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Wang Y, Zhou H, Fu F, Cheng K, Yu Q, Huang R, Lei T, Yang X, Li D, Liao C. Prenatal Diagnosis of Chromosome 16p11.2 Microdeletion. Genes (Basel) 2022; 13:genes13122315. [PMID: 36553582 PMCID: PMC9778018 DOI: 10.3390/genes13122315] [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: 11/06/2022] [Revised: 11/27/2022] [Accepted: 12/06/2022] [Indexed: 12/13/2022] Open
Abstract
(1) Objective: To investigate the prenatal diagnosis and genetic counseling for 16p11.2 microdeletion syndrome and to evaluate its pregnancy outcome. (2) Methods: This study included 4968 pregnant women who selected invasive prenatal diagnoses from 1 January 2017 to 1 August 2022. These 4698 pregnancies underwent chromosomal microarray analysis (CMA), data on 81 fetuses diagnosed with 16p11.2 microdeletion syndrome based on prenatal ultrasound features and genetic test results were recorded, and their pregnancy outcome was evaluated. (3) Results: 1.63% of fetuses (81/4968) were diagnosed with 16p11.2 microdeletion syndrome. Among these, there were skeletal malformations in 48.15% of the 81 fetuses, cardiovascular malformations in 30.86%, central nervous system malformations (CNS) in 11.11%, digestive system structural abnormalities in 6.17%, and isolated ultrasonography markers in 3.70%. (4) Conclusions: 16p11.2 microdeletion syndrome can display various systemic ultrasound abnormalities in the perinatal period but vertebral malformations are the most common. Our study is the first to report that TBX1 and CJA5 are associated with 16p11.2 microdeletion syndrome, expanding the disease spectrum of 16p11.2 microdeletion syndrome. In our study, the ventricular septal defect is the main feature of cardiac structural abnormalities caused by 16p11.2 microdeletion syndrome. In addition, our study highlights the use of CMA in 16p11.2 microdeletion syndrome, analyzed their genetic results, and evaluated the follow-up prognosis, which can be useful for prenatal diagnosis and genetic counseling.
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Affiliation(s)
- You Wang
- The First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
- Department of Prenatal Diagnostic Center, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510620, China
| | - Hang Zhou
- The First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
| | - Fang Fu
- The First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
| | - Ken Cheng
- The First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
- School of Medicine, South China University of Technology, Guangzhou 510641, China
| | - Qiuxia Yu
- The First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
| | - Ruibin Huang
- The First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
| | - Tingying Lei
- The First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
| | - Xin Yang
- The First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
| | - Dongzhi Li
- The First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
| | - Can Liao
- The First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
- Correspondence: ; Tel.: +86-(020)-38076346
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Demura S, Hinoi E, Kawakami N, Handa M, Yokogawa N, Hiraiwa M, Kato S, Shinmura K, Shimizu T, Oku N, Annen R, Kobayashi M, Yamada Y, Nagatani S, Iezaki T, Taniguchi Y, Tsuchiya H. The L-type Amino Acid Transporter (LAT1) Expression in Patients with Scoliosis. Spine Surg Relat Res 2022; 6:402-407. [PMID: 36051676 PMCID: PMC9381085 DOI: 10.22603/ssrr.2021-0189] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 11/11/2021] [Indexed: 01/04/2023] Open
Abstract
Introduction Amino acid transporters are transmembrane proteins that are known to mediate the transfer of amino acids. As one of the amino acid transporters, LAT1, which is encoded by Slc7a5, mediates the cellular uptake of the essential amino acids. Recently, most studies have focused on examining the relationship between LAT1 and skeletal formation in terms of development. However, little is known regarding the clinical features of LAT1 in the cartilage, which might result in the development of skeletal deformities such as scoliosis. Thus, the aim of this study was to investigate the expression of L-type amino acid transporter 1 (LAT1) and its solute carrier transporter 7a5 (Slc7a5) in patients with pediatric scoliosis and to compare with the relationship between LAT1 and Slc7a5 expression and their clinical features. Methods We have prospectively recruited 56 patients who underwent corrective spinal fusion for scoliosis. The patients comprised 40 girls and 16 boys, with a mean age of 13.1 years at the time of surgery. There were 34 idiopathic scoliosis (IS) patients, whereas 22 were congenital scoliosis (CS) patients. During the surgery, an epiphyseal part of the spinous process at apical vertebra was harvested; then, LAT1 and Slc7a5 expressions in the cartilage were evaluated. Results As per our findings, LAT1 expression was observed in the cartilage in 60.7% (34 out of 56) of the patients. LAT1 expression in IS patients was 76%, which were statistically higher compared to 36% in CS patients. When compared with LAT1 expression, no statistical difference was noted in terms of age, gender, body mass index (BMI), Cobb angle, and Risser grade. Meanwhile, the mean Slc7a5 expression in IS patients was determined to be significantly higher than that in CS patients. No significant correlation was observed between Slc7a5 expression and age, BMI, and Cobb angle. Conclusions LAT1 and Slc7a5 expression in IS and CS patients showed significant differences. These expressions were found to be not correlated with age, stature, and severity of the deformity.
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Affiliation(s)
- Satoru Demura
- Department of Orthopaedic Surgery Graduate School of Medical Sciences Kanazawa University, Kanazawa, Japan
| | - Eiichi Hinoi
- Department of Bioactive Molecules, Gifu Pharmaceutical University, Gifu, Japan.,United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu, Japan
| | - Noriaki Kawakami
- Department of Orthopaedic Surgery, Ichinomiya Nishi Hospital, Aichi, Japan
| | - Makoto Handa
- Department of Orthopaedic Surgery Graduate School of Medical Sciences Kanazawa University, Kanazawa, Japan
| | - Noriaki Yokogawa
- Department of Orthopaedic Surgery Graduate School of Medical Sciences Kanazawa University, Kanazawa, Japan
| | - Manami Hiraiwa
- Department of Bioactive Molecules, Gifu Pharmaceutical University, Gifu, Japan
| | - Satoshi Kato
- Department of Orthopaedic Surgery Graduate School of Medical Sciences Kanazawa University, Kanazawa, Japan
| | - Kazuya Shinmura
- Department of Orthopaedic Surgery Graduate School of Medical Sciences Kanazawa University, Kanazawa, Japan
| | - Takaki Shimizu
- Department of Orthopaedic Surgery Graduate School of Medical Sciences Kanazawa University, Kanazawa, Japan
| | - Norihiro Oku
- Department of Orthopaedic Surgery Graduate School of Medical Sciences Kanazawa University, Kanazawa, Japan
| | - Ryohei Annen
- Department of Orthopaedic Surgery Graduate School of Medical Sciences Kanazawa University, Kanazawa, Japan
| | - Motoya Kobayashi
- Department of Orthopaedic Surgery Graduate School of Medical Sciences Kanazawa University, Kanazawa, Japan
| | - Yohei Yamada
- Department of Orthopaedic Surgery Graduate School of Medical Sciences Kanazawa University, Kanazawa, Japan
| | - Satoshi Nagatani
- Department of Orthopaedic Surgery Graduate School of Medical Sciences Kanazawa University, Kanazawa, Japan
| | - Takashi Iezaki
- Department of Bioactive Molecules, Gifu Pharmaceutical University, Gifu, Japan
| | - Yuki Taniguchi
- Department of Orthopaedic Surgery, The University of Tokyo, Tokyo, Japan
| | - Hiroyuki Tsuchiya
- Department of Orthopaedic Surgery Graduate School of Medical Sciences Kanazawa University, Kanazawa, Japan
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Guo T, Lu C, Yang D, Lei C, Liu Y, Xu Y, Yang B, Wang R, Luo H. Case Report: DNAAF4 Variants Cause Primary Ciliary Dyskinesia and Infertility in Two Han Chinese Families. Front Genet 2022; 13:934920. [PMID: 35903363 PMCID: PMC9315306 DOI: 10.3389/fgene.2022.934920] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 06/01/2022] [Indexed: 11/13/2022] Open
Abstract
Background: Primary ciliary dyskinesia (PCD) is a rare genetic disorder, predominantly autosomal recessive. The dynein axonemal assembly factor 4 (DNAAF4) is mainly involved in the preassembly of multisubunit dynein protein, which is fundamental to the proper functioning of cilia and flagella. There are few reports of PCD-related pathogenic variants of DNAAF4, and almost no DNAAF4-related articles focused on sperm phenotype. Moreover, the association between DNAAF4 and scoliosis has never been reported, to the best of our knowledge.Materials and Methods: We recruited two patients with a clinical diagnosis of PCD. One came from a consanguineous and another from a non-consanguineous family. Clinical data, laboratory test results, and imaging data were analyzed. Through whole exome sequencing, immunofluorescence, electron microscopy, high-speed video microscopy analysis, and hematoxylin–eosin (HE) staining, we identified the disease-associated variants and validated the pathogenicity.Results: Proband 1 (P1, F1: II-1), a 19-year-old man, comes from a non-consanguineous family-I, and proband 2 (P2, F2: II-1), a 37-year-old woman, comes from a consanguineous family-II. Both had sinusitis, bronchiectasis, situs inversus, and scoliosis. P1 also had asthenoteratozoospermia, and P2 had an immature uterus. Two homozygous pathogenic variants in DNAAF4 (NM_130810.4), c.988C > T, p.(Arg330Trp), and DNAAF4 (NM_130810.4), c.733 C > T, p.(Arg245*), were identified through whole exome sequencing. High-speed microscopy analysis showed that most of the cilia were static in P1, with complete static of the respiratory cilia in P2. Immunofluorescence showed that the outer dynein arms (ODA) and inner dynein arms (IDA) were absent in the respiratory cilia of both probands, as well as in the sperm flagellum of P1. Transmission electron microscopy revealed the absence of ODA and IDA of respiratory cilia of P2, and HE staining showed irregular, short, absent, coiled, and bent flagella.Conclusion: Our study identified a novel variant c.733C > T, which expanded the spectrum of DNAAF4 variants. Furthermore, we linked DNAAF4 to asthenoteratozoospermia and likely scoliosis in patients with PCD. This study will contribute to a better understanding of PCD.
