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1
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Lee AJ, Pi BK, Nam SH, Kim HS, Choi BO, Chung KW. Nonrecurrent 17p duplications in two patients with developmental and neurological abnormalities. Hum Genome Var 2025; 12:6. [PMID: 40140366 PMCID: PMC11947145 DOI: 10.1038/s41439-025-00310-6] [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: 12/20/2024] [Revised: 02/06/2025] [Accepted: 02/06/2025] [Indexed: 03/28/2025] Open
Abstract
Variable copy number variations (CNVs) in the short arm of chromosome 17 are associated with many neurodevelopmental disorders, including Charcot-Marie-Tooth disease type 1A, Potocki-Lupski syndrome and Yuan-Harel-Lupski syndrome. Here we examined CNVs in two sporadic cases of developmental abnormalities, brain impairment and peripheral neuropathy. We identified novel duplications of approximately 14.1 Mb at 17p11.2-p13.1 (containing PMP22 and RAI1) and 17.6 Mb at 17p11.2-p13.3 (YWHAE, PAFAH1B and PMP22) in each patient. Both duplications were suggested to be produced by de novo mutations of paternal origin. This study suggests that CNVs at 17p should be examined in patients with peripheral neuropathy as well as developmental and brain abnormalities.
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Affiliation(s)
- Ah Jin Lee
- Department of Biological Sciences, Kongju National University, Gongju, Republic of Korea
| | - Byung Kwon Pi
- Department of Biological Sciences, Kongju National University, Gongju, Republic of Korea
| | - Soo Hyun Nam
- Cell and Gene Therapy Institute, Samsung Medical Center, Seoul, Republic of Korea
| | - Hyun Su Kim
- Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Byung-Ok Choi
- Cell and Gene Therapy Institute, Samsung Medical Center, Seoul, Republic of Korea.
- Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
| | - Ki Wha Chung
- Department of Biological Sciences, Kongju National University, Gongju, Republic of Korea.
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2
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Abedini SS, Akhavantabasi S, Liang Y, Heng JIT, Alizadehsani R, Dehzangi I, Bauer DC, Alinejad-Rokny H. A critical review of the impact of candidate copy number variants on autism spectrum disorder. MUTATION RESEARCH. REVIEWS IN MUTATION RESEARCH 2024; 794:108509. [PMID: 38977176 DOI: 10.1016/j.mrrev.2024.108509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Revised: 04/14/2024] [Accepted: 07/02/2024] [Indexed: 07/10/2024]
Abstract
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder (NDD) influenced by genetic, epigenetic, and environmental factors. Recent advancements in genomic analysis have shed light on numerous genes associated with ASD, highlighting the significant role of both common and rare genetic mutations, as well as copy number variations (CNVs), single nucleotide polymorphisms (SNPs) and unique de novo variants. These genetic variations disrupt neurodevelopmental pathways, contributing to the disorder's complexity. Notably, CNVs are present in 10 %-20 % of individuals with autism, with 3 %-7 % detectable through cytogenetic methods. While the role of submicroscopic CNVs in ASD has been recently studied, their association with genomic loci and genes has not been thoroughly explored. In this review, we focus on 47 CNV regions linked to ASD, encompassing 1632 genes, including protein-coding genes and long non-coding RNAs (lncRNAs), of which 659 show significant brain expression. Using a list of ASD-associated genes from SFARI, we detect 17 regions harboring at least one known ASD-related protein-coding gene. Of the remaining 30 regions, we identify 24 regions containing at least one protein-coding gene with brain-enriched expression and a nervous system phenotype in mouse mutants, and one lncRNA with both brain-enriched expression and upregulation in iPSC to neuron differentiation. This review not only expands our understanding of the genetic diversity associated with ASD but also underscores the potential of lncRNAs in contributing to its etiology. Additionally, the discovered CNVs will be a valuable resource for future diagnostic, therapeutic, and research endeavors aimed at prioritizing genetic variations in ASD.
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Affiliation(s)
- Seyedeh Sedigheh Abedini
- UNSW BioMedical Machine Learning Lab (BML), The Graduate School of Biomedical Engineering, UNSW Sydney, Sydney, NSW 2052, Australia; School of Biotechnology & Biomolecular Sciences, UNSW Sydney, Sydney, NSW 2052, Australia
| | - Shiva Akhavantabasi
- Department of Molecular Biology and Genetics, Yeni Yuzyil University, Istanbul, Turkey; Ghiaseddin Jamshid Kashani University, Andisheh University Town, Danesh Blvd, 3441356611, Abyek, Qazvin, Iran
| | - Yuheng Liang
- UNSW BioMedical Machine Learning Lab (BML), The Graduate School of Biomedical Engineering, UNSW Sydney, Sydney, NSW 2052, Australia
| | - Julian Ik-Tsen Heng
- Curtin Health Innovation Research Institute, Curtin University, Bentley 6845, Australia
| | - Roohallah Alizadehsani
- Institute for Intelligent Systems Research and Innovation (IISRI), Deakin University, Victoria, Australia
| | - Iman Dehzangi
- Center for Computational and Integrative Biology, Rutgers University, Camden, NJ 08102, USA; Department of Computer Science, Rutgers University, Camden, NJ 08102, USA
| | - Denis C Bauer
- Transformational Bioinformatics, Commonwealth Scientific and Industrial Research Organisation (CSIRO), Sydney, Australia; Applied BioSciences, Faculty of Science and Engineering, Macquarie University, Macquarie Park, Australia
| | - Hamid Alinejad-Rokny
- UNSW BioMedical Machine Learning Lab (BML), The Graduate School of Biomedical Engineering, UNSW Sydney, Sydney, NSW 2052, Australia; Tyree Institute of Health Engineering (IHealthE), UNSW Sydney, Sydney, NSW 2052, Australia.
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3
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Kushwaha S, Stinnett V, Zou YS, Murry JB. Live-born autosomal ring chromosomes at the Johns Hopkins Hospital Cytogenomics Laboratory: Case series-Spanning 52 years of experience in a single center. Am J Med Genet A 2024; 194:253-267. [PMID: 37807876 DOI: 10.1002/ajmg.a.63429] [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: 07/17/2023] [Revised: 08/29/2023] [Accepted: 09/20/2023] [Indexed: 10/10/2023]
Abstract
Ring chromosomes (RCs) are a structural aberration that can be tolerated better in acrocentric or gonosomal chromosomes. Complete RCs arise from telomere-telomere fusions. Alternatively, genomic imbalances corresponding to the ends of the chromosomal arms can be seen with RC formation. RCs are unstable in mitosis, result in mosaicism, and are associated with a "ring syndrome," which presents with growth and development phenotypes and differs from those features more frequently observed with pure terminal copy number changes. Due to variability in mosaicism, size, and genomic content, clear genotype-phenotype correlations may not always be possible. Given the rarity of RCs, this historical data is invaluable. We performed a retrospective review of individuals bearing RCs to investigate the incidence in our laboratory. This work details the methods and features seen in association with twenty-three autosomal RCs. In decreasing order, the most frequently seen autosomal RCs were 18, 22, 4, 13, 17, and 9. The additional cases detail clinical and cytogenomic events similar to those reported in RCs. As methodologies advance, insights may be gleaned from following up on these cases to improve genotype-phenotype correlations and understand the cryptic differences or other predisposing factors that lead to ring formation and development.
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Affiliation(s)
- Shivani Kushwaha
- Krieger School of Arts and Sciences, Johns Hopkins University, Baltimore, Maryland, USA
| | - Victoria Stinnett
- Johns Hopkins Genomics, Baltimore, Maryland, USA
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Cytogenetics Laboratory, Johns Hopkins Hospital, Baltimore, Maryland, USA
| | - Ying S Zou
- Johns Hopkins Genomics, Baltimore, Maryland, USA
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Cytogenetics Laboratory, Johns Hopkins Hospital, Baltimore, Maryland, USA
| | - Jaclyn B Murry
- Johns Hopkins Genomics, Baltimore, Maryland, USA
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Cytogenetics Laboratory, Johns Hopkins Hospital, Baltimore, Maryland, USA
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4
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Aisa MC, Cappuccini B, Favilli A, Datti A, Nardicchi V, Coata G, Gerli S. Biochemical and Anthropometric Parameters for the Early Recognition of the Intrauterine Growth Restriction and Preterm Neonates at Risk of Impaired Neurodevelopment. Int J Mol Sci 2023; 24:11549. [PMID: 37511307 PMCID: PMC10380875 DOI: 10.3390/ijms241411549] [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: 06/08/2023] [Revised: 07/07/2023] [Accepted: 07/10/2023] [Indexed: 07/30/2023] Open
Abstract
BACKGROUND S100B and Tau are implicated with both brain growth and injury. Their urinary levels in 30-to-40-day-old full-term, preterm, IUGR, and preterm-IUGR subjects were measured to investigate their possible relationship with future delayed neurodevelopment. METHODS Values were related to the neuro-behavioral outcome at two years of age, as well as to brain volumes and urinary NGF assessed at the same postnatal time point. RESULTS Using the Griffiths III test, cognitive and motor performances were determined to establish subgroups characterized by either normal or impaired neuro-behavior. The latter included preterm, IUGR, and preterm-IUGR individuals who exhibited significantly higher and lower S100B and Tau levels, respectively, along with markedly reduced cerebral volumes and urinary NGF, as previously demonstrated. Contrary to NGF, however, Tau and S100B displayed a weak correlation with brain volumes. CONCLUSIONS Delayed cognitive and motor performances observed in two-year-old preterm and IUGR-born individuals were also found to be associated with anomalous urinary levels of S100B and Tau, assessed at 30-40 days of the postnatal period, and their changes did not correlate with brain growth. Thus, our data suggests that, in addition to cerebral volumes and NGF, urinary S100B and Tau can also be considered as valuable parameters for the early detection of future neurodevelopmental abnormalities.
