Editors' ChoiceHuman Genetics

Decoding Neurologic Disorders with Whole-Genome Sequencing

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Science Translational Medicine  17 Mar 2010:
Vol. 2, Issue 23, pp. 23ec42
DOI: 10.1126/scitranslmed.3001044

Charcot-Marie-Tooth (CMT) neuropathy is an incurable and common heritable disorder affecting over 125,000 people in the United States. Individuals with CMT have substantial alterations in sensory perception and motor control of the distal extremities (leading to muscle atrophy and particularly prominent changes of the leg) and foot that limit normal ambulation. Interestingly, single-nucleotide polymorphisms (SNPs) and copy-number variants (CNVs) in over 39 genetic loci and 31 genes are known to confer susceptibility to CMT. Unfortunately, these genetic variations do not often correlate with disease severity, indicating a need to further delineate the genetic architecture of this debilitating neurologic disorder.

Now, Lupski et al. report an improved method to help decode CMT. First, they performed whole-genome DNA sequencing of a proband affected by CMT, identifying all SNPs and CNVs across the genome, but they focused on coding variants in genes that are known to affect nerve conduction. By doing so, they identified two protein-changing SNPs present in the gene SH3TC2—a candidate gene previously associated with CMT. Strikingly, all siblings affected by CMT were compound heterozygotes for both mutations, whereas the unaffected parents and siblings carried only one of the susceptiblility variants. Notably, the single-variant carriers in the family had milder forms of neuropathy that did not satisfy criteria for CMT. This scenario highlights the power of whole-genome sequencing to identify novel variants with modest effects on CMT susceptibility. Going forward, the plummeting costs in DNA sequencing will encourage the use of whole-genome sequencing to define the genetic underpinnings of many common heritable diseases.

J. R. Lupski et al., Whole genome sequencing in a patient with Charcot-Marie-Tooth neuropathy. N. Engl. J. Med. 10 March 2010 (10.1056/NEJMoa0908094). [Full Text]

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