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However, the risk conferred by rare and noncoding variants in\n                    <jats:italic>NOTCH1<\/jats:italic>\n                    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\n                    <jats:italic>NOTCH1<\/jats:italic>\n                    variants in 6% of individuals. Rare or low\u2010frequency missense variants were found in 16% of families. To make a quantitative estimate of the genetic risk posed by variants in\n                    <jats:italic>NOTCH1<\/jats:italic>\n                    for LVOTO, we studied associations of 400 coding and noncoding variants in\n                    <jats:italic>NOTCH1<\/jats:italic>\n                    in 1,085 cases and 332,788 controls from the UK Biobank. Two rare intronic variants in strong linkage disequilibrium displayed significant association with risk for LVOTO amongst European\u2010ancestry individuals. This result was replicated in an independent analysis of 210 cases and 68,762 controls of non\u2010European and mixed ancestry. In conclusion, carrying rare predicted loss of function variants in\n                    <jats:italic>NOTCH1<\/jats:italic>\n                    confer significant risk for LVOTO. In addition, the two intronic variants seem to be associated with an increased risk for these defects. Our approach demonstrates the utility of population\u2010based data sets in quantifying the specific risk of individual variants for disease\u2010related phenotypes.\n                  <\/jats:p>","DOI":"10.1002\/gepi.22176","type":"journal-article","created":{"date-parts":[[2018,12,4]],"date-time":"2018-12-04T04:34:35Z","timestamp":1543898075000},"page":"215-226","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Loss of function, missense, and intronic variants in\n                    <i>NOTCH1<\/i>\n                    confer different risks for left ventricular outflow tract obstructive heart defects in two European cohorts"],"prefix":"10.1002","volume":"43","author":[{"given":"Emmi","family":"Helle","sequence":"first","affiliation":[{"name":"Pediatric Research Center Children's Hospital, University of Helsinki Helsinki Finland"},{"name":"Division of Cardiovascular Medicine Cardiovascular Medicine, Stanford University School of Medicine Stanford CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aldo","family":"C\u00f3rdova\u2010Palomera","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Division of Pediatric Cardiology, Stanford University School of Medicine Stanford CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiina","family":"Ojala","sequence":"additional","affiliation":[{"name":"Pediatric Research Center Children's Hospital, University of Helsinki Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priyanka","family":"Saha","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Division of Pediatric Cardiology, Stanford University School of Medicine Stanford CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Praneetha","family":"Potiny","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Division of Pediatric Cardiology, Stanford University School of Medicine Stanford CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Gustafsson","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences Molecular Epidemiology and Science for Life Laboratory, Uppsala University Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"Ingelsson","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine Cardiovascular Medicine, Stanford University School of Medicine Stanford CA"},{"name":"Department of Medical Sciences Molecular Epidemiology and Science for Life Laboratory, Uppsala University Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Bamshad","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of Washington Seattle WA"},{"name":"Department of Genome Sciences University of Washington Seattle WA"},{"name":"Division of Genetic Medicine Seattle Children's Hospital Seattle Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah","family":"Nickerson","sequence":"additional","affiliation":[{"name":"Department of Genome Sciences University of Washington Seattle WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica X.","family":"Chong","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of Washington Seattle WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"University of Washington Center for Mendelian Genomics","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Euan","family":"Ashley","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine Cardiovascular Medicine, Stanford University School of Medicine Stanford CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8349-4784","authenticated-orcid":false,"given":"James R.","family":"Priest","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine Cardiovascular Medicine, Stanford University School of Medicine Stanford CA"},{"name":"Department of Pediatrics Division of Pediatric Cardiology, Stanford University School of Medicine Stanford CA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,12,4]]},"reference":[{"key":"e_1_2_6_1_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.11.033"},{"key":"e_1_2_6_1_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22717"},{"key":"e_1_2_6_1_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2014.09.048"},{"key":"e_1_2_6_1_5_1","doi-asserted-by":"crossref","unstructured":"Bycroft C. 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