Autosomal and X chromosome structural variants are associated with congenital heart defects in Turner syndrome: The NHLBI GenTAC registry.
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. © 2016 Wiley Periodicals, Inc.
Division of Medical Genetics, Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, Texas.
Siddharth K
SK
Prakash
National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.
Carolyn A
CA
Bondy
Departments of Molecular and Medical Genetics and Pediatrics, Oregon Health & Science University, Portland, Oregon.
Cheryl L
CL
Maslen
Departments of Molecular and Medical Genetics and Pediatrics, Oregon Health & Science University, Portland, Oregon.
Michael
M
Silberbach
Department of Medical Genetics, MassGeneral Hospital for Children, Boston, Massachusetts.
Angela E
AE
Lin
Department of Pediatrics "F. Fede", Seconda Università degli Studi di Napoli, Naples, Italy.
Laura
L
Perrone
Department of Pediatrics "F. Fede", Seconda Università degli Studi di Napoli, Naples, Italy.
Giuseppe
G
Limongelli
Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota.
Hector I
HI
Michelena
Department of Cardiology and Cardiac Surgery, University Hospital "Scuola Medica Salernitana", Salerno, Italy.
Eduardo
E
Bossone
Department of Cardiology and Cardiac Surgery, University Hospital "Scuola Medica Salernitana", Salerno, Italy.
Rodolfo
R
Citro
Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas.
Scott A
SA
Lemaire
Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Simon C
SC
Body
Division of Medical Genetics, Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, Texas.
Dianna M
DM
Milewicz
D000328:Adult; D041321:Chromosomes, Human, X / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D018628:Gene Dosage / Q000235:genetics; D050172:Genes, X-Linked / Q000235:genetics; D005838:Genotype; D051246:Glucose Transport Proteins, Facilitative / Q000235:genetics; D051274:Glucose Transporter Type 3 / Q000235:genetics; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000503:physiopathology; D018398:Homeodomain Proteins / Q000008:administration & dosage / Q000235:genetics; D006801:Humans; D008297:Male; D054555:National Heart, Lung, and Blood Institute (U.S.); D014157:Transcription Factors / Q000008:administration & dosage / Q000235:genetics; D014424:Turner Syndrome / Q000235:genetics* / Q000503:physiopathology; D014481:United States
D051246:Glucose Transport Proteins, Facilitative; D051274:Glucose Transporter Type 3; D018398:Homeodomain Proteins; C552728:NANOGP1 protein, human; C474630:SLC2A14 protein, human; C495687:SLC2A3 protein, human; D014157:Transcription Factors
Turner syndrome; X chromosome; congenital heart defects; genomics; valvular heart disease