<\/p>\n\n\n\n
Background<\/p>\n\n\n\n
The relationship between observed clinical phenotypes and underlying genotypes is blended or skewed in multiple molecular diagnoses, complicating a comprehensive molecular genetic diagnosis.<\/p>\n\n\n\n
Aim<\/p>\n\n\n\n
We report two families with dual diagnoses, using the deafness-associated gene, COL4A6<\/em>, to exemplify its contribution to blended, complex clinical presentations.<\/p>\n\n\n\n Design<\/p>\n\n\n\n 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.<\/p>\n\n\n\n Methods<\/p>\n\n\n\n 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<\/em> variant. Spatial and temporal expression analysis in zebrafish traced col4a6<\/em> 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.<\/p>\n\n\n\n Results<\/p>\n\n\n\n We identified two families affected by multiple genetic disorders. The first family presented a missense COL4A6<\/em> variant (NM_033641.4:c.1480G>A p.(Gly494Arg)), accounting for hearing loss, while a likely pathogenic HEXA<\/em> variant (NM_000520.6:c.902T>G p.(Met301Arg)) explained Tay-Sachs disease features. The second family exhibited a synonymous COL4A6<\/em> 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<\/em> (NM_001353214.3:c.1125\u2009+\u20091G>T p.?), causing the Dyggve-Melchior-Clausen disease phenotype.<\/p>\n\n\n\n Conclusions<\/p>\n\n\n\n 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.<\/p>\n\n\n\n <\/p>\n","protected":false},"excerpt":{"rendered":" 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 […]<\/p>\n","protected":false},"author":151,"featured_media":14796,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[82],"tags":[],"class_list":["post-15507","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-publications"],"acf":[],"yoast_head":"\n