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Affiliation(s)
- Ting Guo
- Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
- Research Unit of Respiratory Disease, Central South University, Changsha, China
- Hunan Diagnosis and Treatment Center of Respiratory Disease, Changsha, China
| | - Chenyang Lu
- Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
- Research Unit of Respiratory Disease, Central South University, Changsha, China
- Hunan Diagnosis and Treatment Center of Respiratory Disease, Changsha, China
| | - Danhui Yang
- Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
- Research Unit of Respiratory Disease, Central South University, Changsha, China
- Hunan Diagnosis and Treatment Center of Respiratory Disease, Changsha, China
| | - Cheng Lei
- Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
- Research Unit of Respiratory Disease, Central South University, Changsha, China
- Hunan Diagnosis and Treatment Center of Respiratory Disease, Changsha, China
| | - Ying Liu
- Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
- Research Unit of Respiratory Disease, Central South University, Changsha, China
- Hunan Diagnosis and Treatment Center of Respiratory Disease, Changsha, China
| | - Yingjie Xu
- Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
- Research Unit of Respiratory Disease, Central South University, Changsha, China
- Hunan Diagnosis and Treatment Center of Respiratory Disease, Changsha, China
| | - Binyi Yang
- Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
- Research Unit of Respiratory Disease, Central South University, Changsha, China
- Hunan Diagnosis and Treatment Center of Respiratory Disease, Changsha, China
| | - Rongchun Wang
- Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
- Research Unit of Respiratory Disease, Central South University, Changsha, China
- Hunan Diagnosis and Treatment Center of Respiratory Disease, Changsha, China
- *Correspondence: Hong Luo, ; Rongchun Wang,
| | - Hong Luo
- Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
- Research Unit of Respiratory Disease, Central South University, Changsha, China
- Hunan Diagnosis and Treatment Center of Respiratory Disease, Changsha, China
- *Correspondence: Hong Luo, ; Rongchun Wang,
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Role of Primary Cilia in Skeletal Disorders. Stem Cells Int 2022; 2022:6063423. [PMID: 35761830 PMCID: PMC9233574 DOI: 10.1155/2022/6063423] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Revised: 05/23/2022] [Accepted: 06/03/2022] [Indexed: 11/26/2022] Open
Abstract
Primary cilia are highly conserved microtubule-based organelles that project from the cell surface into the extracellular environment and play important roles in mechanosensation, mechanotransduction, polarity maintenance, and cell behaviors during organ development and pathological changes. Intraflagellar transport (IFT) proteins are essential for cilium formation and function. The skeletal system consists of bones and connective tissue, including cartilage, tendons, and ligaments, providing support, stability, and movement to the body. Great progress has been achieved in primary cilia and skeletal disorders in recent decades. Increasing evidence suggests that cells with cilium defects in the skeletal system can cause numerous human diseases. Moreover, specific deletion of ciliary proteins in skeletal tissues with different Cre mice resulted in diverse malformations, suggesting that primary cilia are involved in the development of skeletal diseases. In addition, the intact of primary cilium is essential to osteogenic/chondrogenic induction of mesenchymal stem cells, regarded as a promising target for clinical intervention for skeletal disorders. In this review, we summarized the role of primary cilia and ciliary proteins in the pathogenesis of skeletal diseases, including osteoporosis, bone/cartilage tumor, osteoarthritis, intervertebral disc degeneration, spine scoliosis, and other cilium-related skeletal diseases, and highlighted their promising treatment methods, including using mesenchymal stem cells. Our review tries to present evidence for primary cilium as a promising target for clinical intervention for skeletal diseases.
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Developments in Congenital Scoliosis and Related Research from 1992 to 2021: A Thirty-Year Bibliometric Analysis. World Neurosurg 2022; 164:e24-e44. [PMID: 35248773 DOI: 10.1016/j.wneu.2022.02.117] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 02/25/2022] [Accepted: 02/26/2022] [Indexed: 11/21/2022]
Abstract
BACKGROUND Many studies, mainly original articles and reviews, have been reported on congenital scoliosis (CS), but there is a lack of bibliometric analyses. This study aimed to systematically analyze the developments and focuses in CS and related research fields. METHODS Data were retrieved from the Web of Science Core Collection database, and the top 100 most-cited studies were analyzed emphatically. The Web of Science Results Analysis and Citation Report was used to analyze different aspects of the literature. CiteSpace was used to analyze the cooperation network, reference co-citation, burst keywords, and burst citations. RESULTS The final analysis included 749 studies. CS and related research has been rapidly expanding. Several journals have published relevant studies and most-cited studies on this topic. Cooperation was noted among authors, institutions, and countries/regions in multiple instances. Surgical techniques (hemivertebra resection/posterior vertebral column resection/vertical expandable prosthetic titanium rib/double approach/grade 4 osteotomy) was one of the most common research focuses. In addition, research on genetics and molecular biology related to CS has become an emerging trend as a result of advances in basic science. CONCLUSIONS Over time, research on CS and in related fields has gained greater attention and has been expanding continuously, showing a trend toward globalization. We recommend that researchers focus on the progress of surgical techniques, advances in molecular biology and genetics, and characteristics of CS. The top clusters, most-cited articles, and references with the strongest burst citations should be studied further.
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Lu C, Yang D, Lei C, Wang R, Guo T, Luo H. Identification of Two Novel DNAAF2 Variants in Two Consanguineous Families with Primary Ciliary Dyskinesia. PHARMACOGENOMICS & PERSONALIZED MEDICINE 2021; 14:1415-1423. [PMID: 34785929 PMCID: PMC8591118 DOI: 10.2147/pgpm.s338981] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 10/26/2021] [Indexed: 01/16/2023]
Abstract
Background Dynein axonemal assembly factor 2 (DNAAF2) is involved in the early preassembly of dynein in the cytoplasm, which is essential for motile cilia function. Primary ciliary dyskinesia (PCD) associated with DNAAF2 variants has rarely been reported in females with infertility. Moreover, there is no report linking DNAAF2 to scoliosis in human. Materials and Methods We recruited patients from two consanguineous families with a clinical diagnosis of PCD and collected their clinical history, laboratory tests, and radiographic data. Sequencing and bioinformatics analysis were then performed. Immunofluorescence and high-speed microscope analysis were used to support the pathogenicity of the variant. Results Proband 1, a 26-year-old female from family I, exhibited scoliosis, bronchiectasis, sinusitis, situs inversus, and infertility. We found a novel homozygous missense variant in DNAAF2, c.491T>C, p.(Leu164Pro) in this patient. Subsequent immunofluorescence indicated the absence of outer dynein arm and inner dynein arm of cilia, and high-speed microscopy analysis showed that the most of the cilia are static, which support the pathogenicity of this variant. Proband 2, a 53-year-old female, presented with bronchiectasis, sinusitis, and infertility. In this patient, a new homozygous frameshift variant DNAAF2, c.822del, p.(Ala275Profs*10) was identified. The disease-causing variants mentioned above are not included in the current authorized genetic databases. Conclusion Our findings expand the spectrum of DNAAF2 variants and link DNAAF2 to female infertility and likely scoliosis in patients with PCD.
