AUDIOME: a tiered exome sequencing–based comprehensive gene panel for the diagnosis of heterogeneous nonsyndromic sensorineural hearing loss. (December 2018)

• Record Type: Journal Article
• Authors: Guan, Qiaoning; Balciuniene, Jorune; Cao, Kajia; Fan, Zhiqian; Biswas, Sawona; Wilkens, Alisha; Gallo, Daniel; Bedoukian, Emma; Tarpinian, Jennifer; Jayaraman, Pushkala; Sarmady, Mahdi; Dulik, Matthew; Santani, Avni; Spinner, Nancy; Abou Tayoun, Ahmad; Krantz, Ian; Conlin, Laura; Luo, Minjie
• Is Part Of: Genetics in medicine. Volume 20:Number 12(2018)
• Page Start: 1600
• Page End: 1608
• Publication Date: 2018-12
• Subjects: exome sequencing -- hearing loss -- next-generation sequencing panel -- reflex -- tier; Medical genetics -- Periodicals; Genetic disorders -- Periodicals; 616.04205
• DOI: 10.1038/gim.2018.48
• Languages: English
• ISSNs: 1098-3600

Abstract

Abstract Purpose Hereditary hearing loss is highly heterogeneous. To keep up with rapidly emerging disease-causing genes, we developed the AUDIOME test for nonsyndromic hearing loss (NSHL) using an exome sequencing (ES) platform and targeted analysis for the curated genes. Methods A tiered strategy was implemented for this test. Tier 1 includes combined Sanger and targeted deletion analyses of the two most common NSHL genes and two mitochondrial genes. Nondiagnostic tier 1 cases are subjected to ES and array followed by targeted analysis of the remaining AUDIOME genes. Results ES resulted in good coverage of the selected genes with 98.24% of targeted bases at >15 ×. A fill-in strategy was developed for the poorly covered regions, which generally fell within GC-rich or highly homologous regions. Prospective testing of 33 patients with NSHL revealed a diagnosis in 11 (33%) and a possible diagnosis in 8 cases (24.2%). Among those, 10 individuals had variants in tier 1 genes. The ES data in the remaining nondiagnostic cases are readily available for further analysis. Conclusion The tiered and ES-based test provides an efficient and cost-effective diagnostic strategy for NSHL, with the potential to reflex to full exome to identify causal changes outside of the AUDIOME test.