Rare Variants in NR2F2 Cause Congenital Heart Defects in Humans

详细信息    查看全文

• 作者：Saeed Al Turki¹ ; ² ; ²² ; Ashok K. Manickaraj³ ; ²² ; Catherine L. Mercer⁴ ; ²² ; Sebastian S. Gerety¹ ; ²² ; Marc-Phillip Hitz¹ ; Sarah Lindsay¹ ; Lisa C.A. D&rsquo ; Alessandro³ ; G. Jawahar Swaminathan¹ ; Jamie Bentham⁵ ; Anne-Karin Arndt⁶ ; ⁷ ; Jacoba Low⁸ ; ⁹ ; Jeroen Breckpot⁸ ; Marc Gewillig⁹ ; Bernard Thienpont⁸ ; Hashim Abdul-Khaliq¹⁰ ; ¹¹ ; Christine Harnack¹² ; Kirstin Hoff⁷ ; ¹³ ; Hans-Heiner Kramer⁷ ; ¹¹ ; Stephan Schubert¹¹ ; ¹⁴ ; Reiner Siebert¹³ ; Okan Toka¹¹ ; ¹⁵ ; Catherine Cosgrove¹⁶ ; Hugh Watkins¹⁶ ; Anneke M. Lucassen⁴ ; Ita M. O&rsquo ; Kelly⁴ ; Anthony P. Salmon⁴ ; Frances A. Bu&rsquo ; Lock¹⁷ ; Javier Granados-Riveron¹⁸ ; Kerry Setchfield¹⁸ ; Chris Thornborough¹⁷ ; J. David Brook¹⁸ ; Barbara Mulder¹⁹ ; Sabine Klaassen¹¹ ; ¹² ; ²⁰ ; Shoumo Bhattacharya¹⁶ ; Koen Devriendt⁸ ; David F. FitzPatrick²¹ ; UK10K Consortium
• 刊名：The American Journal of Human Genetics
• 出版年：3 April, 2014
• 年：2014
• 卷：94
• 期：4
• 页码：574-585
• 全文大小：2489 K

文摘

Congenital heart defects (CHDs) are the most common birth defect worldwide and are a leading cause of neonatal mortality. Nonsyndromic 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聽脳 10^鈭?) 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聽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.