title: Spectrum of mutations in biopsy-proven CADASIL: implications for diagnostic strategies.
abstract: 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.
authors: Department of Neurology, Neurogenetics Laboratory, Klinikum Grosshadern, Ludwig-Maximilians University, Munich, Germany.
authors: Nils
authors: N
authors: Peters
authors: Christian
authors: C
authors: Opherk
authors: Tanja
authors: T
authors: Bergmann
authors: Mirna
authors: M
authors: Castro
authors: Jürgen
authors: J
authors: Herzog
authors: Martin
authors: M
authors: Dichgans
mesh_terms: 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
chemical_list: C499374:NOTCH3 protein, human; D011518:Proto-Oncogene Proteins; D000071656:Receptor, Notch3; D011956:Receptors, Cell Surface; D051880:Receptors, Notch