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

Ilse Meerschaut, Wouter Steyaert, Thierry Bové, Katrien François, Thomas Martens, Katya De Groote, Hans De Wilde, Laura Muiño Mosquera, Joseph Panzer, Kristof Vandekerckhove, Lara Moons, Petra Vermassen, Sofie Symoens, Paul J. Coucke, Daniël De Wolf, Bert Callewaert

Onderzoeksoutput: Articlepeer review

2 Citaten (Scopus)
26 Downloads (Pure)


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.
Originele taal-2English
Pagina's (van-tot)1-12
Aantal pagina's12
Nummer van het tijdschrift7
StatusPublished - 7 jul 2022

Bibliografische nota

Funding Information:
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.

Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.

Copyright 2022 Elsevier B.V., All rights reserved.


Duik in de onderzoeksthema's van 'Exploring the Mutational Landscape of Isolated Congenital Heart Defects: An Exome Sequencing Study Using Cardiac DNA'. Samen vormen ze een unieke vingerafdruk.

Citeer dit