COL9A3 – Autosomal Recessive Stickler Syndrome

Stickler syndrome is a connective tissue disorder characterized by ophthalmic, articular, orofacial, and auditory manifestations. While most cases are autosomal dominant due to COL2A1 or COL11A1 variants, biallelic loss-of-function variants in COL9A3 have been identified in patients with autosomal recessive Stickler syndrome (COL9A3; Stickler syndrome).

The first report described a consanguineous family with homozygous c.1176_1198del (p.Gln393CysfsTer25) loss-of-function variant in COL9A3 in two affected siblings presenting with sensorineural hearing loss, high myopia, midfacial retrusion, and tibial bowing (PMID:24273071). A subsequent single-patient report identified homozygosity for c.647dup (p.Gly217fsTer?) with similar phenotypic features including retinal changes and early-onset epiphyseal irregularities (PMID:30450842).

A 2022 multi-family study described three unrelated families with novel biallelic loss-of-function variants (c.355del (p.Leu119fsTer?), c.107_116del (p.Pro36fsTer?), c.1204C>T (p.Arg402Ter)) expanding the allelic spectrum of COL9A3-associated Stickler syndrome (PMID:35241111). An earlier 2019 series reported two affected individuals from a COL9A3 pedigree among six recessive Stickler syndrome patients, confirming segregation of c.883G>A (p.Gly295Arg) and c.388G>A (p.Gly130Ser) variants in type IX collagen genes (PMID:31090205).

Patients uniformly exhibit high myopia (HP:0011003), sensorineural hearing impairment (HP:0000407), midface retrusion (HP:0011800) and variable epiphyseal dysplasia. Retinal detachment risk appears lower than in dominant forms but warrants ophthalmic surveillance given reported cases of peripheral lattice degeneration.

Mechanistically, biallelic loss of the α3 chain of type IX collagen disrupts fibrillar collagen network in cartilage and the vitreous base, consistent with haploinsufficiency. No dedicated animal or cellular models for COL9A3-related Stickler syndrome have been reported to date.

In summary, autosomal recessive COL9A3 loss-of-function variants cause a distinctive Stickler syndrome phenotype. Genetic testing panels for congenital hearing loss and myopia should include COL9A3, and diagnosis enables targeted surveillance for ocular and skeletal complications.

References

• American journal of medical genetics. Part A • 2014 • Autosomal recessive Stickler syndrome due to a loss of function mutation in the COL9A3 gene. PMID:24273071
• American journal of medical genetics. Part A • 2018 • Autosomal recessive Stickler syndrome resulting from a COL9A3 mutation. PMID:30450842
• Orphanet journal of rare diseases • 2022 • Identification of three novel homozygous variants in COL9A3 causing autosomal recessive Stickler syndrome. PMID:35241111
• American journal of medical genetics. Part A • 2019 • Homozygous Type IX collagen variants (COL9A1, COL9A2, and COL9A3) causing recessive Stickler syndrome–Expanding the phenotype. PMID:31090205

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