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Affiliation(s)
- Maria Cristina Aisa
- Department of Surgical and Biomedical Sciences, Section of Obstetrics and Gynecology, University of Perugia, 06129 Perugia, Italy
- GeBiSa, Research Foundation, 06129 Perugia, Italy
- Centre of Perinatal and Reproductive Medicine, University of Perugia, 06129 Perugia, Italy
| | | | - Alessandro Favilli
- Department of Surgical and Biomedical Sciences, Section of Obstetrics and Gynecology, University of Perugia, 06129 Perugia, Italy
- GeBiSa, Research Foundation, 06129 Perugia, Italy
- Centre of Perinatal and Reproductive Medicine, University of Perugia, 06129 Perugia, Italy
| | - Alessandro Datti
- Department of Agricultural, Food and Environmental Sciences, University of Perugia, 06121 Perugia, Italy
| | | | - Giuliana Coata
- Department of Surgical and Biomedical Sciences, Section of Obstetrics and Gynecology, University of Perugia, 06129 Perugia, Italy
- Centre of Perinatal and Reproductive Medicine, University of Perugia, 06129 Perugia, Italy
| | - Sandro Gerli
- Department of Surgical and Biomedical Sciences, Section of Obstetrics and Gynecology, University of Perugia, 06129 Perugia, Italy
- GeBiSa, Research Foundation, 06129 Perugia, Italy
- Centre of Perinatal and Reproductive Medicine, University of Perugia, 06129 Perugia, Italy
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5
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Baker EK, Brewer CJ, Ferreira L, Schapiro M, Tenney J, Wied HM, Kline-Fath BM, Smolarek TA, Weaver KN, Hopkin RJ. Further expansion and confirmation of phenotype in rare loss of YWHAE gene distinct from Miller-Dieker syndrome. Am J Med Genet A 2023; 191:526-539. [PMID: 36433683 PMCID: PMC10099970 DOI: 10.1002/ajmg.a.63057] [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: 06/08/2022] [Revised: 09/21/2022] [Accepted: 11/12/2022] [Indexed: 11/27/2022]
Abstract
Deletion of 17p13.3 has varying degrees of severity on brain development based on precise location and size of the deletion. The most severe phenotype is Miller-Dieker syndrome (MDS) which is characterized by lissencephaly, dysmorphic facial features, growth failure, developmental disability, and often early death. Haploinsufficiency of PAFAH1B1 is responsible for the characteristic lissencephaly in MDS. The precise role of YWHAE haploinsufficiency in MDS is unclear. Case reports are beginning to elucidate the phenotypes of individuals with 17p13.3 deletions that have deletion of YWHAE but do not include deletion of PAFAH1B1. Through our clinical genetics practice, we identified four individuals with 17p13.3 deletion that include YWHAE but not PAFAH1B1. These patients have a similar phenotype of dysmorphic facial features, developmental delay, and leukoencephalopathy. In a review of the literature, we identified 19 patients with 17p13.3 microdeletion sparing PAFAH1B1 but deleting YWHAE. Haploinsufficiency of YWHAE is associated with brain abnormalities including cystic changes. These individuals have high frequency of epilepsy, intellectual disability, and dysmorphic facial features including prominent forehead, epicanthal folds, and broad nasal root. We conclude that deletion of 17p13.3 excluding PAFAH1B1 but including YWHAE is associated with a consistent phenotype and should be considered a distinct condition from MDS.
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Affiliation(s)
- Elizabeth K Baker
- Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Casey J Brewer
- Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Leonardo Ferreira
- Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Mark Schapiro
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.,Division of Neurology, Cincinnati Children's Hospital Medicine, Cincinnati, Ohio, USA
| | - Jeffrey Tenney
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.,Division of Neurology, Cincinnati Children's Hospital Medicine, Cincinnati, Ohio, USA
| | - Heather M Wied
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.,Division of Neurology, Cincinnati Children's Hospital Medicine, Cincinnati, Ohio, USA
| | - Beth M Kline-Fath
- Division of Radiology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Teresa A Smolarek
- Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - K Nicole Weaver
- Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Robert J Hopkin
- Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
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6
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Da Silva JD, Gonzaga D, Barreta A, Correia H, Fortuna AM, Soares AR, Tkachenko N. Refining the Clinical Spectrum of the 17p13.3 Microduplication Syndrome: Case-Report of a Familial Small Microduplication. Biomedicines 2022; 10:biomedicines10123078. [PMID: 36551834 PMCID: PMC9775100 DOI: 10.3390/biomedicines10123078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 11/18/2022] [Accepted: 11/26/2022] [Indexed: 12/02/2022] Open
Abstract
The chromosomal region 17p13.3 contains extensive repetitive sequences and is a well-recognized region of genomic instability. The 17p13.3 microduplication syndrome has been associated with a clinical spectrum of moderately non-specific phenotypes, including global developmental delay/intellectual disability, behavioral disorders, autism spectrum disorder and variable dysmorphic features. Depending on the genes involved in the microduplication, it can be categorized in two subtypes with different phenotypes. Here, we report a case of a 7-year-old boy with global developmental delay, speech impairment, hypotonia, behavioral conditions (ADHD and ODD), non-specific dysmorphic features and overgrowth. Genetic testing revealed a small 17p13.3 chromosomal duplication, which included the BHLHA9, CRK and YWHAE genes. Additionally, we observed that this was maternally inherited, and that the mother presented with a milder phenotype including mild learning disabilities, speech impairment and non-specific dysmorphic features, which did not significantly affect her. In conclusion, we present a clinical case of a 17p13.3 duplication that further delineates the clinical spectrum of this syndrome, including its intrafamilial/intergenerational variability.
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Affiliation(s)
- Jorge Diogo Da Silva
- Centro de Genética Médica Doutor Jacinto Magalhães (CGM), Centro Hospitalar Universitário do Porto, 4050-106 Porto, Portugal
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal
- ICVS/3B’s—PT Government Associate Laboratory, 4806-909 Braga, Portugal
- Correspondence:
| | - Diana Gonzaga
- Centro de Genética Médica Doutor Jacinto Magalhães (CGM), Centro Hospitalar Universitário do Porto, 4050-106 Porto, Portugal
- Centro Materno-Infantil do Norte, Centro Hospital Universitário do Porto, 4099-001 Porto, Portugal
| | - Ana Barreta
- Medical Genetics Service, Joaquim Chaves Saúde, 2685-145 Oeiras, Portugal
| | - Hildeberto Correia
- Medical Genetics Service, Joaquim Chaves Saúde, 2685-145 Oeiras, Portugal
| | - Ana Maria Fortuna
- Centro de Genética Médica Doutor Jacinto Magalhães (CGM), Centro Hospitalar Universitário do Porto, 4050-106 Porto, Portugal
- Unit for Multidisciplinary Research in Biomedicine, Abel Salazar Biomedical Sciences Institute, Porto University, 4050-345 Porto, Portugal
| | - Ana Rita Soares
- Centro de Genética Médica Doutor Jacinto Magalhães (CGM), Centro Hospitalar Universitário do Porto, 4050-106 Porto, Portugal
- Unit for Multidisciplinary Research in Biomedicine, Abel Salazar Biomedical Sciences Institute, Porto University, 4050-345 Porto, Portugal
| | - Nataliya Tkachenko
- Centro de Genética Médica Doutor Jacinto Magalhães (CGM), Centro Hospitalar Universitário do Porto, 4050-106 Porto, Portugal
- Unit for Multidisciplinary Research in Biomedicine, Abel Salazar Biomedical Sciences Institute, Porto University, 4050-345 Porto, Portugal
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7
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Liu X, Bennison SA, Robinson L, Toyo-oka K. Responsible Genes for Neuronal Migration in the Chromosome 17p13.3: Beyond Pafah1b1(Lis1), Crk and Ywhae(14-3-3ε). Brain Sci 2021; 12:brainsci12010056. [PMID: 35053800 PMCID: PMC8774252 DOI: 10.3390/brainsci12010056] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Revised: 12/13/2021] [Accepted: 12/23/2021] [Indexed: 01/07/2023] Open
Abstract
The 17p13.3 chromosome region is often deleted or duplicated in humans, resulting in severe neurodevelopmental disorders such as Miller–Dieker syndrome (MDS) and 17p13.3 duplication syndrome. Lissencephaly can also be caused by gene mutations or deletions of a small piece of the 17p13.3 region, including a single gene or a few genes. PAFAH1B1 gene, coding for LIS1 protein, is a responsible gene for lissencephaly and MDS and regulates neuronal migration by controlling microtubules (MTs) and cargo transport along MTs via dynein. CRK is a downstream regulator of the reelin signaling pathways and regulates neuronal migration. YWHAE, coding for 14-3-3ε, is also responsible for MDS and regulates neuronal migration by binding to LIS1-interacting protein, NDEL1. Although these three proteins are known to be responsible for neuronal migration defects in MDS, there are 23 other genes in the MDS critical region on chromosome 17p13.3, and little is known about their functions in neurodevelopment, especially in neuronal migration. This review will summarize the recent progress on the functions of LIS1, CRK, and 14-3-3ε and describe the recent findings of other molecules in the MDS critical regions in neuronal migration.
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Affiliation(s)
- Xiaonan Liu
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA 19129, USA;
- Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USA; (S.A.B.); (L.R.)
| | - Sarah A. Bennison
- Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USA; (S.A.B.); (L.R.)
| | - Lozen Robinson
- Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USA; (S.A.B.); (L.R.)
| | - Kazuhito Toyo-oka
- Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USA; (S.A.B.); (L.R.)
