COL11A2 – Otospondylomegaepiphyseal Dysplasia

Otospondylomegaepiphyseal dysplasia (OSMED) is a rare, autosomal recessive skeletal dysplasia characterized by disproportionately short limbs, large epiphyses, rhizomelic dwarfism, cleft palate, platyspondyly, and early-onset severe sensorineural hearing loss without ocular involvement (PMID:10677296). OSMED overlaps clinically with Stickler and Marshall syndromes but is distinguished by its characteristic skeletal and auditory features.

Multiple unrelated families and case reports have established a robust association between biallelic COL11A2 variants and OSMED. To date, at least 18 unrelated probands from eight families with either homozygous or compound heterozygous loss-of-function (LoF) COL11A2 mutations have been described (PMID:9805126; PMID:10677296; PMID:15558753). Segregation analysis in a consanguineous Bedouin tribe demonstrated five affected individuals homozygous for a COL11A2 nonsense mutation (PMID:15558753).

The variant spectrum comprises glycine substitutions in the triple-helical domain and diverse LoF alleles, including nonsense, frameshift, and splice-site mutations. A representative pathogenic allele is c.190C>T (p.Arg64Ter), identified in a 2-year-old girl with classical OSMED features (PMID:32341816). Recurrent homozygous and compound heterozygous variants have been reported across consanguineous and outbred populations.

Functional studies support haploinsufficiency as the disease mechanism in OSMED. Real-time RT-PCR of a truncating allele (c.2763del) showed incomplete mRNA decay, suggesting a dominant negative or partial LoF effect (PMID:21204229). In zebrafish, CRISPR/Cas9–engineered col11a2 null alleles recapitulated vertebral fusions, and transgenic expression of wild-type but not patient-derived missense variants rescued the phenotype, confirming pathogenicity (PMID:37462524).

No conflicting evidence has been reported. Together, genetic and functional data fulfill ClinGen criteria for a Strong gene-disease association, with extensive segregation and experimental concordance.

Key Take-home: Bi-allelic LoF and glycine-substituting COL11A2 variants cause autosomal recessive OSMED; early molecular diagnosis enables prompt auditory and orthopedic intervention.

References

• American Journal of Human Genetics • 2000 • Autosomal recessive disorder otospondylomegaepiphyseal dysplasia is associated with loss-of-function mutations in the COL11A2 gene. PMID:10677296
• American Journal of Medical Genetics • 1998 • Heterozygous glycine substitution in the COL11A2 gene in the original patient with the Weissenbacher-Zweymüller syndrome demonstrates its identity with heterozygous OSMED (nonocular Stickler syndrome). PMID:9805126
• American Journal of Medical Genetics Part A • 2005 • COL11A2 mutation associated with autosomal recessive Weissenbacher-Zweymuller syndrome: molecular and clinical overlap with otospondylomegaepiphyseal dysplasia (OSMED). PMID:15558753
• Journal of Pediatric Genetics • 2020 • Novel COL11A2 Pathogenic Variants in a Child with Autosomal Recessive Otospondylomegaepiphyseal Dysplasia: A Review of the Literature. PMID:32341816
• American Journal of Medical Genetics Part A • 2011 • A novel homozygous COL11A2 deletion causes a C-terminal protein truncation with incomplete mRNA decay in a Turkish patient. PMID:21204229
• Human Molecular Genetics • 2023 • COL11A2 as a candidate gene for vertebral malformations and congenital scoliosis. PMID:37462524

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