Retinal disorders

Gene: COL11A1

Green List (high evidence)

Comment on mode of inheritance: While heterozygous LOF variants in COL11A1 are known to cause dominant Stickler syndrome / Marshall syndrome / isolated hearing loss, there are also more than 3 unrelated cases reported with biallelic COL11A1 variants and Stickler syndrome with more severe presentation. Variable reported ocular features included retinal atrophy, retinal tears, high myopia, unilateral retinal detachment, hypermetropia, and cataract. These cases did not present with skeletal dysplasia, as they had variants in alternatively spliced exon 9 on one or both alleles (exon 9 is not expressed in mature chondrocytes). Heterozygous parents of these individuals were either asymptomatic, or had mild myopia / mild hearing loss. Hence, the MOI should be changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.

Created: 3 Jun 2026, 3:42 p.m. | Last Modified: 3 Jun 2026, 3:48 p.m.

Panel Version: 9.4

PMID: 32578940 Nixon et al., 2020
Female patient with clinical type 2 Stickler syndrome but with severe hearing loss and severe ocular features including retinal atrophy and retinal tears in childhood. She was comp het for COL11A1 variants: a de novo in frame deletion of COL11A1 (c.4109_4126del) and splice variant c.1245+2T>C which affects splicing of exon 9 (inherited from unaffected mother).
Her parents were nonconsanguineous and had no eye, hearing, joint, or palate abnormalities.
Author explanation of inheritance: "The de novo deletion alone would be expected to result in dominant type 2 Stickler syndrome, but missplicing of exon 9 leads to additional severe hearing loss."
"While exon 9 is expressed in both vitreous and immature chondrocytes, it is not expressed in mature chondrocytes" - so any variants affecting exon 9 do not cause fibrochondrogenesis, but a Stickler syndrome phenotype with severe hearing loss.

PMID: 31833174 Abreu et al., 2020
3yo male proband with pontocerebellar hypoplasia caused by a homozygous AMPD2 p.[Pro734Leu] variant, and Stickler syndrome 2, likely caused by a homozygous COL11A1 c.1168G > T, p.[Glu390Ter] change. He presented with high myopia, mild-to-moderate hearing loss, as well as AMPD2-related profound motor and language delay.

PMID: 23922384 Richards et al., 2013
3 families with recessive form of type 2 Stickler syndrome characterised by particularly profound hearing loss. Heterozygous parents either had minor signs associated with Stickler syndrome, or were asymptomatic.
F1 - proband with cleft palate, hypermetropia, and profound deafness, was comp het for COL11A1 variants: (c.1191delT, p.Asn398Metfs*19) and (c.4259G>T, p.Gly1420Val) - exon 9 and 58, respectively. Age-compatible hearing loss in the mother, and mild-to-moderate hearing loss in the father
F2 - proband with high myopia, Pierre Robin sequence, and profound hearing loss, similarly affected sibling. Comp het for COL11A1 c.1421dupC, p.Gly475Argfs*9 in exon 13 and c.991-24A>G in intron 8 - creating an alternative exon 9 acceptor splice site.
F3 - girl with hearing loss diagnosed at 5 weeks, and retinal dystrophy noted at 2 yrs, also had clinical joint laxity. Parents unaffected, no hearing loss. Comp het c.2607A>G, p.Ala869Ala (shown to affect splicing) and c.5398G>T, p.Gly1800Cys.

PMID: 23026214 Alzahrani et al., 2012
6yo patient with homozygous exon 9 c.1191delT, p.(Asn398Metfs*19) variant in COL11A1; phenotype: unilateral retinal detachment, SNHL, cleft palate, flat midface, micrognathia. Parents unaffected, only mild myopia seen in the father.

