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RRC is a Rogers\u2019 Innovator in Congenital Heart Disease.","id":[{"id":"https:\/\/ror.org\/00cgnj660","id-type":"ROR","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000024","name":"Gouvernement du Canada | Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["161429"],"award-info":[{"award-number":["161429"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004411","name":"Heart and Stroke Foundation of Canada","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004411","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Eur J Hum Genet"],"published-print":{"date-parts":[[2024,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Pathogenic variants in\n                    <jats:italic>NOTCH1<\/jats:italic>\n                    are associated with non-syndromic congenital heart disease (CHD) and Adams\u2013Oliver syndrome (AOS). The clinical presentation of individuals with damaging\n                    <jats:italic>NOTCH1<\/jats:italic>\n                    variants is characterized by variable expressivity and incomplete penetrance; however, data on systematic phenotypic characterization are limited. We report the genotype and phenotype of a cohort of 33 individuals (20 females, 13 males; median age 23.4 years, range 2.5\u201368.3 years) from 11 families with causative\n                    <jats:italic>NOTCH1<\/jats:italic>\n                    variants (9 inherited, 2 de novo; 9 novel), ascertained from a proband with CHD. We describe the cardiac and extracardiac anomalies identified in these 33 individuals, only four of whom met criteria for AOS. The most common CHD identified was tetralogy of Fallot, though various left- and right-sided lesions and septal defects were also present. Extracardiac anomalies identified include cutis aplasia (5\/33), cutaneous vascular anomalies (7\/33), vascular anomalies of the central nervous system (2\/10), Poland anomaly (1\/33), pulmonary hypertension (2\/33), and structural brain anomalies (3\/14). Identification of these findings in a cardiac proband cohort supports\n                    <jats:italic>NOTCH1<\/jats:italic>\n                    -associated CHD and\n                    <jats:italic>NOTCH1<\/jats:italic>\n                    -associated AOS lying on a phenotypic continuum. Our findings also support (1) Broad indications for\n                    <jats:italic>NOTCH1<\/jats:italic>\n                    molecular testing (any familial CHD, simplex tetralogy of Fallot or hypoplastic left heart); (2) Cascade testing in all at-risk relatives; and (3) A thorough physical exam, in addition to cardiac, brain (structural and vascular), abdominal, and ophthalmologic imaging, in all gene-positive individuals. This information is important for guiding the medical management of these individuals, particularly given the high prevalence of\n                    <jats:italic>NOTCH1<\/jats:italic>\n                    variants in the CHD population.\n                  <\/jats:p>","DOI":"10.1038\/s41431-024-01629-4","type":"journal-article","created":{"date-parts":[[2024,5,22]],"date-time":"2024-05-22T14:02:18Z","timestamp":1716386538000},"page":"795-803","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Expanding the phenotypic spectrum of NOTCH1 variants: clinical manifestations in families with congenital heart disease"],"prefix":"10.1038","volume":"32","author":[{"given":"Kaitlin J.","family":"Stanley","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelsey J.","family":"Kalbfleisch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8134-8345","authenticated-orcid":false,"given":"Olivia M.","family":"Moran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajiv R.","family":"Chaturvedi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maian","family":"Roifman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1871-4477","authenticated-orcid":false,"given":"Xin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roozbeh","family":"Manshaei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Martin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simina","family":"McDermott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanda","family":"McNiven","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane","family":"Myles-Reid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lynne E.","family":"Nield","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam S.","family":"Reuter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7643-0862","authenticated-orcid":false,"given":"Marci L. 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Dr. Mital serves on the Advisory Board of Bristol Myers Squibb and Tenaya Therapeutics.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"This study was approved by the Research Ethics Board at The Hospital for Sick Children (SickKids), Toronto, Ontario, Canada (REB# 1000053844) and the University Health Network, Toronto, Ontario Canada (REB# 16-6282).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}}]}}