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Oto-spondylo-megaepiphyseal dysplasia (OSMED) is an autosomal recessive skeletal dysplasia marked by severe sensorineural hearing impairment and enlarged epiphyses with early osteoarthritis. Although COL11A2 mutations have been classically associated with AR OSMED, a single unrelated proband presented with profound bilateral sensorineural hearing loss and radiographic epiphyseal enlargement ([HP:0008625]; [HP:0010580]). Genetic analysis identified a homozygous splice-acceptor variant in COL2A1, c.709-2A>G, absent in population controls and consistent with AR inheritance in the index patient, with no additional affected relatives ([PMID:16189708]). Transcript analysis demonstrated in-frame skipping of exon 11 and combined exon 11/13.
In vitro splicing assays confirmed that c.709-2A>G disrupts normal pre-mRNA processing, producing aberrant COL2A1 transcripts lacking critical regions of the triple-helical domain ([PMID:16189708]). These data expand the genetic heterogeneity of AR OSMED to include COL2A1 and underscore the phenotypic overlap between type II and XI collagenopathies. Additional unrelated cases and segregation studies are required to strengthen clinical validity. Key Take-home: COL2A1 should be incorporated into genetic testing panels for AR OSMED, especially in patients presenting with sensorineural hearing loss and enlarged epiphyses.
Gene–Disease AssociationLimitedSingle autosomal recessive proband with homozygous splice-acceptor variant demonstrating exon skipping ([PMID:16189708]) Genetic EvidenceLimitedOne proband with homozygous c.709-2A>G variant and no additional segregation data Functional EvidenceSupportingIn vitro splicing assays showed exon 11 and 13 skipping leading to in-frame deletion of the collagen triple-helical region ([PMID:16189708]) |