Editors' ChoiceGenetics

Your Genome Is Ready

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Science Translational Medicine  05 May 2010:
Vol. 2, Issue 30, pp. 30ec73
DOI: 10.1126/scitranslmed.3001227

Sequencing of the first human genome was completed a decade ago, at the cost of several hundred million dollars. The hunt began for mutations that drive diseases known to have a genetic component. The hope was that there would be a few common mutations shared by all affected patients, and therefore complete genome sequencing would not be necessary. However, it appears now that the situation is more complex. Even in diseases that follow simple inheritance patterns and thus likely are attributable to a single gene mutation, many potential genes can be involved. For multigenic diseases such as diabetes and cancer, a whole set of mutations is responsible, again with wide variation in the mutated genes from patient to patient. Thus, there is no shortcut: Whole-genome sequencing becomes necessary for understanding the genetic makeup of a given patient and his or her family.

Now, Lupski et al. focused on a family affected by Charcot–Marie–Tooth Neuropathy—a rare form of polyneuropathy that is known to follow simple Mendelian inheritance—and performed whole-genome sequencing in one family member, the proband, in order to look for novel mutations. As expected, when they compared his genome to the reference sequence they found over 3 million differences, mostly in single-nucleotide polymorphisms, but only 9000 of these were found to alter the protein sequence. One of these turned out to be in SH3TC2, a gene expressed in Schwann cells. In the proband, both alleles of SH3TC2 are mutated: One is a mutation already known to be associated with Charcot–Marie–Tooth Neuropathy, and the other is novel. In this large family, the proband’s siblings who are affected by the disorder carry the two mutations, and those that are healthy have either one or no mutations in SH3TC2.

The implications of this study surpass the identification of a novel mutation associated with Charcot–Marie–Tooth Neuropathy. Whole-genome sequencing will soon become easily available, costing about as much as an MRI scan. The main challenge, as illustrated in this study, is mining through the large amounts of data to glean the most pertinent information and identify therapeutic targets so as to ameliorate such diseases.

J. R. Lupski et al., Whole-genome sequencing in a patient with Charcot–Marie–Tooth Neuropathy. N. Engl. J. Med. 362, 1181–1191 (2010). [Abstract]

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