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The Last Day

Luc Smink
| Jun 27, 2012

Packing upIt was difficult to choose between concurrent sessions on the last day of ESHG, so I tried to attend two different ones. I started with the session “Intellectual Disability: From Gene to Function”. Here, as noted in our earlier post, exome talks were again very much in evidence.

Thomas Wieland from the Helmholtz in Munich described sequencing of 213 exomes from 51 parent child trios and 20 control trios. They achieved 97.5% sensitivity with ~112x coverage, as compared to SNP arrays. They also detected de novo non-synonymous mutations in 84% of the patients. The disease group showed a significantly higher number of nonsense/splice/indel variants than the control group. Wieland noted that exome sequencing is a powerful tool for identifying a sizable fraction of disease-causing mutations, both in known and novel genes.

Peter Kravitz (Charite, Berlin) talked about the role of the PIGO gene in causing hyperphosphatasia mental retardation syndrome (HPMR), an autosomal recessive condition. They had previously identified PIGV, a member of the GPI anchor synthesis pathway. The authors performed exome sequencing of two siblings with HPMR that were PIGV negative, identifying PIGO mutations. The identification of two members of the same pathway led them to perform an enrichment approach to capture more genes in the pathway. It was a lovely example of how exome and targeted sequencing experiments move towards a screening panel.

I then moved over to the “Next-Generation Approaches to Heterogeneous Disorders”, for another talk on whole exome sequencing (WES) from Asbjørg Stray-Pedersen from the Baylor College of Medicine in Houston, Texas. Dr Stray-Pedersen focuses on various primary immunodeficiency diseases (PIDs), where it is key to know the exact molecular diagnosis as this will help with treatment as well as predict clinical outcomes. So far, more than 200 genes have been reported as causing PIDs, with a very wide severity spectrum. She gave some examples of exome sequencing and how it helps to reduce diagnosis time, as well as its ability to detect novel variants. She highlighted that WES success really relies on good capture, good coverage, and then the proper informatics approaches to filter the data.

Another very interesting talk was by Carsten Bergman from BioScientia, Ingelheim, Germany. He talked about cilia-related disorders (ciliopathies). This group of diseases is characterized by its clinical and genetic heterogeneity. Symptoms include polycystic kidney disease, retinal degeneration, skeletal features, and defects of the central and peripheral nervous system. The symptoms can be isolated, or occur as part of syndromes such as Bardet-Biedl, Joubert, and Jeune. These researchers created a ciliopathies panel of 131 specific genes targeting 2,412 exons, with utility in clinical diagnosis. The speaker suggested that a panel containing the optimal content may be a better approach then sequencing the clinical exome— It would certainly reduce the data analysis complexities. However negative results would still require follow up with either exome or whole genome sequencing.

So there is still a question of what will happen in the long run. Where will the focus be at ESHG 2013, still on exomes, or will it shift to sequencing panel-based approaches? Check back in with us to find out.