastic left heart syndrome (HLHS) is a severe congenital heart defect (CHD) characterized by hypoplasia of the left ventricle and aorta along with stenosis or atresia of the aortic and mitral valves. HLHS represents only ∼4%-8% of all CHDs but accounts for ∼25% of deaths. HLHS is an isolated defect (i.e., iHLHS) in 70% of families, the vast majority of which are simplex. Despite intense investigation, the genetic basis of iHLHS remains largely unknown. We performed exome sequencing on 331 families with iHLHS aggregated from four independent cohorts. A Mendelian-model-based analysis demonstrated that iHLHS was not due to single, large-effect alleles in genes previously reported to underlie iHLHS or CHD in >90% of families in this cohort. Gene-based association testing identified increased risk for iHLHS associated with variation in CAPN2 (p = 1.8 × 10-5), encoding a protein involved in functional adhesion. Functional validation studies in a vertebrate animal model (Xenopus laevis) confirmed CAPN2 is essential for cardiac ventricle morphogenesis and that in vivo loss of calpain function causes hypoplastic ventricle phenotypes and suggest that human CAPN2707C>T and CAPN21112C>T variants, each found in multiple individuals with iHLHS, are hypomorphic alleles. Collectively, our findings show that iHLHS is typically not a Mendelian condition, demonstrate that CAPN2 variants increase risk of iHLHS, and identify a novel pathway involved in HLHS pathogenesis.
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Affiliation(s)
- Elizabeth E. Blue
- Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA
- Brotman Baty Institute for Precision Medicine, Seattle, WA, USA
| | | | - Michael K. Dush
- Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, NC, USA
| | - William W. Gordon
- Department of Pediatrics, University of Washington, Seattle, WA, USA
| | - Brent H. Wyatt
- Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, NC, USA
| | - Peter White
- Institute for Genomic Medicine, Nationwide Children’s Hospital, and Department of Pediatrics, The Ohio State University, Columbus, OH, USA
| | - Colby T. Marvin
- Department of Pediatrics, University of Washington, Seattle, WA, USA
| | - Emmi Helle
- New Children’s Hospital and Pediatric Research Center, Helsinki University Hospital, Helsinki, Finland
- Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Tiina Ojala
- New Children’s Hospital and Pediatric Research Center, Helsinki University Hospital, Helsinki, Finland
| | - James R. Priest
- Stanford University School of Medicine, Lucile Packard Children’s Hospital, Stanford, CA, USA
| | - Mary M. Jenkins
- National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Lynn M. Almli
- National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Jennita Reefhuis
- National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Faith Pangilinan
- Genetics and Environment Interaction Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
| | - Lawrence C. Brody
- Genetics and Environment Interaction Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
| | - Kim L. McBride
- Center for Cardiovascular Research, Nationwide Children’s Hospital, and Division of Genetic and Genomic Medicine, Department of Pediatrics, The Ohio State University, Columbus, OH, USA
| | - Vidu Garg
- Center for Cardiovascular Research and The Heart Center, Nationwide Children’s Hospital, and Department of Pediatrics, The Ohio State University, Columbus, OH, USA
| | - Gary M. Shaw
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA
| | - Paul A. Romitti
- Department of Epidemiology, College of Public Health, The University of Iowa, Iowa City, IA, USA
| | | | - Marilyn L. Browne
- Birth Defects Registry, New York State Department of Health, Albany, NY, USA
- Department of Epidemiology and Biostatistics, School of Public Health, University at Albany, Rensselaer, NY, USA
| | - Martha M. Werler
- Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA
| | - Denise M. Kay
- Division of Genetics, Wadsworth Center, New York State Department of Health, Albany, NY, USA
| | - National Birth Defects Prevention Study
- Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA
- Brotman Baty Institute for Precision Medicine, Seattle, WA, USA
- Invitae, San Francisco, CA, USA
- Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, NC, USA
- Department of Pediatrics, University of Washington, Seattle, WA, USA
- Institute for Genomic Medicine, Nationwide Children’s Hospital, and Department of Pediatrics, The Ohio State University, Columbus, OH, USA
- New Children’s Hospital and Pediatric Research Center, Helsinki University Hospital, Helsinki, Finland
- Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Stanford University School of Medicine, Lucile Packard Children’s Hospital, Stanford, CA, USA
- National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA, USA
- Genetics and Environment Interaction Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
- Center for Cardiovascular Research, Nationwide Children’s Hospital, and Division of Genetic and Genomic Medicine, Department of Pediatrics, The Ohio State University, Columbus, OH, USA
- Center for Cardiovascular Research and The Heart Center, Nationwide Children’s Hospital, and Department of Pediatrics, The Ohio State University, Columbus, OH, USA
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA
- Department of Epidemiology, College of Public Health, The University of Iowa, Iowa City, IA, USA
- University of Arkansas for Medical Sciences, Little Rock, AR, USA
- Birth Defects Registry, New York State Department of Health, Albany, NY, USA
- Department of Epidemiology and Biostatistics, School of Public Health, University at Albany, Rensselaer, NY, USA
- Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA
- Division of Genetics, Wadsworth Center, New York State Department of Health, Albany, NY, USA
- Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
- Department of Genome Sciences, University of Washington, Seattle, WA, USA
| | - University of Washington Center for Mendelian Genomics
- Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA
- Brotman Baty Institute for Precision Medicine, Seattle, WA, USA
- Invitae, San Francisco, CA, USA
- Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, NC, USA
- Department of Pediatrics, University of Washington, Seattle, WA, USA
- Institute for Genomic Medicine, Nationwide Children’s Hospital, and Department of Pediatrics, The Ohio State University, Columbus, OH, USA
- New Children’s Hospital and Pediatric Research Center, Helsinki University Hospital, Helsinki, Finland
- Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Stanford University School of Medicine, Lucile Packard Children’s Hospital, Stanford, CA, USA
- National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA, USA
- Genetics and Environment Interaction Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
- Center for Cardiovascular Research, Nationwide Children’s Hospital, and Division of Genetic and Genomic Medicine, Department of Pediatrics, The Ohio State University, Columbus, OH, USA
- Center for Cardiovascular Research and The Heart Center, Nationwide Children’s Hospital, and Department of Pediatrics, The Ohio State University, Columbus, OH, USA
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA
- Department of Epidemiology, College of Public Health, The University of Iowa, Iowa City, IA, USA
- University of Arkansas for Medical Sciences, Little Rock, AR, USA
- Birth Defects Registry, New York State Department of Health, Albany, NY, USA
- Department of Epidemiology and Biostatistics, School of Public Health, University at Albany, Rensselaer, NY, USA
- Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA
- Division of Genetics, Wadsworth Center, New York State Department of Health, Albany, NY, USA
- Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
- Department of Genome Sciences, University of Washington, Seattle, WA, USA
| | - Seema Mital
- Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
| | - Jessica X. Chong
- Brotman Baty Institute for Precision Medicine, Seattle, WA, USA
- Department of Pediatrics, University of Washington, Seattle, WA, USA
| | | | - Michael J. Bamshad
- Brotman Baty Institute for Precision Medicine, Seattle, WA, USA
- Department of Pediatrics, University of Washington, Seattle, WA, USA
- Department of Genome Sciences, University of Washington, Seattle, WA, USA
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9
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Paul EA, Cohen J, Geiger MK. Cardiac problems in the fetus: a review for pediatric providers. Curr Opin Pediatr 2023; 35:523-530. [PMID: 37466056 DOI: 10.1097/mop.0000000000001274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/20/2023]
Abstract
PURPOSE OF REVIEW The aim of this study was to provide pediatric providers with a review of the diagnosis and management of fetal cardiac disease in the current era. RECENT FINDINGS Prenatal detection of congenital heart disease (CHD) has improved but is still imperfect. In experienced hands, fetal echocardiography can detect severe CHD as early as the first trimester and a majority of more subtle conditions in the second and third trimesters. Beyond detection, a prenatal diagnosis allows for lesion-specific counseling for families as well as for development of a multidisciplinary perinatal management plan, which may involve in-utero treatment. Given the diversity of cardiac diagnoses and the rarity of some, collaborative multicenter fetal cardiac research has gained momentum in recent years. SUMMARY Accurate diagnosis of fetal cardiac disease allows for appropriate counseling, pregnancy and delivery planning, and optimization of immediate neonatal care. There is potential for improving fetal CHD detection rates. Fetal interventions are available for certain conditions, and fetal and pediatric cardiac centers have developed management plans specific to the expected postnatal physiology.
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Affiliation(s)
- Erin A Paul
- Division of Pediatric Cardiology, Mount Sinai Kravis Children's Hospital, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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10
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Reuter MS, Sokolowski DJ, Javier Diaz-Mejia J, Keunen J, de Vrijer B, Chan C, Wang L, Ryan G, Chiasson DA, Ketela T, Scherer SW, Wilson MD, Jaeggi E, Chaturvedi RR. Decreased left heart flow in fetal lambs causes left heart hypoplasia and pro-fibrotic tissue remodeling. Commun Biol 2023; 6:770. [PMID: 37481629 PMCID: PMC10363152 DOI: 10.1038/s42003-023-05132-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 07/11/2023] [Indexed: 07/24/2023] Open
Abstract
Low blood flow through the fetal left heart is often conjectured as an etiology for hypoplastic left heart syndrome (HLHS). To investigate if a decrease in left heart flow results in growth failure, we generate left ventricular inflow obstruction (LVIO) in mid-gestation fetal lambs by implanting coils in their left atrium using an ultrasound-guided percutaneous technique. Significant LVIO recapitulates important clinical features of HLHS: decreased antegrade aortic valve flow, compensatory retrograde perfusion of the brain and ascending aorta (AAo) from the arterial duct, severe left heart hypoplasia, a non-apex forming LV, and a thickened endocardial layer. The hypoplastic AAo have miRNA-gene pairs annotating to cell proliferation that are inversely differentially expressed by bulk RNA-seq. Single-nucleus RNA-seq of the hypoplastic LV myocardium shows an increase in fibroblasts with a reciprocal decrease in cardiomyocyte nuclei proportions. Fibroblasts, cardiomyocytes and endothelial cells from hypoplastic myocardium have increased expression of extracellular matrix component or fibrosis genes with dysregulated fibroblast growth factor signaling. Hence, a severe sustained ( ~ 1/3 gestation) reduction in fetal left heart flow is sufficient to cause left heart hypoplasia. This is accompanied by changes in cellular composition and gene expression consistent with a pro-fibrotic environment and aberrant induction of mesenchymal programs.
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Affiliation(s)
- Miriam S Reuter
- CGEn, The Hospital for Sick Children, Toronto, ON, Canada
- The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, Canada
- Genetics and Genome Biology, SickKids Research Institute, Toronto, ON, Canada
| | - Dustin J Sokolowski
- Genetics and Genome Biology, SickKids Research Institute, Toronto, ON, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
| | - J Javier Diaz-Mejia
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Johannes Keunen
- Ontario Fetal Centre, Department of Obstetrics & Gynaecology, Mount Sinai Hospital, Toronto, ON, Canada
- Department of Obstetrics & Gynaecology, University of Toronto, Toronto, ON, Canada
| | - Barbra de Vrijer
- Department of Obstetrics & Gynaecology, Western University, London, ON, Canada
- Children's Health Research Institute, London, ON, Canada
- London Health Sciences Centre, Victoria Hospital, London, ON, Canada
| | - Cadia Chan
- Genetics and Genome Biology, SickKids Research Institute, Toronto, ON, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
| | - Liangxi Wang
- Genetics and Genome Biology, SickKids Research Institute, Toronto, ON, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
| | - Greg Ryan
- Ontario Fetal Centre, Department of Obstetrics & Gynaecology, Mount Sinai Hospital, Toronto, ON, Canada
- Department of Obstetrics & Gynaecology, University of Toronto, Toronto, ON, Canada
| | - David A Chiasson
- Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada
- Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Troy Ketela
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Stephen W Scherer
- The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, Canada
- Genetics and Genome Biology, SickKids Research Institute, Toronto, ON, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
- McLaughlin Centre, University of Toronto, Toronto, ON, Canada
| | - Michael D Wilson
- Genetics and Genome Biology, SickKids Research Institute, Toronto, ON, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
| | - Edgar Jaeggi
- Ontario Fetal Centre, Department of Obstetrics & Gynaecology, Mount Sinai Hospital, Toronto, ON, Canada
- Labatt Family Heart Centre, Division of Cardiology, The Hospital for Sick Children, Toronto, ON, Canada
- Department of Paediatrics, University of Toronto, Toronto, ON, Canada
| | - Rajiv R Chaturvedi
- Ontario Fetal Centre, Department of Obstetrics & Gynaecology, Mount Sinai Hospital, Toronto, ON, Canada.
- Labatt Family Heart Centre, Division of Cardiology, The Hospital for Sick Children, Toronto, ON, Canada.
- Department of Paediatrics, University of Toronto, Toronto, ON, Canada.
