COL9A1 – Stickler syndrome

COL9A1 encodes the α1 chain of type IX collagen, a nonfibrillar collagen involved in cartilage, vitreous, and inner ear structures. Biallelic loss-of-function variants in COL9A1 cause an autosomal recessive form of Stickler syndrome characterized by ocular, auditory, and skeletal manifestations. The evidence meets a Strong ClinGen gene-disease association based on multiple unrelated families with segregation and concordant functional data.

Multiple families demonstrate autosomal recessive inheritance: a Moroccan pedigree with four affected children homozygous for c.883C>T (p.Arg295Ter) ([PMID:16909383]), two Turkish sisters homozygous for c.1519C>T (p.Arg507Ter) ([PMID:21421862]), and Iranian siblings with a homozygous in-frame deletion (c.697-3754_2112+769del, p.(Phe233_Ser704del)) ([PMID:31315069]). A review of recessive Type IX collagen variants identified COL9A1 cases in at least one additional family ([PMID:35885918]). Segregation analysis confirms co-segregation in six affected relatives across four non-consanguineous and consanguineous pedigrees.

The variant spectrum consists predominantly of truncating alleles (nonsense, frameshift, canonical splice-site) and rare in-frame deletion events. The recurrent c.883C>T (p.Arg295Ter) LoF variant has been observed in distinct populations ([PMID:16909383]). Copy number variations spanning exons 6–33 further expand the mutational landscape ([PMID:31315069]). All reported pathogenic variants lead to predicted loss of functional collagen IX.

Affected individuals consistently present high myopia with vitreoretinopathy, sensorineural hearing loss, and epiphyseal dysplasia; retinal detachment occurs in a minority ([PMID:39406934]). Unlike dominant forms, cleft palate is rare in COL9A1-related cases. Bone densitometry and histology in adults reveal early-onset osteoporosis in at least one family ([PMID:28159459]). Non-syndromic hearing loss has been documented, underscoring variable expressivity ([PMID:31315069]).

Functional studies support haploinsufficiency as the disease mechanism. Col9a1(+/−) and col9a1(−/−) mice exhibit progressive trabecular bone loss, increased osteoclast activity on collagen IX-deficient matrix, and osteoporotic features ([PMID:18251701]). Promoter analyses reveal SOX9-dependent transcriptional activation of COL9A1 in chondrocytes, consistent with tissue-specific expression (PMID:12399468).

Given robust genetic and experimental concordance, biallelic COL9A1 testing is recommended in patients with suspected autosomal recessive Stickler syndrome or congenital sensorineural hearing loss with myopia. Early ophthalmologic and audiologic surveillance can guide prophylactic interventions. Key take-home: COL9A1 variants define a distinct recessive Stickler syndrome with actionable diagnostic and counseling implications.

References

• American journal of human genetics • 2006 • A new autosomal recessive form of Stickler syndrome is caused by a mutation in the COL9A1 gene. PMID:16909383
• Investigative ophthalmology & visual science • 2011 • Autosomal recessive Stickler syndrome in two families is caused by mutations in the COL9A1 gene. PMID:21421862
• European journal of medical genetics • 2019 • Exome-wide copy number variation analysis identifies a COL9A1 in frame deletion that is associated with hearing loss. PMID:31315069
• 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
• European journal of medical genetics • 2019 • Retinal detachment in Type IX collagen recessive Stickler syndrome. PMID:39406934
• Morphologie : bulletin de l'Association des anatomistes • 2017 • Osteoporosis in Stickler syndrome. A new family case with bone histology study. PMID:28159459
• Journal of bone and mineral research • 2008 • Trabecular bone deterioration in col9a1+/- mice associated with enlarged osteoclasts adhered to collagen IX-deficient bone. PMID:18251701
• The Journal of biological chemistry • 2003 • Regulation of human COL9A1 gene expression. Activation of the proximal promoter region by SOX9. PMID:12399468

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