(about CMT) Personal Genome Sequencing Identifies Mendelian Mutations

October 22, 2009

Personal Genome Sequencing Identifies Mendelian Mutations

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By Davies

October 22, 2009 | HONOLULU – The only downside of holding a major scientific

conference in Hawaii is that, at some point, one has to step inside and attend a

talk or two. But those among the more than 4600 registered attendees at the 2009

American Society of Human Genetics (ASHG) convention who ventured indoors were

treated to some excellent talks on the opening day. In particular, two groups

presented impressive results of next-generation sequencing studies that

conclusively show how it is possible to identify previously unknown mutations

responsible for Mendelian diseases.

Lupski (Baylor College of Medicine) is an authority in the area of

structural variants underlying genetic disorders (and has been for two decades).

In the early 1990s, his team characterized the novel sub-chromosomal duplication

that gave rise to a common form of peripheral neuropathy called

Charcot-Marie-Tooth (CMT) disease. Since then, mutations in some 40 genes have

been shown to give rise to CMT-like diseases. But none of them accounted for one

particularly interested patient: Lupski himself.

Earlier this year, Gibbs, director of the Baylor Genome Center, offered

to sequence Lupksi's entire genome in the hopes of finally identifying the

mystery mutant gene. (Gibbs and Lupski were part of the team that interpreted

the first personal genome delivered by next-gen sequencing, , in

2007.) Using the Life Technologies/Applied Biosystems SOLiD platform, Gibbs and

colleagues sequenced Lupski's DNA to 30-fold coverage.

Not surprisingly, the sequencing produced thousands of single-nucleotide

polymorphisms (SNPs) considered putative disease-causing mutations. Gibbs

applied a series of filters, removing SNPs already catalogued in the database

(and thus considered too common to be the basis of a rare genetic disorder) as

well as those found in HapMap samples. Lupski detailed how 6 SNPs in his genome

were correlated with known behavioral disorders, 32 were cancer associated

(Lupski is a cancer survivor), and 47 were implicated in common diseases.

In the end, Lupski and colleagues found different deleterious mutations in his

two inherited copies of a gene called SH3TC2. The gene encodes a protein

expressed in the membrane of Schwann cells that could have a role in the

myelination of nerve fibers.

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