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

A homozygous splice-site variant in PALM3 causes exon skipping with loss of function affecting all transcripts, in a setting of possible dual diagnosis with OTOA.

Hereditary hearing loss is highly heterogeneous genetically, with growing overlap between genes implicated in early-onset and age-related hearing loss. The authors report a consanguineous family with autosomal recessive non-syndromic hearing loss in which the proband carries 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 showed that the PALM3 variant causes aberrant splicing with exon skipping, resulting in either a frameshift or a large in-frame deletion, both consistent with loss of function affecting all known transcripts. The organ of Corti of 12-month-old heterozygous Palm3 mice showed largely preserved architecture, whereas an earlier study describes auditory dysfunction in knockout mice. The authors conclude that PALM3 is a candidate gene potentially contributing to autosomal recessive hearing loss, without being able to exclude a dual molecular diagnosis.

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

The merit of this paper is its caution: the OTOA variant, in a well-established deafness gene, could explain the phenotype on its own, and the authors resist the temptation of a first-description claim. In practical terms PALM3 should not be reported as a diagnosis today and joins the list of candidates to watch in matchmaking databases. The case above all illustrates a recurring pitfall of consanguinity, where several rare homozygous variants coexist in the same patient.

Analysis by Dr Thibaut Benquey