Abstract
There has been considerable progress in the discovery of deafness-related genes, but clinical application still entails difficulties due to the genetic heterogeneity associated with deafness. Approximately one hundred genes are estimated to cause hereditary hearing loss, but a number of these may result in similar phenotypes that entail no abnormalities other than hearing loss. The costs and time required for screening genes one-by-one are prohibitive, but it is now thought that certain mutations are recurrent. An initial screening strategy that focuses on those frequently reported, recurrent mutations expected to be commonly encountered in the clinical setting, might be an appropriate approach for clinical application. We have developed an advanced screening strategy (Invader assay) focusing on frequently recurring mutations that are most likely to be encountered in the clinical setting that identifies approximately 40% of deafness patients. This indicates that 30-40% of patients have deafness due to commonly found mutations, such as in GJB2 or SLC26A4. In Japan, from 2012 genetic testing using the Invader assay for deafness can be covered by social health insurance. Currently, we first apply the Invader assay for screening 46 known mutations of 13 known deafness genes followed by direct sequencing as necessary.
For the remainder of the patients in whom the etiology is unknown, we are now applying Massively Parallel DNA Sequencing (MPS) of target candidate genes to discover rare causative genes. Exome sequencing using MPS is a new powerful strategy for rare Mendelian disorders such as deafness. Our recent data suggest that targeted exon sequencing of selected genes using the MPS technology will be able to identify rare responsible genes including new candidate genes for individual patients with deafness and improve molecular diagnosis in the clinical setting.
