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Type 2 Stickler syndrome (MONDO:0011493) is an autosomal dominant collagenopathy caused by pathogenic variants in COL11A1 (HGNC:2186). Affected individuals manifest high myopia, retinal detachment, sensorineural hearing loss, and variable joint involvement. Early-onset ocular features often include myopia (HP:0000545) and retinal detachment (HP:0000541), while auditory deficits range from mild to profound (HP:0012714).
Inheritance is predominantly autosomal dominant with both de novo and familial transmission. Segregation has been confirmed in multiple families, including a mother–son pair carrying c.4526A>G (p.Gln1509Arg) (PMID:38299479). Biallelic and hypomorphic variants that affect exon 9 splicing can modify the phenotype, leading to more severe sensorineural hearing loss when inherited in trans with a dominant allele (PMID:32578940).
Case reports and cohort studies have identified over 44 unrelated probands, with a spectrum of glycine substitutions within the Gly-Xaa-Yaa repeat region, splice-site variants, in-frame deletions, and rare nonsense mutations. A novel missense variant c.3032C>A (p.Pro1011Gln) was described in a child with blindness and recurrent fractures misdiagnosed as osteoporosis-pseudoglioma syndrome (PMID:28971234). In a Chinese cohort of 40 type 2 patients, targeted NGS revealed 14 distinct COL11A1 variants, predominantly affecting splice sites and glycine residues (PMID:25240749).
Functional studies support a dominant-negative mechanism. Minigene and exon-trapping assays demonstrated that intronic variants (c.2241+5G>T, c.2809-2A>G, c.3168+5G>C) induce in-frame exon skipping, disrupting the triple-helical domain (PMID:33348901). Alternative splicing of exon 9 modifies the outcome of biallelic null or missense alleles, shifting the presentation from fibrochondrogenesis to a recessive form of type 2 Stickler syndrome with profound hearing loss (PMID:23922384).
Phenotypic variability is pronounced: some individuals exhibit early-onset blindness and skeletal fragility, while others present only ocular or auditory signs. A recent case broadened the spectrum to include microphthalmia and congenital cataract in a mother–son duo with c.4526A>G (p.Gln1509Arg) (PMID:38299479).
While COL11A1 is classically dominant, recessive presentations due to hypomorphic or splice-modifying alleles underscore the need for functional validation and family analysis, especially when intronic changes are detected. No studies to date refute the association, and alternative gene candidates have been excluded in all reports.
Integration of extensive genetic and experimental data over two decades yields a definitive gene–disease relationship. Comprehensive genetic testing—including exome sequencing and targeted panels—and functional assays for splicing variants are essential for accurate diagnosis. Key take-home: COL11A1 testing guides prognosis, informs surveillance for ocular and auditory complications, and enables tailored genetic counseling.
Gene–Disease AssociationDefinitiveOver 44 unrelated probands across multiple cohorts, segregation in families and concordant functional data over >10 years Genetic EvidenceStrong44 variants in 44 probands, including de novo, familial segregation, and biallelic modifiers Functional EvidenceModerateMinigene and exon-trapping assays confirm splice-altering mechanisms; alternative splicing studies support phenotype modification |