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11
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Yagi H, Lo CW. Left-Sided Heart Defects and Laterality Disturbance in Hypoplastic Left Heart Syndrome. J Cardiovasc Dev Dis 2023; 10:jcdd10030099. [PMID: 36975863 PMCID: PMC10054755 DOI: 10.3390/jcdd10030099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 02/17/2023] [Accepted: 02/21/2023] [Indexed: 03/29/2023] Open
Abstract
Hypoplastic left heart syndrome (HLHS) is a complex congenital heart disease characterized by hypoplasia of left-sided heart structures. The developmental basis for restriction of defects to the left side of the heart in HLHS remains unexplained. The observed clinical co-occurrence of rare organ situs defects such as biliary atresia, gut malrotation, or heterotaxy with HLHS would suggest possible laterality disturbance. Consistent with this, pathogenic variants in genes regulating left-right patterning have been observed in HLHS patients. Additionally, Ohia HLHS mutant mice show splenic defects, a phenotype associated with heterotaxy, and HLHS in Ohia mice arises in part from mutation in Sap130, a component of the Sin3A chromatin complex known to regulate Lefty1 and Snai1, genes essential for left-right patterning. Together, these findings point to laterality disturbance mediating the left-sided heart defects associated with HLHS. As laterality disturbance is also observed for other CHD, this suggests that heart development integration with left-right patterning may help to establish the left-right asymmetry of the cardiovascular system essential for efficient blood oxygenation.
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Affiliation(s)
- Hisato Yagi
- Department of Developmental Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15201, USA
| | - Cecilia W Lo
- Department of Developmental Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15201, USA
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12
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Jia Y, Chen J, Zhong J, He X, Zeng L, Wang Y, Li J, Xia S, Ye E, Zhao J, Ke B, Li C. Novel rare mutation in a conserved site of PTPRB causes human hypoplastic left heart syndrome. Clin Genet 2023; 103:79-86. [PMID: 36148623 DOI: 10.1111/cge.14234] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 09/14/2022] [Accepted: 09/16/2022] [Indexed: 12/14/2022]
Abstract
Hypoplastic left heart syndrome (HLHS) is a rare but fatal birth defect in which the left side of the heart is underdeveloped. HLHS accounts for 2% to 4% of congenital heart anomalies. Whole genome sequencing (WGS) was conducted for a family trio consisting of a proband and his parents. A homozygous rare variant was detected in the PTPRB (Protein Tyrosine Phosphatase Receptor Type B) gene of the proband by functional annotation and co-segregation analysis. Sanger sequencing was used to confirm genotypes of the variant. The in silico prediction tools, including Mutation Taster, SpliceAI, and CADD, were used to predict the impact of the mutation. The allele frequencies across populations were compared based on multiple databases, including "1000 genomes" and "gnomAD". We used two vectors (pcMINI and pcDNA3.1) to generate a minigene construct to validate the mutational effect at the transcriptional level. Family-based WGS analyses showed that only a homozygous splice acceptor variant (NC_000012.12: g.70636068T>G, NM_001109754.4: c.56-2A>C, NG_029940.2: g.6373A>C) at the exon-intron border of PTPRB gene associates with HLHS. This variant is also within the region with the enhancer activity based on UCSC genome annotation. Genotyping and Sanger sequencing revealed that the proband's parents are heterozygous for this variant. Evolutionary conservation analysis revealed that the site (NC_000012.12: g.70636068) is extremely conserved across species, supporting the evolutionary functional constraints of the ancestral wild type (T). In silico tools universally predicted a deleterious or disease-causing impact of the mutation from T to G. The mutation was not found in the 1000 genomes and gnomAD databases, which indicates that this mutation is very rare in most human populations. A splicing assay indicated that the mutated minigene caused aberrant splicing of mRNA, in which a 3 bp missing in the second exon resulted in the deletion of one amino acid (NP_001103224.1:p.Glu19del) compared to the normal protein of PRPTB (also the VE-PTP). Structure prediction revealed that the deletion occurred within the C-region of the signal peptide of VE-PTP, suggesting signal peptide-related defects as a potential mechanism for the HLHS cellular pathogeny. We report a rare homozygous variant with splicing error in PTPRB associated with HLHS. Previous model species studies revealed conserved functions of PTPRB in cardiovascular and heart development in mice and zebrafish. Our study is the first report to show the association between PTPRB and HLHS in humans.
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Affiliation(s)
- Yangying Jia
- Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Jianhai Chen
- Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Jie Zhong
- Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Xuefei He
- Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Li Zeng
- The Department of Pediatric Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Yanmin Wang
- Chinese Institute for Brain Research, Beijing, China
| | - Jiakun Li
- Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China.,Department of Urology, Institute of Urology, West China Hospital of Sichuan University, Chengdu, China
| | - Shengqian Xia
- Department of Ecology and Evolution, The University of Chicago, Chicago, Illinois, USA
| | - Erdengqieqieke Ye
- Department of Prenatal Diagnosis, Reproductive Medicine Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Jing Zhao
- Department of Prenatal Diagnosis, Reproductive Medicine Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Bin Ke
- Department of Neurology, Laboratory of Neurodegenerative Disorders, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Chunyu Li
- Department of Neurology, Laboratory of Neurodegenerative Disorders, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
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13
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Luyckx I, Verstraeten A, Goumans MJ, Loeys B. SMAD6-deficiency in human genetic disorders. NPJ Genom Med 2022; 7:68. [DOI: 10.1038/s41525-022-00338-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Accepted: 11/08/2022] [Indexed: 11/23/2022] Open
Abstract
AbstractSMAD6 encodes an intracellular inhibitor of the bone morphogenetic protein (BMP) signalling pathway. Until now, SMAD6-deficiency has been associated with three distinctive human congenital conditions, i.e., congenital heart diseases, including left ventricular obstruction and conotruncal defects, craniosynostosis and radioulnar synostosis. Intriguingly, a similar spectrum of heterozygous loss-of-function variants has been reported to cause these clinically distinct disorders without a genotype–phenotype correlation. Even identical nucleotide changes have been described in patients with either a cardiovascular phenotype, craniosynostosis or radioulnar synostosis. These findings suggest that the primary pathogenic variant alone cannot explain the resultant patient phenotype. In this review, we summarise clinical and (patho)genetic (dis)similarities between these three SMAD6-related conditions, compare published Madh6 mouse models, in which the importance and impact of the genetic background with respect to the observed phenotype is highlighted, and elaborate on the cellular key mechanisms orchestrated by SMAD6 in the development of these three discrete inherited disorders. In addition, we discuss future research needed to elucidate the pathogenetic mechanisms underlying these diseases in order to improve their molecular diagnosis, advance therapeutic strategies and facilitate counselling of patients and their families.
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14
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Zhong G, Shen Y. Statistical models of the genetic etiology of congenital heart disease. Curr Opin Genet Dev 2022; 76:101967. [PMID: 35939966 PMCID: PMC10586490 DOI: 10.1016/j.gde.2022.101967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 06/29/2022] [Accepted: 07/08/2022] [Indexed: 11/03/2022]
Abstract
Congenital heart disease (CHD) is a collection of anatomically and clinically heterogeneous structure anomalies of heart at birth. Finding genetic causes of CHD can not only shed light on developmental biology of heart, but also provide basis for improving clinical care and interventions. The optimal study design and analytical approaches to identify genetic causes depend on the underlying genetic architecture. A few well-known syndromes with CHD as core conditions, such as Noonan and CHARGE, have known monogenic causes. The genetic causes of most of CHD patients, however, are unknown and likely to be complex. In this review, we highlight recent studies that assume a complex genetic architecture of CHD with two main approaches. One is genomic sequencing studies aiming for identifying rare or de novo risk variants with large genetic effect. The other is genome-wide association studies optimized for common variants with moderate genetic effect.
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Affiliation(s)
- Guojie Zhong
- Department of Systems Biology, Columbia University Irving Medical Center, New York, NY, USA; Integrated Program in Cellular, Molecular, and Biological Studies, Columbia University Irving Medical Center, New York, NY, USA
| | - Yufeng Shen
- Department of Systems Biology, Columbia University Irving Medical Center, New York, NY, USA; Department of Biomedical Informatics, Columbia University Irving Medical Center, New York, NY, USA; JP Sulzberger Columbia Genome Center, Columbia University Irving Medical Center, New York, NY, USA.
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15
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Considering the Genetic Architecture of Hypoplastic Left Heart Syndrome. J Cardiovasc Dev Dis 2022; 9:jcdd9100315. [PMID: 36286267 PMCID: PMC9604382 DOI: 10.3390/jcdd9100315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 09/16/2022] [Accepted: 09/16/2022] [Indexed: 11/24/2022] Open
Abstract
Hypoplastic left heart syndrome (HLHS) is among the most severe cardiovascular malformations and understanding its causes is crucial to making progress in prevention and treatment. Genetic analysis is a broadly useful tool for dissecting complex causal mechanisms and it is playing a significant role in HLHS research. However, unlike classical Mendelian disorders where a relatively small number of genes are largely determinative of the occurrence and severity of the disease, the picture in HLHS is complex. De novo single-gene and copy number variant (CNV) disorders make an important contribution, but there is emerging evidence for causal contributions from lower penetrance and common variation. Integrating this emerging knowledge into clinical diagnostics and translating the findings into effective prevention and treatment remain challenges for the future.
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16
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Gabriel GC, Yagi H, Xu X, Lo CW. Novel Insights into the Etiology, Genetics, and Embryology of Hypoplastic Left Heart Syndrome. World J Pediatr Congenit Heart Surg 2022; 13:565-570. [PMID: 36053093 PMCID: PMC10010598 DOI: 10.1177/21501351221102961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Hypoplastic left heart syndrome (HLHS) is a relatively rare severe congenital heart defect (CHD) closely linked to other left ventricular outflow tract (LVOT) lesions including bicuspid aortic valve (BAV), one of the most common heart defects. While HLHS, BAV, and other LVOT lesions have a strong genetic underpinning, their genetic etiology remains poorly understood. Findings from a large-scale mouse mutagenesis screen showed HLHS has a multigenic etiology and is genetically heterogenous, explaining difficulties in identifying the genetic causes of HLHS. In Ohia mice, HLHS shows incomplete penetrance. Some mice exhibited small LV with normal aorta, and others a normal LV with hypoplastic aorta, indicating the LV hypoplasia is not hemodynamically driven. In Ohia mutants, HLHS was found to have a digenic modular construction, with mutation in a chromatin modifier causing the small LV phenotype and mutation in Pcdha9 causing the aorta/aortic valve hypoplasia. The Pcdha9 mutation alone can cause BAV, and in the human genome two common deletion copy number variants spanning PCDHA7-10 are associated with BAV. Hence the digenic etiology of HLHS can account for the close association of HLHS, a rare CHD, with BAV, one of the most common CHD. Functional analysis of Ohia HLHS heart tissue showed severe mitochondrial dysfunction in the small LV, while the normal size RV is also affected but milder, suggesting possible role in vulnerability of surgically palliated HLHS patients to heart failure. These findings suggest insights into the genetics of HLHS may yield new therapies for improving outcome for patients with HLHS.
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Affiliation(s)
- George C Gabriel
- Department of Developmental Biology, 6614University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Hisato Yagi
- Department of Developmental Biology, 6614University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Xinxiu Xu
- Department of Developmental Biology, 6614University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Cecilia W Lo
- Department of Developmental Biology, 6614University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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17
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Rashkin SR, Cleves M, Shaw GM, Nembhard WN, Nestoridi E, Jenkins MM, Romitti PA, Lou XY, Browne ML, Mitchell LE, Olshan AF, Lomangino K, Bhattacharyya S, Witte JS, Hobbs CA, National Birth Defects Prevention Study. A genome-wide association study of obstructive heart defects among participants in the National Birth Defects Prevention Study. Am J Med Genet A 2022; 188:2303-2314. [PMID: 35451555 PMCID: PMC9283270 DOI: 10.1002/ajmg.a.62759] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 02/15/2022] [Accepted: 02/18/2022] [Indexed: 01/19/2023]
Abstract
Obstructive heart defects (OHDs) share common structural lesions in arteries and cardiac valves, accounting for ~25% of all congenital heart defects. OHDs are highly heritable, resulting from interplay among maternal exposures, genetic susceptibilities, and epigenetic phenomena. A genome-wide association study was conducted in National Birth Defects Prevention Study participants (Ndiscovery = 3978; Nreplication = 2507), investigating the genetic architecture of OHDs using transmission/disequilibrium tests (TDT) in complete case-parental trios (Ndiscovery_TDT = 440; Nreplication_TDT = 275) and case-control analyses separately in infants (Ndiscovery_CCI = 1635; Nreplication_CCI = 990) and mothers (case status defined by infant; Ndiscovery_CCM = 1703; Nreplication_CCM = 1078). In the TDT analysis, the SLC44A2 single nucleotide polymorphism (SNP) rs2360743 was significantly associated with OHD (pdiscovery = 4.08 × 10-9 ; preplication = 2.44 × 10-4 ). A CAPN11 SNP (rs55877192) was suggestively associated with OHD (pdiscovery = 1.61 × 10-7 ; preplication = 0.0016). Two other SNPs were suggestively associated (p < 1 × 10-6 ) with OHD in only the discovery sample. In the case-control analyses, no SNPs were genome-wide significant, and, even with relaxed thresholds ( × discovery < 1 × 10-5 and preplication < 0.05), only one SNP (rs188255766) in the infant analysis was associated with OHDs (pdiscovery = 1.42 × 10-6 ; preplication = 0.04). Additional SNPs with pdiscovery < 1 × 10-5 were in loci supporting previous findings but did not replicate. Overall, there was modest evidence of an association between rs2360743 and rs55877192 and OHD and some evidence validating previously published findings.
