Faculty Collaboration Database

Integrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease. PLoS Genet 2021 Jul;17(7):e1009679

Date

07/30/2021

Pubmed ID

34324492

Pubmed Central ID

PMC8354477

DOI

10.1371/journal.pgen.1009679

Scopus ID

2-s2.0-85111770757 (requires institutional sign-in at Scopus site)   14 Citations

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.

Author List

Audain E, Wilsdon A, Breckpot J, Izarzugaza JMG, Fitzgerald TW, Kahlert AK, Sifrim A, Wünnemann F, Perez-Riverol Y, Abdul-Khaliq H, Bak M, Bassett AS, Benson DW, Berger F, Daehnert I, Devriendt K, Dittrich S, Daubeney PE, Garg V, Hackmann K, Hoff K, Hofmann P, Dombrowsky G, Pickardt T, Bauer U, Keavney BD, Klaassen S, Kramer HH, Marshall CR, Milewicz DM, Lemaire S, Coselli JS, Mitchell ME, Tomita-Mitchell A, Prakash SK, Stamm K, Stewart AFR, Silversides CK, Siebert R, Stiller B, Rosenfeld JA, Vater I, Postma AV, Caliebe A, Brook JD, Andelfinger G, Hurles ME, Thienpont B, Larsen LA, Hitz MP

Authors

Michael Edward Mitchell MD Chief, Professor in the Surgery department at Medical College of Wisconsin
Aoy Tomita Mitchell PhD Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

DNA Copy Number Variations
Databases, Genetic
Gene Expression
Gene Expression Profiling
Genetic Predisposition to Disease
Genomics
Haploinsufficiency
Heart Defects, Congenital
Humans
Ion Channels
Membrane Proteins
Polymorphism, Single Nucleotide
Transcriptome