Integrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease

Abstract

Numerous genetic studies have established a role for rare genomic variants in Congenital Heart Disease (CHD) at the copy number variation (CNV) and de novo variant (DNV) level. To identify novel haploinsufficient CHD disease genes, we performed an integrative analysis of CNVs and DNVs identified in probands with CHD including cases with sporadic thoracic aortic aneurysm. We assembled CNV data from 7,958 cases and 14,082 controls and performed a gene-wise analysis of the burden of rare genomic deletions in cases versus controls. In addition, we performed variation rate testing for DNVs identified in 2,489 parent-offspring trios. Our analysis revealed 21 genes which were significantly affected by rare CNVs and/or DNVs in probands. Fourteen of these genes have previously been associated with CHD while the remaining genes (FEZ1, MYO16, ARID1B, NALCN, WAC, KDM5B and WHSC1) have only been associated in small cases series or show new associations with CHD. In addition, a systems level analysis revealed affected protein-protein interaction networks involved in Notch signaling pathway, heart morphogenesis, DNA repair and cilia/centrosome function. Taken together, this approach highlights the importance of re-analyzing existing datasets to strengthen disease association and identify novel disease genes and pathways.

Heart Disease and Stroke Statistics—2023 Update: A Report From the American Heart Association

“…Recently, in addition to previously recognized 14 genes associated with CCDs, 7 new genes ( FEZ1 , MYO16 , ARID1B , NALCN , WAC , KDM5B , and WHSC1 ) have been identified as being associated with CCDs. 71 A recent GWAS in patients of European ancestry with CCDs has identified MACROD2 , GOSR17-2 , WNT3 , and MSX1 to have an essential role in embryonic and postnatal cardiac morphogenesis and to contribute to the development of structural cardiac defects. 72…”

Discovering a new part of the phenotypic spectrum of Coffin-Siris syndrome in a fetal cohort

“…Application of prenatal genome-wide sequencing is rapidly becoming standard care. [11][12][13][14][15] The interpretation of prenatally identified variants can be challenging because of the limited knowledge of prenatal phenotypes, because most genomewide sequencing in diagnostics and research has focused on postnatal phenotypes. CSS is no exception to this rule.…”

Network assisted analysis of de novo variants using protein-protein interaction information identified 46 candidate genes for congenital heart disease

“…Among the un-clustered genes, six are identified after using the network information: ABCE1, UBE2B, SDC1, PYGL, KDM5B, MED20. UBE2B and KDM5B, encoding epigenetic modifiers, have shown suggestive evidence in cardiac development or CHD [72,73] and might be potential CHD genes.…”