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Affiliation(s)
- Chenyang Lu
- Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, People's Republic of China.,Research Unit of Respiratory Disease, Central South University, Changsha, People's Republic of China.,Hunan Diagnosis and Treatment Center of Respiratory Disease, Changsha, People's Republic of China
| | - Danhui Yang
- Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, People's Republic of China.,Research Unit of Respiratory Disease, Central South University, Changsha, People's Republic of China.,Hunan Diagnosis and Treatment Center of Respiratory Disease, Changsha, People's Republic of China
| | - Cheng Lei
- Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, People's Republic of China.,Research Unit of Respiratory Disease, Central South University, Changsha, People's Republic of China.,Hunan Diagnosis and Treatment Center of Respiratory Disease, Changsha, People's Republic of China
| | - Rongchun Wang
- Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, People's Republic of China.,Research Unit of Respiratory Disease, Central South University, Changsha, People's Republic of China.,Hunan Diagnosis and Treatment Center of Respiratory Disease, Changsha, People's Republic of China
| | - Ting Guo
- Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, People's Republic of China.,Research Unit of Respiratory Disease, Central South University, Changsha, People's Republic of China.,Hunan Diagnosis and Treatment Center of Respiratory Disease, Changsha, People's Republic of China
| | - Hong Luo
- Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, People's Republic of China.,Research Unit of Respiratory Disease, Central South University, Changsha, People's Republic of China.,Hunan Diagnosis and Treatment Center of Respiratory Disease, Changsha, People's Republic of China
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Li JY, Liu SZ, Zheng DF, Zhang YS, Yu M. Collagen VI-related myopathy with scoliosis alone: A case report and literature review. World J Clin Cases 2021; 9:5302-5312. [PMID: 34307582 PMCID: PMC8283577 DOI: 10.12998/wjcc.v9.i19.5302] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 04/26/2021] [Accepted: 04/29/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Scoliosis is a complex three-dimensional deformity of spine and one of the common complications of collagen VI-related myopathy, caused by mutations in collagen type VI alpha 1 chain (COL6A1), COL6A2, and COL6A3 genes. The typical clinical presentations of collagen VI-related myopathy include weakness, hypotonia, laxity of distal joints, contractures of proximal joints, and skeletal deformities.
CASE SUMMARY A 28-year-old female presented with scoliosis for 28 years without weakness, hypotonia, laxity of distal joints, and contracture of proximal joints. Computed tomography and magnetic resonance imaging revealed hemivertebra, butterfly vertebra, and the missing vertebral space. Patients underwent orthopedic surgery and paravertebral muscle biopsy. The Cobb angle dropped from 103.4° to 52.9°. However, the muscle biopsy showed neurogenic muscular atrophy with myogenic lesions, suggesting congenital muscular dystrophy. Gene analysis indicated that mutations in COL6A1 (c.1612-10G>A) and COL6A2 (c.115+10G>T, c.2749G>A). Immunohistochemistry staining for collagen VI displayed shallow and discontinuous. Eventually, the patient was diagnosed as collagen VI-related myopathy.
CONCLUSION This newly found subtype of collagen VI-related myopathy has no typical manifestations; however, it is characterized by severe scoliosis and congenital vertebral deformity.
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Affiliation(s)
- Jun-Yu Li
- Department of Orthopaedics, Peking University Third Hospital, Beijing 100083, China
| | - Shuo-Zi Liu
- Department of Hematology, Peking University Third Hospital, Beijing 100083, China
| | - Dan-Feng Zheng
- Department of Pathology, Peking University Third Hospital, Beijing 100083, China
| | - Ying-Shuang Zhang
- Department of Neurology, Peking University Third Hospital, Beijing 100083, China
| | - Miao Yu
- Department of Orthopaedics, Peking University Third Hospital, Beijing 100083, China
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Mathieu H, Patten SA, Aragon-Martin JA, Ocaka L, Simpson M, Child A, Moldovan F. Genetic variant of TTLL11 gene and subsequent ciliary defects are associated with idiopathic scoliosis in a 5-generation UK family. Sci Rep 2021; 11:11026. [PMID: 34040021 PMCID: PMC8155187 DOI: 10.1038/s41598-021-90155-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Accepted: 05/04/2021] [Indexed: 02/07/2023] Open
Abstract
Idiopathic scoliosis (IS) is a complex 3D deformation of the spine with a strong genetic component, most commonly found in adolescent girls. Adolescent idiopathic scoliosis (AIS) affects around 3% of the general population. In a 5-generation UK family, linkage analysis identified the locus 9q31.2-q34.2 as a candidate region for AIS; however, the causative gene remained unidentified. Here, using exome sequencing we identified a rare insertion c.1569_1570insTT in the tubulin tyrosine ligase like gene, member 11 (TTLL11) within that locus, as the IS causative gene in this British family. Two other TTLL11 mutations were also identified in two additional AIS cases in the same cohort. Analyses of primary cells of individuals carrying the c.1569_1570insTT (NM_194252) mutation reveal a defect at the primary cilia level, which is less present, smaller and less polyglutamylated compared to control. Further, in a zebrafish, the knock down of ttll11, and the mutated ttll11 confirmed its role in spine development and ciliary function in the fish retina. These findings provide evidence that mutations in TTLL11, a ciliary gene, contribute to the pathogenesis of IS.
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Affiliation(s)
- Hélène Mathieu
- CHU Sainte-Justine Research Center, 3175 Côte Sainte-Catherine, 2.17.026, Montreal, QC, H3T 1C5, Canada
| | - Shunmoogum A Patten
- INRS-Centre Armand-Frappier Santé et Biotechnologie, Laval, QC, H7V1B7, Canada
| | | | - Louise Ocaka
- Centre for Translational Omics-GOSgene, Department of Genetics and Genomic Medicine, UCL GOSH Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK
| | - Michael Simpson
- Genetics and Molecular Medicine, King's College London, SE1 1UL, London, UK
| | - Anne Child
- Marfan Trust, NHLI, Imperial College, Guy Scadding Building, London, SW3 6LY, UK.
| | - Florina Moldovan
- CHU Sainte-Justine Research Center, 3175 Côte Sainte-Catherine, 2.17.026, Montreal, QC, H3T 1C5, Canada.
- Faculty of Dentistry, Université de Montréal, Montreal, QC, H3T 1J4, Canada.
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Feng X, Cheung JPY, Je JSH, Cheung PWH, Chen S, Yue M, Wang N, Choi VNT, Yang X, Song YQ, Luk KDK, Gao B. Genetic variants of TBX6 and TBXT identified in patients with congenital scoliosis in Southern China. J Orthop Res 2021; 39:971-988. [PMID: 32672867 DOI: 10.1002/jor.24805] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 07/02/2020] [Accepted: 07/09/2020] [Indexed: 02/04/2023]
Abstract
Congenital scoliosis (CS) is a spinal deformity present at birth due to underlying congenital vertebral malformation (CVM) that occurs during embryonic development. Hemivertebrae is the most common anomaly that causes CS. Recently, compound heterozygosity in TBX6 has been identified in Northern Chinese, Japanese, and European CS patient cohorts, which explains about 7%-10% of the affected population. In this report, we recruited 67 CS patients characterized with hemivertebrae in the Southern Chinese population and investigated the TBX6 variant and risk haplotype. We found that two patients with hemivertebrae in the thoracic spine and one patient with hemivertebrae in the lumbar spine carry the previously defined pathogenic TBX6 compound heterozygous variants. In addition, whole exome sequencing of patients with CS and their family members identified a de novo missense mutation (c.G47T: p.R16L) in another member of the T-box family, TBXT. This rare mutation compromised the binding of TBXT to its target sequence, leading to reduced transcriptional activity, and exhibited dominant-negative effect on wild-type TBXT. Our findings further highlight the importance of T-box family genes in the development of congenital scoliosis.
