A translational pipeline for classification of variants of uncertain significance to support gene therapy clinical trial in OTOF-related deafness.

OTOF

Biallelic OTOF variants; functional reclassification of variants of uncertain significance (AAV-mediated expression in Otof-/- mice, splicing assays), with K1992R in cis with E1700Q linked to abnormal otoferlin localisation

In a cohort of 135 deaf patients with biallelic OTOF variants, variants of uncertain significance hinder diagnosis and gene therapy eligibility in half of them. The authors set up a functional evaluation pipeline: coding variants are delivered by AAV into Otof-/- mice, and non-coding variants are assessed with splicing assays. Isolated homozygous E1700Q is compatible with normal hearing, but it always occurs in cis with K1992R in patients, and K1992R correlates with abnormal subcellular localisation of otoferlin. Eight representative variants were reclassified, establishing a molecular diagnosis in 38 patients; seven eligible patients received gene therapy and showed auditory improvement, one reaching near-normal hearing sustained for 1.5 years.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

A concrete example of what reclassifying variants of uncertain significance changes when a targeted therapy exists: it directly determines access to treatment. The E1700Q/K1992R case is a reminder that a variant must be assessed within its haplotype, which phasing from a trio exome or genome can anticipate. In vivo AAV testing in mice is heavy and hard to scale, and gene therapy results in seven patients remain preliminary.

Analysis by Dr Thibaut Benquey