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-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.


METHODS
Screening for NOTCH3 mutations was performed in 125 unrelated German CADASIL patients with biopsy-proven disease by direct sequencing of exons coding for epidermal growth factor-like repeats. Results were compared with those of previously published studies.


RESULTS
We detected 54 distinct mutations (117 missense mutations and 3 in-frame deletions) in 120 (96.0%) of the 125 patients. Of the mutations, 58.3% were located in exon 4 and 85.8% in exons 2 through 6. In 5 patients (4.0%), no mutation was identified.


CONCLUSIONS
Almost 90% of mutations could be detected within a few exons (exons 2-6). Thus, genetic testing should initially be focused on these exons, with some variation depending on the population in whom 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.
Peters
Nils
N
Department of Neurology, Neurogenetics Laboratory, Klinikum Grosshadern, Ludwig-Maximilians University, Munich, Germany.
Opherk
Christian
C
Bergmann
Tanja
T
Castro
Mirna
M
Herzog
Jürgen
J
Dichgans
Martin
M
D001706:Biopsy; D046589:CADASIL / Q000235:genetics*; D004252:DNA Mutational Analysis; D005091:Exons; D005820:Genetic Testing; D006801:Humans; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D000071656:Receptor, Notch3; D011956:Receptors, Cell Surface / Q000235:genetics*; D051880:Receptors, Notch
C499374:NOTCH3 protein, human; D011518:Proto-Oncogene Proteins; D000071656:Receptor, Notch3; D011956:Receptors, Cell Surface; D051880:Receptors, Notch