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.
Highlights
Sneddon syndrome (SS) is a rare disorder, affecting mainly young and predominately female adults [1,2]
A NOTCH3 null mutation was identified in another unrelated patient with similar clinical and MRI features, as well as childhoodonset, originally diagnosed with SS [12,13]
These three patients with SS and a NOTCH3 null mutation exhibit clinical and neuroimaging features that share similarities with those observed in CADASIL patients, we believe that this genetic form of SS and CADASIL are two distinct entities
Summary
Sneddon syndrome (SS) is a rare disorder (about 4 patients per million), affecting mainly young and predominately female adults [1,2]. It is characterized by recurrent strokes and livedo reticularis, a violaceous, netlike patterning of the skin [3]. 11 Institute of Human Genetics, Technical University Munich, Munich, Germany. One explanatory model proposes that the presence of antiphospholipid antibodies might point towards a thrombotic process causing the disease whereas skin biopsies of antibody negative patients suggest a primary inflammatory process with migration and proliferation of smooth muscle cells leading to the narrowing and occlusion of the vessel [3,8]. A homozygous NOTCH3 nonsense mutation was identified in a patient who exhibited livedo reticularis from birth and childhood-onset cavitating leukoencephalopathy with multiple deep lacunar infarcts, disseminated microbleeds and two saccular aneurysms of middle cerebral arteries [12,13]
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