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

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 co...

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Autores principales: Meerschaut, Ilse, Steyaert, Wouter, Bové, Thierry, François, Katrien, Martens, Thomas, De Groote, Katya, De Wilde, Hans, Muiño Mosquera, Laura, Panzer, Joseph, Vandekerckhove, Kristof, Moons, Lara, Vermassen, Petra, Symoens, Sofie, Coucke, Paul J., De Wolf, Daniël, Callewaert, Bert
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9320903/
https://www.ncbi.nlm.nih.gov/pubmed/35885997
http://dx.doi.org/10.3390/genes13071214
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author Meerschaut, Ilse
Steyaert, Wouter
Bové, Thierry
François, Katrien
Martens, Thomas
De Groote, Katya
De Wilde, Hans
Muiño Mosquera, Laura
Panzer, Joseph
Vandekerckhove, Kristof
Moons, Lara
Vermassen, Petra
Symoens, Sofie
Coucke, Paul J.
De Wolf, Daniël
Callewaert, Bert
author_facet Meerschaut, Ilse
Steyaert, Wouter
Bové, Thierry
François, Katrien
Martens, Thomas
De Groote, Katya
De Wilde, Hans
Muiño Mosquera, Laura
Panzer, Joseph
Vandekerckhove, Kristof
Moons, Lara
Vermassen, Petra
Symoens, Sofie
Coucke, Paul J.
De Wolf, Daniël
Callewaert, Bert
author_sort Meerschaut, Ilse
collection PubMed
description 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.
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spelling pubmed-93209032022-07-27 Exploring the Mutational Landscape of Isolated Congenital Heart Defects: An Exome Sequencing Study Using Cardiac DNA Meerschaut, Ilse Steyaert, Wouter Bové, Thierry François, Katrien Martens, Thomas De Groote, Katya De Wilde, Hans Muiño Mosquera, Laura Panzer, Joseph Vandekerckhove, Kristof Moons, Lara Vermassen, Petra Symoens, Sofie Coucke, Paul J. De Wolf, Daniël Callewaert, Bert Genes (Basel) Article 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. MDPI 2022-07-07 /pmc/articles/PMC9320903/ /pubmed/35885997 http://dx.doi.org/10.3390/genes13071214 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Meerschaut, Ilse
Steyaert, Wouter
Bové, Thierry
François, Katrien
Martens, Thomas
De Groote, Katya
De Wilde, Hans
Muiño Mosquera, Laura
Panzer, Joseph
Vandekerckhove, Kristof
Moons, Lara
Vermassen, Petra
Symoens, Sofie
Coucke, Paul J.
De Wolf, Daniël
Callewaert, Bert
Exploring the Mutational Landscape of Isolated Congenital Heart Defects: An Exome Sequencing Study Using Cardiac DNA
title Exploring the Mutational Landscape of Isolated Congenital Heart Defects: An Exome Sequencing Study Using Cardiac DNA
title_full Exploring the Mutational Landscape of Isolated Congenital Heart Defects: An Exome Sequencing Study Using Cardiac DNA
title_fullStr Exploring the Mutational Landscape of Isolated Congenital Heart Defects: An Exome Sequencing Study Using Cardiac DNA
title_full_unstemmed Exploring the Mutational Landscape of Isolated Congenital Heart Defects: An Exome Sequencing Study Using Cardiac DNA
title_short Exploring the Mutational Landscape of Isolated Congenital Heart Defects: An Exome Sequencing Study Using Cardiac DNA
title_sort exploring the mutational landscape of isolated congenital heart defects: an exome sequencing study using cardiac dna
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9320903/
https://www.ncbi.nlm.nih.gov/pubmed/35885997
http://dx.doi.org/10.3390/genes13071214
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