The diagnostic value of next generation sequencing in familial nonsyndromic congenital heart defects.
To determine the diagnostic value of massive parallel sequencing of a panel of known cardiac genes in familial nonsyndromic congenital heart defects (CHD), targeted sequencing of the coding regions of 57 genes previously implicated in CHD was performed in 36 patients from 13 nonsyndromic CHD families with probable autosomal dominant inheritance. Following variant analysis and Sanger validation, we identified six potential disease causing variants in three genes (MYH6, NOTCH1, and TBX5), which may explain the defects in six families. Several problematic situations were encountered when performing genotype-phenotype correlations in the families to confirm the causality of these variants. In conclusion, by screening known CHD-associated genes in well-selected nonsyndromic CHD families and cautious variant interpretation, potential causative variants were identified in less than half of the families (6 out of 13; 46%). Variant interpretation remains a major challenge reflecting the complex genetic cause of CHD.
Department of Human Genetics, KU Leuven, Leuven, Belgium.
Yaojuan
Y
Jia
Department of Human Genetics, KU Leuven, Leuven, Belgium.|Department of Congenital and Pediatric Cardiology, University Hospitals Leuven, Leuven, Belgium.
Jacoba J
JJ
Louw
Department of Human Genetics, KU Leuven, Leuven, Belgium.|Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium.
Jeroen
J
Breckpot
Center for Medical Genetics, University of Ghent, Ghent, Belgium.
Bert
B
Callewaert
Department of Congenital and Pediatric Cardiology, Universit, é, Catholique de Louvain, Brussels, Belgium.
Catherine
C
Barrea
Center for Human Genetics, Université Catholique de Louvain, Brussels, Belgium.
Yves
Y
Sznajer
Department of Congenital and Pediatric Cardiology, University Hospitals Leuven, Leuven, Belgium.
Marc
M
Gewillig
Department of Human Genetics, KU Leuven, Leuven, Belgium.
Erika
E
Souche
Department of Human Genetics, KU Leuven, Leuven, Belgium.
Luc
L
Dehaspe
Department of Human Genetics, KU Leuven, Leuven, Belgium.
Joris Robert
JR
Vermeesch
Department of Oncology, KU Leuven, Leuven, Belgium.|Vesalius Research Center, VIB, Leuven, Belgium.
Diether
D
Lambrechts
Department of Human Genetics, KU Leuven, Leuven, Belgium.
Koenraad
K
Devriendt
Department of Human Genetics, KU Leuven, Leuven, Belgium.
Anniek
A
Corveleyn
D005260:Female; D006330:Heart Defects, Congenital / Q000175:diagnosis* / Q000235:genetics; D006801:Humans; D008297:Male; D010375:Pedigree
congenital heart defects; genetic testing; massive parallel sequencing