ClinVar

In a female proband of European and Asian ancestry with Adams-Oliver syndrome-5 (AOS5; 616028), Stittrich et al. (2014) identified heterozygosity for a de novo c.4487G-A transition (chr9:139,399,861; GRCh37) in the NOTCH1 gene, resulting in a cys1496-to-tyr (C1496Y) substitution at a highly conserved residue within the extracellular negative regulatory region (NRR) of the second Lin-12 NOTCH repeat (LNR) domain. Stittrich et al. (2014) noted that the NRR sterically inhibits processing of NOTCH1 in the absence of ligand stimulation; thus, destabilization of this domain could increase constitutive Notch signaling and result in a gain of function. The mutation was not found in the proband's unaffected parents or in more than 10,000 control genomes or exomes. The patient was born with severe aplasia cutis affecting most of the scalp superior to the ears as well as the posterior neck. She had bilateral prominent tortuous scalp vessels, truncal cutis marmorata, and bilateral toe hypoplasia with absent toenails. Neuroimaging at day 1 of life showed small focal areas of bilateral parietal and left frontal white matter acute infarction and partial superior sagittal sinus thrombosis; repeat imaging at 1 week showed evolving biparietal and left frontal lobe infarcts, near-complete sagittal sinus thrombosis, and biparietal cortical venous thromboses, with stabilization and improvement over the next several months. She also had mild mitral valve annulus hypoplasia and multiperforated patent foramen ovale with insignificant shunting; severe pulmonary hypertension on day 1 of life resolved by day 10.