PMID: 21035103 Tompson et al., 2010
2 individuals with Fibrochondrogenesis (severe skeletal dysplasia).
Family 1 - proband of European descent, comp het for COL11A1 variants c.1786dupG, (p.Ala596GlyfsX8), and c.3124G>A, (p.Gly1042Arg); presented with skeletal dysplasia (no note of hearing assessment); mother had myopia and normal hearing, father had hearing loss and wore glasses since childhood.
Family 2 - male proband (European and African American descent) comp het for COL11A1 c.2386G>C (p.Gly796Arg) and c.3943G>T, (p.Gly1315X) variants; he has fibrochondrogenesis, mild-moderate hearing loss, high myopia and left cataract. Father had mild hearing loss, mother - mild myopia (normal hearing), otherwise asymptomatic. Authors pose that LOF variants lead to dominant hearing loss.

Created: 3 Jun 2026, 3:38 p.m. | Last Modified: 3 Jun 2026, 3:51 p.m.

Panel Version: 9.4

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Deafness, autosomal dominant 37, 618533; Marshall syndrome, 154780; Stickler syndrome, type II, 604841; Fibrochondrogenesis 1, 228520

Publications

• 32578940
• 31833174
• 23922384
• 23026214
• 21035103

Green List (high evidence)

The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.

Created: 6 Feb 2023, 8:16 a.m. | Last Modified: 6 Feb 2023, 8:16 a.m.

Panel Version: 3.29

There is sufficient evidence linking COL11A1 with retinal disorders (retinal detachment and vitreoretinal degeneration/ type 2 vitreous phenotype) caused by autosomal dominant inheritance. This gene is associated with both Stickler syndrome and Marshall syndrome in OMIM and G2P. This gene is green on Stickler syndrome panel (https://panelapp.genomicsengland.co.uk/panels/3/gene/COL11A1/)

It has previously been decided (2019) in consultation with Gavin Arno (UCL Institute of Ophthalmology/Moorfields Eye Hospital) that this gene can stay red in this panel. Given this gene has recently been proposed for this panel by an expert, I am recommending that the Test Evaluation Working Group review and define the panel scope, and reach consensus as to whether this gene is appropriate for inclusion.

Created: 8 Jan 2023, 6:47 p.m. | Last Modified: 8 Jan 2023, 6:47 p.m.

Panel Version: 3.13

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Marshall syndrome, OMIM:154780; Stickler syndrome, type II, OMIM:604841

Publications

• 10486316
• 17318849

Review submitted on behalf of Robert Henderson, Mr Chien Wong, Mr CK Patel. Publications: Ang, A., Ung, T., Puvanachandra, N., Wilson, L., Howard, F., Ryalls, M., Richards, A., Meredith, S., Laidlaw, M., Poulson, A., Scott, J., Snead, M. Vitreous phenotype: a key diagnostic sign in Stickler syndrome types 1 and 2 complicated by double heterozygosity. Am. J. Med. Genet. 143A: 604-607, 2007; Annunen, S., Korkko, J., Czarny, M., Warman, M. L., Brunner, H. G., Kaariainen, H., Mulliken, J. B., Tranebjaerg, L., Brooks, D. G., Cox, G. F., Cruysberg, J. R., Curtis, M. A., and 13 others. Splicing mutations of 54-bp exons in the COL11A1 gene cause Marshall syndrome, but other mutations cause overlapping Marshall/Stickler phenotypes. Am. J. Hum. Genet. 65: 974-983, 1999

Created: 21 Dec 2022, 4:51 p.m. | Last Modified: 21 Dec 2022, 4:51 p.m.

Panel Version: 3.6

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Stickler syndrome, Marshall syndrome,, beaded vitreous, early onset hearing loss, retinal detachment

Red List (low evidence)

COL11A1 is a green gene on the Stickler syndrome panel (code 3, version 2.0). After discussion with Gavin Arno (UCL Institute of Ophthalmology/Moorfields Eye Hospital) it was decided that it is all right to leave COL11A1 off this panel (Retinal disorders)

Created: 30 Aug 2019, 2:52 p.m. | Last Modified: 30 Aug 2019, 2:52 p.m.

Panel Version: 1.160

Green List (high evidence)

overlapping phenotype - Stickler

Created: 30 Aug 2019, 2:12 p.m. | Last Modified: 30 Aug 2019, 2:12 p.m.

Panel Version: 1.159