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Affiliation(s)
- Xin Feng
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Jason Pui Yin Cheung
- Department of Orthopaedics and Traumatology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Jimmy S H Je
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Prudence W H Cheung
- Department of Orthopaedics and Traumatology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Shuxia Chen
- The State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China
| | - Ming Yue
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Ni Wang
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Vanessa N T Choi
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Xueyan Yang
- The State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China
| | - You-Qiang Song
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Keith D K Luk
- Department of Orthopaedics and Traumatology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Bo Gao
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
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10
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Submicroscopic aberrations of chromosome 16 in prenatal diagnosis. Mol Cytogenet 2019; 12:36. [PMID: 31391865 PMCID: PMC6681493 DOI: 10.1186/s13039-019-0448-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Accepted: 07/10/2019] [Indexed: 12/27/2022] Open
Abstract
Background Nearly 9.89% of chromosome 16 consists of segmental duplications, which makes it prone to non-homologous recombination. The present study aimed to investigate the incidence and perinatal characteristics of submicroscopic chromosome 16 aberrations in prenatal diagnosis. Results A total of 2,414 consecutive fetuses that underwent prenatal chromosomal microarray analysis (CMA) between January 2016 and December 2018 were reviewed. Submicroscopic anomalies of chromosome 16 accounted for 11.1% (15/134) of all submicroscopic anomalies detected in fetuses with normal karyotype, which was larger than the percentage of anomalies in any other chromosome. The 15 submicroscopic anomalies of chromosome 16 were identified in 14 cases; 12 of them had ultrasound abnormalities. They were classified as pathogenic (N = 7), and variants of uncertain significance (N = 8). Seven fetuses with variants of uncertain significance were ended in live-born, and the remaining were end in pregnancy termination. Conclusion Submicroscopic aberrations of chromosome 16 are frequent findings in prenatal diagnosis, which emphasize the challenge of genetic counseling and the value of CMA. Prenatal diagnosis should lead to long-term monitoring of children with such chromosomal abnormalities for better understanding of the phenotype of chromosome 16 microdeletion and microduplication syndromes.
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11
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Tewes AC, Hucke J, Römer T, Kapczuk K, Schippert C, Hillemanns P, Wieacker P, Ledig S. Sequence Variants in TBX6 Are Associated with Disorders of the Müllerian Ducts: An Update. Sex Dev 2019; 13:35-40. [DOI: 10.1159/000496819] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/03/2018] [Indexed: 12/22/2022] Open
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12
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Mackel CE, Jada A, Samdani AF, Stephen JH, Bennett JT, Baaj AA, Hwang SW. A comprehensive review of the diagnosis and management of congenital scoliosis. Childs Nerv Syst 2018; 34:2155-2171. [PMID: 30078055 DOI: 10.1007/s00381-018-3915-6] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Accepted: 07/11/2018] [Indexed: 02/07/2023]
Abstract
PURPOSE To provide the reader with a comprehensive but concise understanding of congenital scoliosis METHODS: We have undertaken to summarize available literature on the pathophysiology, epidemiology, and management of congenital scoliosis. RESULTS Congenital scoliosis represents 10% of pediatric spine deformity and is a developmental error in segmentation, formation, or a combination of both leading to curvature of the spine. Treatment options are complicated by balancing growth potential with curve severity. Often associated abnormalities of cardiac, genitourinary, or intraspinal systems are concurrent and should be evaluated as part of the diagnostic work-up. Management balances the risk of progression, growth potential, lung development/function, and associated risks. Surgical treatment options involve growth-permitting systems or fusions. CONCLUSION Congenital scoliosis is a complex spinal problem associated with many other anomalous findings. Treatment options are diverse but enable optimization of management and care of these children.
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Affiliation(s)
- Charles E Mackel
- Department of Neurosurgery, Tufts Medical Center and Floating Hospital for Children, 800 Washington St, Boston, 02111, MA, USA
| | - Ajit Jada
- Department of Neurological Surgery, Weill Cornell Medical College, Box 99, 525 E 68th St, New York, 10065, NY, USA
| | - Amer F Samdani
- Shriners Hospitals for Children-Philadelphia, 3551 N Broad Street, Philadelphia, PA, 19140, USA
| | - James H Stephen
- Department of Neurosurgery, University of Pennsylvania, 3400 Spruce St, Philadelphia, 19104, PA, USA
| | - James T Bennett
- Department of Orthopaedic Surgery, Lewis Katz School of Medicine at Temple University, 3500 N Broad St, Philadelphia, 19140, PA, USA
| | - Ali A Baaj
- Department of Neurological Surgery, Weill Cornell Medical College, Box 99, 525 E 68th St, New York, 10065, NY, USA
| | - Steven W Hwang
- Shriners Hospitals for Children-Philadelphia, 3551 N Broad Street, Philadelphia, PA, 19140, USA.
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13
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Liu J, Zhou Y, Liu S, Song X, Yang XZ, Fan Y, Chen W, Akdemir ZC, Yan Z, Zuo Y, Du R, Liu Z, Yuan B, Zhao S, Liu G, Chen Y, Zhao Y, Lin M, Zhu Q, Niu Y, Liu P, Ikegawa S, Song YQ, Posey JE, Qiu G, Zhang F, Wu Z, Lupski JR, Wu N. The coexistence of copy number variations (CNVs) and single nucleotide polymorphisms (SNPs) at a locus can result in distorted calculations of the significance in associating SNPs to disease. Hum Genet 2018; 137:553-567. [PMID: 30019117 DOI: 10.1007/s00439-018-1910-3] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2018] [Accepted: 07/07/2018] [Indexed: 01/25/2023]
Abstract
With the recent advance in genome-wide association studies (GWAS), disease-associated single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) have been extensively reported. Accordingly, the issue of incorrect identification of recombination events that can induce the distortion of multi-allelic or hemizygous variants has received more attention. However, the potential distorted calculation bias or significance of a detected association in a GWAS due to the coexistence of CNVs and SNPs in the same genomic region may remain under-recognized. Here we performed the association study within a congenital scoliosis (CS) cohort whose genetic etiology was recently elucidated as a compound inheritance model, including mostly one rare variant deletion CNV null allele and one common variant non-coding hypomorphic haplotype of the TBX6 gene. We demonstrated that the existence of a deletion in TBX6 led to an overestimation of the contribution of the SNPs on the hypomorphic allele. Furthermore, we generalized a model to explain the calculation bias, or distorted significance calculation for an association study, that can be 'induced' by CNVs at a locus. Meanwhile, overlapping between the disease-associated SNPs from published GWAS and common CNVs (overlap 10%) and pathogenic/likely pathogenic CNVs (overlap 99.69%) was significantly higher than the random distribution (p < 1 × 10-6 and p = 0.034, respectively), indicating that such co-existence of CNV and SNV alleles might generally influence data interpretation and potential outcomes of a GWAS. We also verified and assessed the influence of colocalizing CNVs to the detection sensitivity of disease-associated SNP variant alleles in another adolescent idiopathic scoliosis (AIS) genome-wide association study. We proposed that detecting co-existent CNVs when evaluating the association signals between SNPs and disease traits could improve genetic model analyses and better integrate GWAS with robust Mendelian principles.