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Affiliation(s)
- Sara R. Rashkin
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA 94158, US
| | - Mario Cleves
- Department of Pediatrics, Morsani College of Medicine, University of South Florida, Health Informatics Institute, Tampa, FL 33612, US
| | - Gary M. Shaw
- Dept of Pediatrics, Stanford University, Stanford, CA 94305, US
| | - Wendy N. Nembhard
- University of Arkansas for Medical Sciences, Department of Epidemiology and Arkansas Center for Birth Defects and Prevention, University of Arkansas for Medical Sciences, Little Rock, AR 72205, US
| | - Eirini Nestoridi
- Massachusetts Center for Birth Defects Research and Prevention, Massachusetts Department of Public Health, Boston, MA 02108, US
| | - Mary M. Jenkins
- National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA 30333, US
| | - Paul A. Romitti
- Department of Epidemiology, University of Iowa, Iowa City, IA 52242, US
| | - Xiang-Yang Lou
- Department of Biostatistics, College of Public Health and Health Professions & College of Medicine, University of Florida, Gainesville, FL 32603, US
| | - Marilyn L. Browne
- Birth Defects Research Section, New York State Department of Health, Albany, NY 12203, US; Department of Epidemiology and Biostatistics, School of Public Health, University at Albany, Rensselaer, NY 12114, US
| | - Laura E. Mitchell
- Department of Epidemiology, Human Genetics, and Environmental Sciences, UTHealth School of Public Health, Houston, TX 77030, US
| | - Andrew F. Olshan
- Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27599, US
| | | | - Sudeepa Bhattacharyya
- Bioinformatics and Data Science at University of Arkansas, Little Rock, AR 72204, US
| | - John S. Witte
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA 94158, US
- These authors contributed equally to this work
| | - Charlotte A. Hobbs
- Rady Children’s Institute for Genomic Medicine, San Diego, CA 92123, US
- These authors contributed equally to this work
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18
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High heritability of ascending aortic diameter and trans-ancestry prediction of thoracic aortic disease. Nat Genet 2022; 54:772-782. [PMID: 35637384 DOI: 10.1038/s41588-022-01070-7] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Accepted: 03/31/2022] [Indexed: 12/24/2022]
Abstract
Enlargement of the aorta is an important risk factor for aortic aneurysm and dissection, a leading cause of morbidity in the developed world. Here we performed automated extraction of ascending aortic diameter from cardiac magnetic resonance images of 36,021 individuals from the UK Biobank, followed by genome-wide association. We identified lead variants across 41 loci, including genes related to cardiovascular development (HAND2, TBX20) and Mendelian forms of thoracic aortic disease (ELN, FBN1). A polygenic score significantly predicted prevalent risk of thoracic aortic aneurysm and the need for surgical intervention for patients with thoracic aneurysm across multiple ancestries within the UK Biobank, FinnGen, the Penn Medicine Biobank and the Million Veterans Program (MVP). Additionally, we highlight the primary causal role of blood pressure in reducing aortic dilation using Mendelian randomization. Overall, our findings provide a roadmap for using genetic determinants of human anatomy to understand cardiovascular development while improving prediction of diseases of the thoracic aorta.
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19
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Gordon DM, Cunningham D, Zender G, Lawrence PJ, Penaloza JS, Lin H, Fitzgerald-Butt SM, Myers K, Duong T, Corsmeier DJ, Gaither JB, Kuck HC, Wijeratne S, Moreland B, Kelly BJ, Baylor-Johns Hopkins Center for Mendelian Genomics, Garg V, White P, McBride KL. Exome sequencing in multiplex families with left-sided cardiac defects has high yield for disease gene discovery. PLoS Genet 2022; 18:e1010236. [PMID: 35737725 PMCID: PMC9258875 DOI: 10.1371/journal.pgen.1010236] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 07/06/2022] [Accepted: 05/04/2022] [Indexed: 11/18/2022] Open
Abstract
Congenital heart disease (CHD) is a common group of birth defects with a strong genetic contribution to their etiology, but historically the diagnostic yield from exome studies of isolated CHD has been low. Pleiotropy, variable expressivity, and the difficulty of accurately phenotyping newborns contribute to this problem. We hypothesized that performing exome sequencing on selected individuals in families with multiple members affected by left-sided CHD, then filtering variants by population frequency, in silico predictive algorithms, and phenotypic annotations from publicly available databases would increase this yield and generate a list of candidate disease-causing variants that would show a high validation rate. In eight of the nineteen families in our study (42%), we established a well-known gene/phenotype link for a candidate variant or performed confirmation of a candidate variant’s effect on protein function, including variants in genes not previously described or firmly established as disease genes in the body of CHD literature: BMP10, CASZ1, ROCK1 and SMYD1. Two plausible variants in different genes were found to segregate in the same family in two instances suggesting oligogenic inheritance. These results highlight the need for functional validation and demonstrate that in the era of next-generation sequencing, multiplex families with isolated CHD can still bring high yield to the discovery of novel disease genes. Congenital heart disease is a common group of birth defects that are a leading cause of death in children under one year of age. There is strong evidence that genetics plays a role in causing congenital heart disease. While studies using individual cases have identified causative genes for those with a heart defect when accompanied by other birth defects or intellectual disabilities, for individuals who have only a heart defect without other problems, a genetic cause can be found in fewer than 10%. In this study, we enrolled families where there was more than one individual with a heart defect. This allowed us to take advantage of inheritance by searching for potential disease-causing genetic variants in common among all affected individuals in the family. Among 19 families studied, we were able to find a plausible disease-causing variant in eight of them and identified new genes that may cause or contribute to the presence of a heart defect. Two families had potential disease-causing variants in two different genes. We designed assays to test if the variants led to altered function of the protein coded by the gene, demonstrating a functional consequence that support the gene and variant as contributing to the heart defect. These findings show that studying families may be more effective than using individuals to find causes of heart defects. In addition, this family-based method suggests that changes in more than one gene may be required for a heart defect to occur.
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Affiliation(s)
- David M. Gordon
- Computational Genomics Group, The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, Ohio, United States of America
| | - David Cunningham
- Center for Cardiovascular Research and The Heart Center, Nationwide Children’s Hospital, Columbus, Ohio, United States of America
| | - Gloria Zender
- Center for Cardiovascular Research and The Heart Center, Nationwide Children’s Hospital, Columbus, Ohio, United States of America
| | - Patrick J. Lawrence
- Computational Genomics Group, The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, Ohio, United States of America
- Center for Cardiovascular Research and The Heart Center, Nationwide Children’s Hospital, Columbus, Ohio, United States of America
| | - Jacqueline S. Penaloza
- Computational Genomics Group, The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, Ohio, United States of America
| | - Hui Lin
- Center for Cardiovascular Research and The Heart Center, Nationwide Children’s Hospital, Columbus, Ohio, United States of America
| | - Sara M. Fitzgerald-Butt
- Center for Cardiovascular Research and The Heart Center, Nationwide Children’s Hospital, Columbus, Ohio, United States of America
- Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, Ohio, United States of America
| | - Katherine Myers
- Center for Cardiovascular Research and The Heart Center, Nationwide Children’s Hospital, Columbus, Ohio, United States of America
| | - Tiffany Duong
- Center for Cardiovascular Research and The Heart Center, Nationwide Children’s Hospital, Columbus, Ohio, United States of America
| | - Donald J. Corsmeier
- Computational Genomics Group, The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, Ohio, United States of America
| | - Jeffrey B. Gaither
- Computational Genomics Group, The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, Ohio, United States of America
| | - Harkness C. Kuck
- Computational Genomics Group, The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, Ohio, United States of America
| | - Saranga Wijeratne
- Computational Genomics Group, The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, Ohio, United States of America
| | - Blythe Moreland
- Computational Genomics Group, The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, Ohio, United States of America
| | - Benjamin J. Kelly
- Computational Genomics Group, The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, Ohio, United States of America
| | | | - Vidu Garg
- Center for Cardiovascular Research and The Heart Center, Nationwide Children’s Hospital, Columbus, Ohio, United States of America
- Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, Ohio, United States of America
- * E-mail: (VG); (PW); (KLM)
| | - Peter White
- Computational Genomics Group, The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, Ohio, United States of America
- Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, Ohio, United States of America
- * E-mail: (VG); (PW); (KLM)
| | - Kim L. McBride
- Center for Cardiovascular Research and The Heart Center, Nationwide Children’s Hospital, Columbus, Ohio, United States of America
- Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, Ohio, United States of America
- * E-mail: (VG); (PW); (KLM)
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Anfinson M, Fitts RH, Lough JW, James JM, Simpson PM, Handler SS, Mitchell ME, Tomita-Mitchell A. Significance of α-Myosin Heavy Chain ( MYH6) Variants in Hypoplastic Left Heart Syndrome and Related Cardiovascular Diseases. J Cardiovasc Dev Dis 2022; 9:144. [PMID: 35621855 PMCID: PMC9147009 DOI: 10.3390/jcdd9050144] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 04/27/2022] [Accepted: 04/29/2022] [Indexed: 02/04/2023] Open
Abstract
Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease (CHD) with complex genetic inheritance. HLHS segregates with other left ventricular outflow tract (LVOT) malformations in families, and can present as either an isolated phenotype or as a feature of a larger genetic disorder. The multifactorial etiology of HLHS makes it difficult to interpret the clinical significance of genetic variants. Specific genes have been implicated in HLHS, including rare, predicted damaging MYH6 variants that are present in >10% of HLHS patients, and which have been shown to be associated with decreased transplant-free survival in our previous studies. MYH6 (α-myosin heavy chain, α-MHC) variants have been reported in HLHS and numerous other CHDs, including LVOT malformations, and may provide a genetic link to these disorders. In this paper, we outline the MYH6 variants that have been identified, discuss how bioinformatic and functional studies can inform clinical decision making, and highlight the importance of genetic testing in HLHS.
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Affiliation(s)
- Melissa Anfinson
- Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA; (M.A.); (J.W.L.)
- Herma Heart Institute, Children’s Wisconsin, Milwaukee, WI 53226, USA; (S.S.H.); (M.E.M.)
| | - Robert H. Fitts
- Department of Biological Sciences, Marquette University, Milwaukee, WI 53233, USA;
| | - John W. Lough
- Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA; (M.A.); (J.W.L.)
| | - Jeanne M. James
- Department of Pediatrics, Children’s Mercy, Kansas City, MO 64108, USA;
| | - Pippa M. Simpson
- Department of Pediatrics, Division of Quantitative Health Sciences, Medical College of Wisconsin, Milwaukee, WI 53226, USA;
| | - Stephanie S. Handler
- Herma Heart Institute, Children’s Wisconsin, Milwaukee, WI 53226, USA; (S.S.H.); (M.E.M.)
- Department of Pediatrics, Division of Pediatric Cardiology, Children’s Wisconsin, Milwaukee, WI 53226, USA
| | - Michael E. Mitchell
- Herma Heart Institute, Children’s Wisconsin, Milwaukee, WI 53226, USA; (S.S.H.); (M.E.M.)
- Department of Surgery, Division of Congenital Heart Surgery, Children’s Wisconsin, Milwaukee, WI 53226, USA
| | - Aoy Tomita-Mitchell
- Herma Heart Institute, Children’s Wisconsin, Milwaukee, WI 53226, USA; (S.S.H.); (M.E.M.)
- Department of Surgery, Division of Congenital Heart Surgery, Children’s Wisconsin, Milwaukee, WI 53226, USA
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21
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Theis JL, Olson TM. Whole Genome Sequencing in Hypoplastic Left Heart Syndrome. J Cardiovasc Dev Dis 2022; 9:jcdd9040117. [PMID: 35448093 PMCID: PMC9028226 DOI: 10.3390/jcdd9040117] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Revised: 04/13/2022] [Accepted: 04/13/2022] [Indexed: 12/03/2022] Open
Abstract
Hypoplastic left heart syndrome (HLHS) is a genetically complex disorder. Whole genome sequencing enables comprehensive scrutiny of single nucleotide variants and small insertions/deletions, within both coding and regulatory regions of the genome, revolutionizing susceptibility-gene discovery research. Because millions of rare variants comprise an individual genome, identification of alleles linked to HLHS necessitates filtering algorithms based on various parameters, such as inheritance, enrichment, omics data, known genotype–phenotype associations, and predictive or experimental modeling. In this brief review, we highlight family and cohort-based strategies used to analyze whole genome sequencing datasets and identify HLHS candidate genes. Key findings include compound and digenic heterozygosity among several prioritized genes and genetic associations between HLHS and bicuspid aortic valve or cardiomyopathy. Together with findings of independent genomic investigations, MYH6 has emerged as a compelling disease gene for HLHS and other left-sided congenital heart diseases.
