{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T18:00:41Z","timestamp":1778695241297,"version":"3.51.4"},"reference-count":17,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2020,6,24]],"date-time":"2020-06-24T00:00:00Z","timestamp":1592956800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000735","name":"University of Cambridge","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000735","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp;amp; Gen Med"],"published-print":{"date-parts":[[2020,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Type 2 Stickler syndrome is usually a dominant disorder resulting from pathogenic variants in <jats:italic>COL11A1<\/jats:italic> encoding the alpha 1 chain of type XI collagen. Typical molecular changes result in either substitution of an obligate glycine within the Gly\u2010Xaa\u2010Yaa amino acid sequence repeat region of the molecule, mRNA missplicing or deletions\/duplications that typically leaves the message in\u2010frame. Clinical features include myopia, retinal detachment, craniofacial, joint, and hearing problems. Fibrochondrogenesis is also a <jats:italic>COL11A1<\/jats:italic> related disorder, but here disease\u2010associated variants are recessive and may be either null alleles or substitutions of glycine, and the condition is usually lethal in infancy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The patient was assessed in the NHS England Stickler syndrome diagnostic service. DNA from the patient and family were analyzed with Next Generation Sequencing on a panel of genes known to cause Stickler Syndrome. The effect of sequence variants was assessed using minigene analysis. Allele\u2010specific RT\u2010PCR was performed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>This patient had clinical type 2 Stickler syndrome but with severe hearing loss and severe ocular features including retinal atrophy and retinal tears in childhood. We identified a de novo in frame deletion of <jats:italic>COL11A1<\/jats:italic> (c.4109_4126del) consistent with dominantly inherited Stickler syndrome but also a second inherited variant (c.1245+2T&gt;C), on the other allele, affecting normal splicing of <jats:italic>COL11A1<\/jats:italic> exon 9.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Exon 9 of <jats:italic>COL11A1<\/jats:italic> is alternatively expressed and disease causing changes affecting only this exon modify the phenotype resulting from biallelic <jats:italic>COL11A1<\/jats:italic> disease\u2010associated variants and, instead of fibrochondrogenesis, produce a form of Stickler syndrome with severe hearing loss. Disease phenotypes from de novo pathogenic variants can be modified by inherited recessive variants on the other allele. This highlights the need for functional and family analysis to confirm the mode of inheritance in <jats:italic>COL11A1<\/jats:italic>\u2010related disorders, particularly for those variants that may alter normal pre\u2010mRNA splicing.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.1354","type":"journal-article","created":{"date-parts":[[2020,6,24]],"date-time":"2020-06-24T09:32:11Z","timestamp":1592991131000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Inherited and de novo biallelic pathogenic variants in <i>COL11A1<\/i> result in type 2 Stickler syndrome with severe hearing loss"],"prefix":"10.1002","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2790-1135","authenticated-orcid":false,"given":"Thomas","family":"Nixon","sequence":"first","affiliation":[{"name":"School of Clinical Medicine University of Cambridge Addenbrooke\u2019s Hospital Cambridge UK"},{"name":"Vitreoretinal Service 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