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

TitleFamily Based Whole Exome Sequencing Reveals the Multifaceted Role of Notch Signaling in Congenital Heart Disease.
Publication TypeJournal Article
Year of Publication2016
AuthorsPreuss, C, Capredon, M, Wünnemann, F, Chetaille, P, Prince, A, Godard, B, Leclerc, S, Sobreira, N, Ling, H, Awadalla, P, Thibeault, M, Khairy, P, Samuels, ME, Andelfinger, G
Corporate AuthorsMIBAVA Leducq consortium
JournalPLoS Genet
Volume12
Issue10
Paginatione1006335
Date Published2016 Oct
ISSN1553-7404
KeywordsAortic Valve, Codon, Nonsense, Constriction, Pathologic, Exome, Female, Genetic Association Studies, Genetic Linkage, Genome, Human, Heart Defects, Congenital, Humans, Male, Pedigree, Receptor, Notch1, Receptors, Notch, Sequence Deletion, Signal Transduction, Ventricular Outflow Obstruction
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

DOI10.1371/journal.pgen.1006335
Alternate JournalPLoS Genet.
PubMed ID27760138
PubMed Central IDPMC5070860
Grant ListU54 HG006542 / HG / NHGRI NIH HHS / United States