- Correspondence: ; Tel.: +1-(215)-991-8288
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8
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Farra C, Abdouni L, Hani A, Dirani L, Hamdar L, Souaid M, Awwad J. 17p13.3 Microduplication Syndrome: Further Delineating the Clinical Spectrum. J Pediatr Genet 2021; 10:239-244. [PMID: 34504729 DOI: 10.1055/s-0040-1713673] [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: 10/09/2019] [Accepted: 05/05/2020] [Indexed: 10/23/2022]
Abstract
17p13.3 microduplication syndrome has been associated with a clinical spectrum of phenotypes, and depending on the genes involved in the microduplication, it is categorized into two classes (Class I and Class II). We herein, describe two patients diagnosed with Class I 17p13.3 microduplication by BACs-on-Beads (BoBs) assay and further confirmed by fluorescence in situ hybridization (FISH). Our patients (Patient 1: 4-year-old male; Patient 2: 2-year-old male) presented with developmental delay, intellectual disability, and dysmorphic facial features. When compared with the literature, our patients manifested distinctive features (Patient 1: primary hypothyroidism; Patient 2: bilateral cryptorchidism) that were not previously described in the duplication 17p13.3 spectrum.
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Affiliation(s)
- Chantal Farra
- Department of Pathology and Laboratory Medicine, Division of Medical Genetics, American University of Beirut Medical Center, Beirut, Lebanon
| | - Lina Abdouni
- Department of Pathology and Laboratory Medicine, Division of Medical Genetics, American University of Beirut Medical Center, Beirut, Lebanon
| | - Abeer Hani
- Department of Pediatrics and Internal Medicine, Lebanese American University, Beirut, Lebanon
| | - Leyla Dirani
- Department of Psychiatry, American University of Beirut Medical Center, Beirut, Lebanon
| | - Layal Hamdar
- Department of Obstetrics and Gynecology, American University of Beirut Medical Center, Beirut, Lebanon
| | - Mirna Souaid
- Department of Pathology and Laboratory Medicine, Division of Medical Genetics, American University of Beirut Medical Center, Beirut, Lebanon
| | - Johnny Awwad
- Department of Obstetrics and Gynecology, American University of Beirut Medical Center, Beirut, Lebanon
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9
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Markova ZG, Minzhenkova ME, Bessonova LA, Shilova NV. A new case of 17p13.3p13.1 microduplication resulted from unbalanced translocation: clinical and molecular cytogenetic characterization. Mol Cytogenet 2021; 14:41. [PMID: 34465353 PMCID: PMC8408977 DOI: 10.1186/s13039-021-00562-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Accepted: 07/29/2021] [Indexed: 11/30/2022] Open
Abstract
Copy number gain 17 p13.3p13.1 was detected by chromosomal microarray (CMA) in a girl with developmental/speech delay and facial dysmorphism. FISH studies made it possible to establish that the identified genomic imbalance is the unbalanced t(9;17) translocation of maternal origin. Clinical features of the patient are also discussed. The advisability of using the combination of CMA and FISH analysis is shown. Copy number gains detected by clinical CMA should be confirmed using FISH analysis in order to determine the physical location of the duplicated segment. Parental follow-up studies is an important step to determine the origin of genomic imbalance. This approach not only allows a most comprehensive characterization of an identified chromosomal/genomic imbalance but also provision of an adequate medical and genetic counseling for a family taking into account a balanced chromosomal rearrangement.
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Affiliation(s)
- Zhanna G Markova
- Research Centre for Medical Genetics, Moskvorechye St., 1, Moscow, Russia, 115522.
| | - Marina E Minzhenkova
- Research Centre for Medical Genetics, Moskvorechye St., 1, Moscow, Russia, 115522
| | - Lyudmila A Bessonova
- Research Centre for Medical Genetics, Moskvorechye St., 1, Moscow, Russia, 115522
| | - Nadezda V Shilova
- Research Centre for Medical Genetics, Moskvorechye St., 1, Moscow, Russia, 115522
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10
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Blazejewski SM, Bennison SA, Ha NT, Liu X, Smith TH, Dougherty KJ, Toyo-Oka K. Rpsa Signaling Regulates Cortical Neuronal Morphogenesis via Its Ligand, PEDF, and Plasma Membrane Interaction Partner, Itga6. Cereb Cortex 2021; 32:770-795. [PMID: 34347028 DOI: 10.1093/cercor/bhab242] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 06/25/2021] [Accepted: 06/25/2021] [Indexed: 12/25/2022] Open
Abstract
Neuromorphological defects underlie neurodevelopmental disorders and functional defects. We identified a function for Rpsa in regulating neuromorphogenesis using in utero electroporation to knockdown Rpsa, resulting in apical dendrite misorientation, fewer/shorter extensions, and decreased spine density with altered spine morphology in upper neuronal layers and decreased arborization in upper/lower cortical layers. Rpsa knockdown disrupts multiple aspects of cortical development, including radial glial cell fiber morphology and neuronal layering. We investigated Rpsa's ligand, PEDF, and interacting partner on the plasma membrane, Itga6. Rpsa, PEDF, and Itga6 knockdown cause similar phenotypes, with Rpsa and Itga6 overexpression rescuing morphological defects in PEDF-deficient neurons in vivo. Additionally, Itga6 overexpression increases and stabilizes Rpsa expression on the plasma membrane. GCaMP6s was used to functionally analyze Rpsa knockdown via ex vivo calcium imaging. Rpsa-deficient neurons showed less fluctuation in fluorescence intensity, suggesting defective subthreshold calcium signaling. The Serpinf1 gene coding for PEDF is localized at chromosome 17p13.3, which is deleted in patients with the neurodevelopmental disorder Miller-Dieker syndrome. Our study identifies a role for Rpsa in early cortical development and for PEDF-Rpsa-Itga6 signaling in neuromorphogenesis, thus implicating these molecules in the etiology of neurodevelopmental disorders like Miller-Dieker syndrome and identifying them as potential therapeutics.
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Affiliation(s)
- Sara M Blazejewski
- Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USA
| | - Sarah A Bennison
- Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USA
| | - Ngoc T Ha
- Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USA
| | - Xiaonan Liu
- Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USA
| | - Trevor H Smith
- Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USA
| | - Kimberly J Dougherty
- Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USA
| | - Kazuhito Toyo-Oka
- Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USA
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11
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Yanagishita T, Imaizumi T, Yamamoto-Shimojima K, Yano T, Okamoto N, Nagata S, Yamamoto T. Breakpoint junction analysis for complex genomic rearrangements with the caldera volcano-like pattern. Hum Mutat 2020; 41:2119-2127. [PMID: 32906213 DOI: 10.1002/humu.24108] [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: 06/21/2020] [Revised: 08/25/2020] [Accepted: 09/06/2020] [Indexed: 12/16/2022]
Abstract
Chromosomal triplications can be classified into recurrent and nonrecurrent triplications. Most of the nonrecurrent triplications are embedded in duplicated segments, and duplication-inverted triplication-duplication (DUP-TRP/INV-DUP) has been established as one of the mechanisms of triplication. This study aimed to reveal the underlying mechanism of the TRP-DUP-TRP pattern of chromosomal aberrations, in which the appearance of moving averages obtained through array-based comparative genomic hybridization analysis is similar to the shadows of the caldera volcano-like pattern, which were first identified in two patients with neurodevelopmental disabilities. For this purpose, whole-genome sequencing using long-read Nanopore sequencing was carried out to confirm breakpoint junctions. Custom array analysis and Sanger sequencing were also used to detect all breakpoint junctions. As a result, the TRP-DUP-TRP pattern consisted of only two patterns of breakpoint junctions in both patients. In patient 1, microhomologies were identified in breakpoint junctions. In patient 2, more complex architectures with insertional segments were identified. Thus, replication-based mechanisms were considered as a mechanism of the TRP-DUP-TRP pattern.
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Affiliation(s)
- Tomoe Yanagishita
- Department of Pediatrics, Tokyo Women's Medical University, Tokyo, Japan.,Department of Genomic Medicine, Tokyo Women's Medical University, Tokyo, Japan
| | - Taichi Imaizumi
- Department of Genomic Medicine, Tokyo Women's Medical University, Tokyo, Japan.,Department of Pediatrics, St. Marianna University School of Medicine, Kawasaki, Japan
| | | | - Tamami Yano
- Department of Pediatrics, Akita University, Akita, Japan
| | - Nobuhiko Okamoto
- Department of Medical Genetics, Osaka Women's and Children's Hospital, Osaka, Japan
| | - Satoru Nagata
- Department of Pediatrics, Tokyo Women's Medical University, Tokyo, Japan
| | - Toshiyuki Yamamoto
- Department of Pediatrics, Tokyo Women's Medical University, Tokyo, Japan.,Department of Genomic Medicine, Tokyo Women's Medical University, Tokyo, Japan.,Department of Pediatrics, St. Marianna University School of Medicine, Kawasaki, Japan.,Institute for Integrated Medical Sciences, Tokyo Women's Medical University, Tokyo, Japan
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12
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Analyses of breakpoint junctions of complex genomic rearrangements comprising multiple consecutive microdeletions by nanopore sequencing. J Hum Genet 2020; 65:735-741. [PMID: 32355308 DOI: 10.1038/s10038-020-0762-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2019] [Revised: 04/01/2020] [Accepted: 04/04/2020] [Indexed: 12/19/2022]
Abstract
The widespread use of genomic copy number analysis has revealed many previously unknown genomic structural variations, including some which are more complex. In this study, three consecutive microdeletions were identified in the same chromosome by microarray-based comparative genomic hybridization (aCGH) analysis for a patient with a neurodevelopmental disorder. Subsequent fluorescence in situ hybridization (FISH) analyses unexpectedly suggested complicated translocations and inversions. For better understanding of the mechanism, breakpoint junctions were analyzed by nanopore sequencing, as a new long-read whole-genome sequencing (WGS) tool. The results revealed a new chromosomal disruption, giving rise to four junctions in chromosome 7. According the sequencing results of breakpoint junctions, all junctions were considered as the consequence of multiple double-strand breaks and the reassembly of DNA fragments by nonhomologous end-joining, indicating chromothripsis. KMT2E, located within the deletion region, was considered as the gene responsible for the clinical features of the patient. Combinatory usage of aCGH and FISH analyses would be recommended for interpretation of structural variations analyzed through WGS.
