Comprehensive genetic testing in the clinical evaluation of 1119 patients with hearing loss

作者：Christina Sloan-Heggen, Amanda O. Bierer, A. Eliot Shearer, Diana L. Kolbe, Carla Nishimura, Kathy L. Frees, Sean S. Ephraim, Seiji B. Shibata, Kevin T. Booth, Colleen A. Campbell, Paul T. Ranum, Amy E. Weaver, E. Ann Black-Ziegelbein, Donghong Wang, Héla Azaiez, Richard J. Smith · 发表于：Human Genetics · 年份：2016 · DOI：10.1007/s00439-016-1648-8 · 被引用次数：600 · 研究领域：Hearing, Cochlea, Tinnitus, Genetics、Ear Surgery and Otitis Media、Genomics and Phylogenetic Studies

Hearing loss is the most common sensory deficit in humans, affecting 1 in 500 newborns. Due to its genetic heterogeneity, comprehensive diagnostic testing has not previously been completed in a large multiethnic cohort. To determine the aggregate contribution inheritance makes to non-syndromic hearing loss, we performed comprehensive clinical genetic testing with targeted genomic enrichment and massively parallel sequencing on 1119 sequentially accrued patients. No patient was excluded based on phenotype, inheritance or previous testing. Testing resulted in identification of the underlying genetic cause for hearing loss in 440 patients (39%). Pathogenic variants were found in 49 genes and included missense variants (49%), large copy number changes (18%), small insertions and deletions (18%), nonsense variants (8%), splice-site alterations (6%), and promoter variants (<1%). The diagnostic rate varied considerably based on phenotype and was highest for patients with a positive family history of hearing loss or when the loss was congenital and symmetric. The spectrum of implicated genes showed wide ethnic variability. These findings support the more efficient utilization of medical resources through the development of evidence-based algorithms for the diagnosis of hearing loss.