期刊
AMERICAN JOURNAL OF HUMAN GENETICS
卷 94, 期 4, 页码 574-585出版社
CELL PRESS
DOI: 10.1016/j.ajhg.2014.03.007
关键词
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资金
- Wellcome Trust [WT098051, WT091310]
- MRC
- Little Hearts Matter and the Competence Network for Congenital Heart Defects/National Register for Congenital Heart Defects (Germany)
- Federal Ministry of Education and Research (BMBF) [FKZ 01GI0601]
- DZHK (German Centre for Cardiovascular Research)
- Heart and Stroke Foundation of Canada research fellowship
- WHI Sequencing Project [HL-102924]
- Broad GO Sequencing Project [HL-102925]
- Lung GO Sequencing Project [HL-102923]
- Seattle GO Sequencing Project [HL-102926]
- Heart GO Sequencing Project [HL-103010]
- MRC [MC_PC_U127561093, MC_U127561093] Funding Source: UKRI
- British Heart Foundation [RG/13/10/30376, RG/07/010/23676, PG/07/045/22690, RG/10/17/28553] Funding Source: researchfish
- Medical Research Council [MC_PC_U127561093, MC_U127561093] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0510-10268] Funding Source: researchfish
Congenital heart defects (CHDs) are the most common birth defect worldwide and are a leading cause of neonatal mortality. Non-syndromic atrioventricular septal defects (AVSDs) are an important subtype of CHDs for which the genetic architecture is poorly understood. We performed exome sequencing in 13 parent-offspring trios and 112 unrelated individuals with nonsyndromic AVSDs and identified five rare missense variants (two of which arose de novo) in the highly conserved gene NR2F2, a very significant enrichment (p 7.7 x 10(-7)) compared to 5,194 control subjects. We identified three additional CHD-affected families with other variants in NR2F2 including a de novo balanced chromosomal translocation, a de novo substitution disrupting a splice donor site, and a 3 bp duplication that cosegregated in a multiplex family. NR2F2 encodes a pleiotropic developmental transcription factor, and decreased dosage of NR2F2 in mice has been shown to result in abnormal development of atrioventricular septa. Via luciferase assays, we showed that all six coding sequence variants observed in individuals significantly alter the activity of NR2F2 on target promoters.
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