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Affiliation(s)
- Jeanne L. Theis
- Cardiovascular Genetics Research Laboratory, Mayo Clinic, Rochester, MN 55905, USA;
| | - Timothy M. Olson
- Cardiovascular Genetics Research Laboratory, Mayo Clinic, Rochester, MN 55905, USA;
- Department of Pediatric and Adolescent Medicine, Division of Pediatric Cardiology, Mayo Clinic, Rochester, MN 55905, USA
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN 55905, USA
- Correspondence:
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22
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Karunakaran KB, Gabriel GC, Balakrishnan N, Lo CW, Ganapathiraju MK. Novel Protein-Protein Interactions Highlighting the Crosstalk between Hypoplastic Left Heart Syndrome, Ciliopathies and Neurodevelopmental Delays. Genes (Basel) 2022; 13:genes13040627. [PMID: 35456433 PMCID: PMC9032108 DOI: 10.3390/genes13040627] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 03/08/2022] [Accepted: 03/08/2022] [Indexed: 02/06/2023] Open
Abstract
Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease (CHD) affecting 1 in 5000 newborns. We constructed the interactome of 74 HLHS-associated genes identified from a large-scale mouse mutagenesis screen, augmenting it with 408 novel protein-protein interactions (PPIs) using our High-Precision Protein-Protein Interaction Prediction (HiPPIP) model. The interactome is available on a webserver with advanced search capabilities. A total of 364 genes including 73 novel interactors were differentially regulated in tissue/iPSC-derived cardiomyocytes of HLHS patients. Novel PPIs facilitated the identification of TOR signaling and endoplasmic reticulum stress modules. We found that 60.5% of the interactome consisted of housekeeping genes that may harbor large-effect mutations and drive HLHS etiology but show limited transmission. Network proximity of diabetes, Alzheimer's disease, and liver carcinoma-associated genes to HLHS genes suggested a mechanistic basis for their comorbidity with HLHS. Interactome genes showed tissue-specificity for sites of extracardiac anomalies (placenta, liver and brain). The HLHS interactome shared significant overlaps with the interactomes of ciliopathy- and microcephaly-associated genes, with the shared genes enriched for genes involved in intellectual disability and/or developmental delay, and neuronal death pathways, respectively. This supported the increased burden of ciliopathy variants and prevalence of neurological abnormalities observed among HLHS patients with developmental delay and microcephaly, respectively.
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Affiliation(s)
- Kalyani B. Karunakaran
- Supercomputer Education and Research Centre, Indian Institute of Science, Bangalore 560012, India; (K.B.K.); (N.B.)
| | - George C. Gabriel
- Department of Developmental Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15201, USA; (G.C.G.); (C.W.L.)
| | - Narayanaswamy Balakrishnan
- Supercomputer Education and Research Centre, Indian Institute of Science, Bangalore 560012, India; (K.B.K.); (N.B.)
| | - Cecilia W. Lo
- Department of Developmental Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15201, USA; (G.C.G.); (C.W.L.)
| | - Madhavi K. Ganapathiraju
- Department of Biomedical Informatics, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15206, USA
- Intelligent Systems Program, School of Computing and Information, University of Pittsburgh, Pittsburgh, PA 15260, USA
- Correspondence:
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23
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Theis JL, Niaz T, Sundsbak RS, Fogarty ZC, Bamlet WR, Hagler DJ, Olson TM. CELSR1 Risk Alleles in Familial Bicuspid Aortic Valve and Hypoplastic Left Heart Syndrome. Circ Genom Precis Med 2022; 15:e003523. [PMID: 35133174 DOI: 10.1161/circgen.121.003523] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
BACKGROUND Whole-genome sequencing in families enables deciphering of congenital heart disease causes. A shared genetic basis for familial bicuspid aortic valve (BAV) and hypoplastic left heart syndrome (HLHS) was postulated. METHODS Whole-genome sequencing was performed in affected members of 6 multiplex BAV families, an HLHS cohort of 197 probands and 546 relatives, and 813 controls. Data were filtered for rare, predicted-damaging variants that cosegregated with familial BAV and disrupted genes associated with congenital heart disease in humans and mice. Candidate genes were further prioritized by rare variant burden testing in HLHS cases versus controls. Modifier variants in HLHS proband-parent trios were sought to account for the severe developmental phenotype. RESULTS In 5 BAV families, missense variants in 6 ontologically diverse genes for structural (SPTBN1, PAXIP1, and FBLN1) and signaling (CELSR1, PLXND1, and NOS3) proteins fulfilled filtering metrics. CELSR1, encoding cadherin epidermal growth factor laminin G seven-pass G-type receptor, was identified as a candidate gene in 2 families and was the only gene demonstrating rare variant enrichment in HLHS probands (P=0.003575). HLHS-associated CELSR1 variants included 16 missense, one splice site, and 3 noncoding variants predicted to disrupt canonical transcription factor binding sites, most of which were inherited from a parent without congenital heart disease. Filtering whole-genome sequencing data for rare, predicted-damaging variants inherited from the other parent revealed 2 cases of CELSR1 compound heterozygosity, one case of CELSR1-CELSR3 synergistic heterozygosity, and 4 cases of CELSR1-MYO15A digenic heterozygosity. CONCLUSIONS CELSR1 is a susceptibility gene for familial BAV and HLHS, further implicating planar cell polarity pathway perturbation in congenital heart disease.
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Affiliation(s)
- Jeanne L Theis
- Cardiovascular Genetics Research Laboratory (J.L.T., R.S.S., T.M.O.), Mayo Clinic, Rochester, MN
| | - Talha Niaz
- Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine (T.N., D.J.H., T.M.O.), Mayo Clinic, Rochester, MN
| | - Rhianna S Sundsbak
- Cardiovascular Genetics Research Laboratory (J.L.T., R.S.S., T.M.O.), Mayo Clinic, Rochester, MN
| | - Zachary C Fogarty
- Division of Computational Biology, Department of Quantitative Health Sciences (Z.C.F.), Mayo Clinic, Rochester, MN
| | - William R Bamlet
- Division of Clinical Trials and Biostatistics, Department of Quantiative Health Sciences (W.R.B.), Mayo Clinic, Rochester, MN
| | - Donald J Hagler
- Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine (T.N., D.J.H., T.M.O.), Mayo Clinic, Rochester, MN.,Department of Cardiovascular Medicine (D.J.H., T.M.O.), Mayo Clinic, Rochester, MN
| | - Timothy M Olson
- Cardiovascular Genetics Research Laboratory (J.L.T., R.S.S., T.M.O.), Mayo Clinic, Rochester, MN.,Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine (T.N., D.J.H., T.M.O.), Mayo Clinic, Rochester, MN.,Department of Cardiovascular Medicine (D.J.H., T.M.O.), Mayo Clinic, Rochester, MN
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24
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Blum KM, Mirhaidari G, Breuer CK. Tissue engineering: Relevance to neonatal congenital heart disease. Semin Fetal Neonatal Med 2022; 27:101225. [PMID: 33674254 PMCID: PMC8390581 DOI: 10.1016/j.siny.2021.101225] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Congenital heart disease (CHD) represents a large clinical burden, representing the most common cause of birth defect-related death in the newborn. The mainstay of treatment for CHD remains palliative surgery using prosthetic vascular grafts and valves. These devices have limited effectiveness in pediatric patients due to thrombosis, infection, limited endothelialization, and a lack of growth potential. Tissue engineering has shown promise in providing new solutions for pediatric CHD patients through the development of tissue engineered vascular grafts, heart patches, and heart valves. In this review, we examine the current surgical treatments for congenital heart disease and the research being conducted to create tissue engineered products for these patients. While much research remains to be done before tissue engineering becomes a mainstay of clinical treatment for CHD patients, developments have been progressing rapidly towards translation of tissue engineering devices to the clinic.
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Affiliation(s)
- Kevin M Blum
- Center for Regenerative Medicine, The Abigail Wexner Research Institute, Nationwide Childrens Hospital, Columbus, OH, USA; Department of Biomedical Engineering, The Ohio State University, Columbus, OH, USA.
| | - Gabriel Mirhaidari
- Center for Regenerative Medicine, The Abigail Wexner Research Institute, Nationwide Childrens Hospital, Columbus OH, USA,Biomedical Sciences Graduate Program, The Ohio State University College of Medicine, Columbus OH, USA
| | - Christopher K Breuer
- Center for Regenerative Medicine, The Abigail Wexner Research Institute, Nationwide Childrens Hospital, Columbus, OH, USA.
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25
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Abstract
The application of next-generation sequencing to study congenital heart disease (CHD) is increasingly providing new insights into the causes and mechanisms of this prevalent birth anomaly. Whole-exome sequencing analysis identifies damaging gene variants altering single or contiguous nucleotides that are assigned pathogenicity based on statistical analyses of families and cohorts with CHD, high expression in the developing heart and depletion of damaging protein-coding variants in the general population. Gene classes fulfilling these criteria are enriched in patients with CHD and extracardiac abnormalities, evidencing shared pathways in organogenesis. Developmental single-cell transcriptomic data demonstrate the expression of CHD-associated genes in particular cell lineages, and emerging insights indicate that genetic variants perturb multicellular interactions that are crucial for cardiogenesis. Whole-genome sequencing analyses extend these observations, identifying non-coding variants that influence the expression of genes associated with CHD and contribute to the estimated ~55% of unexplained cases of CHD. These approaches combined with the assessment of common and mosaic genetic variants have provided a more complete knowledge of the causes and mechanisms of CHD. Such advances provide knowledge to inform the clinical care of patients with CHD or other birth defects and deepen our understanding of the complexity of human development. In this Review, we highlight known and candidate CHD-associated human genes and discuss how the integration of advances in developmental biology research can provide new insights into the genetic contributions to CHD.
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Affiliation(s)
- Sarah U Morton
- Division of Newborn Medicine, Department of Medicine, Boston Children's Hospital, Boston, MA, USA
- Department of Pediatrics, Harvard Medical School, Boston, MA, USA
- Department of Genetics, Harvard Medical School, Boston, MA, USA
| | - Daniel Quiat
- Department of Pediatrics, Harvard Medical School, Boston, MA, USA
- Department of Genetics, Harvard Medical School, Boston, MA, USA
- Department of Cardiology, Boston Children's Hospital, Boston, MA, USA
| | | | - Christine E Seidman
- Department of Genetics, Harvard Medical School, Boston, MA, USA.
- Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
- Howard Hughes Medical Institute, Harvard University, Boston, MA, USA.
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26
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Ahmad A, Fitzgerald-Butt SM, Ware SM, Ison HE, Elmore LR, Helm BM. Assessing genetic counselors' graduate school education and training in congenital heart defects. J Genet Couns 2021; 31:735-745. [PMID: 34877755 DOI: 10.1002/jgc4.1540] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 11/19/2021] [Accepted: 11/25/2021] [Indexed: 11/10/2022]
Abstract
Genetic counselors are one of the many providers involved in caring for patients with congenital heart defects (CHDs); however, little is known about the cardiovascular genetics training they receive by their graduate programs. To explore the recalled education experiences regarding CHDs by practicing genetic counselors, we surveyed graduates of programs primarily accredited by the American Council on Genetic Counseling (ACGC) about their graduate training in this area, the depth of CHD-specific education they received, and whether CHDs are a substantial referral indication in their current practice. Genetic counselors were recruited from the National Society of Genetic Counselors and Twitter (n = 112), and participants reflecting multiple specialties and 35 graduate programs completed an online survey which included questions about fieldwork placements and lectures in cardiovascular genetics, exposure to classification schemes regarding cardiac embryology, and education in counseling strategies for CHDs and CHD-related topics during their graduate training. When asked whether CHDs are a substantial referral indication seen in their current practice, 55% (62/112) responded yes. Most participants (79%, 88/112) recalled receiving some education about CHDs, but 91% (80/88) reported receiving little to no education regarding embryologic classification of CHDs and how to apply classification schemes to their counseling. Both participating prenatal and pediatric GCs reported that CHDs can be a common referral indication, yet they reported receiving limited education on teratogens associated with CHDs, family screening recommendations, and recurrence risk counseling for CHDs. Based on participant responses, the majority of respondents reported receiving sufficient education on syndromes with CHDs which can be beneficial in specialties such as pediatrics. This exploratory study provides insight into opportunities to further support genetic counseling educational opportunities for CHDs. These findings suggest genetic counseling graduate programs could consider implementing education on CHD counseling strategies as a standardized component of the curriculum and that practicing genetic counselors could benefit from educational opportunities and resources with updated information on this topic.
