title: Family Based Whole Exome Sequencing Reveals the Multifaceted Role of Notch Signaling in Congenital Heart Disease.
abstract: 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.
authors.affiliation: Cardiovascular Genetics, Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Montreal, Québec, Canada.
authors.forename: Christoph
authors.initials: C
authors.lastname: Preuss
authors.affiliation: Cardiovascular Genetics, Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Montreal, Québec, Canada.
authors.forename: Melanie
authors.initials: M
authors.lastname: Capredon
authors.affiliation: Cardiovascular Genetics, Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Montreal, Québec, Canada.|Faculty of Biology, University of Muenster, Muenster, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Wünnemann
authors.affiliation: Department of Pediatrics, Centre Mère Enfants Soleil, Centre Hospitalier de l'Université (CHU) de Québec, Quebec City, Québec, Canada.
authors.forename: Philippe
authors.initials: P
authors.lastname: Chetaille
authors.affiliation: Cardiovascular Genetics, Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Montreal, Québec, Canada.
authors.forename: Andrea
authors.initials: A
authors.lastname: Prince
authors.affiliation: Omics-Ethics Research Group, Research Institute of Public Health, Université de Montréal, Montréal Québec, Canada.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Godard
authors.affiliation: Cardiovascular Genetics, Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Montreal, Québec, Canada.
authors.forename: Severine
authors.initials: S
authors.lastname: Leclerc
authors.affiliation: McKusick Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Nara
authors.initials: N
authors.lastname: Sobreira
authors.affiliation: McKusick Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Hua
authors.initials: H
authors.lastname: Ling
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: Philip
authors.initials: P
authors.lastname: Awadalla
authors.affiliation: Cardiovascular Genetics, Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Montreal, Québec, Canada.
authors.forename: Maryse
authors.initials: M
authors.lastname: Thibeault
authors.affiliation: Montreal Heart Institute, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Paul
authors.initials: P
authors.lastname: Khairy
authors.affiliation: Centre de Recherche CHU Sainte Justine, Université de Montreal, Montréal, Québec, Canada.|Department of Medicine, Université de Montreal, Montréal, Québec, Canada.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Samuels
authors.affiliation: Cardiovascular Genetics, Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Montreal, Québec, Canada.
authors.forename: Gregor
authors.initials: G
authors.lastname: Andelfinger
mesh_terms: D001021:Aortic Valve / Q000503:physiopathology; D018389:Codon, Nonsense; D003251:Constriction, Pathologic / Q000235:genetics* / Q000503:physiopathology; D059472:Exome / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D008040:Genetic Linkage; D015894:Genome, Human; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D008297:Male; D010375:Pedigree; D051881:Receptor, Notch1 / Q000235:genetics*; D051880:Receptors, Notch / Q000235:genetics; D017384:Sequence Deletion; D015398:Signal Transduction / Q000235:genetics; D014694:Ventricular Outflow Obstruction / Q000235:genetics* / Q000503:physiopathology
chemical_list: D018389:Codon, Nonsense; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D051880:Receptors, Notch