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13
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Romano C, Ferranti S, Mencarelli MA, Longo I, Renieri A, Grosso S. 17p13.3 microdeletion including YWHAE and CRK genes: towards a clinical characterization. Neurol Sci 2020; 41:2259-2262. [PMID: 32323081 DOI: 10.1007/s10072-020-04424-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2019] [Accepted: 04/13/2020] [Indexed: 11/25/2022]
Abstract
INTRODUCTION The short arm of chromosome 17 is characterized by a high density of low copy repeats, creating the opportunity for non-allelic homologous recombination to occur. Microdeletions of the 17p13.3 region are responsible for neuronal migration disorders including isolated lissencephaly sequence and Miller-Dieker syndrome. CASE REPORT We describe the case of a 4-year and 2-month-old female with peculiar somatic traits and neurodevelopmental delay. At the age of 6 months, she started to present with infantile spasms syndrome; therefore, we administered vigabatrin followed by two cycles of adrenocorticotropic hormone, with good response. The coexistence of epileptic activity, neuropsychological delay, brain imaging abnormalities, and peculiar somatic features oriented us towards the hypothesis of a genetic etiology that could explain her clinical picture. Array CGH identified a 730 Kb deletion in the p13.3 region of the short arm of chromosome 17 including eleven genes, among these are YWHAE and CRK. DISCUSSION Microdeletions of the 17p13.3 region involving only YWHAE and CRK, sparing PAFAH1B1, result in neurodevelopmental delay, growth retardation, craniofacial dysmorphisms, and mild structural brain abnormalities. Differently from the previously described patients carrying YWHAE and CRK deletions, the main complaint of our patient was represented by seizures. The absence of clear neuronal migration defects and mutations of the PAFAH1B1 gene in our patient underlines the central role of additional genes located in the 17p13.3 chromosomal region in the pathogenesis of epilepsy and helps to expand the phenotype of 17p13.3 microdeletion syndrome.
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Affiliation(s)
- Chiara Romano
- Dipartimento di Medicina Molecolare e dello Sviluppo, Universita' degli Studi di Siena, viale Bracci 16, 53100, Siena, Italy
| | - Silvia Ferranti
- Dipartimento di Medicina Molecolare e dello Sviluppo, Universita' degli Studi di Siena, viale Bracci 16, 53100, Siena, Italy.
| | | | - Ilaria Longo
- Genetica Medica, Azienda Ospedaliera Universitaria Senese, viale Bracci 2, 53100, Siena, Italy
| | - Alessandra Renieri
- Genetica Medica, Azienda Ospedaliera Universitaria Senese, viale Bracci 2, 53100, Siena, Italy
- Medical Genetics, University of Siena, viale Bracci 2, 53100, Siena, Italy
| | - Salvatore Grosso
- Dipartimento di Medicina Molecolare e dello Sviluppo, Universita' degli Studi di Siena, viale Bracci 16, 53100, Siena, Italy
- U.O.C. Pediatria, Azienda Ospedaliera Universitaria Senese, viale Bracci 16, 53100, Siena, Italy
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14
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Polymicrogyria associated with 17p13.3p13.2 duplication: Case report and review of the literature. Eur J Med Genet 2019; 63:103774. [PMID: 31585183 DOI: 10.1016/j.ejmg.2019.103774] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Revised: 06/26/2019] [Accepted: 09/22/2019] [Indexed: 11/20/2022]
Abstract
We present the case of a male infant with bilateral perisylvian polymicrogyria associated with a de novo duplication of chromosome region 17p13.3p13.2. To our knowledge, this is the first report of polymicrogyria associated with the 17p13.3 contiguous gene duplication syndrome. Testing for known monogenic causes of polymicrogyria was negative and there was no clinical evidence of an acquired prenatal cause. Given the critical, dose-sensitive role that the 17p13.3 region plays in brain development, we suggest that the chromosome duplication is the most likely explanation for the polymicrogyria. Clinical and functional studies have demonstrated deleterious effects of increased LIS1 expression on the developing brain and the contribution of YWHAE to the brain phenotype of the 17p13 duplication syndrome. There is also evidence that CRK, the other candidate gene in this region, via interaction with LIS1, plays a critical role in cortical development. In addition to LIS1, YWHAE and CRK, our patient's chromosome duplication involves at least 100 other genes, less than half of which are annotated at the time of writing. It is expected that the ongoing use of chromosome microarray and next-generation sequencing to investigate the genetic causes of brain malformations will continue to extend our understanding of the 17p13 region and of the contributions of the genes in this region to cortical development.
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15
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Wang S, Wang W, Han X, Wang Y, Ge Y, Tan Z. Dysregulation of miR484-TUSC5 axis takes part in the progression of hepatocellular carcinoma. J Biochem 2019; 166:271-279. [PMID: 31157375 DOI: 10.1093/jb/mvz034] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Accepted: 04/25/2019] [Indexed: 12/18/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. miR-484 is previously reported to be a crucial modulator during the process from precancerous lesion to cancer. Tumour suppressor candidate 5 (TUSC5) is a potential tumour suppressor, but its expression and function in HCC are obscure. In this study, we aimed to explore the roles of miR-484 and TUSC5 in HCC, and clarify the relationship between them. We demonstrated that miR-484 was significantly up-regulated in HCC, while TUSC5 was down-regulated. TUSC5 was validated as the target gene of miR-484 and both of them were associated with the prognosis of HCC patients. miR-484 mimics markedly promoted the malignant phenotypes while TUSC5 plasmid had the opposite effect. In conclusion, miR-484/TUSC5 is potential diagnostic biomarkers and therapy targets for HCC.
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Affiliation(s)
- Shanzong Wang
- Department of Pathology, The Third People's Hospital of Linyi, Huaxia Road No. 117, Linyi Economic and Technological Development Zone, Linyi, Shandong, China
| | - Weijuan Wang
- Department of Gynaecology, The Third People's Hospital of Linyi, Huaxia Road No. 117, Linyi Economic and Technological Development Zone, Linyi, Shandong, China
| | - Xiaoguang Han
- Department of Internal Medicine, The Third People's Hospital of Linyi, Huaxia Road No. 117, Linyi Economic and Technological Development Zone, Linyi, Shandong, China
| | - Youli Wang
- Department of Pathology, The Third People's Hospital of Linyi, Huaxia Road No. 117, Linyi Economic and Technological Development Zone, Linyi, Shandong, China
| | - Yunzhen Ge
- Department of Pathology, The Third People's Hospital of Linyi, Huaxia Road No. 117, Linyi Economic and Technological Development Zone, Linyi, Shandong, China
| | - Zhen Tan
- Department of Pathology, The Third People's Hospital of Linyi, Huaxia Road No. 117, Linyi Economic and Technological Development Zone, Linyi, Shandong, China
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16
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Zhou R, Jiang G, Tian X, Wang X. Progress in the molecular mechanisms of genetic epilepsies using patient-induced pluripotent stem cells. Epilepsia Open 2018; 3:331-339. [PMID: 30187003 PMCID: PMC6119748 DOI: 10.1002/epi4.12238] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/25/2018] [Indexed: 12/29/2022] Open
Abstract
Research findings on the molecular mechanisms of epilepsy almost always originate from animal experiments, and the development of induced pluripotent stem cell (iPSC) technology allows the use of human cells with genetic defects for studying the molecular mechanisms of genetic epilepsy (GE) for the first time. With iPSC technology, terminally differentiated cells collected from GE patients with specific genetic etiologies can be differentiated into many relevant cell subtypes that carry all of the GE patient's genetic information. iPSCs have opened up a new research field involving the pathogenesis of GE. Using this approach, studies have found that gene mutations induce GE by altering the balance between neuronal excitation and inhibition, which is associated. among other factors, with neuronal developmental disturbances, ion channel abnormalities, and synaptic dysfunction. Simultaneously, astrocyte activation, mitochondrial dysfunction, and abnormal signaling pathway activity are also important factors in the molecular mechanisms of GE.
