Clinical exomes for hearing loss: surprising diagnoses and better yields. L. H. Hoefsloot1, I. Feenstra2, I. J. de Wijs2, M. H. Siers2, H. P. M. Kunst3, R. J. Admiraal3, R. J. E. Pennings3, H. Scheffer2, H. Kremer2,3, H. G. Yntema2 1) Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands; 2) Department of Human Genetics, Radboud university medical center, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands; 3) Department of Otorhinolaryngology, Head and Neck Surgery, Radboud university medical center, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.

   Clinical exome sequencing is a test that can be used for causative mutation detection, but also for the discovery of novel gene - disease associations. Because of its high heterogeneity, non-syndromic hearing loss is an excellent disorder for exome sequencing in a diagnostic setting. Hearing loss affects one in every 1000 newborns, with approximately half of cases with a genetic background. In 30% of these, additional features lead to the diagnosis of syndromic hearing loss, but in 70% hearing loss is the only finding. We performed clinical exome sequencing in a group of 200 probands with hearing loss. In a two-tier analysis, variants in 120 genes known to be associated with hearing loss were analysed first, followed by analysis of the full exome data set in case no causative mutations were identified. Analysis of variants in the panel of deafness-associated disease genes, allowed us to establish a diagnosis in 15% of cases. In another 30% of cases further studies were needed. These studies include segregation analysis for variants of unknown pathogenicity, analysis of the entire coding region and/or MLPA analysis to detect a second mutation in recessive genes, and reverse phenotyping for cases with likely-causative mutations in genes associated with syndromic hearing loss. The second tier, analyzing the exome in patients without a diagnosis in the first tier with the use of a high stringent filter (truncating, and missense variants with a PhyloP score >3.5) is ongoing. Preliminary results are for instance a homozygous mutation in the SGSH gene that was detected in a child with hearing loss and mild intellectual disability. Reverse phenotyping confirmed the diagnosis of mucopolysaccharidosis type IIIA. Furthermore, we found truncating mutations in genes that are likely candidates for deafness (based on expression pattern or homology to known deafness genes) in 3 patients. Although further studies are needed, our first results indicate that another 25% might be solved by analysis of the entire exome. In conclusion, exome sequencing with bioinformatic filtering for genes associated with hearing loss led to a molecular diagnosis in 15-45% of the patients. Exome wide analysis has revealed new candidate genes in selected cases and might add another 25% to the final diagnostic yield. More importantly, it has provided patients with a molecular diagnosis that was not anticipated, and much earlier than classic diagnostics would have revealed.

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