TY - JOUR
T1 - Autosomal and X chromosome structural variants are associated with congenital heart defects in Turner syndrome
T2 - The NHLBI GenTAC registry
AU - BAVCon Investigators, GenTAC Registry Investigators
AU - Prakash, Siddharth K.
AU - Bondy, Carolyn A.
AU - Maslen, Cheryl L.
AU - Silberbach, Michael
AU - Lin, Angela E.
AU - Perrone, Laura
AU - Limongelli, Giuseppe
AU - Michelena, Hector I.
AU - Bossone, Eduardo
AU - Citro, Rodolfo
AU - Lemaire, Scott A.
AU - Body, Simon C.
AU - Milewicz, Dianna M.
N1 - Funding Information:
We thank the study participants and team members who contributed to these studies. Access to genotypes and clinical information from the LVOTO cohort was generously provided by John W. Belmont, M.D., Ph.D. and Neil Hanchard, M.D., Ph.D., of Baylor College of Medicine (supported by 1U54HD083092, 5R01HD039056, 5R01HL090506 and 5R01HL091771) and Kim McBride, M.D., of The Ohio State University and Nationwide Children's Hospital (supported by 5R01HL109758). The GenTAC Registry has been supported by US Federal Government contracts HHSN268200648199C and HHSN268201000048C from the National Heart Lung and Blood Institute and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (Bethesda, M.D.). The datasets used for the analyses described in this manuscript were obtained from the Genetic Architecture of Smoking and Smoking Cessation Study found at dbGaP accession phs000404.v1.p1, the NEI Refractive Error Collaboration (NEIREC) Database found at dbGaP accession phs000303.v1.p1, the Health and Retirement Study (HRS) found at dbGaP accession phs000428.v1.p1, and the Genetics of Fuchs’ Endothelial Corneal Dystrophy (FECD) Study found at dbGaP accession phs000421.v1.p1. FECD was primarily supported by grants R01EY016514 (DUEC, PI: Gordon Klintworth), R01EY016482 (CWRU, PI: Sudha Iyengar) and 1 × 01HG006619-01 (PI: Sudha Iyengar, Natalie Afshari). The HRS genetic data was sponsored by the National Institute on Aging (grants U01AG009740, RC2AG036495 and RC4AG039029) and was conducted by the University of Michigan. Funding support for NEIREC was provided by the National Eye Institute. Genotyping for the Genetic Architecture of Smoking and Smoking Cessation Study, which was performed at the Center for Inherited Disease Research (CIDR), was funded by 1 × 01HG005274-01. CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. Assistance with genotype cleaning, as well as with general study coordination for the Genetic Architecture of Smoking and Smoking Cessation Study was provided by the Gene Environment Association Studies (GENEVA) Coordinating Center (U01 HG004446). Funding support for collection of the Genetic Architecture of Smoking and Smoking Cessation Study datasets and samples was provided by the Collaborative Genetic Study of Nicotine Dependence (COGEND; P01 CA089392) and the University of Wisconsin Transdisciplinary Tobacco Use Research Center (P50 DA019706, P50 CA084724). We would like to thank the FECD participants, NEIREC participants and the NEIREC and FECD Research Groups for their valuable contribution to this research. The authors are indebted to the International Bicuspid Aortic Valve Consortium (BAVCon) and the National Registry of Genetically Triggered Aneurysms and Cardiovascular Conditions (GenTAC) for providing samples and clinical data. A complete list of BAVCon and GenTAC investigators and their affiliations is available in the Supplementary Online Material.
Publisher Copyright:
© 2016 Wiley Periodicals, Inc.
PY - 2016/12/1
Y1 - 2016/12/1
N2 - Turner Syndrome (TS) is a developmental disorder caused by partial or complete loss of one sex chromosome. Bicuspid aortic valve and other left-sided congenital heart lesions (LSL), including thoracic aortic aneurysms and acute aortic dissections, are 30–50 times more frequent in TS than in the general population. In 454 TS subjects, we found that LSL are significantly associated with reduced dosage of Xp genes and increased dosage of Xq genes. We also showed that genome-wide copy number variation is increased in TS and identify a common copy number variant (CNV) in chromosome 12p13.31 that is associated with LSL with an odds ratio of 3.7. This CNV contains three protein-coding genes (SLC2A3, SLC2A14, and NANOGP1) and was previously implicated in congenital heart defects in the 22q11 deletion syndrome. In addition, we identified a subset of rare and recurrent CNVs that are also enriched in non-syndromic BAV cases. These observations support our hypothesis that X chromosome and autosomal variants affecting cardiac developmental genes may interact to cause the increased prevalence of LSL in TS.
AB - Turner Syndrome (TS) is a developmental disorder caused by partial or complete loss of one sex chromosome. Bicuspid aortic valve and other left-sided congenital heart lesions (LSL), including thoracic aortic aneurysms and acute aortic dissections, are 30–50 times more frequent in TS than in the general population. In 454 TS subjects, we found that LSL are significantly associated with reduced dosage of Xp genes and increased dosage of Xq genes. We also showed that genome-wide copy number variation is increased in TS and identify a common copy number variant (CNV) in chromosome 12p13.31 that is associated with LSL with an odds ratio of 3.7. This CNV contains three protein-coding genes (SLC2A3, SLC2A14, and NANOGP1) and was previously implicated in congenital heart defects in the 22q11 deletion syndrome. In addition, we identified a subset of rare and recurrent CNVs that are also enriched in non-syndromic BAV cases. These observations support our hypothesis that X chromosome and autosomal variants affecting cardiac developmental genes may interact to cause the increased prevalence of LSL in TS.
KW - Turner syndrome
KW - X chromosome
KW - congenital heart defects
KW - genomics
KW - valvular heart disease
UR - http://www.scopus.com/inward/record.url?scp=84995743347&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84995743347&partnerID=8YFLogxK
U2 - 10.1002/ajmg.a.37953
DO - 10.1002/ajmg.a.37953
M3 - Article
C2 - 27604636
AN - SCOPUS:84995743347
SN - 1552-4825
VL - 170
SP - 3157
EP - 3164
JO - American Journal of Medical Genetics, Part A
JF - American Journal of Medical Genetics, Part A
IS - 12
ER -