Biological Sciences Division
Published April 8, 2016 | Version v1
Journal article Open

De Novo and Rare Variants at Multiple Loci Support the Oligogenic Origins of Atrioventricular Septal Heart Defects

Creators

  • 1. Stanford University
  • 2. University of California San Francisco
  • 3. Pennsylvania State University
  • 4. University of Iowa
  • 5. University of Chicago
  • 6. Wellcome Trust Sanger Institute
  • 7. Yale University
  • 8. University of Washington
  • 9. Howard Hughes Medical Institute
  • 10. University of Toronto
  • 11. Icahn School of Medicine at Mt. Sinai

Description

Congenital heart disease (CHD) has a complex genetic etiology, and recent studies suggest that high penetrance de novo mutations may account for only a small fraction of disease. In a multi-institutional cohort surveyed by exome sequencing, combining analysis of 987 individuals (discovery cohort of 59 affected trios and 59 control trios, and a replication cohort of 100 affected singletons and 533 unaffected singletons) we observe variation at novel and known loci related to a specific cardiac malformation the atrioventricular septal defect (AVSD). In a primary analysis, by combining developmental coexpression networks with inheritance modeling, we identify a de novo mutation in the DNA binding domain of NR1D2 (p.R175W). We show that p.R175W changes the transcriptional activity of Nr1d2 using an in vitro transactivation model in HUVEC cells. Finally, we demonstrate previously unrecognized cardiovascular malformations in the Nr1d2tm1-Dgen knockout mouse. In secondary analyses we map genetic variation to protein-interaction networks suggesting a role for two collagen genes in AVSD, which we corroborate by burden testing in a second replication cohort of 100 AVSDs and 533 controls (p = 8.37e-08). Finally, we apply a rare-disease inheritance model to identify variation in genes previously associated with CHD (ZFPM2, NSD1, NOTCH1, VCAN, and MYH6), cardiac malformations in mouse models (ADAM17, CHRD, IFT140, PTPRJ, RYR1 and ATE1), and hypomorphic alleles of genes causing syndromic CHD (EHMT1, SRCAP, BBS2, NOTCH2, and KMT2D) in 14 of 59 trios, greatly exceeding variation in control trios without CHD (p = 9.60e-06). In total, 32% of trios carried at least one putatively disease-associated variant across 19 loci,suggesting that inherited and de novo variation across a heterogeneous group of loci may contribute to disease risk.

Data availability

Exome data can be found at the dbGAP repository maintained by NIH for researchers who meet the criteria for access to confidential data. Application procedures for dbGAP can be found at (https://dbgap.ncbi.nlm.nih.gov/aa/wga.cgi?page=login). Exome data from the Toronto single samples is freely available at the EGA repository for researchers who meet the criteria for access to confidential data. Application procedures for EGA cat be found at (https://www.ebi.ac.uk/ega/about/access) Sage gene expression data from mouse organ development can be found at http://www.mouseatlas.org/. The RNAseq data from the second heart field and DMP generated by the Moskowitz lab has been submitted to GEO (GSE75077).

Files

journal.pgen.1005963.pdf

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Additional details

Identifiers

DOI
10.1371/journal.pgen.1005963
Other
oai:uchicago.tind.io:7333

Funding

NICHD
Pediatric Scientist Development Program
NHLBI
X01HL115206-01
Yale Center for Medelian Genomics
U54HG006493-04
NHLBI
R01 HL092153

UChicago Information

Division(s)
Biological Sciences Division
Department(s)
Pathology