{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T02:46:24Z","timestamp":1785379584089,"version":"3.55.0"},"reference-count":44,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T00:00:00Z","timestamp":1760486400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004807","name":"DFG","doi-asserted-by":"publisher","award":["VO 2138\/7-1"],"award-info":[{"award-number":["VO 2138\/7-1"]}],"id":[{"id":"10.13039\/100004807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004807","name":"DFG","doi-asserted-by":"publisher","award":["469177153"],"award-info":[{"award-number":["469177153"]}],"id":[{"id":"10.13039\/100004807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004807","name":"DFG","doi-asserted-by":"publisher","award":["VO 2138\/8-1"],"award-info":[{"award-number":["VO 2138\/8-1"]}],"id":[{"id":"10.13039\/100004807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004807","name":"DFG","doi-asserted-by":"publisher","award":["543719215"],"award-info":[{"award-number":["543719215"]}],"id":[{"id":"10.13039\/100004807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004807","name":"DFG","doi-asserted-by":"publisher","award":["CR 937\/2-1"],"award-info":[{"award-number":["CR 937\/2-1"]}],"id":[{"id":"10.13039\/100004807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Office of Research Infrastructure Program","award":["R24OD034438"],"award-info":[{"award-number":["R24OD034438"]}]},{"DOI":"10.13039\/100008907","name":"Oklahoma Medical Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008907","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The relationship between observed clinical phenotypes and underlying genotypes is blended or skewed in multiple molecular diagnoses, complicating a comprehensive molecular genetic diagnosis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Aim<\/jats:title>\n                    <jats:p>We report two families with dual diagnoses, using the deafness-associated gene, COL4A6, to exemplify its contribution to blended, complex clinical presentations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Design<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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\u2009days post-fertilization. Structural modeling was used to estimate variant impact on protein structure.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We identified two families affected by multiple genetic disorders. The first family presented a missense COL4A6 variant (NM_033641.4: c.1480G&amp;gt;A p.(Gly494Arg)), accounting for hearing loss, while a likely pathogenic HEXA variant (NM_000520.6: c.902T&amp;gt;G p.(Met301Arg)) explained Tay-Sachs disease features. The second family exhibited a synonymous COL4A6 variant (NM_033641.4: c.1767G&amp;gt;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\u2009+\u20091G&amp;gt;T p.?), causing the Dyggve-Melchior-Clausen disease.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/qjmed\/hcaf246","type":"journal-article","created":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T12:10:05Z","timestamp":1760530205000},"page":"187-197","source":"Crossref","is-referenced-by-count":3,"title":["Uncovering dual molecular diagnoses in families with complex 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Islamabad,","place":["Pakistan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Preobraschenski","sequence":"additional","affiliation":[{"name":"Institute for Auditory Neuroscience and InnerEarLab, University Medical Center G\u00f6ttingen , G\u00f6ttingen,","place":["Germany"]},{"name":"Collaborative Research Center 1690 (CRC1690), University of G\u00f6ttingen , G\u00f6ttingen,","place":["Germany"]},{"name":"Cluster of Excellence \u201cMultiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells\u201d (MBExC), University of G\u00f6ttingen , G\u00f6ttingen,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaurav K","family":"Varshney","sequence":"additional","affiliation":[{"name":"Genes and Human Disease Research Program, Oklahoma Medical Research Foundation , Oklahoma City, 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