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Affiliation(s)
- Aaliya Ahmad
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Sara M Fitzgerald-Butt
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Stephanie M Ware
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA.,Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Hannah E Ison
- Stanford Center for Inherited Cardiovascular Disease, Stanford Health Care, Stanford, California, USA
| | - Lindsey R Elmore
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Benjamin M Helm
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA.,Department of Epidemiology, Indiana University Fairbanks School of Public Health, Indianapolis, Indiana, USA
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27
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Eicken A, Kaemmerer H. Aortenisthmusstenose – eine lebenslange Systemerkrankung. AKTUELLE KARDIOLOGIE 2021. [DOI: 10.1055/a-1493-6462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
ZusammenfassungKoarktation der Aorta (CoA) ist eine Systemerkrankung aller prästenotischen Arterien.
Während im Säuglingsalter die chirurgische Behandlung im Vordergrund steht, werden erwachsene
Patienten mit CoA oder Re-CoA nach chirurgischer Initialbehandlung, heute überwiegend mit
Stents behandelt, wenn dies technisch möglich ist. Trotz erfolgreicher Beseitigung der
aortalen Enge bleiben viele Patienten hypertensiv. Die Ursache des arteriellen Hypertonus ist
multifaktoriell. Erwachsene CoA-Patienten müssen zum einen regelmäßig in einem EMAH-Zentrum
evaluiert werden und benötigen zum anderen häufig eine permanente antihypertensive
medikamentöse Therapie.
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Affiliation(s)
- Andreas Eicken
- Klinik für Kinderkardiologie und angeborene Herzfehler, Deutsches Herzzentrum München, Technische Universität München, München, Deutschland
| | - Harald Kaemmerer
- Klinik für Kinderkardiologie und angeborene Herzfehler, Deutsches Herzzentrum München, Technische Universität München, München, Deutschland
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28
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Ison HE, Griffin EL, Parrott A, Shikany AR, Meyers L, Thomas MJ, Syverson E, Demo EM, Fitzgerald KK, Fitzgerald-Butt S, Ziegler KL, Schartman AF, Stone KM, Helm BM. Genetic counseling for congenital heart disease - Practice resource of the national society of genetic counselors. J Genet Couns 2021; 31:9-33. [PMID: 34510635 DOI: 10.1002/jgc4.1498] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Revised: 08/02/2021] [Accepted: 08/02/2021] [Indexed: 12/11/2022]
Abstract
Congenital heart disease (CHD) is an indication which spans multiple specialties across various genetic counseling practices. This practice resource aims to provide guidance on key considerations when approaching counseling for this particular indication while recognizing the rapidly changing landscape of knowledge within this domain. This resource was developed with consensus from a diverse group of certified genetic counselors utilizing literature relevant for CHD genetic counseling practice and is aimed at supporting genetic counselors who encounter this indication in their practice both pre- and postnatally.
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Affiliation(s)
- Hannah E Ison
- Stanford Center for Inherited Cardiovascular Disease, Stanford Health Care, Stanford, California, USA
| | - Emily L Griffin
- Department of Pediatrics, Columbia University Medical Center, New York, New York, USA
| | | | - Amy R Shikany
- Cincinnati Children's Hospital Medical Center, The Heart Institute, Cincinnati, Ohio, USA
| | | | - Matthew J Thomas
- Department of Pediatrics, Division of Genetics, University of Virginia School of Medicine, Charlottesville, Virginia, USA
| | - Erin Syverson
- Department of Pediatrics, Division of Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Erin M Demo
- Sibley Heart Center Cardiology at Children's Healthcare of Atlanta, Atlanta, Georgia, USA
| | - Kristi K Fitzgerald
- Nemours Cardiac Center, Alfred I. DuPont Hospital for Children, Wilmington, Delaware, USA
| | - Sara Fitzgerald-Butt
- Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | | | - Allison F Schartman
- Department of Obstetrics & Gynecology, Division of Maternal Fetal Medicine, Indiana University Health, Indianapolis, Indiana, USA
| | - Kristyne M Stone
- Department of Obstetrics & Gynecology, Division of Maternal Fetal Medicine, Indiana University Health, Indianapolis, Indiana, USA
| | - Benjamin M Helm
- Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA.,Department of Epidemiology, Indiana University Fairbanks School of Public Health, Indianapolis, Indiana, USA
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29
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Teekakirikul P, Zhu W, Gabriel GC, Young CB, Williams K, Martin LJ, Hill JC, Richards T, Billaud M, Phillippi JA, Wang J, Wu Y, Tan T, Devine W, Lin JH, Bais AS, Klonowski J, de Bellaing AM, Saini A, Wang MX, Emerel L, Salamacha N, Wyman SK, Lee C, Li HS, Miron A, Zhang J, Xing J, McNamara DM, Fung E, Kirshbom P, Mahle W, Kochilas LK, He Y, Garg V, White P, McBride KL, Benson DW, Gleason TG, Mital S, Lo CW. Common deletion variants causing protocadherin-α deficiency contribute to the complex genetics of BAV and left-sided congenital heart disease. HGG ADVANCES 2021; 2:100037. [PMID: 34888534 PMCID: PMC8653519 DOI: 10.1016/j.xhgg.2021.100037] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Accepted: 05/21/2021] [Indexed: 11/11/2022] Open
Abstract
Bicuspid aortic valve (BAV) with ~1%-2% prevalence is the most common congenital heart defect (CHD). It frequently results in valve disease and aorta dilation and is a major cause of adult cardiac surgery. BAV is genetically linked to rare left-heart obstructions (left ventricular outflow tract obstructions [LVOTOs]), including hypoplastic left heart syndrome (HLHS) and coarctation of the aorta (CoA). Mouse and human studies indicate LVOTO is genetically heterogeneous with a complex genetic etiology. Homozygous mutation in the Pcdha protocadherin gene cluster in mice can cause BAV, and also HLHS and other LVOTO phenotypes when accompanied by a second mutation. Here we show two common deletion copy number variants (delCNVs) within the PCDHA gene cluster are associated with LVOTO. Analysis of 1,218 white individuals with LVOTO versus 463 disease-free local control individuals yielded odds ratios (ORs) at 1.47 (95% confidence interval [CI], 1.13-1.92; p = 4.2 × 10-3) for LVOTO, 1.47 (95% CI, 1.10-1.97; p = 0.01) for BAV, 6.13 (95% CI, 2.75-13.7; p = 9.7 × 10-6) for CoA, and 1.49 (95% CI, 1.07-2.08; p = 0.019) for HLHS. Increased OR was observed for all LVOTO phenotypes in homozygous or compound heterozygous PCDHA delCNV genotype comparison versus wild type. Analysis of an independent white cohort (381 affected individuals, 1,352 control individuals) replicated the PCDHA delCNV association with LVOTO. Generalizability of these findings is suggested by similar observations in Black and Chinese individuals with LVOTO. Analysis of Pcdha mutant mice showed reduced PCDHA expression at regions of cell-cell contact in aortic smooth muscle and cushion mesenchyme, suggesting potential mechanisms for BAV pathogenesis and aortopathy. Together, these findings indicate common variants causing PCDHA deficiency play a significant role in the genetic etiology of common and rare LVOTO-CHD.
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Affiliation(s)
- Polakit Teekakirikul
- Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Centre for Cardiovascular Genomics and Medicine, Division of Cardiology, and Division of Medical Sciences, Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong SAR, China
| | - Wenjuan Zhu
- Centre for Cardiovascular Genomics and Medicine, Division of Cardiology, and Division of Medical Sciences, Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong SAR, China
| | - George C. Gabriel
- Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Cullen B. Young
- Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Kylia Williams
- Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Lisa J. Martin
- Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, and Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati, OH, USA
| | - Jennifer C. Hill
- Department of Cardiothoracic Surgery and Department of Bioengineering, McGowan Institute for Regenerative Medicine, and Center for Vascular Remodeling and Regeneration, University of Pittsburgh, Pittsburgh, PA, USA
| | - Tara Richards
- Department of Cardiothoracic Surgery and Department of Bioengineering, McGowan Institute for Regenerative Medicine, and Center for Vascular Remodeling and Regeneration, University of Pittsburgh, Pittsburgh, PA, USA
| | - Marie Billaud
- Department of Cardiothoracic Surgery and Department of Bioengineering, McGowan Institute for Regenerative Medicine, and Center for Vascular Remodeling and Regeneration, University of Pittsburgh, Pittsburgh, PA, USA
| | - Julie A. Phillippi
- Department of Cardiothoracic Surgery and Department of Bioengineering, McGowan Institute for Regenerative Medicine, and Center for Vascular Remodeling and Regeneration, University of Pittsburgh, Pittsburgh, PA, USA
| | - Jianbin Wang
- School of Life Sciences, Tsinghua University, Beijing, China
| | - Yijen Wu
- Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Tuantuan Tan
- Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - William Devine
- Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Jiuann-huey Lin
- Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Abha S. Bais
- Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Jonathan Klonowski
- Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Anne Moreau de Bellaing
- Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Department of Pediatric Cardiology, Necker-Sick Children Hospital and University of Paris Descartes, Paris, France
| | - Ankur Saini
- Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Michael X. Wang
- Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Leonid Emerel
- Department of Cardiothoracic Surgery and Department of Bioengineering, McGowan Institute for Regenerative Medicine, and Center for Vascular Remodeling and Regeneration, University of Pittsburgh, Pittsburgh, PA, USA
| | - Nathan Salamacha
- Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Samuel K. Wyman
- Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Carrie Lee
- Centre for Cardiovascular Genomics and Medicine, Division of Cardiology, and Division of Medical Sciences, Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong SAR, China
| | - Hung Sing Li
- Centre for Cardiovascular Genomics and Medicine, Division of Cardiology, and Division of Medical Sciences, Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong SAR, China
| | - Anastasia Miron
- Division of Cardiology, Labatt Family Heart Centre, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
| | - Jingyu Zhang
- Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Jianhua Xing
- Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Dennis M. McNamara
- Heart and Vascular Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Erik Fung
- Centre for Cardiovascular Genomics and Medicine, Division of Cardiology, and Division of Medical Sciences, Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong SAR, China
- Laboratory for Heart Failure and Circulation Research, Li Ka Shing Institute of Health Sciences, Prince of Wales Hospital, CARE Programme, Lui Che Woo Institute of Innovative Medicine, and Gerald Choa Cardiac Research Centre, Chinese University of Hong Kong, Hong Kong SAR, China
| | - Paul Kirshbom
- Sanger Heart & Vascular Institute, Charlotte, NC, USA
| | - William Mahle
- Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, Atlanta, GA, USA
| | - Lazaros K. Kochilas
- Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, Atlanta, GA, USA
| | - Yihua He
- Department of Ultrasound, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Vidu Garg
- Center for Cardiovascular Research, The Heart Center, Nationwide Children’s Hospital and Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA
| | - Peter White
- The Institute for Genomic Medicine, Center for Cardiovascular Research, Nationwide Children’s Hospital and Department of Pediatrics, Ohio State University College of Medicine, Columbus, OH, USA
| | - Kim L. McBride
- Center for Cardiovascular Research, The Heart Center, Nationwide Children’s Hospital and Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA
| | - D. Woodrow Benson
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Thomas G. Gleason
- Division of Cardiac Surgery, Department of Surgery, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
| | - Seema Mital
- Division of Cardiology, Labatt Family Heart Centre, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
| | - Cecilia W. Lo
- Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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30
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Martin LJ, Benson DW. Focused Strategies for Defining the Genetic Architecture of Congenital Heart Defects. Genes (Basel) 2021; 12:827. [PMID: 34071175 PMCID: PMC8228798 DOI: 10.3390/genes12060827] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 05/24/2021] [Accepted: 05/26/2021] [Indexed: 12/14/2022] Open
Abstract
Congenital heart defects (CHD) are malformations present at birth that occur during heart development. Increasing evidence supports a genetic origin of CHD, but in the process important challenges have been identified. This review begins with information about CHD and the importance of detailed phenotyping of study subjects. To facilitate appropriate genetic study design, we review DNA structure, genetic variation in the human genome and tools to identify the genetic variation of interest. Analytic approaches powered for both common and rare variants are assessed. While the ideal outcome of genetic studies is to identify variants that have a causal role, a more realistic goal for genetic analytics is to identify variants in specific genes that influence the occurrence of a phenotype and which provide keys to open biologic doors that inform how the genetic variants modulate heart development. It has never been truer that good genetic studies start with good planning. Continued progress in unraveling the genetic underpinnings of CHD will require multidisciplinary collaboration between geneticists, quantitative scientists, clinicians, and developmental biologists.
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Affiliation(s)
- Lisa J. Martin
- Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
- Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati, OH 45229, USA
| | - D. Woodrow Benson
- Department of Pediatrics, Medical College of Wisconsin, Wauwatosa, WI 53226, USA;
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31
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Majumdar U, Yasuhara J, Garg V. In Vivo and In Vitro Genetic Models of Congenital Heart Disease. Cold Spring Harb Perspect Biol 2021; 13:cshperspect.a036764. [PMID: 31818859 DOI: 10.1101/cshperspect.a036764] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Congenital cardiovascular malformations represent the most common type of birth defect and encompass a spectrum of anomalies that range from mild to severe. The etiology of congenital heart disease (CHD) is becoming increasingly defined based on prior epidemiologic studies that supported the importance of genetic contributors and technological advances in human genome analysis. These have led to the discovery of a growing number of disease-contributing genetic abnormalities in individuals affected by CHD. The ever-growing population of adult CHD survivors, which are the result of reductions in mortality from CHD during childhood, and this newfound genetic knowledge have led to important questions regarding recurrence risks, the mechanisms by which these defects occur, the potential for novel approaches for prevention, and the prediction of long-term cardiovascular morbidity in adult CHD survivors. Here, we will review the current status of genetic models that accurately model human CHD as they provide an important tool to answer these questions and test novel therapeutic strategies.
