Exome sequencing allows for rapid gene identification in a Charcot-Marie-Tooth family

Gladys Montenegro, Eric Powell, Jia Huang, Fiorella Speziani, Yvonne J K Edwards, Gary W Beecham, William Hulme, Carly Siskind, Jeffery M Vance, Michael Shy, Stephan L Zuchner

Research output: Contribution to journalArticle

93 Citations (Scopus)

Abstract

Objective: Charcot-Marie-Tooth (CMT) disease comprises a large number of genetically distinct forms of inherited peripheral neuropathies. The relative uniform phenotypes in many patients with CMT make it difficult to decide which of the over 35 known CMT genes are affected in a given patient. Genetic testing decision trees are therefore broadly based on a small number of major subtypes (eg, CMT1, CMT2) and the observed mutation frequency for CMT genes. Since conventional genetic testing is expensive many rare genes are not being tested for at all. Methods: Whole-exome sequencing has recently been introduced as a novel and alternative approach. This method is capable of resequencing a nearly complete set of coding exons in an individual. We performed whole-exome sequencing in an undiagnosed family with CMT. Results: Within over 24,000 variants detected in 2 exomes of a CMT family, we identified a nonsynonymous GJB1 (Cx32) mutation. This variant had been reported previously as pathogenic in X-linked CMT families. Sanger sequencing confirmed complete cosegregation in the family. Affected individuals had a marked early involvement of the upper distal extremities and displayed a mild reduction of nerve conduction velocities. Interpretation: We have shown for the first time in a genetically highly heterogeneous dominant disease that exome sequencing is a valuable method for comprehensive medical diagnosis. Further improvements of exon capture design, next-generation sequencing accuracy, and a constant price decline will soon lead to the adoption of genomic approaches in gene testing of Mendelian disease.

Original languageEnglish
Pages (from-to)464-470
Number of pages7
JournalAnnals of Neurology
Volume69
Issue number3
DOIs
StatePublished - Mar 1 2011

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Exome
Tooth
Genes
Genetic Testing
Exons
Charcot-Marie-Tooth Disease
Decision Trees
Neural Conduction
Mutation Rate
Upper Extremity
Phenotype
Mutation

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Exome sequencing allows for rapid gene identification in a Charcot-Marie-Tooth family. / Montenegro, Gladys; Powell, Eric; Huang, Jia; Speziani, Fiorella; Edwards, Yvonne J K; Beecham, Gary W; Hulme, William; Siskind, Carly; Vance, Jeffery M; Shy, Michael; Zuchner, Stephan L.

In: Annals of Neurology, Vol. 69, No. 3, 01.03.2011, p. 464-470.

Research output: Contribution to journalArticle

Montenegro, G, Powell, E, Huang, J, Speziani, F, Edwards, YJK, Beecham, GW, Hulme, W, Siskind, C, Vance, JM, Shy, M & Zuchner, SL 2011, 'Exome sequencing allows for rapid gene identification in a Charcot-Marie-Tooth family', Annals of Neurology, vol. 69, no. 3, pp. 464-470. https://doi.org/10.1002/ana.22235
Montenegro, Gladys ; Powell, Eric ; Huang, Jia ; Speziani, Fiorella ; Edwards, Yvonne J K ; Beecham, Gary W ; Hulme, William ; Siskind, Carly ; Vance, Jeffery M ; Shy, Michael ; Zuchner, Stephan L. / Exome sequencing allows for rapid gene identification in a Charcot-Marie-Tooth family. In: Annals of Neurology. 2011 ; Vol. 69, No. 3. pp. 464-470.
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