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Affiliation(s)
- Ruijiao Zhou
- Department of Neurology the First Affiliated Hospital of Chongqing Medical University Chongqing Key Laboratory of Neurology Chongqing China
| | - Guohui Jiang
- Department of Neurology Institute of Neurological Diseases Affiliated Hospital of North Sichuan Medical College Nanchong China
| | - Xin Tian
- Department of Neurology the First Affiliated Hospital of Chongqing Medical University Chongqing Key Laboratory of Neurology Chongqing China
| | - Xuefeng Wang
- Department of Neurology the First Affiliated Hospital of Chongqing Medical University Chongqing Key Laboratory of Neurology Chongqing China
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17
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Blazejewski SM, Bennison SA, Smith TH, Toyo-Oka K. Neurodevelopmental Genetic Diseases Associated With Microdeletions and Microduplications of Chromosome 17p13.3. Front Genet 2018; 9:80. [PMID: 29628935 PMCID: PMC5876250 DOI: 10.3389/fgene.2018.00080] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Accepted: 02/26/2018] [Indexed: 01/24/2023] Open
Abstract
Chromosome 17p13.3 is a region of genomic instability that is linked to different rare neurodevelopmental genetic diseases, depending on whether a deletion or duplication of the region has occurred. Chromosome microdeletions within 17p13.3 can result in either isolated lissencephaly sequence (ILS) or Miller-Dieker syndrome (MDS). Both conditions are associated with a smooth cerebral cortex, or lissencephaly, which leads to developmental delay, intellectual disability, and seizures. However, patients with MDS have larger deletions than patients with ILS, resulting in additional symptoms such as poor muscle tone, congenital anomalies, abnormal spasticity, and craniofacial dysmorphisms. In contrast to microdeletions in 17p13.3, recent studies have attracted considerable attention to a condition known as a 17p13.3 microduplication syndrome. Depending on the genes involved in their microduplication, patients with 17p13.3 microduplication syndrome may be categorized into either class I or class II. Individuals in class I have microduplications of the YWHAE gene encoding 14-3-3ε, as well as other genes in the region. However, the PAFAH1B1 gene encoding LIS1 is never duplicated in these patients. Class I microduplications generally result in learning disabilities, autism, and developmental delays, among other disorders. Individuals in class II always have microduplications of the PAFAH1B1 gene, which may include YWHAE and other genetic microduplications. Class II microduplications generally result in smaller body size, developmental delays, microcephaly, and other brain malformations. Here, we review the phenotypes associated with copy number variations (CNVs) of chromosome 17p13.3 and detail their developmental connection to particular microdeletions or microduplications. We also focus on existing single and double knockout mouse models that have been used to study human phenotypes, since the highly limited number of patients makes a study of these conditions difficult in humans. These models are also crucial for the study of brain development at a mechanistic level since this cannot be accomplished in humans. Finally, we emphasize the usefulness of the CRISPR/Cas9 system and next generation sequencing in the study of neurodevelopmental diseases.
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Affiliation(s)
- Sara M Blazejewski
- Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA, United States
| | - Sarah A Bennison
- Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA, United States
| | - Trevor H Smith
- Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA, United States
| | - Kazuhito Toyo-Oka
- Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA, United States
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18
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Coppola A, Morrogh D, Farrell F, Balestrini S, Hernandez-Hernandez L, Krithika S, Sander JW, Waters JJ, Sisodiya SM. Ring Chromosome 17 Not Involving the Miller-Dieker Region: A Case with Drug-Resistant Epilepsy. Mol Syndromol 2018; 9:38-44. [PMID: 29456482 DOI: 10.1159/000479949] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/07/2017] [Indexed: 11/19/2022] Open
Abstract
Chromosomal abnormalities are often identified in people with neurodevelopmental disorders including intellectual disability, autism, and epilepsy. Ring chromosomes, which usually involve gene copy number loss, are formed by fusion of subtelomeric or telomeric chromosomal regions. Some ring chromosomes, including ring 14, 17, and 20, are strongly associated with seizure disorders. We report an individual with a ring chromosome 17, r(17)(p13.3q25.3), with a terminal 17q25.3 deletion and no short arm copy number loss, and with a phenotype characterized by intellectual disability and drug-resistant epilepsy, including a propensity for nonconvulsive status epilepticus.
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Affiliation(s)
- Antonietta Coppola
- Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK.,Chalfont Centre for Epilepsy, Chalfont St Peter, UK.,Department of Neuroscience, Reproductive and Odontostomatological Sciences, Epilepsy Centre, Federico II University of Naples, Naples, Italy
| | - Deborah Morrogh
- North East Thames Regional Genetics Laboratory Service, Hospital for Children NHS Foundation Trust, London, UK
| | - Fiona Farrell
- Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK.,Chalfont Centre for Epilepsy, Chalfont St Peter, UK
| | - Simona Balestrini
- Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK.,Chalfont Centre for Epilepsy, Chalfont St Peter, UK.,Neuroscience Department, Marche Polytechnic University, Ancona, Italy
| | - Laura Hernandez-Hernandez
- Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK.,Chalfont Centre for Epilepsy, Chalfont St Peter, UK
| | - S Krithika
- Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK.,Chalfont Centre for Epilepsy, Chalfont St Peter, UK
| | - Josemir W Sander
- Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK.,Chalfont Centre for Epilepsy, Chalfont St Peter, UK.,Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede, The Netherlands
| | - Jonathan J Waters
- North East Thames Regional Genetics Laboratory Service, Hospital for Children NHS Foundation Trust, London, UK
| | - Sanjay M Sisodiya
- Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK.,Chalfont Centre for Epilepsy, Chalfont St Peter, UK
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19
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Chen CP, Ko TM, Wang LK, Chern SR, Wu PS, Chen SW, Lai ST, Chuang TY, Yang CW, Lee CC, Wang W. Prenatal diagnosis of a 0.7-Mb 17p13.3 microdeletion encompassing YWHAE and CRK but not PAFAH1B1 in a fetus without ultrasound abnormalities. Taiwan J Obstet Gynecol 2018; 57:128-132. [DOI: 10.1016/j.tjog.2017.12.022] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/03/2017] [Indexed: 01/20/2023] Open
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20
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Enhanced expression of Pafah1b1 causes over-migration of cerebral cortical neurons into the marginal zone. Brain Struct Funct 2017; 222:4283-4291. [PMID: 28836069 DOI: 10.1007/s00429-017-1497-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2016] [Accepted: 08/09/2017] [Indexed: 10/19/2022]
Abstract
Mutations of PAFAH1B1 cause classical lissencephaly in humans. In addition, duplications and triplications of PAFAH1B1 are found in individuals with intellectual disability and other neurological disorders suggesting that proper brain development is highly sensitive to the PAFAH1B1 dosage. To examine the effect of PAFAH1B1 over-dosage in neural development, especially in migration of neurons and layer formation during cerebral cortical development, we overexpressed Pafah1b1 in migrating neurons in the mouse embryonic cortex using in utero electroporation. Enhanced expression of Pafah1b1 in radially-migrating neurons resulted in their over-migration into the marginal zone. Neurons that invaded the marginal zone were oriented abnormally. Layer distribution of Pafaha1b1-overexpressing neurons shifted more superficially than control neurons. Some of the Pafaha1b1-overexpressing future layer 4 neurons changed their positions to layers 2/3. Furthermore, they also changed their layer marker expression from layer 4 to layers 2/3. These results suggest that overexpression of Pafah1b1 affects the migration of neurons and disrupts layer formation in the developing cerebral cortex, and further support the idea that appropriate dosage of Pafah1b1 is crucial for the proper development of the brain.
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21
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Venø MT, Venø ST, Rehberg K, van Asperen JV, Clausen BH, Holm IE, Pasterkamp RJ, Finsen B, Kjems J. Cortical Morphogenesis during Embryonic Development Is Regulated by miR-34c and miR-204. Front Mol Neurosci 2017; 10:31. [PMID: 28232790 PMCID: PMC5299138 DOI: 10.3389/fnmol.2017.00031] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2016] [Accepted: 01/26/2017] [Indexed: 01/26/2023] Open
Abstract
The porcine brain closely resembles the human brain in aspects such as development and morphology. Temporal miRNA profiling in the developing embryonic porcine cortex revealed a distinct set of miRNAs, including miR-34c and miR-204, which exhibited a highly specific expression profile across the time of cortical folding. These miRNAs were found to target Doublecortin (DCX), known to be involved in neuron migration during cortical folding of gyrencephalic brains. In vivo modulation of miRNA expression in mouse embryos confirmed that miR-34c and miR-204 can control neuronal migration and cortical morphogenesis, presumably by posttranscriptional regulation of DCX.
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Affiliation(s)
- Morten T Venø
- Department of Molecular Biology and Genetics, Interdisciplinary Nanoscience Center, Aarhus University Aarhus, Denmark
| | - Susanne T Venø
- Department of Molecular Biology and Genetics, Interdisciplinary Nanoscience Center, Aarhus University Aarhus, Denmark
| | - Kati Rehberg
- Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht Utrecht, Netherlands
| | - Jessy V van Asperen
- Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht Utrecht, Netherlands
| | - Bettina H Clausen
- Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark Odense, Denmark
| | - Ida E Holm
- Laboratory for Experimental Neuropathology, Department of Pathology, Randers Hospital Randers, Denmark
| | - R Jeroen Pasterkamp
- Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht Utrecht, Netherlands
| | - Bente Finsen
- Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark Odense, Denmark
| | - Jørgen Kjems
- Department of Molecular Biology and Genetics, Interdisciplinary Nanoscience Center, Aarhus University Aarhus, Denmark
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22
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Matsuo M, Yamauchi A, Ito Y, Sakauchi M, Yamamoto T, Okamoto N, Tsurusaki Y, Miyake N, Matsumoto N, Saito K. Mandibulofacial dysostosis with microcephaly: A case presenting with seizures. Brain Dev 2017; 39:177-181. [PMID: 27670155 DOI: 10.1016/j.braindev.2016.08.008] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2016] [Revised: 08/03/2016] [Accepted: 08/22/2016] [Indexed: 12/31/2022]
Abstract
We report a case of mandibulofacial dysostosis with microcephaly presenting with seizures. The proband, a 6-year-old Korean boy, had microcephaly, malar and mandibular hypoplasia, and deafness. He showed developmental delay and had suffered recurrent seizures beginning at 21months of age. Electroencephalography revealed occasional spike discharges from the right frontal area. Head magnetic resonance imaging revealed dilatation of the lateral ventricles and a small frontal lobe volume. Whole exome sequencing revealed a de novo frame shift mutation, c.2698_2701 del, of EFTUD2. The epileptic focus was consistent with the reduced frontal lobe volume on head magnetic resonance imaging. Seizures are thus a main feature of mandibulofacial dysostosis with microcephaly, which results from an embryonic development defect due to the EFTUD2 mutation.
