De Novo and Rare Variants at Multiple Loci Support the Oligogenic Origins of Atrioventricular Septal Heart Defects
| Autor: | Daniel Bernstein, Seema Mital, Kazutoyo Osoegawa, Daryl Waggott, Ivan P. Moskowitz, Euan A. Ashley, Deborah A. Nickerson, Santhosh Girirajan, Todd E. Scheetz, Richard P. Lifton, Jeffrey D. Steimle, Sushma Reddy, Michael A. Portman, Evan E. Eichler, Val C. Sheffield, Edward J. Lammer, Michael J. Bamshad, Kathleen Schultz, Nebil Mohammed, Ramendra K. Kundu, Vivek Nanda, Francois Haddad, James R. Priest, Thomas Quertermous, Matthew E. Hurles, Xinan Yang, Trudy L. Burns, Bruce D. Gelb |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Proteomics
Male 0301 basic medicine BBS2 Cancer Research Gene Expression Genetic Networks 030204 cardiovascular system & hematology medicine.disease_cause Bioinformatics Biochemistry Mice 0302 clinical medicine Medicine and Health Sciences Morphogenesis Genetics (clinical) Exome sequencing Mice Knockout Genetics Mutation Homozygote Heart Genomics Congenital Heart Defects Pedigree 3. Good health Protein Interaction Networks Female Anatomy Network Analysis Research Article Computer and Information Sciences Heterozygote lcsh:QH426-470 Cardiology Biology 03 medical and health sciences EHMT1 Genetic variation Congenital Disorders medicine Animals Humans Birth Defects Allele Molecular Biology Gene Alleles Ecology Evolution Behavior and Systematics Heart Septal Defects Biology and Life Sciences Computational Biology Genome Analysis lcsh:Genetics 030104 developmental biology Genetic Loci Genetics of Disease Cardiovascular Anatomy MYH6 Developmental Biology |
| Zdroj: | PLoS Genetics, Vol 12, Iss 4, p e1005963 (2016) PLoS Genetics |
| ISSN: | 1553-7404 1553-7390 |
| Popis: | 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. Author Summary Congenital heart disease (CHD) is a leading cause of childhood morbidity in the developed world. There are few prevalent clinical risk factors and though it is possible that up to 90% of risk for CHD may be genetic, the number of genes clinically associated with disease is small. Rather than grouping disparate CHD phenotypes as other studies have done, we studied a single specific malformation- the atrioventricular septal defect (AVSD). Instead of recurrent variation in a handful of genes, we observed de novo and inherited variation in 19 genes associated with human disease, syndromic loci, and genes implicated in cardiac development by mouse knockout. The number of loci identified support the longstanding hypothesis of a complex oligogenic inheritance for a single malformation and suggest that analyses of CHD data to include inherited variation may uncover additional loci contributing risk for cardiac malformations. |
| Databáze: | OpenAIRE |
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