Differential genetic diagnoses of adult post-lingual hearing loss according to the audiogram pattern and novel candidate gene evaluation

John Hoon Rim,Jung Ah Kim,Hye-Youn Kim,Jae Young Choi,Byunghwa Noh,Young Ik Koh,Jin Woong Bok,Kyung Seok Oh,Jinsei Jung,Heon Yung Gee,Da Hye Kim,Jee Eun Yoo,Seung-Tae Lee,Min Goo Lee,Sun Young Joo,Kyumin Kim

doi:10.1007/s00439-021-02367-z

Abstract

Ski-slope hearing loss (HL), which refers to increased auditory threshold at high frequencies, is common in adults. However, genetic contributions to this post-lingual HL remain largely unknown. Here, we prospectively investigated deafness-associated and novel candidate genes causing ski-slope HL. We analyzed 192 families with post-lingual HL via gene panel and/or exome sequencing. With an overall molecular diagnostic rate of 35.4% (68/192) in post-lingual HL, ski-slope HL showed a lower diagnostic rate (30.7%) compared with other conditions (40.7%). In patients who showed HL onset before the age of 40, genetic diagnostic probability was significantly lower for ski-slope HL than for other conditions. Further analysis of 51 genetically undiagnosed patients in the ski-slope HL group identified three variants in delta-like ligand 1 (DLL1), a Notch ligand, which presented in vitro gain-of-function effects on Notch downstream signaling. In conclusion, genetic diagnostic rates in post-lingual HL varied according to audiogram patterns with age-of-onset as a confounding factor. DLL1 was identified as a candidate gene causing ski-slope HL.

Highlights

Hearing loss (HL) is the most common sensory disorder, affecting approximately one in every 500 newborns worldwide (Wilson et al 2017)
When patients with post-lingual HL were classified into three subgroups according to age of onset, the probability for genetic diagnosis by known HL genes was significantly lower for the ski-slope group than for the other HL group in patients with HL onset under 40 years (Fig. 2b, Supplementary Fig. S1a, b)
Few studies have investigated the diagnostic rates of genetic testing in relation to audiogram patterns (Song et al 2020), which is the first-line diagnostic tool in HL evaluation

Summary

Introduction

Hearing loss (HL) is the most common sensory disorder, affecting approximately one in every 500 newborns worldwide (Wilson et al 2017). For post-lingual HL, the audiogram serves as one of the most widely used phenotypic evaluation tools for HL and can provide decisive clues, in terms of genotype–phenotype correlations (Taylor et al 2013). Because a specific subset of genes determines hearing frequencies affected in various hearing impairments, physicians can predict the causative genes that correspond to certain types of audiograms with affected frequencies. Because post-lingual ski-slope HL is one of the most common HL types and patients commonly neglect the chances for diagnosis and treatment, the identification of genetic components for ski-slope HL is essential for both diagnostic and prognostic purposes

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Conclusion