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Exomes, anyone?

Luc Smink
| Jun 26, 2012

inheritance resized 600One of the observations from this year’s ESHG is the sheer number of exomes that are being sequenced. This topic was discussed extensively in “Next Generation Sequencing Going Clinical”, a very well-attended session. A long anticipated entrance to this important market seems to finally be taking place on a broader level.

Marjolen Kriek started the session talking about exome sequencing and the lessons learned from their last experience. One of the key points is the importance of establishing the right phenotype and the right disease before moving to exome sequencing. Why? Well, as shown during the presentation, some seemingly similar traits are not always the same disease. But this also highlights the power of exome sequencing in the clinic to identify diseases on a genetic level.

Marcel Nelen presented on how exome sequencing has been introduced to the clinical space in Nijmegen. Routine testing for some of the relevant disorders are now being carried out by this lab using NGS and exome sequencing. It was interesting to hear about the data filtering to avoid the need to report on un-asked clinical questions.

David Cockburn followed up with efforts made in Leeds using sequencing for mainstream diagnostics of genetic disease. The efforts have led to sequencing tests for a broad number of conditions, such as breast cancer, pheochromocytoma, Marfan syndrome, and Li-Fraumeni syndrome, among others. Dr. Cockburn showed that in Leeds, the number of requests for next-generation sequencing testing is increasing compared to other testing methods. Decreased turn around time of these requested tests really highlights the adoption of NGS in the clinic. This group has produced more than 1,900 patient reports over the last two years. Another interesting point was that validation of findings showed 100% concordance with capillary sequencing. In fact, a question from the audience prompted the comment from Dr. Cockburn that they are considering dropping capillary sequencing validation.

In the session on “Intellectual disability: genes, proteins, and model organisms” there was another great talk on exomes from Jay Shendure from the University of Washington in Seattle. Professor Shendure talked about the enormous increase in exome sequencing and the number of Mendelian disorders that have been solved by exome sequencing. He then posed the question about whether exome sequencing can help in complex disease. They sequenced 209 parent-child trios, or 627 exomes. They found 263 de novo mutations linked to autism, which was published in Nature Genetics. He then talked about new work where another 607 exomes were sequenced from 189 new trios, 20 from the previous study, as well as the exomes from 50 unaffected siblings. They showed that the de novo point mutations were overwhelmingly paternal in bias (4:1 ratio) and positively correlated with the age of the father. This work also been published, and the same Nature issue contains two further papers on exome sequencing in the autistic spectrum. Exome sequencing is clearly a great tool to elucidate the causes of Mendelian disease but also shows promise for solving complex diseases.