PALM3 and hearing loss: a potential dual diagnosis interfering with novel gene discovery

Hereditary hearing loss is highly genetically heterogeneous, with emerging overlap between genes implicated in early-onset and age-related hearing loss. We report a consanguineous family with autosomal recessive, non-syndromic hearing loss in which the proband harbors a homozygous splice-site variant in PALM3 NM_001145028.2:c.314+1G>A and a homozygous missense variant in OTOA NM_144672.4:c.1939G>C p.(Gly647Arg). A minigene assay for the PALM3 variant demonstrated aberrant splicing with exon skipping, resulting in either a frameshift or a large in-frame deletion, both consistent with loss of function and impacting all known transcripts. While the organ of Corti from 12-month-old heterozygous Palm3 mice showed preserved overall architecture, a study describing Palm3 knockout mice exhibit auditory dysfunction, supporting a possible auditory phenotype with loss of function. Although a dual molecular diagnosis cannot be excluded, the combined genetic, functional, and comparative data support PALM3 as a candidate gene potentially contributing to autosomal recessive hearing loss.