Uncovering dual molecular diagnoses in families with complex phenotypes through structural and clinical studies of novel COL4A6 variants
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Le résumé fourni par la source
BACKGROUND: The relationship between observed clinical phenotypes and underlying genotypes is blended or skewed in multiple molecular diagnoses, complicating a comprehensive molecular genetic diagnosis. AIM: We report two families with dual diagnoses, using the deafness-associated gene, COL4A6, to exemplify its contribution to blended, complex clinical presentations. DESIGN: This 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. METHODS: Families 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. RESULTS: We 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. CONCLUSIONS: Our 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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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé, mais le titre doit être comparé manuellement.
- Titre Crossref
- Uncovering dual molecular diagnoses in families with complex phenotypes through structural and clinical studies of novel <i>COL4A6</i> variants
- Date Crossref
- 15/10/2025
- Éditeur
- Oxford University Press (OUP)
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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German Primate Center pays non établi dans la noticeStructure de recherche
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Collaborative Research Group pays non établi dans la noticeStructure de recherche
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Universitätsmedizin Göttingen pays non établi dans la noticeÉtablissement de santé
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European Neuroscience Institute Göttingen pays non établi dans la noticeStructure de recherche
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University of Göttingen Collaborative Research Center 1690 (CRC1690) pays non établi dans la noticeUniversité ou école supérieure
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University of Rostock pays non établi dans la noticeUniversité ou école supérieure
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Oklahoma Medical Research Foundation Genes and Human Disease Research Program pays non établi dans la noticeOrganisation à but non lucratif
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University of Karachi pays non établi dans la noticeUniversité ou école supérieure
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Pakistan Institute of Medical Sciences pays non établi dans la noticeÉtablissement de santé
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Broad Institute Program in Medical and Population Genetics pays non établi dans la noticeOrganisation à but non lucratif
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Brigham and Women's Hospital Department of Obstetrics and Gynecology pays non établi dans la noticeÉtablissement de santé
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Auditory Neuroscience and Optogenetics Laboratory German Primate Center pays non établi dans la noticeStructure de recherche
German Primate Center, Collaborative Research Group et Universitätsmedizin Göttingen, avec 9 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.