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Affiliation(s)
- Jiaqi Liu
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, No.1 Shuaifuyuan, Beijing, 100730, China.,Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, 100730, China.,Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Yangzhong Zhou
- Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, 100730, China.,Department of Internal Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Sen Liu
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, No.1 Shuaifuyuan, Beijing, 100730, China.,Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, 100730, China.,Medical Research Center of Orthopedics, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Xiaofei Song
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Xin-Zhuang Yang
- Department of Central Laboratory, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Yanhui Fan
- School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China
| | - Weisheng Chen
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, No.1 Shuaifuyuan, Beijing, 100730, China.,Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, 100730, China.,Medical Research Center of Orthopedics, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Zeynep Coban Akdemir
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Zihui Yan
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, No.1 Shuaifuyuan, Beijing, 100730, China.,Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, 100730, China.,Medical Research Center of Orthopedics, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Yuzhi Zuo
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, No.1 Shuaifuyuan, Beijing, 100730, China.,Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, 100730, China.,Medical Research Center of Orthopedics, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Renqian Du
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Zhenlei Liu
- Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, 100730, China.,Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
| | - Bo Yuan
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Sen Zhao
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, No.1 Shuaifuyuan, Beijing, 100730, China.,Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, 100730, China.,Medical Research Center of Orthopedics, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Gang Liu
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, No.1 Shuaifuyuan, Beijing, 100730, China.,Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, 100730, China.,Medical Research Center of Orthopedics, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Yixin Chen
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, No.1 Shuaifuyuan, Beijing, 100730, China.,Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, 100730, China.,Medical Research Center of Orthopedics, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Yanxue Zhao
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, No.1 Shuaifuyuan, Beijing, 100730, China.,Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, 100730, China.,Medical Research Center of Orthopedics, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Mao Lin
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, No.1 Shuaifuyuan, Beijing, 100730, China.,Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, 100730, China.,Medical Research Center of Orthopedics, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Qiankun Zhu
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, No.1 Shuaifuyuan, Beijing, 100730, China.,Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, 100730, China.,Medical Research Center of Orthopedics, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Yuchen Niu
- Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, 100730, China.,Medical Research Center of Orthopedics, Chinese Academy of Medical Sciences, Beijing, 100730, China.,Department of Central Laboratory, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Pengfei Liu
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Shiro Ikegawa
- Laboratory of Bone and Joint Diseases, Center for Integrative Medical Sciences, RIKEN, Tokyo, 108-8639, Japan
| | - You-Qiang Song
- School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China
| | - Jennifer E Posey
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Guixing Qiu
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, No.1 Shuaifuyuan, Beijing, 100730, China.,Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, 100730, China.,Medical Research Center of Orthopedics, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | | | - Feng Zhang
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, 200433, China.,Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, 200433, China
| | - Zhihong Wu
- Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, 100730, China.,Medical Research Center of Orthopedics, Chinese Academy of Medical Sciences, Beijing, 100730, China.,Department of Central Laboratory, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - James R Lupski
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.,Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA.,Texas Children's Hospital, Houston, TX, 77030, USA
| | - Nan Wu
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, No.1 Shuaifuyuan, Beijing, 100730, China. .,Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, 100730, China. .,Medical Research Center of Orthopedics, Chinese Academy of Medical Sciences, Beijing, 100730, China.
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14
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Chen W, Liu J, Yuan D, Zuo Y, Liu Z, Liu S, Zhu Q, Qiu G, Huang S, Giampietro PF, Zhang F, Wu N, Wu Z. Progress and perspective of TBX6 gene in congenital vertebral malformations. Oncotarget 2018; 7:57430-57441. [PMID: 27437870 PMCID: PMC5302999 DOI: 10.18632/oncotarget.10619] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Accepted: 05/16/2016] [Indexed: 02/05/2023] Open
Abstract
Congenital vertebral malformation is a series of significant health problems affecting a large number of populations. It may present as an isolated condition or as a part of an underlying syndromes occurring with other malformations and/or clinical features. Disruption of the genesis of paraxial mesoderm, somites or axial bones can result in spinal deformity. In the course of somitogenesis, the segmentation clock and the wavefront are the leading factors during the entire process in which TBX6 gene plays an important role. TBX6 is a member of the T-box gene family, and its important pathogenicity in spinal deformity has been confirmed. Several TBX6 gene variants and novel pathogenic mechanisms have been recently revealed, and will likely have significant impact in understanding the genetic basis for CVM. In this review, we describe the role which TBX6 plays during human spine development including its interaction with other key elements during the process of somitogenesis. We then systematically review the association between TBX6 gene variants and CVM associated phenotypes, highlighting an important and emerging role for TBX6 and human malformations.
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Affiliation(s)
- Weisheng Chen
- Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.,Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jiaqi Liu
- Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China.,Breast Surgical Oncology, Cancer Hospital of Chinese Academy of Medical Sciences, Beijing, China
| | - Dongtang Yuan
- Department of Orthopaedics, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, Jiangsu, China
| | - Yuzhi Zuo
- Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Zhenlei Liu
- Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Sen Liu
- Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.,Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China
| | - Qiankun Zhu
- Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Guixing Qiu
- Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.,Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China
| | - Shishu Huang
- Department of Orthopaedic Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Philip F Giampietro
- Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Feng Zhang
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
| | - Nan Wu
- Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.,Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China.,Medical Research Center of Orthopaedics, Chinese Academy of Medical Sciences, Beijing, China
| | - Zhihong Wu
- Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China.,Department of Central Laboratory, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
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15
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Abstract
The Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome [MIM 277000] is characterised by the absence of a uterus and vagina in otherwise phenotypically normal women with karyotype 46,XX. Clinically, the MRKH can be subdivided into two subtypes: an isolated or type I form can be delineated from a type II form, which is characterised by extragenital malformations. The so-called Müllerian hypoplasia, renal agenesis, cervicothoracic somite dysplasia (MURCS) association can be seen as the most severe phenotypic outcome. The MRKH syndrome affects at least 1 in 4000 to 5000 female new-borns. Although most of the cases are sporadic, familial clustering has also been described, indicating a genetic cause of the disease. However, the mode of inheritance is autosomal-dominant inheritance with reduced penetrance. High-resolution array-CGH and MLPA analysis revealed recurrent aberrations in different chromosomal regions such as TAR susceptibility locus in 1q21.1, chromosomal regions 16p11.2, and 17q12 and 22q11.21 microduplication and -deletion regions in patients with MRKH. Sequential analysis of the genes LHX1, TBX6 and RBM8A, which are located in chromosomal regions 17q12, 16p11.2 and 1q21.1, yielded in the detection of MRKH-associated mutations. In a subgroup of patients with signs of hyperandrogenaemia mutations of WNT4 have been found to be causative. Analysis of another member of the WNT family, WNT9B, resulted in the detection of some causative mutations in MRKH patients.
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Affiliation(s)
- Susanne Ledig
- Institute of Human Genetics, Westfälische Wilhelms-Universität, Vesaliusweg 12–14, 48149 Münster, Germany
| | - Peter Wieacker
- Institute of Human Genetics, Westfälische Wilhelms-Universität, Vesaliusweg 12–14, 48149 Münster, Germany
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16
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Chromosomal contacts connect loci associated with autism, BMI and head circumference phenotypes. Mol Psychiatry 2017; 22:836-849. [PMID: 27240531 PMCID: PMC5508252 DOI: 10.1038/mp.2016.84] [Citation(s) in RCA: 62] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2015] [Revised: 03/18/2016] [Accepted: 04/18/2016] [Indexed: 12/20/2022]
Abstract
Copy number variants (CNVs) are major contributors to genomic imbalance disorders. Phenotyping of 137 unrelated deletion and reciprocal duplication carriers of the distal 16p11.2 220 kb BP2-BP3 interval showed that these rearrangements are associated with autism spectrum disorders and mirror phenotypes of obesity/underweight and macrocephaly/microcephaly. Such phenotypes were previously associated with rearrangements of the non-overlapping proximal 16p11.2 600 kb BP4-BP5 interval. These two CNV-prone regions at 16p11.2 are reciprocally engaged in complex chromatin looping, as successfully confirmed by 4C-seq, fluorescence in situ hybridization and Hi-C, as well as coordinated expression and regulation of encompassed genes. We observed that genes differentially expressed in 16p11.2 BP4-BP5 CNV carriers are concomitantly modified in their chromatin interactions, suggesting that disruption of chromatin interplays could participate in the observed phenotypes. We also identified cis- and trans-acting chromatin contacts to other genomic regions previously associated with analogous phenotypes. For example, we uncovered that individuals with reciprocal rearrangements of the trans-contacted 2p15 locus similarly display mirror phenotypes on head circumference and weight. Our results indicate that chromosomal contacts' maps could uncover functionally and clinically related genes.
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17
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Vissarionov SV, Larionova VI, Kazarian IV, Filippova AN, Kostik MM, Voitovich AN, Rotchev EV. The gene polymorphisms of COL1A1 and VDR in children with scoliosis. PEDIATRIC TRAUMATOLOGY, ORTHOPAEDICS AND RECONSTRUCTIVE SURGERY 2017; 5:5-12. [DOI: 10.17816/ptors515-12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/09/2025]
Abstract
Background. Identification of the genetic prerequisites for development of spinal deformity.
Aim. The aim of the study was to assess the frequency of distribution of alleles and genotypes for polymorphisms -3731A/G (Cdx2) and +61968T/C (TaqI) of the VDR gene and -1997G/T and +1245G/T (Sp1) of the COL1A1 gene in children with scoliosis of various etiologies and in healthy children.
Materials and methods. Clinical genetic testing was performed in 154 children with congenital scoliosis, 145 children with idiopathic scoliosis, and 278 children without an orthopedic pathology. The molecular genetic testing was performed by PCR.
Results. Genotype tt/GG VDR gene incidence is twice as high in children with congenital scoliosis than in children who do not have scoliosis (11% and 5.2% of cases, respectively; χ² = 4.17; df = 1; p = 0.04).
