Abstract
Pathogenic missense variants in COCH are associated with DFNA9, an autosomal dominantly inherited type of progressive sensorineural hearing loss with or without vestibular dysfunction. This study is a comprehensive overview of genotype-phenotype correlations using the PRISMA and HuGENet guidelines. Study characteristics, risk of bias, genotyping and data on the self-reported age of onset, symptoms of vestibular dysfunction, normative test results for vestibular function, and results of audiovestibular examinations were extracted for each underlying pathogenic COCH variant. The literature search yielded 48 studies describing the audiovestibular phenotypes of 27 DFNA9-associated variants in COCH. Subsequently, meta-analysis of audiometric data was performed by constructing age-related typical audiograms and by performing non-linear regression analyses on the age of onset and progression of hearing loss. Significant differences were found between the calculated ages of onset and progression of the audiovestibular phenotypes of subjects with pathogenic variants affecting either the LCCL domain of cochlin or the vWFA2 and Ivd1 domains. We conclude that the audiovestibular phenotypes associated with DFNA9 are highly variable. Variants affecting the LCCL domain of cochlin generally lead to more progression of hearing loss when compared to variants affecting the other domains. This review serves as a reference for prospective natural history studies in anticipation of mutation-specific therapeutic interventions.
Highlights
A search was conducted in relevant databases (PubMed, NCBI’s Gene database, EMBASE, the Cochrane Library and Web of Science) focusing on DFNA9 genotype-phenotype correlation studies
No restrictions were placed on the inclusion of Biomolecules 2022, 12, x articles based on bias
The systematic review of this study provides a comprehensive overview of the audiovestibular phenotype of all (n = 27) currently (June 2021) known variants in COCH
Summary
Hearing loss (HL) is one of the most common sensory impairments and is estimated to affect 432 million people worldwide [1]. HL is caused by genetic conditions in more than half of the cases. HL is much more complex and is caused by a combination of environmental and genetic (risk) factors [2]. A growing number of dominantly inherited types of HL is associated with an adult-onset: e.g., DFNA10 (EYA4 MIM: 601316), DFNA15 (POU3F4, MIM: 602459), DFNA21 (RIPOR2, MIM: 607017), and DFNA22 (MYO6, MIM: 606346) [3,4,5,6]. A growing number of dominantly inherited types of HL is associated with an adult-onset: e.g., DFNA10 (EYA4 MIM: 601316), DFNA15 (POU3F4, MIM: 602459), DFNA21 (RIPOR2, MIM: 607017), and DFNA22 (MYO6, MIM: 606346) [3,4,5,6]. 4.0/).
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