Complete genomics finds its first diseases

Ewen Callaway, reporterWhole-genome sequencing is touted as the tech that will finally unmask our genetic "dark matter" - as-yet unknown disease-drivers that are missed by current gene scans. It hasn't done that yet, but for the first time two separate groups of researchers have used it to uncover mutations underlying rare diseases. The breakthrough shows both the promise and challenges facing the field of personal genomics. Right now, most personal genomics is based on
gene scans that identify single-letter mutations in the genetic code
known as SNPs, which can indicate that someone is at higher risk of various disorders. But complete genome sequences might tell us a lot more. This week's breakthroughs give us a taste of what that might be like.One team identified a previously unknown mutation that almost certainly causes a neuromuscular disorder by sequencing the genome of one of its members, James Lupski, who has Charcot-Marie-Tooth syndrome. Mutations in more than two dozen genes have previously been linked to the diseases but Lupski, a medical geneticist at Baylor College of Medicine in Houston, Texas, is negative for all of them.Whole-genome sequencing revealed that Lupski has two mutations in both copies of a gene called SH3TC2. The gene has previously been linked to neurological disease, but these specific mutations have not. "Lupski's three sick siblings also had both of these mutations, whereas his four healthy siblings and parents (who do not have the disease) carried only one mutated gene," ScienceNOW reports.
Meanwhile another team, led by Leroy Hood - a pioneer of DNA sequencing
- and  David Galas, both at the Institute for Systems Biology in
Seattle, sequenced the complete genomes of a family of four to figure out
which genes are responsible for a craniofacial condition called Miller syndrome and another rare disease called primary ciliary dyskinesia.
Unlike Lupski's team, they didn't home in on a single gene for each
condition, but they did narrow it down to four candidate genes. "The
basic problem here is that we're still extremely bad at differentiating
between mutations causing serious disease and perfectly benign
polymorphisms," notes the blog Genetic Future. Nonetheless,
researchers are confident that as whole-genome sequencing gets cheaper, it will deliver further on its promise of uncovering new,
disease-causing mutations - at least in rare conditions caused by
single genes, such as the ones identified in these studies. A
bigger challenge will be to identify the exact genetics underlying
diseases caused by large numbers of mutations, such as cancer and
mental illnesses such as schizophrenia, which have mostly evaded studies based on scanning for single-letter differences peppered across the genome.