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POLD3 encodes the accessory subunit of DNA polymerase δ, essential for DNA synthesis and genome integrity. RNAScope analysis demonstrates robust expression of Pold3 in mouse auditory and vestibular neurons, consistent with a direct role in inner ear function (PMID:39414923).
In a multigenerational Lebanese pedigree, a heterozygous pathogenic POLD3 variant segregated in twelve individuals, of whom eight exhibited bilateral adult-onset sensorineural hearing impairment and two showed unilateral vestibular weakness around ages 40–50 (PMID:39414923). This segregation of the variant with disease in ten affected relatives supports autosomal dominant inheritance via haploinsufficiency.
Clinical evaluation included audiometry and vestibular function testing, confirming a non-syndromic sensorineural hearing loss with variable vestibular involvement. Exome sequencing excluded pathogenic variants in known hearing impairment genes, strengthening the specificity of POLD3 involvement (PMID:39414923).
Gene expression profiling via RNAscope confirmed Pold3 localization to both auditory and vestibular neuronal populations in mice, mirroring sites of pathology in affected individuals (PMID:39414923). This functional evidence aligns with an allelic haploinsufficiency mechanism.
No studies to date have disputed this association. Overall, the combined genetic segregation and functional expression data fulfill criteria for a ClinGen Moderate classification. POLD3 haploinsufficiency should be considered in diagnostic evaluation of adult-onset progressive sensorineural hearing loss.
Key Take-home: Heterozygous POLD3 variants cause an autosomal dominant, adult-onset, progressive hearing and vestibular disorder with clear clinical and experimental support.
Gene–Disease AssociationModerateSegregation of variant with disease in ten affected relatives within one pedigree ([PMID:39414923]); supportive expression data in relevant neuronal tissues ([PMID:39414923]). Genetic EvidenceModerateOne extended family with segregation in 10 affected carriers, autosomal dominant inheritance established ([PMID:39414923]). Functional EvidenceSupportingRNAscope demonstrates Pold3 expression in auditory and vestibular neurons, consistent with affected tissues ([PMID:39414923]). |