Exome sequencing allows for rapid gene identification in a CMT family

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Ann Neurol. 2011 Jan 20. doi: 10.1002/ana.22235. [Epub ahead of print]

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

family.

Montenegro G, E, Huang J, Speziani F, YJ, Beecham G, Hulme W,

Siskind C, Vance J, Shy M, Züchner S.

P. Hussman Institute for Human Genomics, University of Miami School

of Medicine, Miami, FL.

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.