Genotype-Phenotype Correlations of Pathogenic COCH Variants in DFNA9: A HuGE Systematic Review and Audiometric Meta-Analysis

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.

Keywords: COCH; DFNA9; autosomal dominant hearing loss; genotype-phenotype correlations; systematic review; vestibular diseases.

Figure 1

Flowchart of literature search. Detailing the systematic identification and inclusion of relevant studies on genotype-phenotype correlations in DFNA9, according to the preferred reporting items for systematic reviews and meta-analysis (PRISMA) statement.

Figure 2

Risk of bias assessment. Review authors’ judgements about each risk of bias item presented as percentages across all included studies.

Figure 3

Self-reported age of onset of hearing loss and vestibular dysfunction. In total, 42 studies reported an age of onset of either hearing loss (red) or vestibular impairment (blue). Horizontal lines represent the reported range in decades, whereas a vertical line depicts means in years. The secondary y-axis shows the specific cochlin domains the variant affects.

Figure 4

Age-Related Typical Audiograms (ARTA) for fourteen COCH mutations. ARTA are derived from cross-sectional linear regression analysis of last visit audiograms of affected subjects. Downward arrows indicate either out-of-scale measurements or underestimation of mean thresholds due to the exclusion of such measurements. Yr: age in years, dB HL: decibel hearing level, kHz: kilohertz.

Figure 5

A phenotypic analysis of DFNA9; the calculated age of onset and annual threshold deterioration (ATD) across variants affecting cochlin within the LCCL, the Ivd1, and the vWFA2 domain. (A) ATD of the pure-tone average across PTA_0,5-4kHz with increasing age. Longitudinal data from single subjects are shown as a semi-transparent line between successive time points. A non-linear logistic fit shows the average PTA over time for the LCCL domain (blue), the Ivd1 domain (black), and the vWFA2 domain (red). (B) The parameter estimates and their 95% confidence intervals for the calculated age of onset (arbitrarily set at 25 dB) and the ATD (dB/year) for the various variants within the LCCL domain (blue), the vWFA2 domain (red), and the Ivd1 domain (black). The dashed line shows the averaged calculated onset and ATD across all variants (unweighted for differences between the number of subjects for each variant).