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Rare variants in NR2F2 cause congenital heart defects in humans.

ABSTRACT: 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 × 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.

SUBMITTER: Al Turki S

PROVIDER: S-EPMC3980509 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Rare variants in NR2F2 cause congenital heart defects in humans.

Al Turki Saeed S Manickaraj Ashok K AK Mercer Catherine L CL Gerety Sebastian S SS Hitz Marc-Phillip MP Lindsay Sarah S D'Alessandro Lisa C A LC Swaminathan G Jawahar GJ Bentham Jamie J Arndt Anne-Karin AK Louw Jacoba J Low Jacoba J Breckpot Jeroen J Gewillig Marc M Gewillig Marc M Thienpont Bernard B Abdul-Khaliq Hashim H Harnack Christine C Hoff Kirstin K Kramer Hans-Heiner HH Schubert Stephan S Siebert Reiner R Toka Okan O Cosgrove Catherine C Watkins Hugh H Lucassen Anneke M AM O'Kelly Ita M IM Salmon Anthony P AP Bu'lock Frances A FA Granados-Riveron Javier J Setchfield Kerry K Thornborough Chris C Brook J David JD Mulder Barbara B Klaassen Sabine S Bhattacharya Shoumo S Devriendt Koen K Fitzpatrick David F DF Wilson David I DI Mital Seema S Hurles Matthew E ME

American journal of human genetics 20140401 4

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 signifi ...[more]

PMID: 24702954

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Project description:BackgroundHeterotaxy (Htx) syndrome comprises a class of congenital disorders resulting from malformations in left-right body patterning. Approximately 90% of patients with heterotaxy have serious congenital heart diseases; as a result, the survival rate and outcomes of Htx patients are not satisfactory. However, the underlying etiology and mechanisms in the majority of Htx cases remain unknown. The aim of this study was to investigate the function of rare copy number variants (CNVs) in the pathogenesis of Htx.MethodsWe collected 63 sporadic Htx patients with congenital heart defects and identified rare CNVs using an Affymetrix CytoScan HD microarray and real-time polymerase chain reaction. Potential candidate genes associated with the rare CNVs were selected by referring to previous literature related to left-right development. The expression patterns and function of candidate genes were further analyzed by whole mount in situ hybridization, morpholino knockdown, clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9)-mediated mutation, and over-expressing methods with zebrafish models.ResultsNineteen rare CNVs were identified for the first time in patients with Htx. These CNVs include 5 heterozygous genic deletions, 4 internal genic duplications, and 10 complete duplications of at least one gene. Further analyses of the 19 rare CNVs identified six novel potential candidate genes (NUMB, PACRG, TCTN2, DANH10, RNF115, and TTC40) linked to left-right patterning. These candidate genes exhibited early expression patterns in zebrafish embryos. Functional testing revealed that downregulation and over-expression of five candidate genes (numb, pacrg, tctn2, dnah10, and rnf115) in zebrafish resulted in disruption of cardiac looping and abnormal expression of lefty2 or pitx2, molecular markers of left-right patterning.ConclusionsOur findings show that Htx with congenital heart defects in some sporadic patients may be attributed to rare CNVs. Furthermore, DNAH10 and RNF115 are Htx candidate genes involved in left-right patterning which have not previously been reported in either humans or animals. Our results also advance understanding of the genetic components of Htx.

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Rare variants in NR2F2 cause congenital heart defects in humans.

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Rare variants in NR2F2 cause congenital heart defects in humans.

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