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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.

Cerebral Cavernous Malformations (CCM/MIM 604214) are vascular malformations characterised by abnormally enlarged capillary cavities without intervening brain parenchyma. Clinical manifestations include seizures, cerebral haemorrhages and focal neurological deficits. They occur as a sporadic or autosomal dominant condition. Most often, sporadic cases have only one lesion and familial cases are characterised by a high frequency of multiple lesions. Three CCM loci were previously mapped on 7q (CCM1), 7p (CCM2) and 3q (CCM3) and CCM1 gene was identified as coding Krit1, a protein of unknown function, which was shown initially to interact in yeast two hybrid assays with Rap1A, a small ras GTPase and more recently to Icap1alpha, a modulator of beta1 integrin signal transduction. Herein, we screened KRIT1 gene in 121 unrelated, consecutively recruited, CCM probands having at least one affected relative and/or showing multiple lesions on cerebral MRI. Fifty-two of these probands (43%) were shown to carry a KRIT1 mutation. Forty-two distinct mutations were identified including six recurrent ones. Three-quarters of these mutations were located in the C-terminal half of the gene, mostly within exons 13, 15 and 17. All of them are predicted to lead to a premature stop codon. No missense mutation was identified. The only two nucleotide substitutions predicted to be missense mutations led in fact to an abnormal splicing and a premature stop codon. Altogether these data suggest that KRIT1 mRNA decay due to the presence of premature stop codons and Krit1 haploinsufficiency may be the underlying mechanism of CCM.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) has been recently reported as a cause of stroke. It is characterized, in the absence of hypertension, by recurrent subcortical ischaemic strokes, starting in early or midadulthood and leading in some patients to dementia. Magnetic resonance imaging and pathological examination show numerous small subcortical infarcts and a diffuse leukoencephalopathy underlaid by a non-arteriosclerotic, non-amyloid angiopathy. We performed genetic linkage analysis in two unrelated families and assigned the disease locus to chromosome 19q12. Multilocus analysis with the location scores method established the best estimate for the location of the affected gene within a 14 centimorgan interval bracketed by D19S221 and D19S222 loci.