Exploring the Mutational Landscape of Isolated Congenital Heart Defects: An Exome Sequencing Study Using Cardiac DNA

Genes (Basel). 2022 Jul 7;13(7):1214. doi: 10.3390/genes13071214.

Abstract

Congenital heart defects (CHD) are the most common congenital anomalies in liveborn children. In contrast to syndromic CHD (SCHD), the genetic basis of isolated CHD (ICHD) is complex, and the underlying pathogenic mechanisms appear intricate and are incompletely understood. Next to rare Mendelian conditions, somatic mosaicism or a complex multifactorial genetic architecture are assumed for most ICHD. We performed exome sequencing (ES) in 73 parent-offspring ICHD trios using proband DNA extracted from cardiac tissue. We identified six germline de novo variants and 625 germline rare inherited variants with 'damaging' in silico predictions in cardiac-relevant genes expressed in the developing human heart. There were no CHD-relevant somatic variants. Transmission disequilibrium testing (TDT) and association testing (AT) yielded no statistically significant results, except for the AT of missense variants in cilia genes. Somatic mutations are not a common cause of ICHD. Rare de novo and inherited protein-damaging variants may contribute to ICHD, possibly as part of an oligogenic or polygenic disease model. TDT and AT failed to provide informative results, likely due to the lack of power, but provided a framework for future studies in larger cohorts. Overall, the diagnostic value of ES on cardiac tissue is limited in individual ICHD cases.

Keywords: association testing; congenital heart defects; exome sequencing; oligogenic inheritance; polygenic inheritance; somatic variation; transmission disequilibrium testing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Child
  • DNA
  • Exome Sequencing
  • Exome* / genetics
  • Heart Defects, Congenital* / diagnosis
  • Heart Defects, Congenital* / genetics
  • Humans
  • Mutation

Substances

  • DNA

Grants and funding

This project was funded by the Research Foundation Flanders (FWO) (grant G028415N) and the Ghent University Methusalem grant to Anne De Paepe (grant BOFMET2015000401). B.C. is a senior clinical investigator of the Research Foundation Flanders (FWO). The computational resources (Stevin Supercomputer Infrastructure) and services used in this work were provided by the VSC (Flemish Supercomputer Center), funded by Ghent University, FWO, and the Flemish Government—department EWI.