title: Charcot-Marie-Tooth disease: frequency of genetic subtypes and guidelines for genetic testing.
abstract: BACKGROUND
  Charcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous group of diseases with approximately 45 different causative genes described. The aims of this study were to determine the frequency of different genes in a large cohort of patients with CMT and devise guidelines for genetic testing in practice.
  
  
  METHODS
  The genes known to cause CMT were sequenced in 1607 patients with CMT (425 patients attending an inherited neuropathy clinic and 1182 patients whose DNA was sent to the authors for genetic testing) to determine the proportion of different subtypes in a UK population.
  
  
  RESULTS
  A molecular diagnosis was achieved in 62.6% of patients with CMT attending the inherited neuropathy clinic; in 80.4% of patients with CMT1 (demyelinating CMT) and in 25.2% of those with CMT2 (axonal CMT). Mutations or rearrangements in PMP22, GJB1, MPZ and MFN2 accounted for over 90% of the molecular diagnoses while mutations in all other genes tested were rare.
  
  
  CONCLUSIONS
  Four commonly available genes account for over 90% of all CMT molecular diagnoses; a diagnostic algorithm is proposed based on these results for use in clinical practice. Any patient with CMT without a mutation in these four genes or with an unusual phenotype should be considered for referral for an expert opinion to maximise the chance of reaching a molecular diagnosis.
authors.affiliation: MRC Centre for Neuromuscular Disease, National Hospital for Neurology and Neurosurgery, London WC1N 3BG, UK.
authors.forename: Sinead M
authors.initials: SM
authors.lastname: Murphy
authors.forename: Matilde
authors.initials: M
authors.lastname: Laura
authors.forename: Katherine
authors.initials: K
authors.lastname: Fawcett
authors.forename: Amelie
authors.initials: A
authors.lastname: Pandraud
authors.forename: Yo-Tsen
authors.initials: YT
authors.lastname: Liu
authors.forename: Gabrielle L
authors.initials: GL
authors.lastname: Davidson
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Rossor
authors.forename: James M
authors.initials: JM
authors.lastname: Polke
authors.forename: Victoria
authors.initials: V
authors.lastname: Castleman
authors.forename: Hadi
authors.initials: H
authors.lastname: Manji
authors.forename: Michael P T
authors.initials: MP
authors.lastname: Lunn
authors.forename: Karen
authors.initials: K
authors.lastname: Bull
authors.forename: Gita
authors.initials: G
authors.lastname: Ramdharry
authors.forename: Mary
authors.initials: M
authors.lastname: Davis
authors.forename: Julian C
authors.initials: JC
authors.lastname: Blake
authors.forename: Henry
authors.initials: H
authors.lastname: Houlden
authors.forename: Mary M
authors.initials: MM
authors.lastname: Reilly
mesh_terms: D002607:Charcot-Marie-Tooth Disease / Q000145:classification / Q000175:diagnosis / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005820:Genetic Testing / Q000379:methods / Q000592:standards*; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics; D017410:Practice Guidelines as Topic