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Affiliation(s)
- Mari Matsuo
- Institute of Medical Genetics, Tokyo Women's Medical University, Tokyo, Japan
| | - Akemi Yamauchi
- Institute of Medical Genetics, Tokyo Women's Medical University, Tokyo, Japan
| | - Yasushi Ito
- Department of Pediatrics, Tokyo Women's Medical University, Tokyo, Japan
| | - Masako Sakauchi
- Department of Pediatrics, Tokyo Women's Medical University, Tokyo, Japan
| | - Toshiyuki Yamamoto
- Institute for Integrated Medical Sciences, Tokyo Women's Medical University, Tokyo, Japan
| | - Nobuhiko Okamoto
- Department of Medical Genetics, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan
| | - Yoshinori Tsurusaki
- Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Noriko Miyake
- Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Naomichi Matsumoto
- Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Kayoko Saito
- Institute of Medical Genetics, Tokyo Women's Medical University, Tokyo, Japan.
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23
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Barros Fontes MI, Dos Santos AP, Rossi Torres F, Lopes-Cendes I, Cendes F, Appenzeller S, Kawasaki de Araujo T, Lopes Monlleó I, Gil-da-Silva-Lopes VL. 17p13.3 Microdeletion: Insights on Genotype-Phenotype Correlation. Mol Syndromol 2016; 8:36-41. [PMID: 28232781 DOI: 10.1159/000452753] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/09/2016] [Indexed: 01/13/2023] Open
Abstract
Microdeletions in the chromosomal region 17p13.3 are associated with neuronal migration disorders, and PAFAB1H1 is the main gene involved. The largest genomic imbalances, including the YWHAE and CRK genes, cause more severe structural abnormalities of the brain and other associated dysmorphic features. Here, we describe a 3-year-old boy with a microdeletion in 17p13.3 presenting with minor facial dysmorphisms, a cleft palate, neurodevelopmental delay, and behavioral disorder with no structural malformation of the brain. The patient was evaluated by a clinician using a standard protocol. Laboratory investigation included GTG-banding, whole-genome AGH, and array-CGH. Whole-genome AGH and array-CGH analysis identified an estimated 2.1-Mb deletion in the 17p13.3 region showing haploinsufficiency of the YWHAE, CRK, H1C1, and OVCA1 genes and no deletion of PAFAH1B1. The complex gene interaction on brain development and function is illustrated in the genotype-phenotype correlation described here. This report reinforces the importance of the 17p13.3 region in developmental abnormalities and highlights the weak implication of the HIC1 and OVCA1 genes in palatogenesis.
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Affiliation(s)
- Marshall I Barros Fontes
- Department of Medical Genetics, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, Brazil; Department of Medical Genetics Sector, State University of Health Sciences of Alagoas (UNCISAL), Maceió, Brazil
| | - Ana P Dos Santos
- Department of Medical Genetics, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, Brazil
| | - Fábio Rossi Torres
- Department of Medical Genetics, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, Brazil
| | - Iscia Lopes-Cendes
- Department of Medical Genetics, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, Brazil
| | - Fernando Cendes
- Department of Neurology, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, Brazil
| | - Simone Appenzeller
- Department of Internal Medicine, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, Brazil
| | - Tânia Kawasaki de Araujo
- Department of Medical Genetics, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, Brazil
| | - Isabella Lopes Monlleó
- Department of Clinical Genetics Service, Faculty of Medicine, University Hospital, Federal University of Alagoas (UFAL), Maceió, Brazil
| | - Vera L Gil-da-Silva-Lopes
- Department of Medical Genetics, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, Brazil
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Shimojima K, Okumura A, Yamamoto T. A de novo microdeletion involving PAFAH1B (LIS1) related to lissencephaly phenotype. Data Brief 2016; 4:488-91. [PMID: 26958590 PMCID: PMC4773278 DOI: 10.1016/j.dib.2015.07.017] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2015] [Revised: 07/10/2015] [Accepted: 07/13/2015] [Indexed: 11/17/2022] Open
Abstract
Lissencephaly is a type of the congenital malformation of the brain. Due to the impairments of neuronal migration, patients show absence of brain convolution manifesting smooth brain surfaces. One of the human genes responsible for lissencephaly is the platelet-activating factor acetylhydrolase 1b gene (PAFAH1B; also known as LIS1) located on 17p13.3. Patients with heterozygous deletion of this chromosomal region exhibit lissencephaly. Recently, we encountered a male patient who showed typical lissencephaly. Using a microarray analysis, we identified a 1.3 Mb submicroscopic deletion in 17p13.3. This deletion included PAFAH1B. Both of the parents showed no deletion in this region. Therefore, this was determined to be derived from de novo origin. After obtaining the written informed consent, skin fibroblasts were provided from this patient and disease-specific induced pluripotent stem (iPS) cells were generated and used for medical research (Shimojima K, Okumura A, Hayashi M, Kondo T, Inoue H, and Yamamoto T. CHCHD2 is down-regulated in neuronal cells differentiated from iPS cells derived from patients with lissencephaly. Genomics, in press).
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Affiliation(s)
- Keiko Shimojima
- Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency (JST), Kawaguchi, Japan
- Tokyo Women׳s Medical University Institute for Integrated Medical Sciences (TIIMS), Tokyo, Japan
| | - Akihisa Okumura
- Department of Pediatrics, Juntendo University, Tokyo, Japan
- Department of Pediatrics, Aichi Medical University, Nagakute, Japan
| | - Toshiyuki Yamamoto
- Tokyo Women׳s Medical University Institute for Integrated Medical Sciences (TIIMS), Tokyo, Japan
- Corresponding author.
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Shimojima K, Okamoto N, Yamamoto T. A novel
TUBB3
mutation in a sporadic patient with asymmetric cortical dysplasia. Am J Med Genet A 2016; 170A:1076-9. [DOI: 10.1002/ajmg.a.37545] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2015] [Accepted: 12/21/2015] [Indexed: 11/06/2022]
Affiliation(s)
- Keiko Shimojima
- Precursory Research for Embryonic Science and Technology (PRESTO)Japan Science and Technology Agency (JST)KawaguchiJapan
- Tokyo Women's Medical University Institute for Integrated Medical SciencesTokyoJapan
| | - Nobuhiko Okamoto
- Department of Medical GeneticsOsaka Medical Center and Research Institute for Maternal and Child HealthOsakaJapan
| | - Toshiyuki Yamamoto
- Tokyo Women's Medical University Institute for Integrated Medical SciencesTokyoJapan
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26
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CHCHD2 is down-regulated in neuronal cells differentiated from iPS cells derived from patients with lissencephaly. Genomics 2015; 106:196-203. [DOI: 10.1016/j.ygeno.2015.07.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2015] [Revised: 06/17/2015] [Accepted: 07/01/2015] [Indexed: 12/20/2022]
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Dimassi S, Labalme A, Lesca G, Rudolf G, Bruneau N, Hirsch E, Arzimanoglou A, Motte J, de Saint Martin A, Boutry-Kryza N, Cloarec R, Benitto A, Ameil A, Edery P, Ryvlin P, De Bellescize J, Szepetowski P, Sanlaville D. A subset of genomic alterations detected in rolandic epilepsies contains candidate or known epilepsy genes includingGRIN2AandPRRT2. Epilepsia 2013; 55:370-8. [DOI: 10.1111/epi.12502] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/31/2013] [Indexed: 01/08/2023]
Affiliation(s)
- Sarra Dimassi
- Department of Genetics; Lyon University Hospital; Lyon France
- Claude Bernard Lyon I University; Lyon France
- CRNL; CNRS UMR 5292; INSERM U1028; Lyon France
| | - Audrey Labalme
- Department of Genetics; Lyon University Hospital; Lyon France
- The French EPILAND (Epilepsy, Language and Development) Consortium; Marseille France
| | - Gaetan Lesca
- Department of Genetics; Lyon University Hospital; Lyon France
- Claude Bernard Lyon I University; Lyon France
- CRNL; CNRS UMR 5292; INSERM U1028; Lyon France
- The French EPILAND (Epilepsy, Language and Development) Consortium; Marseille France
| | - Gabrielle Rudolf
- The French EPILAND (Epilepsy, Language and Development) Consortium; Marseille France
- Department of Neurology; Strasbourg University Hospital; Strasbourg France
- UMR_S; INSERM U1119; Strasbourg France
| | - Nadine Bruneau
- The French EPILAND (Epilepsy, Language and Development) Consortium; Marseille France
- INSERM Unit U901; Marseille France
- Mediterranean Institute of Neurobiology (INMED); Marseille France
- UMR_S901; Aix-Marseille University; Marseille France
| | - Edouard Hirsch
- The French EPILAND (Epilepsy, Language and Development) Consortium; Marseille France
- Department of Neurology; Strasbourg University Hospital; Strasbourg France
| | - Alexis Arzimanoglou
- CRNL; CNRS UMR 5292; INSERM U1028; Lyon France
- The French EPILAND (Epilepsy, Language and Development) Consortium; Marseille France
- Departments of Epilepsy, Sleep and Pediatric Neurophysiology (ESEFNP); University Hospitals of Lyon (HCL); Lyon France
| | - Jacques Motte
- The French EPILAND (Epilepsy, Language and Development) Consortium; Marseille France
- Department of Pediatry A; American Memorial Hospital; Reims University Hospital; Reims France
| | - Anne de Saint Martin
- The French EPILAND (Epilepsy, Language and Development) Consortium; Marseille France
- Department of Pediatry I; Strasbourg University Hospital; Strasbourg France
| | - Nadia Boutry-Kryza
