De novo and recessive forms of congenital heart disease have distinct genetic and phenotypic landscapes

W Scott Watkins,Thomas A Miller,E Javier Hernandez,Yufeng Shen,Mark Yandell,Brent W Bisgrove,Gordon Lemmon,Jane W Newburger,Bruce D Gelb,H Joseph Yost,Christine E Seidman,Ryan T Sunderland,Wendy K Chung,Bradley L Demarest,Sergiusz Wesołowski ,Martina Brueckner,Daniel Bernstein,Elizabeth Goldmuntz,Edwin Lin,Martin Tristani‐Firouzi

doi:10.1038/s41467-019-12582-y

Abstract

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.

Highlights

The genetic architecture of sporadic congenital heart disease (CHD) is characterized by enrichment in damaging de novo variants in chromatin-modifying genes
Support for the contribution of recessive genotypes to CHD was reported in a study of 2645 parent–offspring trios ascertained by the Pediatric Cardiac Genomics Consortium (PCGC)
As the potential number of combinations of these categories is intractably large, we examine those with prior association with CHD or logical relationship to CHD etiology

Summary

Introduction

The genetic architecture of sporadic congenital heart disease (CHD) is characterized by enrichment in damaging de novo variants in chromatin-modifying genes. Large WES datasets make it possible to associate classes of genes with particular phenotypes and outcomes, and to measure the strength of those associations, so as to discover and describe the large-scale genetic and phenotypic landscapes of a complex disease via a process similar to category-wide association testing, or CWAS2 Toward this end, we analyze 2391 trios from the PCGC, using a methodology that allows us to identify additional gene-damaging compound recessive genotypes and new disease genes, while at the same time controlling for the confounding effects of ancestry, sequencing methodologies, and differences in genetic burden between genes and across functional classes of genes. Our findings demonstrate that amid the considerable genetic and phenotypic heterogeneity of CHD, there exists a network of highly significant associations between genotypes, gene functions and phenotypes

Methods

Results

Conclusion