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Whole Exome Sequencing Moves Beyond the Study of Mendelian Disorders

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Exome sequencing — which has already been established as a go-to tool for uncovering the genetic causes of Mendelian diseases — is now being applied to studies of more complex diseases, according to talks at the American Society of Human Genetics meeting held last month in Washington, DC.

Exome sequencing burst onto the scene in 2009 when the University of Washington's Jay Shendure and his team used it to identify the gene mutation that causes Freeman-Sheldon syndrome. Shendure and his colleagues have since applied the method to their studies of Miller syndrome and, more recently, Kabuki syndrome. In a plenary session at ASHG, Washington's Mark Hannibal described how the group found the de novo genetic event that often causes this rare congenital disorder. As they reported in Nature Genetics in September, the researchers homed in on a mutation in MLL2 by sequencing 10 exomes. "Exome sequencing is a powerful strategy that can be applied to relatively few cases," Hannibal said at ASHG.

While interest in using exome sequencing for Mendelian diseases has ramped up, researchers are now turning their attention to more complex diseases, including autism, mitochondrial disorders, and celiac disease.

To search for variants involved in autism susceptibility, Shendure and his team analyzed exomes from 20 parent-child trios, selecting them from pedigrees indicative of sporadic autism cases. In these exomes, they searched for de novo mutations by filtering out known mutations. After reviewing them manually, the team was left with four candidates. After validation by Sanger sequencing, only two confirmed de novo events remained. One of them was a mutation in GRIN2B, which Shendure said was high on the list of genes possibly involved in autism, and the other was a mutation in FOXP1, whose sister FOXP2 is involved in speech and language disorders. "With 60 exomes, we were able to identify four plausible candidate genes for autism," Shendure said.

In addition, the University College Dublin's Jillian Casey used exome sequencing to pinpoint a variant involved in mitochondrial disorders that affect the Irish Traveller sub-population. Her team looked at four exomes along with data from SNP homozygosity maps to narrow down potential candidates and were left with a single, non-synonymous variant that mapped to LARS, the gene that codes for a cytoplasm leucyl-tRNA synthetase.

However, applying exome sequencing to complex disorders is not always straightforward. Bart and The London's Vanisha Mistry and her team sequenced 66 exomes — 35 from large, multi-generation families, and 31 from smaller families — to search for a genetic cause of celiac disease. From their analysis, the team zeroed in on IL21R, which had also been implicated in a genome-wide association study of the disease. However, Sanger confirmation studies showed that four unaffected family members had the SNP and four affected people did not. "I want to highlight the difficulties in finding potential mutation," Mistry said.