- Claude Bernard Lyon I University; Lyon France
- CRNL; CNRS UMR 5292; INSERM U1028; Lyon France
- The French EPILAND (Epilepsy, Language and Development) Consortium; Marseille France
- Department of Molecular Genetics; Lyon University Hospital; Lyon France
| | - Robin Cloarec
- The French EPILAND (Epilepsy, Language and Development) Consortium; Marseille France
- INSERM Unit U901; Marseille France
- Mediterranean Institute of Neurobiology (INMED); Marseille France
- UMR_S901; Aix-Marseille University; Marseille France
| | - Afaf Benitto
- Department of Pediatry A; American Memorial Hospital; Reims University Hospital; Reims France
| | - Agnès Ameil
- Department of Pediatry A; American Memorial Hospital; Reims University Hospital; Reims France
| | - Patrick Edery
- Department of Genetics; Lyon University Hospital; Lyon France
- Claude Bernard Lyon I University; Lyon France
- CRNL; CNRS UMR 5292; INSERM U1028; Lyon France
| | - Philippe Ryvlin
- Claude Bernard Lyon I University; Lyon France
- CRNL; CNRS UMR 5292; INSERM U1028; Lyon France
- The French EPILAND (Epilepsy, Language and Development) Consortium; Marseille France
- Department of Neurology; Lyon University Hospital; Lyon France
| | - Julitta De Bellescize
- The French EPILAND (Epilepsy, Language and Development) Consortium; Marseille France
- Departments of Epilepsy, Sleep and Pediatric Neurophysiology (ESEFNP); University Hospitals of Lyon (HCL); Lyon France
| | - Pierre Szepetowski
- The French EPILAND (Epilepsy, Language and Development) Consortium; Marseille France
- INSERM Unit U901; Marseille France
- Mediterranean Institute of Neurobiology (INMED); Marseille France
- UMR_S901; Aix-Marseille University; Marseille France
| | - Damien Sanlaville
- Department of Genetics; Lyon University Hospital; Lyon France
- Claude Bernard Lyon I University; Lyon France
- CRNL; CNRS UMR 5292; INSERM U1028; Lyon France
- The French EPILAND (Epilepsy, Language and Development) Consortium; Marseille France
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Curry CJ, Rosenfeld JA, Grant E, Gripp KW, Anderson C, Aylsworth AS, Saad TB, Chizhikov VV, Dybose G, Fagerberg C, Falco M, Fels C, Fichera M, Graakjaer J, Greco D, Hair J, Hopkins E, Huggins M, Ladda R, Li C, Moeschler J, Nowaczyk MJM, Ozmore JR, Reitano S, Romano C, Roos L, Schnur RE, Sell S, Suwannarat P, Svaneby D, Szybowska M, Tarnopolsky M, Tervo R, Tsai ACH, Tucker M, Vallee S, Wheeler FC, Zand DJ, Barkovich AJ, Aradhya S, Shaffer LG, Dobyns WB. The duplication 17p13.3 phenotype: analysis of 21 families delineates developmental, behavioral and brain abnormalities, and rare variant phenotypes. Am J Med Genet A 2013; 161A:1833-52. [PMID: 23813913 DOI: 10.1002/ajmg.a.35996] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2012] [Accepted: 03/31/2013] [Indexed: 11/11/2022]
Abstract
Chromosome 17p13.3 is a gene rich region that when deleted is associated with the well-known Miller-Dieker syndrome. A recently described duplication syndrome involving this region has been associated with intellectual impairment, autism and occasional brain MRI abnormalities. We report 34 additional patients from 21 families to further delineate the clinical, neurological, behavioral, and brain imaging findings. We found a highly diverse phenotype with inter- and intrafamilial variability, especially in cognitive development. The most specific phenotype occurred in individuals with large duplications that include both the YWHAE and LIS1 genes. These patients had a relatively distinct facial phenotype and frequent structural brain abnormalities involving the corpus callosum, cerebellar vermis, and cranial base. Autism spectrum disorders were seen in a third of duplication probands, most commonly in those with duplications of YWHAE and flanking genes such as CRK. The typical neurobehavioral phenotype was usually seen in those with the larger duplications. We did not confirm the association of early overgrowth with involvement of YWHAE and CRK, or growth failure with duplications of LIS1. Older patients were often overweight. Three variant phenotypes included cleft lip/palate (CLP), split hand/foot with long bone deficiency (SHFLD), and a connective tissue phenotype resembling Marfan syndrome. The duplications in patients with clefts appear to disrupt ABR, while the SHFLD phenotype was associated with duplication of BHLHA9 as noted in two recent reports. The connective tissue phenotype did not have a convincing critical region. Our experience with this large cohort expands knowledge of this diverse duplication syndrome.
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Yamamoto T, Shimada S, Shimojima K. Fiber-fluorescence in situ hybridization analyses as a diagnostic application for orientation of microduplications. World J Med Genet 2013; 3:5-8. [DOI: 10.5496/wjmg.v3.i2.5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2013] [Revised: 05/14/2013] [Accepted: 06/04/2013] [Indexed: 02/06/2023] Open
Abstract
Microduplications are normally invisible under microscopy and were not recognized before chromosomal microarray testing was available. Although it is difficult to confirm the orientation of duplicated segments by standard fluorescence in situ hybridization (FISH), our data indicates that fiber-FISH analysis has the potential to reveal the orientation of duplicated and triplicated segments of chromosomes. Recurrent microduplications reciprocal to microdeletions show tandem orientations of the duplicated segments, which is consistent with a non-allelic homologous recombination mechanism. Several random duplications showed tandem configurations and inverted duplications are rare. Further analysis is required to fully elucidate the basic mechanisms underlying such duplications/triplications.
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Classen S, Goecke T, Drechsler M, Betz B, Nickel N, Beier M, Schaper J, Karenfort M, Royer-Pokora B. A novel inverted 17p13.3 microduplication disrupting PAFAH1B1 (LIS1) in a girl with syndromic lissencephaly. Am J Med Genet A 2013; 161A:1453-8. [PMID: 23633430 DOI: 10.1002/ajmg.a.35904] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2012] [Accepted: 01/25/2013] [Indexed: 11/08/2022]
Abstract
We describe a female patient with mild lissencephaly (pachygyria), severe intellectual disability, and facial dysmorphisms with an inverted 1.4 Mb microduplication of chromosome 17p13.3. The 17p13.3 microduplication syndrome is associated with mild intellectual disabiltiy and contains, among others, the PAFAH1B1 (LIS1) gene, whereas microdeletions of the same segment cause Miller-Dieker syndrome (MDS) with severe to profound retardation. The duplication identified in our patient encompasses 29 genes, including CRK and YWHAE. The proximal breakpoint of the duplication is located in the first intron of the PAFAH1B1 gene. Analysis of total RNA showed that only one PAFAH1B1 allele is expressed. Therefore, this patient has a unique alteration: a duplication including YWHAE and CRK and haploinsufficiency of PAFAH1B1. Overexpression of YWHAE is associated with macrosomia, mild developmental delay, autism and facial dysmorphisms, and deletion of PAFAH1B1 alone leads to isolated lissencephaly (ILS). The patient described here shares features with MDS, but she is affected to a lesser degree. Her facial features are similar to MDS, and she has manifestations seen in other cases with YWHAE duplication.
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Affiliation(s)
- Sabrina Classen
- Institute of Human Genetics and Anthropology, Department of Diagnostic and Interventional Radiology, Heinrich-Heine-University Duesseldorf, Medical Faculty, Duesseldorf, Germany
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31
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Yamamoto T, Matsuo M, Shimada S, Sangu N, Shimojima K, Aso S, Saito K. De novo triplication of 11q12.3 in a patient with developmental delay and distinctive facial features. Mol Cytogenet 2013; 6:15. [PMID: 23552394 PMCID: PMC3626894 DOI: 10.1186/1755-8166-6-15] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2013] [Accepted: 03/01/2013] [Indexed: 01/08/2023] Open
Abstract
Background Triplication is a rare chromosomal anomaly. We identified a de novo triplication of 11q12.3 in a patient with developmental delay, distinctive facial features, and others. In the present study, we discuss the mechanism of triplications that are not embedded within duplications and potential genes which may contribute to the phenotype. Results The identified triplication of 11q12.3 was 557 kb long and not embedded within the duplicated regions. The aberrant region was overlapped with the segment reported to be duplicated in 2 other patients. The common phenotypic features in the present patient and the previously reported patient were brain developmental delay, finger abnormalities (including arachnodactuly, camptodactyly, brachydactyly, clinodactyly, and broad thumbs), and preauricular pits. Conclusions Triplications that are not embedded within duplicated regions are rare and sometimes observed as the consequence of non-allelic homologous recombination. The de novo triplication identified in the present study is novel and not embedded within the duplicated region. In the 11q12.3 region, many copy number variations were observed in the database. This may be the trigger of this rare triplication. Because the shortest region of overlap contained 2 candidate genes, STX5 and CHRM1, which show some relevance to neuronal functions, we believe that the genomic copy number gains of these genes may be responsible for the neurological features seen in these patients.
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Affiliation(s)
- Toshiyuki Yamamoto
- Tokyo Women's Medical University Institute for Integrated Medical Sciences, 8-1 Kawada-cho, Shinjuku-ward, Tokyo, 162-8666, Japan.
