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PLoS Genet. 2016 Oct 19;12(10):e1006335. doi: 10.1371/journal.pgen.1006335. eCollection 2016 Oct.

Family Based Whole Exome Sequencing Reveals the Multifaceted Role of Notch Signaling in Congenital Heart Disease.

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Cardiovascular Genetics, Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Montreal, Québec, Canada.
Faculty of Biology, University of Muenster, Muenster, Germany.
Department of Pediatrics, Centre Mère Enfants Soleil, Centre Hospitalier de l'Université (CHU) de Québec, Quebec City, Québec, Canada.
Omics-Ethics Research Group, Research Institute of Public Health, Université de Montréal, Montréal Québec, Canada.
McKusick Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
Montreal Heart Institute, Université de Montréal, Montréal, Québec, Canada.
Centre de Recherche CHU Sainte Justine, Université de Montreal, Montréal, Québec, Canada.
Department of Medicine, Université de Montreal, Montréal, Québec, Canada.


Left-ventricular outflow tract obstructions (LVOTO) encompass a wide spectrum of phenotypically heterogeneous heart malformations which frequently cluster in families. We performed family based whole-exome and targeted re-sequencing on 182 individuals from 51 families with multiple affected members. Central to our approach is the family unit which serves as a reference to identify causal genotype-phenotype correlations. Screening a multitude of 10 overlapping phenotypes revealed disease associated and co-segregating variants in 12 families. These rare or novel protein altering mutations cluster predominantly in genes (NOTCH1, ARHGAP31, MAML1, SMARCA4, JARID2, JAG1) along the Notch signaling cascade. This is in line with a significant enrichment (Wilcoxon, p< 0.05) of variants with a higher pathogenicity in the Notch signaling pathway in patients compared to controls. The significant enrichment of novel protein truncating and missense mutations in NOTCH1 highlights the allelic and phenotypic heterogeneity in our pediatric cohort. We identified novel co-segregating pathogenic mutations in NOTCH1 associated with left and right-sided cardiac malformations in three independent families with a total of 15 affected individuals. In summary, our results suggest that a small but highly pathogenic fraction of family specific mutations along the Notch cascade are a common cause of LVOTO.

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