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Article

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

1
Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium
2
Department of Pediatric Cardiology, Ghent University Hospital, 9000 Ghent, Belgium
3
Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
4
Department of Cardiac Surgery, Ghent University Hospital, 9000 Ghent, Belgium
5
Department of Pediatric Cardiology, Brussels University Hospital, 1090 Brussels, Belgium
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editors: Andreas Brodehl, Hendrik Milting and Brenda Gerull
Genes 2022, 13(7), 1214; https://doi.org/10.3390/genes13071214
Received: 12 June 2022 / Revised: 2 July 2022 / Accepted: 4 July 2022 / Published: 7 July 2022
(This article belongs to the Special Issue Recent Advance in Cardiovascular Genetics)
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. View Full-Text
Keywords: congenital heart defects; exome sequencing; somatic variation; oligogenic inheritance; polygenic inheritance; transmission disequilibrium testing; association testing congenital heart defects; exome sequencing; somatic variation; oligogenic inheritance; polygenic inheritance; transmission disequilibrium testing; association testing
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MDPI and ACS Style

Meerschaut, I.; Steyaert, W.; Bové, T.; François, K.; Martens, T.; De Groote, K.; De Wilde, H.; Muiño Mosquera, L.; Panzer, J.; Vandekerckhove, K.; Moons, L.; Vermassen, P.; Symoens, S.; Coucke, P.J.; De Wolf, D.; Callewaert, B. Exploring the Mutational Landscape of Isolated Congenital Heart Defects: An Exome Sequencing Study Using Cardiac DNA. Genes 2022, 13, 1214. https://doi.org/10.3390/genes13071214

AMA Style

Meerschaut I, Steyaert W, Bové T, François K, Martens T, De Groote K, De Wilde H, Muiño Mosquera L, Panzer J, Vandekerckhove K, Moons L, Vermassen P, Symoens S, Coucke PJ, De Wolf D, Callewaert B. Exploring the Mutational Landscape of Isolated Congenital Heart Defects: An Exome Sequencing Study Using Cardiac DNA. Genes. 2022; 13(7):1214. https://doi.org/10.3390/genes13071214

Chicago/Turabian Style

Meerschaut, Ilse, 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, and Bert Callewaert. 2022. "Exploring the Mutational Landscape of Isolated Congenital Heart Defects: An Exome Sequencing Study Using Cardiac DNA" Genes 13, no. 7: 1214. https://doi.org/10.3390/genes13071214

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