Exploring the Mutational Landscape of Isolated Congenital Heart Defects: An Exome Sequencing Study Using Cardiac DNA
| Autor: | 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 |
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| Přispěvatelé: | Pediatrics, Clinical sciences |
| Rok vydání: | 2022 |
| Předmět: |
SPORADIC TETRALOGY
Heart Defects Congenital somatic variation GENETICS polygenic inheritance SOMATIC NKX2-5 MUTATIONS DISEASE transmission disequilibrium testing All institutes and research themes of the Radboud University Medical Center CILIA Exome Sequencing Medicine and Health Sciences Genetics Humans oligogenic inheritance Exome Child Genetics (clinical) Biology and Life Sciences congenital heart defects exome sequencing association testing Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] DNA FALLOT FRAMEWORK FAMILY MORPHOGENESIS Mutation HAND1 |
| Zdroj: | Genes; Volume 13; Issue 7; Pages: 1214 GENES Genes, 13, 7 Genes, 13 |
| ISSN: | 2073-4425 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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