De novo and recessive forms of congenital heart disease have distinct genetic and phenotypic landscapes
| Autor: | Yufeng Shen, Ryan T. Sunderland, Thomas A. Miller, Wendy K. Chung, Mark Yandell, Bradley L. Demarest, H. Joseph Yost, Martin Tristani-Firouzi, Brent W. Bisgrove, Daniel Bernstein, Sergiusz Wesolowski, Christine E. Seidman, Edwin Lin, W. Scott Watkins, Elizabeth Goldmuntz, Gordon Lemmon, Jane W. Newburger, Martina Brueckner, E. Javier Hernandez, Bruce D. Gelb |
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| Rok vydání: | 2019 |
| Předmět: |
Heart Defects
Congenital Male 0301 basic medicine Genotype Science General Physics and Astronomy Genes Recessive Genomics Genome-wide association study 030204 cardiovascular system & hematology Biology medicine.disease_cause Compound heterozygosity Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences 0302 clinical medicine Exome Sequencing medicine Humans Genetic Predisposition to Disease lcsh:Science Child Gene Exome sequencing Genes Dominant Genetics Mutation Multidisciplinary Cardiovascular genetics General Chemistry Genetic architecture Computational biology and bioinformatics Phenotype 030104 developmental biology Congenital heart defects Case-Control Studies Next-generation sequencing lcsh:Q Female Genome-Wide Association Study |
| Zdroj: | Nature Communications Nature Communications, Vol 10, Iss 1, Pp 1-12 (2019) |
| ISSN: | 2041-1723 |
| Popis: | The genetic architecture of sporadic congenital heart disease (CHD) is characterized by enrichment in damaging de novo variants in chromatin-modifying genes. To test the hypothesis that gene pathways contributing to de novo forms of CHD are distinct from those for recessive forms, we analyze 2391 whole-exome trios from the Pediatric Cardiac Genomics Consortium. We deploy a permutation-based gene-burden analysis to identify damaging recessive and compound heterozygous genotypes and disease genes, controlling for confounding effects, such as background mutation rate and ancestry. Cilia-related genes are significantly enriched for damaging rare recessive genotypes, but comparatively depleted for de novo variants. The opposite trend is observed for chromatin-modifying genes. Other cardiac developmental gene classes have less stratification by mode of inheritance than cilia and chromatin-modifying gene classes. Our analyses reveal dominant and recessive CHD are associated with distinct gene functions, with cilia-related genes providing a reservoir of rare segregating variation leading to CHD. Large whole-exome sequencing studies have suggested that the genetic architecture of syndromic congenital heart disease (CHD) is different from sporadic forms. Here, Watkins et al. estimate the relative contribution of damaging recessive and de novo genotypes to CHD in 2391 trios and find them to be associated with different gene functions. |
| Databáze: | OpenAIRE |
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