Precise cross-domain phenotyping as a link between auditory function and genetic causes

Precise auditory phenotyping is essential to establish a causal link between genetic variants and their functional consequences in untimely age-related hearing loss (uARHL), defined here as hearing loss occurring at least 20 years earlier than expected based on age-appropriate normative hearing thresholds, in absence of identifiable non-genetic causes (e.g., noise exposure, ototoxic medication). Individuals with uARHL (≥40 years) and age-matched controls with normal hearing are characterised using a clinically applicable cross-domain test battery that includes, among others, pure-tone audiometry, suprathreshold psychoacoustic measures (speech intelligibility in noise, tone detection in noise, and categorical loudness scaling), as well as electrophysiological and vestibular measures. Parallel genotyping, performed in collaboration with the Institut de l’Audition in Paris, enables the first genotype–phenotype investigation in monogenetically caused uARHL. Preliminary results reveal distinct auditory phenotypes in uARHL, including reduced masking release for speech in fluctuating noise, elevated tone-in-noise thresholds at 2 kHz, and steeper loudness growth functions compared to controls, with some effects interacting with age and/or pure-tone average. These findings emphasise the importance of suprathreshold processing measures for capturing functional deficits beyond audibility. By directly linking pathogenic variants to specific auditory performance profiles, this study provides first insights into the phenotypes of monogenetically caused uARHL and demonstrates the potential of integrated genotyping and phenotyping for precision diagnostics and profiling of age-related hearing loss.