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

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. W...

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Bibliographic Details
Published in:Human genetics 2022-04, Vol.141 (3-4), p.915-927
Main Authors: Rim, John Hoon, Noh, Byunghwa, Koh, Young Ik, Joo, Sun Young, Oh, Kyung Seok, Kim, Kyumin, Kim, Jung Ah, Kim, Da Hye, Kim, Hye-Youn, Yoo, Jee Eun, Lee, Seung-Tae, Bok, Jin Woong, Lee, Min Goo, Jung, Jinsei, Choi, Jae Young, Gee, Heon Yung
Format: Article
Language:English
Subjects:
Adult
Age
Biomedical and Life Sciences
Biomedicine
Comparative analysis
Deafness
Ethylenediaminetetraacetic acid
Gene Function
Genes
Hearing loss
Hearing Loss - diagnosis
Hearing Loss - genetics
Hearing Loss, Sensorineural - genetics
Hearing Tests
Human Genetics
Humans
Investigations
Ligands
Metabolic Diseases
Molecular Medicine
Original Investigation
Pathology, Molecular
Pedigree
Ski resorts
The Molecular Genetics of Hearing and Deafness
Whole Exome Sequencing
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Summary: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.
ISSN:0340-6717
1432-1203
DOI:10.1007/s00439-021-02367-z