Spectrum of mutations in biopsy-proven CADASIL: implications for diagnostic strategies

Background: Mutations in the NOTCH3 gene are the cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which is an important cause of stroke in young adults. Mutations are typically located within epidermal growth factor (EGF) -like repeat domains in the extracellular part of the Notch3 receptor. Identification of the mutation is critical for genetic counseling and testing of relatives at risk.

Objective: To identify the spectrum of NOTCH3 mutations in CADASIL and to discuss the implications for diagnostic strategies.

Design: Screening for NOTCH3 mutations was performed in 125 unrelated german CADASIL patients with biopsy-proven disease by direct sequencing of exons coding for EGF repeats. Results were compared to previously published studies.

Results: We detected 54 distinct mutations (117 missense mutations and three in-frame deletions) in 120 of the 125 patients (96%). Sixty percent of the mutations were located in exon 4 and 86% in exons 2 through 6. In five patients (4%) no mutation was identified.

Conclusions: Almost 90% of mutations could be detected within a limited number of exons (2–6). Thus, genetic testing should initially be focussed on these exons, with some variation depending on the population in which it is being performed. Yet, genetic testing for CADASIL is associated with a nameable proportion of false negative results. Cases with a high index of clinical suspicion should be investigated by skin biopsy if genetic testing is negative.