Observational studyQJM : monthly journal of the Association of Physicians2026
Uncovering dual molecular diagnoses in families with complex phenotypes through structural and clinical studies of novel COL4A6 variants.
Observational study in QJM : monthly journal of the Association of Physicians, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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Who cites it
1 citing paper in PubMed.
- PALM3 and hearing loss: a potential dual diagnosis interfering with novel gene discovery.European journal of human genetics : EJHG · 2026Article
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13 authors.
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Abstract
backgroundThe relationship between observed clinical phenotypes and underlying genotypes is blended or skewed in multiple molecular diagnoses, complicating a comprehensive molecular genetic diagnosis.
aimWe report two families with dual diagnoses, using the deafness-associated gene, COL4A6, to exemplify its contribution to blended, complex clinical presentations.
designThis is an observational study within a large, ethnically diverse rare disease cohort, focusing on families with hearing loss and suspected dual diagnoses, followed by functional and structural studies of novel variants.
methodsFamilies were identified through a large rare disease sequencing initiative. Exome or genome sequencing was performed, with follow-up RNA studies for a synonymous COL4A6 variant. Spatial and temporal expression analysis in zebrafish traced col4a6 expression in the otic vesicle and ear from 1 to 5 days post-fertilization. Structural modeling was used to estimate variant impact on protein structure.
resultsWe identified two families affected by multiple genetic disorders. The first family presented a missense COL4A6 variant (NM_033641.4: c.1480G>A p.(Gly494Arg)), accounting for hearing loss, while a likely pathogenic HEXA variant (NM_000520.6: c.902T>G p.(Met301Arg)) explained Tay-Sachs disease features. The second family exhibited a synonymous COL4A6 variant (NM_033641.4: c.1767G>A p.(Pro589=)), leading to partial exon skipping and hearing loss, along with a pathogenic splice-site variant in DYM (NM_001353214.3: c.1125 + 1G>T p.?), causing the Dyggve-Melchior-Clausen disease.
conclusionsOur findings highlight the importance of recognizing dual molecular diagnoses to untangle blended phenotypes, as well as the diagnostic relevance of synonymous variants with predicted splicing effects.
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