학술논문
Expanding the phenotypic spectrum of NOTCH1variants: clinical manifestations in families with congenital heart disease
Document Type
Article
Author
Stanley, Kaitlin J.; Kalbfleisch, Kelsey J.; Moran, Olivia M.; Chaturvedi, Rajiv R.; Roifman, Maian; Chen, Xin; Manshaei, Roozbeh; Martin, Nicole; McDermott, Simina; McNiven, Vanda; Myles-Reid, Diane; Nield, Lynne E.; Reuter, Miriam S.; Schwartz, Marci L. B.; Shannon, Patrick; Silver, Rachel; Somerville, Cherith; Teitelbaum, Ronni; Zahavich, Laura; Bassett, Anne S.; Kim, Raymond H.; Mital, Seema; Chitayat, David; Jobling, Rebekah K.
Source
European Journal of Human Genetics: EJHG; July 2024, Vol. 32 Issue: 7 p795-803, 9p
Subject
Language
ISSN
10184813; 14765438
Abstract
Pathogenic variants in NOTCH1are associated with non-syndromic congenital heart disease (CHD) and Adams–Oliver syndrome (AOS). The clinical presentation of individuals with damaging NOTCH1variants 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 2.5–68.3 years) from 11 families with causative NOTCH1variants (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 NOTCH1-associated CHD and NOTCH1-associated AOS lying on a phenotypic continuum. Our findings also support (1) Broad indications for NOTCH1molecular 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 NOTCH1variants in the CHD population.