Expanding the phenotypic spectrum of NOTCH1 variants: clinical manifestations in families with congenital heart disease

Abstract

Pathogenic variants in NOTCH1 are associated with non-syndromic congenital heart disease (CHD) and Adams-Oliver syndrome (AOS). The clinical presentation of individuals with damaging NOTCH1 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 2.5-68.3 years) from 11 families with causative NOTCH1 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 NOTCH1-associated CHD and NOTCH1-associated AOS lying on a phenotypic continuum. Our findings also support (1) Broad indications for NOTCH1 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 NOTCH1 variants in the CHD population.

Fig. 1. Pedigree structures of families with identified NOTCH1 variants, ascertained through a proband with congenital heart disease.

A–K are labeled for the family name referenced in the text (e.g., Family A is depicted in (A)). Probands are marked by a black arrow. The genetic status of all 47 individuals who had genetic testing is included, with “+” denoting the NOTCH1 wildtype allele and “−” denoting the NOTCH1 variant allele. Individuals shaded in solid black had clinically known, structural cardiac disease (confirmed by review of echocardiogram where possible). Individuals shaded in hatched grey had extracardiac vascular features.

Fig. 2. Images depicting the extracardiac features of select individuals with NOTCH1 variants.

A Cutaneous vascular malformation on the lower back of individual B-II:1. B Cutaneous vascular malformation on the forearm of individual C-I:2. C Toe brachydactyly and hypoplastic nails on individual H-III:1. D Cutis aplasia on the scalp of individual H-II:2. E Cutis aplasia on the scalp of individual H-III:3.

Fig. 3. The extracardiac phenotype of individuals with a clinically relevant NOTCH1 variant, based on results from the cohort studied.

Features include cutis aplasia involving the scalp, structural brain anomalies, intracranial/posterior circulation vascular anomalies, portal vein hypoplasia, cutaneous vascular malformations (including cutis marmorata), and limb anomalies.