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Affiliation(s)
- Uddalak Majumdar
- Center for Cardiovascular Research, Nationwide Children's Hospital, Columbus, Ohio 43205, USA.,The Heart Center, Nationwide Children's Hospital, Columbus, Ohio 43205, USA
| | - Jun Yasuhara
- Center for Cardiovascular Research, Nationwide Children's Hospital, Columbus, Ohio 43205, USA.,The Heart Center, Nationwide Children's Hospital, Columbus, Ohio 43205, USA
| | - Vidu Garg
- Center for Cardiovascular Research, Nationwide Children's Hospital, Columbus, Ohio 43205, USA.,The Heart Center, Nationwide Children's Hospital, Columbus, Ohio 43205, USA.,Department of Pediatrics, The Ohio State University, Columbus, Ohio 43205, USA.,Department of Molecular Genetics, The Ohio State University, Columbus, Ohio 43205, USA
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32
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Klein J, Donofrio MT. Fetal Echocardiography for the General Pediatrician. Pediatr Ann 2021; 50:e121-e127. [PMID: 34038649 DOI: 10.3928/19382359-20210217-03] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Fetal echocardiography is now commonly used to assess fetuses for congenital heart disease. To care for their patients, it is important for the pediatrician to understand the utility of the test, the benefits, and the limitations of the results. This review outlines the indications, components, and limitations of fetal echocardiography with a focus on the care that the pediatrician provides to newborns and their families. An understanding of the fetal cardiac examination can assist the pediatrician in caring for patients with either normal or abnormal test results. The need for and timing of postnatal cardiology follow-up, and guidance on referral for fetal echocardiogram for future pregnancies are all critical roles that the pediatrician can play. Most importantly, an understanding of the limitations, including difficult-to-diagnose lesions, allows the pediatrician to maintain a high level of suspicion for cardiac defects regardless of fetal echocardiography findings. [Pediatr Ann. 2021;50(3):e121-e127.].
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33
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Menahem S, Sehgal A, Meagher S. Early detection of significant congenital heart disease: The contribution of fetal cardiac ultrasound and newborn pulse oximetry screening. J Paediatr Child Health 2021; 57:323-327. [PMID: 33529483 DOI: 10.1111/jpc.15355] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 01/05/2021] [Accepted: 01/06/2021] [Indexed: 12/19/2022]
Abstract
Fetal cardiac and newborn pulse oximetry screening has greatly facilitated the detection of cardiac abnormalities, which may be serious with potentially dire neonatal consequences. The prenatal diagnosis of a serious cardiac abnormality allows the attending obstetrician to organise the much safer in-utero transfer of the fetus for delivery at a tertiary centre, particularly if there is evidence of a duct-dependent lesion that may require the infusion of Prostaglandin E1 to maintain duct patency pending surgical intervention. Newborn pulse oximetry alerts the paediatrician that the baby may have a significant cardiac abnormality, which warrants further elucidation prior to discharge, rather than for the baby to represent unwell a few days later. Despite these advances, serious cardiac abnormalities may be missed on screening. Their detection then falls back onto the clinical acumen of the attending paediatrician/family physician to review the history, carefully elicit and evaluate the clinical signs further aided by whatever investigations that may be available at the birthing hospital, frequently less resourced than the tertiary centres. At the outset, a brief synopsis is provided of the clinical findings that may point to a cardiac abnormality. That is followed by a critical review of the accuracy of prenatal and newborn pulse oximetry screening with emphasis on the lesions that may be missed. Suggestions are made as to how to improve the diagnostic accuracy.
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Affiliation(s)
- Samuel Menahem
- Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia.,School of Clinical Services, Monash University, Melbourne, Victoria, Australia
| | - Arvind Sehgal
- Monash Newborn, Monash Children's Hospital, Melbourne, Victoria, Australia.,Department of Paediatrics, Monash University, Melbourne, Victoria, Australia
| | - Simon Meagher
- Department of Perinatal Medicine, University of Melbourne, Melbourne, Victoria, Australia.,Monash Ultrasound for Women, Melbourne, Victoria, Australia
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34
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Lou XY, Hou TT, Liu SY, Xu HM, Lin F, Tang X, MacLeod SL, Cleves MA, Hobbs CA. Innovative approach to identify multigenomic and environmental interactions associated with birth defects in family-based hybrid designs. Genet Epidemiol 2021; 45:171-189. [PMID: 32996630 PMCID: PMC8495752 DOI: 10.1002/gepi.22363] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 09/08/2020] [Accepted: 09/11/2020] [Indexed: 11/09/2022]
Abstract
Genes, including those with transgenerational effects, work in concert with behavioral, environmental, and social factors via complex biological networks to determine human health. Understanding complex relationships between causal factors underlying human health is an essential step towards deciphering biological mechanisms. We propose a new analytical framework to investigate the interactions between maternal and offspring genetic variants or their surrogate single nucleotide polymorphisms (SNPs) and environmental factors using family-based hybrid study design. The proposed approach can analyze diverse genetic and environmental factors and accommodate samples from a variety of family units, including case/control-parental triads, and case/control-parental dyads, while minimizing potential bias introduced by population admixture. Comprehensive simulations demonstrated that our innovative approach outperformed the log-linear approach, the best available method for case-control family data. The proposed approach had greater statistical power and was capable to unbiasedly estimate the maternal and child genetic effects and the effects of environmental factors, while controlling the Type I error rate against population stratification. Using our newly developed approach, we analyzed the associations between maternal and fetal SNPs and obstructive and conotruncal heart defects, with adjustment for demographic and lifestyle factors and dietary supplements. Fourteen and 11 fetal SNPs were associated with obstructive and conotruncal heart defects, respectively. Twenty-seven and 17 maternal SNPs were associated with obstructive and conotruncal heart defects, respectively. In addition, maternal body mass index was a significant risk factor for obstructive defects. The proposed approach is a powerful tool for interrogating the etiological mechanism underlying complex traits.
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Affiliation(s)
- Xiang-Yang Lou
- Department of Biostatistics, College of Public Health and Health Professions and College of Medicine, University of Florida, Gainesville, Florida, USA
| | - Ting-Ting Hou
- Department of Biostatistics, College of Public Health and Health Professions and College of Medicine, University of Florida, Gainesville, Florida, USA
- Institute of Bioinformatics and Institute of Crop Science, College of Agriculture and Biotechnology, Zhejiang University, Hangzhou, China
| | - Shou-Ye Liu
- Institute of Bioinformatics and Institute of Crop Science, College of Agriculture and Biotechnology, Zhejiang University, Hangzhou, China
| | - Hai-Ming Xu
- Institute of Bioinformatics and Institute of Crop Science, College of Agriculture and Biotechnology, Zhejiang University, Hangzhou, China
| | - Feng Lin
- Institute of Bioinformatics and Institute of Crop Science, College of Agriculture and Biotechnology, Zhejiang University, Hangzhou, China
| | - Xinyu Tang
- The US Food and Drug Administration, Silver Spring, Maryland, USA
| | | | - Mario A. Cleves
- Department of Pediatrics, Morsani College of Medicine, Health Informatics Institute, University of South Florida, Tampa, Florida, USA
| | - Charlotte A. Hobbs
- Rady Children’s Institute for Genomic Medicine, San Diego, California, USA
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35
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Lin H, McBride KL, Garg V, Zhao MT. Decoding Genetics of Congenital Heart Disease Using Patient-Derived Induced Pluripotent Stem Cells (iPSCs). Front Cell Dev Biol 2021; 9:630069. [PMID: 33585486 PMCID: PMC7873857 DOI: 10.3389/fcell.2021.630069] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 01/04/2021] [Indexed: 12/20/2022] Open
Abstract
Congenital heart disease (CHD) is the most common cause of infant death associated with birth defects. Recent next-generation genome sequencing has uncovered novel genetic etiologies of CHD, from inherited and de novo variants to non-coding genetic variants. The next phase of understanding the genetic contributors of CHD will be the functional illustration and validation of this genome sequencing data in cellular and animal model systems. Human induced pluripotent stem cells (iPSCs) have opened up new horizons to investigate genetic mechanisms of CHD using clinically relevant and patient-specific cardiac cells such as cardiomyocytes, endothelial/endocardial cells, cardiac fibroblasts and vascular smooth muscle cells. Using cutting-edge CRISPR/Cas9 genome editing tools, a given genetic variant can be corrected in diseased iPSCs and introduced to healthy iPSCs to define the pathogenicity of the variant and molecular basis of CHD. In this review, we discuss the recent progress in genetics of CHD deciphered by large-scale genome sequencing and explore how genome-edited patient iPSCs are poised to decode the genetic etiologies of CHD by coupling with single-cell genomics and organoid technologies.
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Affiliation(s)
- Hui Lin
- Center for Cardiovascular Research, The Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH, United States.,The Heart Center, Nationwide Children's Hospital, Columbus, OH, United States.,Division of Genetic and Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, United States
| | - Kim L McBride
- Center for Cardiovascular Research, The Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH, United States.,The Heart Center, Nationwide Children's Hospital, Columbus, OH, United States.,Division of Genetic and Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, United States.,Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, United States
| | - Vidu Garg
- Center for Cardiovascular Research, The Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH, United States.,The Heart Center, Nationwide Children's Hospital, Columbus, OH, United States.,Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, United States.,Department of Molecular Genetics, The Ohio State University, Columbus, OH, United States
| | - Ming-Tao Zhao
- Center for Cardiovascular Research, The Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH, United States.,The Heart Center, Nationwide Children's Hospital, Columbus, OH, United States.,Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, United States
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36
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Abstract
Congenital heart disease is the most common congenital defect observed in newborns. Within the spectrum of congenital heart disease are left‐sided obstructive lesions (LSOLs), which include hypoplastic left heart syndrome, aortic stenosis, bicuspid aortic valve, coarctation of the aorta, and interrupted aortic arch. These defects can arise in isolation or as a component of a defined syndrome; however, nonsyndromic defects are often observed in multiple family members and associated with high sibling recurrence risk. This clear evidence for a heritable basis has driven a lengthy search for disease‐causing variants that has uncovered both rare and common variants in genes that, when perturbed in cardiac development, can result in LSOLs. Despite advancements in genetic sequencing platforms and broadening use of exome sequencing, the currently accepted LSOL‐associated genes explain only 10% to 20% of patients. Further, the combinatorial effects of common and rare variants as a cause of LSOLs are emerging. In this review, we highlight the genes and variants associated with the different LSOLs and discuss the strengths and weaknesses of the present genetic associations. Furthermore, we discuss the research avenues needed to bridge the gaps in our current understanding of the genetic basis of nonsyndromic congenital heart disease.
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Affiliation(s)
- Lauren E Parker
- Division of Cardiology Department of Pediatrics Duke University School of Medicine Durham NC
| | - Andrew P Landstrom
- Division of Cardiology Department of Pediatrics Duke University School of Medicine Durham NC.,Department of Cell Biology Duke University School of Medicine Durham NC
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37
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Tcheandjieu C, Zanetti D, Yu M, Priest JR. Inherited Extremes of Aortic Diameter Confer Risk for a Specific Class of Congenital Heart Disease. CIRCULATION-GENOMIC AND PRECISION MEDICINE 2020; 13:e003170. [PMID: 33191768 DOI: 10.1161/circgen.120.003170] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Catherine Tcheandjieu
- Division of Pediatric Cardiology, Department of Pediatrics (C.T., M.Y., J.R.P.), Stanford University School of Medicine, CA.,Division of Cardiovascular Medicine, Department of Medicine (C.T., D.Z.), Stanford University School of Medicine, CA.,Stanford Cardiovascular Institute, Stanford University, CA (C.T., D.Z., M.Y., J.R.P.)
| | - Daniela Zanetti
- Division of Cardiovascular Medicine, Department of Medicine (C.T., D.Z.), Stanford University School of Medicine, CA.,Stanford Cardiovascular Institute, Stanford University, CA (C.T., D.Z., M.Y., J.R.P.)
| | - Mengyao Yu
- Division of Pediatric Cardiology, Department of Pediatrics (C.T., M.Y., J.R.P.), Stanford University School of Medicine, CA.,Stanford Cardiovascular Institute, Stanford University, CA (C.T., D.Z., M.Y., J.R.P.)
| | - James R Priest
- Division of Pediatric Cardiology, Department of Pediatrics (C.T., M.Y., J.R.P.), Stanford University School of Medicine, CA.,Stanford Cardiovascular Institute, Stanford University, CA (C.T., D.Z., M.Y., J.R.P.).,Chan-Zuckerberg Biohub, San Francisco, CA (J.R.P.)
