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Exome Sequencing Studies Tackle Increasingly Complex Diseases

By Andrea Anderson

VANCOUVER, BRITISH COLUMBIA (GenomeWeb News) – As exome sequencing moves from Mendelian to complex diseases, researchers are becoming more creative about the sorts of approaches they use to track down culprit mutations, University of Washington genome sciences researcher Jay Shendure said at the American College of Medical Genetics annual clinical genetics meeting this week.

During a session on the use of exome sequencing for gene discovery and medical practice moderated by Beth Israel Deaconess Medical Center and Harvard Medical school researcher Sibel Kantarci, Shendure first discussed how his team has used exome sequencing to find genes involved in Mendelian disease — particularly Miller syndrome and Kabuki syndrome.

The team is continuing to study Kabuki syndrome, he noted, since the gene identified in their initial study — MLL2 — was not mutated in three of the 10 individuals tested.

Indeed, he explained, MLL2 itself was identified, in part, because the team eventually sub-stratified individuals diagnosed with Kabuki syndrome using additional phenotypic and genotypic information.

Subsequent follow-up on around 100 individuals has turned up MLL2 mutations in roughly 70 percent of those diagnosed with Kabuki syndrome, Shendure explained.

He and his collaborators are now doing additional exome sequencing studies on the remaining Kabuki cases to try to determine if individuals who do not carry mutations in MLL2 might have other, non-coding mutations in and around the gene that affect its function or whether there is another, yet unidentified gene behind the syndrome.

Shendure and his collaborators are also using exome sequencing to tackle autism spectrum disorder, a condition that is both behaviorally and genetically complex.

Just as studies by collaborator and fellow University of Washington researcher Evan Eichler have linked some rare, de novo copy number variations to neurocognitive disorders, Shendure explained, the team speculated that rare, de novo SNPs might also contribute to such conditions.

To explore this in more detail, they have been doing exome sequencing on individuals with autism and their parents, focusing specifically on de novo point mutations in sporadic autism cases.

Data generated from these exomes is being analyzed using a strategy dubbed "Haystack," Shendure said. After filtering apparent de novo mutations against more than 1,000 other exomes, researchers annotate the possible disease-related changes and verify them using Sanger sequencing.

So far, the team has sequenced 20 parent-child trios and has been finding a single coding mutation per trio, on average. About half of these mutations produce changes that are expected to alter protein function.

Though they are finding less than one de novo mutation per exome, Shendure explained, the team has already found at least four suspect genes in the 20 exome trios that are found in children with sporadic autism but not in either of their parents.

While they don't have enough data yet to show that any of these candidate genes are truly "autism genes," Shendure said, a number of the candidate genes at least "look good on paper." For instance, he noted, preliminary data points to sporadic autism-associated mutations in a gene that functions in collusion with the neural plasticity gene FOXP2, and in a gene that has been implicated in another neurodevelopment-related condition.