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Loss of function, missense, and intronic variants in NOTCH1 confer different risks for left ventricular outflow tract obstructive heart defects in two European cohorts

By Emmi Helle, Aldo Córdova-Palomera, Tiina Ojala, Priyanka Saha, Praneetha Potiny, Stefan Gustafsson, Erik Ingelsson, Michael Bamshad, Deborah Nickerson, Jessica X. Chong, University of Washington Center for Mendelian Genomics, Euan Ashley, James R. Priest

Posted 07 Nov 2017
bioRxiv DOI: 10.1101/215301 (published DOI: 10.1002/gepi.22176)

Loss of function variants in NOTCH1 cause left ventricular outflow tract obstructive defects (LVOTO) in a small percentage of families. Clinical surveys report an increased prevalence of missense variants in NOTCH1 in family members of individuals with LVOTO and other types of congenital heart disease (CHD). However, the risk conferred by rare variants in NOTCH1 for LVOTO remains largely uncharacterized. In a cohort of 49 families affected by hypoplastic left heart syndrome, a severe form of LVOTO, we discovered predicted loss of function NOTCH1 variants in 6% of individuals. Rare missense variants were found in an additional 16% of families. To make a quantitative estimate of the genetic risk posed by variants in NOTCH1 for LVOTO, we studied associations of 400 coding and non-coding variants in NOTCH1 in 271 adult cases and 333,571 controls from the UK Biobank. Two rare intronic variants in strong linkage disequilibrium displayed significant association with risk for LVOTO (g.chr9:139427582C>T, Odds Ratio 16.9, p=3.12e-6; g.chr9:139435649C>T, Odds Ratio 19.6, p = 2.44e-6) amongst European-ancestry British individuals. This result was replicated in an independent analysis of 51 cases and 68,901 controls of non-European and mixed ancestry. We conclude that carrying rare predicted loss of function variants or either of two intronic variants in NOTCH1 confer significant risk for LVOTO. Our approach demonstrates the utility of population-based datasets in quantifying the specific risk of individual variants for disease related phenotypes.

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