Mutational Screening of NOTCH3 Gene Reveals Two Novel Mutations: Complexity of CADASIL Diagnosis

Cerebral autosomal dominant arteriopathywith sub- cortical infarcts and leukoencephalopathy (CADASIL) is an adult onset hereditary vascular disease with neurological man- ifestations. The classical clinical course is relentlessly progres- sive with early transient ischaemic attacks (TIA) or strokes, dementia and finally death in the mid-1960s. The disorder is inherited in an autosomal dominant fashion, with high pene- trance and broad variable clinical course even within family. It is caused by mutations in the NOTCH3 gene; all causative mutations result in gain or loss of a cysteine residue within the extracellular domain, with exons 3 and 4 reported as hot spot mutational sites. Mutation analysis of the NOTCH3 gene was performed through direct sequencing of the 2-23 exons con- taining all EGF-like domains. Patients underwent genetic counselling pre and post testing. Here, we report two novel mutations located in exons 6 and 15 of the NOTCH3 gene; clinical description for the probands and for available relatives is enclosed. No reliable data onincidence or prevalence rates of this disease are available: it is therefore essential that the diagnosis is obtained in all suspected cases through the exten- sive analysis of the NOTCH3 gene and that all cases are brought to the attention of the scientific community.