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38
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Lowry RB, Bedard T, Crawford S, Grevers X, Bernier FP, Thomas MA. Prevalence rates study of selected isolated non-Mendelian congenital anomalies in the Hutterite population of Alberta, 1980-2016. Am J Med Genet A 2020; 182:2594-2604. [PMID: 32893972 DOI: 10.1002/ajmg.a.61834] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 07/29/2020] [Accepted: 08/01/2020] [Indexed: 11/10/2022]
Abstract
A study of the prevalence rates for selected isolated non-Mendelian congenital anomalies in the Hutterite Brethren of Alberta, Canada was undertaken to further examine longitudinal data in this isolated community that was last reported in 1985 (Lowry et al., 1985), although there are numerous publications on recessive disorders (Boycott et al., 2008; Triggs-Raine et al., 2016). Cases were ascertained from the Alberta Congenital Anomaly Surveillance System for the years 1997-2016. Since our initial results showed some surprising findings in the Hutterite Brethren, such as zero cases of spina bifida, cleft lip and palate, gastroschisis, and omphalocele, and a significant excess of cases with hypospadias, we extended the study to prior years (1980-1996) for selected anomalies. For the extended study period (1980-2016), there was a significant increased prevalence of hypospadias, tetralogy of Fallot and tricuspid atresia in the Hutterite population, and although not statistically significant, zero cases of cleft lip with cleft palate, gastroschisis and omphalocele were confirmed. Further research is needed to determine the precise effects of rural environmental exposures, lifestyle factors, and genetic associations for selected multifactorial congenital anomalies.
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Affiliation(s)
- R Brian Lowry
- Alberta Congenital Anomalies Surveillance System, Alberta Health Services, Calgary, Alberta, Canada.,Department of Pediatrics, University of Calgary and Alberta Children's Hospital, Calgary, Alberta, Canada.,Department of Medical Genetics, University of Calgary and Alberta Children's Hospital, Calgary, Alberta, Canada.,Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Tanya Bedard
- Alberta Congenital Anomalies Surveillance System, Alberta Health Services, Calgary, Alberta, Canada
| | - Susan Crawford
- Alberta Perinatal Health Program, Alberta Health Services, Calgary, Alberta, Canada
| | - Xin Grevers
- Alberta Congenital Anomalies Surveillance System, Alberta Health Services, Calgary, Alberta, Canada
| | - François P Bernier
- Department of Pediatrics, University of Calgary and Alberta Children's Hospital, Calgary, Alberta, Canada.,Department of Medical Genetics, University of Calgary and Alberta Children's Hospital, Calgary, Alberta, Canada.,Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Mary Ann Thomas
- Alberta Congenital Anomalies Surveillance System, Alberta Health Services, Calgary, Alberta, Canada.,Department of Pediatrics, University of Calgary and Alberta Children's Hospital, Calgary, Alberta, Canada.,Department of Medical Genetics, University of Calgary and Alberta Children's Hospital, Calgary, Alberta, Canada.,Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
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39
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Abstract
Bicuspid aortic valve (BAV) is the most common congenital heart defect, found in up to 2% of the population and associated with a 30% lifetime risk of complications. BAV is inherited as an autosomal dominant trait with incomplete penetrance and variable expressivity due to a complex genetic architecture that involves many interacting genes. In this review, we highlight the current state of knowledge about BAV genetics, principles and methods for BAV gene discovery, clinical applications of BAV genetics, and important future directions.
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40
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Cribbs MG. Coarctation: A Review. US CARDIOLOGY REVIEW 2020. [DOI: 10.15420/usc.2019.15.2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Coarctation of the aorta occurs in 0.04% of the population, and accounts for approximately 10% of lesions in adults with congenital heart disease. It can occur as an isolated lesion or as a part of a complex defect, and is most commonly associated with bicuspid aortic valve, ventricular septal defect, and mitral valve abnormalities. Since the first surgical repair in 1944, the available treatment options have expanded greatly. Perhaps one of the most important advances in the management of coarctation of the aorta has been the development of transcatheter therapy for both native and especially recurrent coarctation of the aorta. Late complications, even after apparently successful treatment, are not uncommon. For this reason, lifelong follow-up is vital.
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Affiliation(s)
- Marc G Cribbs
- Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL, US
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41
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Bahado-Singh RO, Vishweswaraiah S, Aydas B, Yilmaz A, Saiyed NM, Mishra NK, Guda C, Radhakrishna U. Precision cardiovascular medicine: artificial intelligence and epigenetics for the pathogenesis and prediction of coarctation in neonates. J Matern Fetal Neonatal Med 2020; 35:457-464. [PMID: 32019381 DOI: 10.1080/14767058.2020.1722995] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Background: Advances in omics and computational Artificial Intelligence (AI) have been said to be key to meeting the objectives of precision cardiovascular medicine. The focus of precision medicine includes a better assessment of disease risk and understanding of disease mechanisms. Our objective was to determine whether significant epigenetic changes occur in isolated, non-syndromic CoA. Further, we evaluated the AI analysis of DNA methylation for the prediction of CoA.Methods: Genome-wide DNA methylation analysis of newborn blood DNA was performed in 24 isolated, non-syndromic CoA cases and 16 controls using the Illumina HumanMethylation450 BeadChip arrays. Cytosine nucleotide (CpG) methylation changes in CoA in each of 450,000 CpG loci were determined. Ingenuity pathway analysis (IPA) was performed to identify molecular and disease pathways that were epigenetically dysregulated. Using methylation data, six artificial intelligence (AI) platforms including deep learning (DL) was used for CoA detection.Results: We identified significant (FDR p-value ≤ .05) methylation changes in 65 different CpG sites located in 75 genes in CoA subjects. DL achieved an AUC (95% CI) = 0.97 (0.80-1) with 95% sensitivity and 98% specificity. Gene ontology (GO) analysis yielded epigenetic alterations in important cardiovascular developmental genes and biological processes: abnormal morphology of cardiovascular system, left ventricular dysfunction, heart conduction disorder, thrombus formation, and coronary artery disease.Conclusion: In an exploratory study we report the use of AI and epigenomics to achieve important objectives of precision cardiovascular medicine. Accurate prediction of CoA was achieved using a newborn blood spot. Further, we provided evidence of a significant epigenetic etiology in isolated CoA development.
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Affiliation(s)
- Ray O Bahado-Singh
- Department of Obstetrics and Gynecology, Oakland University William Beaumont School of Medicine, Royal Oak, Michigan, USA
| | - Sangeetha Vishweswaraiah
- Department of Obstetrics and Gynecology, Oakland University William Beaumont School of Medicine, Royal Oak, Michigan, USA
| | - Buket Aydas
- Department of Mathematics & Computer Science, Albion College, Albion, Michigan, USA
| | - Ali Yilmaz
- Department of Obstetrics and Gynecology, Oakland University William Beaumont School of Medicine, Royal Oak, Michigan, USA
| | - Nazia M Saiyed
- Nirma Institute of Science, Nirma University, Ahmedabad, India
| | - Nitish K Mishra
- Department of Genetics, Cell Biology & Anatomy College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Chittibabu Guda
- Department of Genetics, Cell Biology & Anatomy College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Uppala Radhakrishna
- Department of Obstetrics and Gynecology, Oakland University William Beaumont School of Medicine, Royal Oak, Michigan, USA
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42
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Bjornsson T, Thorolfsdottir RB, Sveinbjornsson G, Sulem P, Norddahl GL, Helgadottir A, Gretarsdottir S, Magnusdottir A, Danielsen R, Sigurdsson EL, Adalsteinsdottir B, Gunnarsson SI, Jonsdottir I, Arnar DO, Helgason H, Gudbjartsson T, Gudbjartsson DF, Thorsteinsdottir U, Holm H, Stefansson K. A rare missense mutation in MYH6 associates with non-syndromic coarctation of the aorta. Eur Heart J 2019; 39:3243-3249. [PMID: 29590334 PMCID: PMC6127890 DOI: 10.1093/eurheartj/ehy142] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Accepted: 03/02/2018] [Indexed: 12/13/2022] Open
Abstract
Aims Coarctation of the aorta (CoA) accounts for 4–8% of congenital heart defects (CHDs) and confers substantial morbidity despite treatment. It is increasingly recognized as a highly heritable condition. The aim of the study was to search for sequence variants that affect the risk of CoA. Methods and results We performed a genome-wide association study of CoA among Icelanders (120 cases and 355 166 controls) based on imputed variants identified through whole-genome sequencing. We found association with a rare (frequency = 0.34%) missense mutation p.Arg721Trp in MYH6 (odds ratio = 44.2, P = 5.0 × 10−22), encoding the alpha-heavy chain subunit of cardiac myosin, an essential sarcomere protein. Approximately 20% of individuals with CoA in Iceland carry this mutation. We show that p.Arg721Trp also associates with other CHDs, in particular bicuspid aortic valve. We have previously reported broad effects of p.Arg721Trp on cardiac electrical function and strong association with sick sinus syndrome and atrial fibrillation. Conclusion Through a population approach, we found that a rare missense mutation p.Arg721Trp in the sarcomere gene MYH6 has a strong effect on the risk of CoA and explains a substantial fraction of the Icelanders with CoA. This is the first mutation associated with non-familial or sporadic form of CoA at a population level. The p.Arg721Trp in MYH6 causes a cardiac syndrome with highly variable expressivity and emphasizes the importance of sarcomere integrity for cardiac development and function.
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Affiliation(s)
| | | | | | - Patrick Sulem
- deCODE genetics/Amgen, Inc., Sturlugata 8, Reykjavik, Iceland
| | | | | | | | | | - Ragnar Danielsen
- Department of Medicine, Landspitali-The National University Hospital of Iceland, Hringbraut, Reykjavik, Iceland
| | - Emil L Sigurdsson
- Department of Family Medicine, University of Iceland, Vatnsmyrarvegur 16, Reykjavik, Iceland.,Department of Development, Primary Health Care of the Capital Area, Alfabakki 16, Reykjavik, Iceland
| | - Berglind Adalsteinsdottir
- Department of Cardiology, Haukeland University Hospital, Jonas Lies vei 83, Bergen, Norway.,Faculty of Medicine, University of Iceland, Vatnsmyrarvegur 16, Reykjavik, Iceland
| | - Sverrir I Gunnarsson
- Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, 600 Highland Ave, Madison, WI, USA
| | - Ingileif Jonsdottir
- deCODE genetics/Amgen, Inc., Sturlugata 8, Reykjavik, Iceland.,Faculty of Medicine, University of Iceland, Vatnsmyrarvegur 16, Reykjavik, Iceland.,Department of Immunology, Landspitali-The National University Hospital of Iceland, Hringbraut, Reykjavik, Iceland
| | - David O Arnar
- deCODE genetics/Amgen, Inc., Sturlugata 8, Reykjavik, Iceland.,Department of Medicine, Landspitali-The National University Hospital of Iceland, Hringbraut, Reykjavik, Iceland.,Faculty of Medicine, University of Iceland, Vatnsmyrarvegur 16, Reykjavik, Iceland
| | - Hrodmar Helgason
- Children's Hospital, Landspitali-The National University Hospital of Iceland, Hringbraut, Reykjavik, Iceland
| | - Tomas Gudbjartsson
- Faculty of Medicine, University of Iceland, Vatnsmyrarvegur 16, Reykjavik, Iceland.,Department of Cardiothoracic Surgery, Landspitali-The National University Hospital of Iceland, Hringbraut, Reykjavik, Iceland
| | - Daniel F Gudbjartsson
- deCODE genetics/Amgen, Inc., Sturlugata 8, Reykjavik, Iceland.,School of Engineering and Natural Sciences, University of Iceland, Hjardarhagi 4, Reykjavik, Iceland
| | - Unnur Thorsteinsdottir
- deCODE genetics/Amgen, Inc., Sturlugata 8, Reykjavik, Iceland.,Faculty of Medicine, University of Iceland, Vatnsmyrarvegur 16, Reykjavik, Iceland
| | - Hilma Holm
- deCODE genetics/Amgen, Inc., Sturlugata 8, Reykjavik, Iceland
| | - Kari Stefansson
- deCODE genetics/Amgen, Inc., Sturlugata 8, Reykjavik, Iceland.,Faculty of Medicine, University of Iceland, Vatnsmyrarvegur 16, Reykjavik, Iceland
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43
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Ellesøe SG, Workman CT, Bouvagnet P, Loffredo CA, McBride KL, Hinton RB, van Engelen K, Gertsen EC, Mulder BJM, Postma AV, Anderson RH, Hjortdal VE, Brunak S, Larsen LA. Familial co-occurrence of congenital heart defects follows distinct patterns. Eur Heart J 2019; 39:1015-1022. [PMID: 29106500 PMCID: PMC6018923 DOI: 10.1093/eurheartj/ehx314] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Accepted: 06/01/2017] [Indexed: 12/16/2022] Open
Abstract
Aims Congenital heart defects (CHD) affect almost 1% of all live born children and the number of adults with CHD is increasing. In families where CHD has occurred previously, estimates of recurrence risk, and the type of recurring malformation are important for counselling and clinical decision-making, but the recurrence patterns in families are poorly understood. We aimed to determine recurrence patterns, by investigating the co-occurrences of CHD in 1163 families with known malformations, comprising 3080 individuals with clinically confirmed diagnosis. Methods and results We calculated rates of concordance and discordance for 41 specific types of malformations, observing a high variability in the rates of concordance and discordance. By calculating odds ratios for each of 1640 pairs of discordant lesions observed between affected family members, we were able to identify 178 pairs of malformations that co-occurred significantly more or less often than expected in families. The data show that distinct groups of cardiac malformations co-occur in families, suggesting influence from underlying developmental mechanisms. Analysis of human and mouse susceptibility genes showed that they were shared in 19% and 20% of pairs of co-occurring discordant malformations, respectively, but none of malformations that rarely co-occur, suggesting that a significant proportion of co-occurring lesions in families is caused by overlapping susceptibility genes. Conclusion Familial CHD follow specific patterns of recurrence, suggesting a strong influence from genetically regulated developmental mechanisms. Co-occurrence of malformations in families is caused by shared susceptibility genes.