Conclusion. We have found that children with the allele carriers t(C) and genotype tt(CC) in patients with congenital scoliosis were significantly more likely than children without scoliosis spinal deformity.
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18
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Yang Y, Wang BQ, Wu ZH, Zhang HY, Qiu GX, Shen JX, Zhang JG, Zhao Y, Wang YP, Fei Q. Five known tagging DLL3 SNPs are not associated with congenital scoliosis: A case-control association study in a Chinese Han population. Medicine (Baltimore) 2016; 95:e4347. [PMID: 27472720 PMCID: PMC5265857 DOI: 10.1097/md.0000000000004347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Genetic etiology hypothesis is widely accepted in the development of congenital scoliosis (CS). The delta-like 3 (DLL3) gene, a member of the Notch signaling pathway, was implicated to contribute to human CS. In this study, a case-control association study was conducted to determine the association of single nucleotide polymorphism (SNP) in the DLL3 gene with CS in a Chinese Han Population. Five known tagging SNPs of the DLL3 gene were genotyped among 270 Chinese Han subjects (128 nonsyndromic CS patients and 142 matched controls). CS patients were divided into 3 types: type I-failure of formation (29 cases), type II-failure of segmentation (50 cases), and type III-mixed defects (49 cases). The 5 SNPs were analyzed by the allelic and genotypic association analysis, genotype-phenotype association analysis, and haplotype analysis. Allele frequencies of 5 tagging SNPs (SNP1: rs1110627, SNP2: rs3212276, SNP3: rs2304223, SNP4: rs2304222, and SNP5: rs2304214) in CS cases and controls were comparable and there were no available inheritance models. The SNPs were not associated with clinical phenotypes. Moreover, the 5 makers in the DLL3 gene were found to be in strong linkage disequilibrium (LD). Both global haplotype and individual haplotype analyses showed that the haplotypes of SNP1/SNP2/SNP3/SNP4/SNP5 did not correlate with the disease (P >0.05). Together, these data suggest that genetic variants of the DLL3 gene are not associated with CS in the Chinese Han population.
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Affiliation(s)
- Yong Yang
- Department of Orthopaedics, Beijing Friendship Hospital, Capital Medical University
| | - Bing-Qiang Wang
- Department of Orthopaedics, Beijing Friendship Hospital, Capital Medical University
| | - Zhi-Hong Wu
- Department of Orthopaedics, Peking Union Medical College Hospital
| | - Hai-Yan Zhang
- Department of Cell Biology, Capital Medical University, Xicheng, Beijing, China
| | - Gui-Xing Qiu
- Department of Orthopaedics, Peking Union Medical College Hospital
| | - Jian-Xiong Shen
- Department of Orthopaedics, Peking Union Medical College Hospital
| | - Jian-Guo Zhang
- Department of Orthopaedics, Peking Union Medical College Hospital
| | - Yu Zhao
- Department of Orthopaedics, Peking Union Medical College Hospital
| | - Yi-Peng Wang
- Department of Orthopaedics, Peking Union Medical College Hospital
| | - Qi Fei
- Department of Orthopaedics, Beijing Friendship Hospital, Capital Medical University
- Correspondence: Qi Fei, Department of Orthopaedics, Beijing Friendship Hospital, Capital Medical University, Xicheng, Beijing, China (e-mail: )
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19
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Abstract
STUDY DESIGN A hypothesis-driven study was conducted in a familial cohort to determine the potential association between variants within the TBX6 gene and Familial Idiopathic Scoliosis (FIS). OBJECTIVE To determine if variants within exons of the TBX6 gene segregate with the FIS phenotype within a sample of families with FIS. SUMMARY OF BACKGROUND DATA Idiopathic Scoliosis (IS) is a structural curvature of the spine whose underlying genetic etiology has not been established. IS has been reported to occur at a higher rate than expected in family members of individuals with congenital scoliosis (CS), suggesting that the two diseases might have a shared etiology. The TBX6 gene on chromosome 16p, essential to somite development, has been associated with CS in a Chinese population. Previous studies have identified linkage to this locus in families with FIS, and specifically with rs8060511, located in an intron of the TBX6 gene. METHODS Parent-offspring trios from 11 families (13 trios, 42 individuals) with FIS were selected for Sanger sequencing of the TBX6 gene. Trios were selected from a large population of families with FIS in which a genome-wide scan had resulted in linkage to 16p. RESULTS Sequencing analyses of the subset of families resulted in the identification of five coding variants. Three of the five variants were novel; the remaining two variants were previously characterized and account for 90% of the observed variants in these trios. In all cases, there was no correlation between transmission of the TBX6 variant allele and FIS phenotype. However, an analysis of regulatory markers in osteoblasts showed that rs8060511 is in a putative enhancer element. CONCLUSIONS Although this study did not identify any TBX6 coding variants that segregate with FIS, we identified a variant that is located in a potential TBX6 enhancer element. Therefore, further investigation of the region is needed.
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20
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Tewes AC, Rall KK, Römer T, Hucke J, Kapczuk K, Brucker S, Wieacker P, Ledig S. Variations in RBM8A and TBX6 are associated with disorders of the müllerian ducts. Fertil Steril 2015; 103:1313-8. [DOI: 10.1016/j.fertnstert.2015.02.014] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2014] [Revised: 02/10/2015] [Accepted: 02/10/2015] [Indexed: 01/15/2023]
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Wu N, Ming X, Xiao J, Wu Z, Chen X, Shinawi M, Shen Y, Yu G, Liu J, Xie H, Gucev ZS, Liu S, Yang N, Al-Kateb H, Chen J, Zhang J, Hauser N, Zhang T, Tasic V, Liu P, Su X, Pan X, Liu C, Wang L, Shen J, Shen J, Chen Y, Zhang T, Zhang J, Choy KW, Wang J, Wang Q, Li S, Zhou W, Guo J, Wang Y, Zhang C, Zhao H, An Y, Zhao Y, Wang J, Liu Z, Zuo Y, Tian Y, Weng X, Sutton VR, Wang H, Ming Y, Kulkarni S, Zhong TP, Giampietro PF, Dunwoodie SL, Cheung SW, Zhang X, Jin L, Lupski JR, Qiu G, Zhang F. TBX6 null variants and a common hypomorphic allele in congenital scoliosis. N Engl J Med 2015; 372:341-50. [PMID: 25564734 PMCID: PMC4326244 DOI: 10.1056/nejmoa1406829] [Citation(s) in RCA: 232] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Congenital scoliosis is a common type of vertebral malformation. Genetic susceptibility has been implicated in congenital scoliosis. METHODS We evaluated 161 Han Chinese persons with sporadic congenital scoliosis, 166 Han Chinese controls, and 2 pedigrees, family members of which had a 16p11.2 deletion, using comparative genomic hybridization, quantitative polymerase-chain-reaction analysis, and DNA sequencing. We carried out tests of replication using an additional series of 76 Han Chinese persons with congenital scoliosis and a multicenter series of 42 persons with 16p11.2 deletions. RESULTS We identified a total of 17 heterozygous TBX6 null mutations in the 161 persons with sporadic congenital scoliosis (11%); we did not observe any null mutations in TBX6 in 166 controls (P<3.8×10(-6)). These null alleles include copy-number variants (12 instances of a 16p11.2 deletion affecting TBX6) and single-nucleotide variants (1 nonsense and 4 frame-shift mutations). However, the discordant intrafamilial phenotypes of 16p11.2 deletion carriers suggest that heterozygous TBX6 null mutation is insufficient to cause congenital scoliosis. We went on to identify a common TBX6 haplotype as the second risk allele in all 17 carriers of TBX6 null mutations (P<1.1×10(-6)). Replication studies involving additional persons with congenital scoliosis who carried a deletion affecting TBX6 confirmed this compound inheritance model. In vitro functional assays suggested that the risk haplotype is a hypomorphic allele. Hemivertebrae are characteristic of TBX6-associated congenital scoliosis. CONCLUSIONS Compound inheritance of a rare null mutation and a hypomorphic allele of TBX6 accounted for up to 11% of congenital scoliosis cases in the series that we analyzed. (Funded by the National Basic Research Program of China and others.).
