A comparative survey of functional evidence use in hearing and vision loss genetics

Despite advances in sequencing and standardized guidelines, many variants, particularly in genetically heterogeneous disorders such as hearing and vision loss, remain of uncertain significance. Multiplexed assays of variant effects (MAVEs) offer a solution to resolve these uncertainties, but their clinical integration is limited. We aimed to assess the utilization of functional evidence in hearing and vision loss genetics.

We surveyed 82 hearing and ocular genetics experts, collecting quantitative and qualitative data on their practices, confidence in functional assays and perceived barriers to integrating functional evidence into clinical workflows.

Here we show that hearing and vision loss experts frequently encounter variants of uncertain significance and note that functional data often fails to resolve uncertainty due to limited availability or inconsistent quality. Confidence is highest in transcript assays, patient-derived cell models and computational predictors, while familiarity and trust are lower for non-mammalian models and high-throughput assays like MAVEs. Respondents highlight the need for improved data accessibility, standardized evaluation guidelines and training to support functional evidence integration.

Our survey identifies both common and domain-specific challenges in applying functional evidence for variant classification in hearing and ocular genetics, emphasizing the need for frameworks that account for biological complexity, methodological limitations, and barriers to data accessibility.