A NOTCH3 homozygous nonsense mutation in familial Sneddon syndrome with pediatric stroke
Elli K. Greisenegger, Sara Llufriú, Ángel Chamorro, Álvaro Cervera, Adriano Jiménez‐Escrig, Klemens Rappersberger, Wolfgang Marik, Stefan Greisenegger, Elisabeth Stögmann, Tamara Kopp, Tim M. Strom, Jörg Henes, Anne Joutel, Alexander Zimprich
Abstract
Sneddon syndrome is a rare disorder affecting small and medium-sized blood vessels that is characterized by the association of livedo reticularis and stroke. We performed whole-exome sequencing (WES) in 2 affected siblings of a consanguineous family with childhood-onset stroke and identified a homozygous nonsense mutation within the epidermal growth factor repeat (EGFr) 19 of NOTCH3, p.(Arg735Ter). WES of 6 additional cases with adult-onset stroke revealed 2 patients carrying heterozygous loss-of-function variants in putative NOTCH3 downstream genes, ANGPTL4, and PALLD. Our findings suggest that impaired NOTCH3 signaling is one underlying disease mechanism and that bi-allelic loss-of-function mutation in NOTCH3 is a cause of familial Sneddon syndrome with pediatric stroke.