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Affiliation(s)
- N Wu
- The authors' affiliations are listed in the Appendix
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Association of LMX1A genetic polymorphisms with susceptibility to congenital scoliosis in Chinese Han population. Spine (Phila Pa 1976) 2014; 39:1785-91. [PMID: 25099324 DOI: 10.1097/brs.0000000000000536] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
STUDY DESIGN A genetic association study of single nucleotide polymorphisms (SNPs) for the LMX1A gene with congenital scoliosis (CS) in the Chinese Han population. OBJECTIVE To determine whether LMX1A genetic polymorphisms are associated with susceptibility to CS. SUMMARY OF BACKGROUND DATA CS is a lateral curvature of the spine due to congenital vertebral defects, whose exact genetic cause has not been well established. The LMX1A gene was suggested as a potential human candidate gene for CS. However, no genetic study of LMX1A in CS has ever been reported. METHODS We genotyped 13 SNPs of the LMX1A gene in 154 patients with CS and 144 controls with matched sex and age. After conducting the Hardy-Weinberg equilibrium test, the data of 13 SNPs were analyzed by the allelic and genotypic association with logistic regression analysis. Furthermore, the genotype-phenotype association and haplotype association analysis were also performed. RESULTS The 13 SNPs of the LMX1A gene met Hardy-Weinberg equilibrium in the controls, which was not in the cases. None of the allelic and genotypic frequencies of these SNPs showed significant difference between case and control groups (P > 0.05). However, the genotypic frequencies of rs1354510 and rs16841013 in the LMX1A gene were associated with CS predisposition in the unconditional logistic regression analysis (P = 0.02 and 0.018, respectively). Genotypic frequencies of 3 SNPs at rs6671290, rs1354510, and rs16841013 were found to exhibit significant differences between patients with CS with failure of formation and the healthy controls (P = 0.019, 0.007, and 0.006, respectively). Besides, in the model analysis by using unconditional logistic regression analysis, the optimized model for the 3 genotypic positive SNPs with failure of formation were rs6671290 (codominant; P = 0.025, Akaike information value = 316.6, Bayesian information criterion = 333.9), rs1354510 (overdominant; P = 0.0017, Akaike information value = 312.1, Bayesian information criterion = 325.9), and rsl6841013 (overdominant; P = 0.0016, Akaike information value = 311.1, Bayesian information criterion = 325), respectively. However, the haplotype distributions in the case group were not significantly different from those of the control group in the 3 haplotype blocks. CONCLUSION To our knowledge, this is the first study to identify that the SNPs of the LMX1A gene might be associated with the susceptibility to CS and different clinical phenotypes of CS in the Chinese Han population. LEVEL OF EVIDENCE 4.
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Sandbacka M, Laivuori H, Freitas É, Halttunen M, Jokimaa V, Morin-Papunen L, Rosenberg C, Aittomäki K. TBX6, LHX1 and copy number variations in the complex genetics of Müllerian aplasia. Orphanet J Rare Dis 2013; 8:125. [PMID: 23954021 PMCID: PMC3847609 DOI: 10.1186/1750-1172-8-125] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2013] [Accepted: 08/14/2013] [Indexed: 12/16/2022] Open
Abstract
Background Müllerian aplasia (MA) is a congenital disorder of the female reproductive tract with absence of uterus and vagina with paramount impact on a woman’s life. Despite intense research, no major genes have been found to explain the complex genetic etiology. Methods and Results We have used several genetic methods to study 112 patients with MA. aCGH identified CNVs in 8/50 patients (16%), including 16p11.2 and 17q12 deletions previously associated with MA. Subsequently, another four patients were shown to carry the ~0.53 Mb deletion in 16p11.2. More importantly, sequencing of TBX6, residing within 16p11.2, revealed two patients carrying a splice site mutation. Two previously reported TBX6 variants in exon 4 and 6 were shown to have a significantly higher frequency in patients (8% and 5%, respectively) than in controls (2% each). We also sequenced LHX1 and found three apparently pathogenic missense variants in 5/112 patients. Altogether, we identified either CNVs or variations in TBX6 or LHX1 in 30/112 (26.8%) MA patients. CNVs were found in 12/112 (10.7%), patients, novel variants in TBX6 or LHX1 in 7/112 (6.3%), and rare variants in TBX6 in 15/112 (13.4%) patients. Furthermore, four of our patients (4/112, 3.6%) were shown to carry variants in both TBX6 and LHX1 or a CNV in combination with TBX6 variants lending support to the complex genetic etiology of MA. Conclusions We have identified TBX6 as a new gene associated with MA. Our results also support the relevance of LHX1 and CNVs in the development of this congenital malformation.
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Giampietro PF, Raggio CL, Blank RD, McCarty C, Broeckel U, Pickart MA. Clinical, genetic and environmental factors associated with congenital vertebral malformations. Mol Syndromol 2013; 4:94-105. [PMID: 23653580 DOI: 10.1159/000345329] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Congenital vertebral malformations (CVM) pose a significant health problem because they can be associated with spinal deformities, such as congenital scoliosis and kyphosis, in addition to various syndromes and other congenital malformations. Additional information remains to be learned regarding the natural history of congenital scoliosis and related health problems. Although significant progress has been made in understanding the process of somite formation, which gives rise to vertebral bodies, there is a wide gap in our understanding of how genetic factors contribute to CVM development. Maternal diabetes during pregnancy most commonly contributes to the occurrence of CVM, followed by other factors such as hypoxia and anticonvulsant medications. This review highlights several emerging clinical issues related to CVM, including pulmonary and orthopedic outcome in congenital scoliosis. Recent breakthroughs in genetics related to gene and environment interactions associated with CVM development are discussed. The Klippel-Feil syndrome which is associated with cervical segmentation abnormalities is illustrated as an example in which animal models, such as the zebrafish, can be utilized to provide functional evidence of pathogenicity of identified mutations.
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Affiliation(s)
- P F Giampietro
- Department of Pediatrics, University of Wisconsin-Madison, Madison, Wisc., USA
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Zufferey F, Sherr EH, Beckmann ND, Hanson E, Maillard AM, Hippolyte L, Macé A, Ferrari C, Kutalik Z, Andrieux J, Aylward E, Barker M, Bernier R, Bouquillon S, Conus P, Delobel B, Faucett WA, Goin-Kochel RP, Grant E, Harewood L, Hunter JV, Lebon S, Ledbetter DH, Martin CL, Männik K, Martinet D, Mukherjee P, Ramocki MB, Spence SJ, Steinman KJ, Tjernagel J, Spiro JE, Reymond A, Beckmann JS, Chung WK, Jacquemont S. A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders. J Med Genet 2013; 49:660-8. [PMID: 23054248 PMCID: PMC3494011 DOI: 10.1136/jmedgenet-2012-101203] [Citation(s) in RCA: 209] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Background The recurrent ∼600 kb 16p11.2 BP4-BP5 deletion is among the most frequent known genetic aetiologies of autism spectrum disorder (ASD) and related neurodevelopmental disorders. Objective To define the medical, neuropsychological, and behavioural phenotypes in carriers of this deletion. Methods We collected clinical data on 285 deletion carriers and performed detailed evaluations on 72 carriers and 68 intrafamilial non-carrier controls. Results When compared to intrafamilial controls, full scale intelligence quotient (FSIQ) is two standard deviations lower in carriers, and there is no difference between carriers referred for neurodevelopmental disorders and carriers identified through cascade family testing. Verbal IQ (mean 74) is lower than non-verbal IQ (mean 83) and a majority of carriers require speech therapy. Over 80% of individuals exhibit psychiatric disorders including ASD, which is present in 15% of the paediatric carriers. Increase in head circumference (HC) during infancy is similar to the HC and brain growth patterns observed in idiopathic ASD. Obesity, a major comorbidity present in 50% of the carriers by the age of 7 years, does not correlate with FSIQ or any behavioural trait. Seizures are present in 24% of carriers and occur independently of other symptoms. Malformations are infrequently found, confirming only a few of the previously reported associations. Conclusions The 16p11.2 deletion impacts in a quantitative and independent manner FSIQ, behaviour and body mass index, possibly through direct influences on neural circuitry. Although non-specific, these features are clinically significant and reproducible. Lastly, this study demonstrates the necessity of studying large patient cohorts ascertained through multiple methods to characterise the clinical consequences of rare variants involved in common diseases.