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32
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Reiner O. LIS1 and DCX: Implications for Brain Development and Human Disease in Relation to Microtubules. SCIENTIFICA 2013; 2013:393975. [PMID: 24278775 PMCID: PMC3820303 DOI: 10.1155/2013/393975] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/08/2013] [Accepted: 02/07/2013] [Indexed: 05/29/2023]
Abstract
Proper lamination of the cerebral cortex requires the orchestrated motility of neurons from their place of birth to their final destination. Improper neuronal migration may result in a wide range of diseases, including brain malformations, such as lissencephaly, mental retardation, schizophrenia, and autism. Ours and other studies have implicated that microtubules and microtubule-associated proteins play an important role in the regulation of neuronal polarization and neuronal migration. Here, we will review normal processes of brain development and neuronal migration, describe neuronal migration diseases, and will focus on the microtubule-associated functions of LIS1 and DCX, which participate in the regulation of neuronal migration and are involved in the human developmental brain disease, lissencephaly.
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Affiliation(s)
- Orly Reiner
- Department of Molecular Genetics, The Weizmann Institute of Science, 76100 Rehovot, Israel
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33
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Enomoto K, Kishitani Y, Tominaga M, Ishikawa A, Furuya N, Aida N, Masuno M, Yamada KI, Kurosawa K. Expression analysis of a 17p terminal deletion, including YWHAE, but not PAFAH1B1, associated with normal brain structure on MRI in a young girl. Am J Med Genet A 2012; 158A:2347-52. [PMID: 22887762 DOI: 10.1002/ajmg.a.35542] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2011] [Accepted: 06/01/2012] [Indexed: 01/09/2023]
Abstract
Tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, epsilon polypeptide (YWHAE), on chromosome 17p13.3, has been shown to play a crucial role in neuronal development. The deletion of YWHAE, but not platelet-activating factor acetylhydrolase, isoform 1b, subunit 1 (PAFAH1B1), underlies a newly recognized neurodevelopmental disorder, characterized by significant growth retardation, developmental delay/intellectual disability (DD/ID), distinctive facial appearance, and brain abnormalities. Here, we report on a girl with a terminal deletion of 17p13.3, including YWHAE but not PAFAH1B1, showing normal brain structure on MRI. She had mild developmental delay, a distinctive facial appearance, and severe growth retardation despite normal growth hormone levels, which was improved by growth hormone therapy. Expression analysis of YWHAE and PAFAH1B1 yielded results consistent with array CGH and FISH results. These results indicate that the dosage effect of YWHAE varies from severe to very mild structural brain abnormalities, and suggest that the expression of YWHAE is associated with a complex mechanism of neuronal development.
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Affiliation(s)
- Keisuke Enomoto
- Division of Medical Genetics, Kanagawa Children's Medical Center, Yokohama, Japan
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Morales D, Skoulakis ECM, Acevedo SF. 14-3-3s are potential biomarkers for HIV-related neurodegeneration. J Neurovirol 2012; 18:341-53. [PMID: 22811265 DOI: 10.1007/s13365-012-0121-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2012] [Revised: 06/06/2012] [Accepted: 06/27/2012] [Indexed: 02/07/2023]
Abstract
Over the last decade, it has become evident that 14-3-3 proteins are essential for primary cell functions. These proteins are abundant throughout the body, including the central nervous system and interact with other proteins in both cell cycle and apoptotic pathways. Examination of cerebral spinal fluid in humans suggests that 14-3-3s including 14-3-3ε (YWHAE) are up-regulated in several neurological diseases, and loss or duplication of the YWHAE gene leads to Miller-Dieker syndrome. The goal of this review is to examine the utility of 14-3-3s as a marker of human immune deficiency virus (HIV)-dependent neurodegeneration and also as a tool to track disease progression. To that end, we describe mechanisms implicating 14-3-3s in neurological diseases and summarize evidence of its interactions with HIV accessory and co-receptor proteins.
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Affiliation(s)
- Diana Morales
- Department of Physiology, Pharmacology, and Toxicology, Ponce School of Medicine and Health Sciences, Ponce 00732, Puerto Rico
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35
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Subtelomeric deletions of 1q43q44 and severe brain impairment associated with delayed myelination. J Hum Genet 2012; 57:593-600. [PMID: 22718018 DOI: 10.1038/jhg.2012.77] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Subtelomeric deletions of 1q44 cause mental retardation, developmental delay and brain anomalies, including abnormalities of the corpus callosum (ACC) and microcephaly in most patients. We report the cases of six patients with 1q44 deletions; two patients with interstitial deletions of 1q44; and four patients with terminal deletions of 1q. One of the patients showed an unbalanced translocation between chromosome 5. All the deletion regions overlapped with previously reported critical regions for ACC, microcephaly and seizures, indicating the recurrent nature of the core phenotypic features of 1q44 deletions. The four patients with terminal deletions of 1q exhibited severe volume loss in the brain as compared with patients who harbored interstitial deletions of 1q44. This indicated that telomeric regions have a role in severe volume loss of the brain. In addition, two patients with terminal deletions of 1q43, beyond the critical region for 1q44 deletion syndrome exhibited delayed myelination. As the deletion regions identified in these patients extended toward centromere, we conclude that the genes responsible for delayed myelination may be located in the neighboring region of 1q43.
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Abstract
Disruptions to LIS1 gene expression result in neuronal migration abnormalities. LIS1 heterozygosity is a significant cause of lissencephaly, while overexpression has recently been noted in cases of microcephaly, ventriculomegaly, and dysgenesis of the corpus callosum with normal cortical gyration. We report a partial LIS1 duplication in a child with microcephaly, neurodevelopmental delays, and profound white matter atrophy in the absence of overt lissencephaly. The duplicated genetic segment was contained entirely within the first intron of LIS1, a segment that often contains inducers of transcription. Normal gyral patterns with mild volume loss were observed at birth. Follow-up cranial imaging revealed further white matter loss, diminished sulcation, and ventriculomegaly, suggesting expanding hydrocephalus ex vacuo. The radiographic pattern has not been documented in the presence of a LIS1 gene abnormality, and suggests that altered expression of LIS1 has wider phenotypic manifestations than currently defined.
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Affiliation(s)
- Jason P Lockrow
- Department of Neurosciences (Neurology), Medical University of South Carolina, Charleston, SC, USA
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37
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Shimojima K, Okumura A, Natsume J, Aiba K, Kurahashi H, Kubota T, Yokochi K, Yamamoto T. Spinocerebellar ataxias type 27 derived from a disruption of the fibroblast growth factor 14 gene with mimicking phenotype of paroxysmal non-kinesigenic dyskinesia. Brain Dev 2012; 34:230-3. [PMID: 21600715 DOI: 10.1016/j.braindev.2011.04.014] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2010] [Revised: 04/27/2011] [Accepted: 04/27/2011] [Indexed: 11/24/2022]
Abstract
Many types of spinocerebellar ataxias (SCAs) manifest as progressive disorders with cerebellar involvement. SCA type 27 (SCA27) is a rare type of SCA caused by mutations in the fibroblast growth factor 14 gene (FGF14). FGF14 disruption caused by a de novo reciprocal chromosomal translocation between chromosomes 13 and 21 was identified in a patient with the phenotype of paroxysmal non-kinesigenic dyskinesia (PNKD). This indicated genetic heterogeneity of PNKD, since 60% of the patients with PNKD exhibit mutations in another gene responsible for PNKD, the myofibrillogenesis regulator 1 gene (MR-1). We hypothesized that the remaining 40% of patients with PNKD may have FGF14 mutations; therefore, the nucleotide sequences of MR-1 and FGF14 were analyzed in another six patients with PNKD, but no nucleotide alterations were observed in these genes for these patients. Further studies should be conducted on the phenotypic heterogeneity of FGF14 mutations and/or haploinsufficiency in SCA27 and PNKD.
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Affiliation(s)
- Keiko Shimojima
- Tokyo Women's Medical University Institute for Integrated Medical Sciences, Shinjuku-ward, Tokyo, Japan
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38
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Sapir T, Frotscher M, Levy T, Mandelkow EM, Reiner O. Tau's role in the developing brain: implications for intellectual disability. Hum Mol Genet 2011; 21:1681-92. [PMID: 22194194 DOI: 10.1093/hmg/ddr603] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Microdeletions encompassing the MAPT (Tau) locus resulting in intellectual disability raised the hypothesis that Tau may regulate early functions in the developing brain. Our results indicate that neuronal migration was inhibited in mouse brains following Tau reduction. In addition, the leading edge of radially migrating neurons was aberrant in spite of normal morphology of radial glia. Furthermore, intracellular mitochondrial transport and morphology were affected. In early postnatal brains, a portion of Tau knocked down neurons reached the cortical plate. Nevertheless, they exhibited far less developed dendrites and a striking reduction in connectivity evident by the size of boutons. Our novel results strongly implicate MAPT as a dosage-sensitive gene in this locus involved in intellectual disability. Furthermore, our results are likely to impact our understanding of other diseases involving Tau.
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Affiliation(s)
- Tamar Sapir
- Department of Molecular Genetics, Weizmann Institute of Science, 76100 Rehovot, Israel
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39
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Liang JS, Shimojima K, Takayama R, Natsume J, Shichiji M, Hirasawa K, Imai K, Okanishi T, Mizuno S, Okumura A, Sugawara M, Ito T, Ikeda H, Takahashi Y, Oguni H, Imai K, Osawa M, Yamamoto T. CDKL5 alterations lead to early epileptic encephalopathy in both genders. Epilepsia 2011; 52:1835-42. [DOI: 10.1111/j.1528-1167.2011.03174.x] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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