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Affiliation(s)
- Sabrina G Ellesøe
- Programme for Disease Systems Biology, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen, Denmark
| | - Christopher T Workman
- Department of Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, Denmark
| | - Patrice Bouvagnet
- Laboratoire Cardiogénétique, Hospices Civils de Lyon, Groupe Hospitalier Est, 59 boulevard Pinel, CBPE, 69677, Bron, France
| | - Christopher A Loffredo
- Department of Oncology, Georgetown University Medical Center, 3970 Reservoir Road, Washington, DC 20057-1472, USA
| | - Kim L McBride
- Center for Cardiovascular Research, Nationwide Children's Hospital, and Department of Pediatrics, Ohio State University, 700 Children's Drive Columbus, OH 43205, Columbus, OH, USA
| | - Robert B Hinton
- Division of Cardiology, The Heart Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, MLC 2003, Cincinnati, OH, 45229, USA
| | - Klaartje van Engelen
- Department of Clinical Genetics, Academic Medical Centre, Meibergdreef 15, Amsterdam 1105 AZ, The Netherlands.,Department of Clinical Genetics, VU University, De Boelelaan 1117, NL-1081 HV Amsterdam, The Netherlands
| | - Emma C Gertsen
- Department of Clinical Genetics, Academic Medical Centre, Meibergdreef 15, Amsterdam 1105 AZ, The Netherlands
| | - Barbara J M Mulder
- Department of Cardiology, Academic Medical Centre, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands
| | - Alex V Postma
- Department of Clinical Genetics, Academic Medical Centre, Meibergdreef 15, Amsterdam 1105 AZ, The Netherlands.,Department of Anatomy, Embryology & Physiology, Academic Medical Centre, Meibergdreef 15, Amsterdam 1105 AZ, The Netherlands
| | - Robert H Anderson
- Institute of Genetic Medicine, Newcastle University, Central Pkwy, Newcastle upon Tyne NE1 3BZ, UK
| | - Vibeke E Hjortdal
- Department of Cardiothoracic Surgery, Aarhus University Hospital, Skejby, Palle Juul-Jensens Boulevard 99, 8200 Aarhus N, Denmark
| | - Søren Brunak
- Programme for Disease Systems Biology, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen, Denmark
| | - Lars A Larsen
- Wilhelm Johannsen Centre for Functional Genome Research, Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen, Denmark
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44
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Saraf A, Book WM, Nelson TJ, Xu C. Hypoplastic left heart syndrome: From bedside to bench and back. J Mol Cell Cardiol 2019; 135:109-118. [PMID: 31419439 PMCID: PMC10831616 DOI: 10.1016/j.yjmcc.2019.08.005] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2019] [Revised: 08/07/2019] [Accepted: 08/12/2019] [Indexed: 02/09/2023]
Abstract
Hypoplastic Left Heart Syndrome (HLHS) is a complex Congenital Heart Disease (CHD) that was almost universally fatal until the advent of the Norwood operation in 1981. Children with HLHS who largely succumbed to the disease within the first year of life, are now surviving to adulthood. However, this survival is associated with multiple comorbidities and HLHS infants have a higher mortality rate as compared to other non-HLHS single ventricle patients. In this review we (a) discuss current clinical challenges associated in the care of HLHS patients, (b) explore the use of systems biology in understanding the molecular framework of this disease, (c) evaluate induced pluripotent stem cells as a translational model to understand molecular mechanisms and manipulate them to improve outcomes, and (d) investigate cell therapy, gene therapy, and tissue engineering as a potential tool to regenerate hypoplastic cardiac structures and improve outcomes.
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Affiliation(s)
- Anita Saraf
- Division of Cardiology, Emory University School of Medicine, Atlanta, GA 30322, USA.
| | - Wendy M Book
- Division of Cardiology, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Timothy J Nelson
- Division of General Internal Medicine, Center for Regenerative Medicine, Pediatric Cardiothoracic Surgery, Division of Cardiovascular Diseases, Transplant Center, Division of Biomedical Statistics and Informatics, Division of Pediatric Cardiology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA
| | - Chunhui Xu
- Division of Pediatric Cardiology, Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA 30322, USA; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30322, USA
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45
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Ganigara M, Doshi A, Naimi I, Mahadevaiah GP, Buddhe S, Chikkabyrappa SM. Preoperative Physiology, Imaging, and Management of Coarctation of Aorta in Children. Semin Cardiothorac Vasc Anesth 2019; 23:379-386. [PMID: 31535945 DOI: 10.1177/1089253219873004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Coarctation of the aorta (CoA) is a narrowing of the proximal thoracic aorta typically located at the junction of the aorta with the ductus arteriosus. While it is a simple lesion to understand, considerable variation exists in the anatomy and pathophysiology, leading to varied clinical presentation, management options, and prognosis. On the one hand critical CoA manifests in the neonatal period as a duct-dependent lesion, while less severe forms of obstruction present later in childhood or adulthood as hypertension or incidentally noted precordial murmurs. While transthoracic echocardiography is usually adequate, older children and adults may need more advanced imaging modalities like computed tomography and magnetic resonance imaging prior to intervention. Depending on the type of lesion, management options currently available include surgery and percutaneous balloon angioplasty and stenting. Even after successful interventions, these patients need life-long surveillance for residual aortic obstruction and systemic hypertension with variable long-term clinical outcomes.
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Affiliation(s)
- Madhusudan Ganigara
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, New York, NY, USA
| | - Arpan Doshi
- Children's Mercy Hospitals and Clinics, Wichita, KS, USA
| | - Iman Naimi
- Seattle Children's Hospital, University of Washington, Seattle, WA, USA
| | | | - Sujatha Buddhe
- Seattle Children's Hospital, University of Washington, Seattle, WA, USA
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46
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Lee A, Wei S, Schwertani A. A Notch more: Molecular players in bicuspid aortic valve disease. J Mol Cell Cardiol 2019; 134:62-68. [DOI: 10.1016/j.yjmcc.2019.05.018] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Revised: 05/07/2019] [Accepted: 05/23/2019] [Indexed: 12/20/2022]
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47
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Shikany AR, Parrott A, James J, Madueme P, Nicole Weaver K, Cassidy C, Khoury PR, Miller EM. Left ventricular outflow tract obstruction: Uptake of familial cardiac screening and parental knowledge from a single tertiary care center. J Genet Couns 2019; 28:779-789. [PMID: 30907979 DOI: 10.1002/jgc4.1117] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Revised: 02/20/2019] [Accepted: 02/21/2019] [Indexed: 11/06/2022]
Abstract
Left ventricular outflow tract obstruction (LVOTO) malformations exhibit higher heritability than other cardiac lesions and cardiac screening is encouraged for first-degree relatives. This study sought to determine the uptake of familial cardiac screening in families with an infant with an LVOTO and assess parental knowledge regarding genetics and heritability of LVOTO. A chart review of the period 2010-2015 identified 69 families who received genetic counseling regarding a diagnosis of LVOTO in an infant. Surveys assessing familial cardiac screening and parental knowledge were completed by a parent in 24 families (completion rate of 35%). Forty percent (36/89) of all at-risk first-degree family members completed cardiac screening. The presence of additional congenital malformations in the affected infant was the only significant factor reducing the uptake of familial cardiac screening (p = 0.003). The reported uptake of screening for subsequent at-risk pregnancies was 11/12 (92%) compared to 25/77 (32%) of living at-risk relatives. Survey respondents answered seven knowledge questions with an average score of 5.2 and all correctly identified that LVOTO can run in families. Uptake of familial cardiac screening is occurring in less than half of at-risk individuals, despite parents demonstrating basic knowledge and receiving genetic counseling. Follow-up counseling in the outpatient setting to review familial screening recommendations should be considered to increase uptake and optimize outcomes.
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Affiliation(s)
- Amy R Shikany
- Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Ashley Parrott
- Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Jeanne James
- Division of Cardiology, Children's Hospital of Wisconsin, Milwaukee, Wisconsin
| | - Peace Madueme
- Nemours Cardiac Center, Nemours Children's Hospital, Orlando, Florida
| | - Kathryn Nicole Weaver
- Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Christine Cassidy
- Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Philip R Khoury
- Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Erin M Miller
- Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
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48
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Martin LJ, Pilipenko V, Benson DW. Role of Segregation for Variant Discovery in Multiplex Families Ascertained by Probands With Left Sided Cardiovascular Malformations. Front Genet 2019; 9:729. [PMID: 30687393 PMCID: PMC6336695 DOI: 10.3389/fgene.2018.00729] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Accepted: 12/22/2018] [Indexed: 12/31/2022] Open
Abstract
Cardiovascular malformations (CVM) are common birth defects (incidence of 2-5/100 live births). Although a genetic basis is established, in most cases the cause remains unknown. Analysis of whole exome sequencing (WES) in left sided CVM case and trio series has identified large numbers of potential variants but evidence of causality has remained elusive except in a small percentage of cases. We sought to determine whether variant segregation in families would aid in novel gene discovery. The objective was to compare conventional and co-segregation approaches for WES in multiplex families. WES was performed on 52 individuals from 4 multiplex families ascertained by probands with hypoplastic left heart syndrome (HLHS). We identified rare variants with informatics support (RVIS, minor allele frequency ≤0.01 and Combined Annotation Dependent Depletion score ≥20) in probands. Non-RVIS variants did not meet these criteria. Family specific two point logarithm of the odds (LOD) scores identified co-segregating variants (C-SV) using a dominant model and 80% penetrance. In families, 702 RVIS in 668 genes were identified, but only 1 RVIS was also a C-SV (LOD ≥ 1). On the other hand, there were 109 non-RVIS variants with LOD ≥ 1. Among 110 C-SV, 97% were common (MAF > 1%). These results suggest that conventional variant identification methods focused on RVIS, miss most C-SV. For diseases such as left sided CVM, which exhibit strong familial transmission, co-segregation can identify novel candidates.
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Affiliation(s)
- Lisa J Martin
- Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.,Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati, OH, United States
| | - Valentina Pilipenko
- Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
| | - D Woodrow Benson
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, United States
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50
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Pierpont ME, Brueckner M, Chung WK, Garg V, Lacro RV, McGuire AL, Mital S, Priest JR, Pu WT, Roberts A, Ware SM, Gelb BD, Russell MW. Genetic Basis for Congenital Heart Disease: Revisited: A Scientific Statement From the American Heart Association. Circulation 2018; 138:e653-e711. [PMID: 30571578 PMCID: PMC6555769 DOI: 10.1161/cir.0000000000000606] [Citation(s) in RCA: 387] [Impact Index Per Article: 55.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
This review provides an updated summary of the state of our knowledge of the genetic contributions to the pathogenesis of congenital heart disease. Since 2007, when the initial American Heart Association scientific statement on the genetic basis of congenital heart disease was published, new genomic techniques have become widely available that have dramatically changed our understanding of the causes of congenital heart disease and, clinically, have allowed more accurate definition of the pathogeneses of congenital heart disease in patients of all ages and even prenatally. Information is presented on new molecular testing techniques and their application to congenital heart disease, both isolated and associated with other congenital anomalies or syndromes. Recent advances in the understanding of copy number variants, syndromes, RASopathies, and heterotaxy/ciliopathies are provided. Insights into new research with congenital heart disease models, including genetically manipulated animals such as mice, chicks, and zebrafish, as well as human induced pluripotent stem cell-based approaches are provided to allow an understanding of how future research breakthroughs for congenital heart disease are likely to happen. It is anticipated that this review will provide a large range of health care-related personnel, including pediatric cardiologists, pediatricians, adult cardiologists, thoracic surgeons, obstetricians, geneticists, genetic counselors, and other related clinicians, timely information on the genetic aspects of congenital heart disease. The objective is to provide a comprehensive basis for interdisciplinary care for those with congenital heart disease.
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