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Affiliation(s)
- Flore Zufferey
- Service de Génétique Médicale, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
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Moon ES, Kim HS, Sharma V, Park JO, Lee HM, Moon SH, Chong HS. Analysis of single nucleotide polymorphism in adolescent idiopathic scoliosis in Korea: for personalized treatment. Yonsei Med J 2013; 54:500-9. [PMID: 23364988 PMCID: PMC3575984 DOI: 10.3349/ymj.2013.54.2.500] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
PURPOSE The incidence of adolescent idiopathic scoliosis (AIS) has rapidly increased, and with it, physician consultations and expenditures (about one and a half times) in the last 5 years. Recent etiological studies reveal that AIS is a complex genetic disorder that results from the interaction of multiple gene loci and the environment. For personalized treatment of AIS, a tool that can accurately measure the progression of Cobb's angle would be of great use. Gene analysis utilizing single nucleotide polymorphism (SNP) has been developed as a diagnostic tool for use in Caucasians but not Koreans. Therefore, we attempted to reveal AIS-related genes and their relevance in Koreans, exploring the potential use of gene analysis as a diagnostic tool for personalized treatment of AIS therein. MATERIALS AND METHODS A total of 68 Korean AIS and 35 age- and sex-matched, healthy adolescents were enrolled in this study and were examined for 10 candidate scoliosis gene SNPs. RESULTS This study revealed that the SNPs of rs2449539 in lysosomal-associated transmembrane protein 4 beta (LAPTM4B) and rs5742612 in upstream and insulin-like growth factor 1 (IGF1) were associated with both susceptibility to and curve severity in AIS. The results suggested that both LAPTM4B and IGF1 genes were important in AIS predisposition and progression. CONCLUSION Thus, on the basis of this study, if more SNPs or candidate genes are studied in a larger population in Korea, personalized treatment of Korean AIS patients might become a possibility.
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Affiliation(s)
- Eun Su Moon
- Department of Orthopaedic Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Hak Sun Kim
- Department of Orthopaedic Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Veushj Sharma
- Department of Orthopaedic Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Jin Oh Park
- Department of Orthopaedic Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Hwan Mo Lee
- Department of Orthopaedic Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Sung Hwan Moon
- Department of Orthopaedic Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Hyon Su Chong
- Department of Orthopaedic Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
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Ouellet J, Odent T. Animal models for scoliosis research: state of the art, current concepts and future perspective applications. EUROPEAN SPINE JOURNAL : OFFICIAL PUBLICATION OF THE EUROPEAN SPINE SOCIETY, THE EUROPEAN SPINAL DEFORMITY SOCIETY, AND THE EUROPEAN SECTION OF THE CERVICAL SPINE RESEARCH SOCIETY 2013; 22 Suppl 2:S81-95. [PMID: 23099524 PMCID: PMC3616476 DOI: 10.1007/s00586-012-2396-7] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/09/2012] [Revised: 05/21/2012] [Accepted: 05/28/2012] [Indexed: 11/24/2022]
Abstract
PURPOSE The purpose of this study was to provide the readers with a reliable source of animal models currently being utilized to perform state-of-the-art scoliotic research. MATERIALS AND METHODS A comprehensive search was undertaken to review all publications on animal models for the study of scoliosis within the database from 1946 to January 2011. RESULTS The animal models have been grouped under specific headings reflecting the underlying pathophysiology behind the development of the spinal deformities produced in the animals: genetics, neuroendocrine, neuromuscular, external constraints, internal constraints with or without tissue injury, vertebral growth modulation and iatrogenic congenital malformations, in an attempt to organize and classify these multiple scoliotic animal models. As it stands, there are no animal models that mimic the human spinal anatomy with all its constraints and weaknesses, which puts it at risk of developing scoliosis. What we do have are a multitude of models, which produce spinal deformities that come close to the idiopathic scoliosis deformity. CONCLUSION All these different animal models compel us to believe that the clinical phenotype of what we call idiopathic scoliosis may well be caused by a variety of different underlying pathologies.
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Affiliation(s)
- Jean Ouellet
- />McGill Scoliosis and Spinal Research Chair, Deputy Chief Shriners Hospital, Montreal, Canada
- />Division of Orthopaedic Surgery, McGill University Health Hospital, Centre, Montreal Children Hospital, 2300 Tupper Street, Montreal, QC H3H 1P3 Canada
| | - Thierry Odent
- />Department of Orthopaedic Surgery, Hopital des Enfants Malade, Necker, Paris Descartes, France
- />Université Paris Descartes - Sorbonne Paris Cité - Service d’orthopédie pédiatrique - Hôpital Universitaire Necker - Enfants-Malades, Paris, France
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Giampietro PF. Genetic aspects of congenital and idiopathic scoliosis. SCIENTIFICA 2012; 2012:152365. [PMID: 24278672 PMCID: PMC3820596 DOI: 10.6064/2012/152365] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/10/2012] [Accepted: 11/11/2012] [Indexed: 06/02/2023]
Abstract
Congenital and idiopathic scoliosis represent disabling conditions of the spine. While congenital scoliosis (CS) is caused by morphogenic abnormalities in vertebral development, the cause(s) for idiopathic scoliosis is (are) likely to be varied, representing alterations in skeletal growth, neuromuscular imbalances, disturbances involving communication between the brain and spine, and others. Both conditions are characterized by phenotypic and genetic heterogeneities, which contribute to the difficulties in understanding their genetic basis that investigators face. Despite the differences between these two conditions there is observational and experimental evidence supporting common genetic mechanisms. This paper focuses on the clinical features of both CS and IS and highlights genetic and environmental factors which contribute to their occurrence. It is anticipated that emerging genetic technologies and improvements in phenotypic stratification of both conditions will facilitate improved understanding of the genetic basis for these conditions and enable targeted prevention and treatment strategies.
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Affiliation(s)
- Philip F. Giampietro
- Waisman Center, University of Wisconsin-Madison, 1500 Highland Avenue, Madison, WI 53705, USA
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Abstract
One of the most striking features of the human vertebral column is its periodic organization along the anterior-posterior axis. This pattern is established when segments of vertebrates, called somites, bud off at a defined pace from the anterior tip of the embryo's presomitic mesoderm (PSM). To trigger this rhythmic production of somites, three major signaling pathways--Notch, Wnt/β-catenin, and fibroblast growth factor (FGF)--integrate into a molecular network that generates a traveling wave of gene expression along the embryonic axis, called the "segmentation clock." Recent systems approaches have begun identifying specific signaling circuits within the network that set the pace of the oscillations, synchronize gene expression cycles in neighboring cells, and contribute to the robustness and bilateral symmetry of somite formation. These findings establish a new model for vertebrate segmentation and provide a conceptual framework to explain human diseases of the spine, such as congenital scoliosis.
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Affiliation(s)
- Olivier Pourquié
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS (UMR 7104), Inserm U964, Université de Strasbourg, Illkirch F-67400, France
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Shen Y, Chen X, Wang L, Guo J, Shen J, An Y, Zhu H, Zhu Y, Xin R, Bao Y, Gusella JF, Zhang T, Wu BL. Intra-family phenotypic heterogeneity of 16p11.2 deletion carriers in a three-generation Chinese family. Am J Med Genet B Neuropsychiatr Genet 2011; 156:225-32. [PMID: 21302351 DOI: 10.1002/ajmg.b.31147] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2010] [Accepted: 10/26/2010] [Indexed: 11/10/2022]
Abstract
The 16p11.2 deletion is a recurrent genomic event and a significant risk factor for autism spectrum disorders (ASD). This genomic disorder also exhibits extensive phenotypic variability and diverse clinical phenotypes. The full extent of phenotypic heterogeneity associated with the 16p11.2 deletion disorder and the factors that modify the clinical phenotypes are currently unknown. Multiplex families with deletion offer unique opportunities for exploring the degree of heterogeneity and implicating modifiers. Here we reported the clinical and genomic characteristics of three 16p11.2 deletion carriers in a Chinese family. The father carries a de novo 16p11.2 deletion, and it was transmitted to the proband and sib. The proband presented with ASD, intellectual disability, learning difficulty, congenital malformations such as atrial septal defect, scoliosis. His dysmorphic features included myopia and strabismus, flat and broad nasal bridge, etc. While the father shared same neurodevelopmental problems as the proband, the younger brother did not show many of the proband's phenotypes. The possible unmasked mutation of TBX6 and MVP gene in this deleted region and the differential distribution of other genomic CNVs were explored to explain the phenotypic heterogeneity in these carriers. This report demonstrated the different developmental trajectory and discordant phenotypes among family members with the same 16p11.2 deletion, thus further illustrated the phenotypic complexity and heterogeneity of the 16p11.2 deletion.
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Affiliation(s)
- Yiping Shen
- Department of Laboratory Medicine, Children's Hospital Boston, Boston, Massachusetts, USA
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