Heterozygous COL9A3 variants cause severe peripheral vitreoretinal degeneration and retinal detachment

• Published in: European journal of human genetics : EJHG 2021-05, Vol.29 (5), p.881-886
• Main Authors: Nash, Benjamin M, Watson, Christopher J G, Hughes, Edward, Hou, Alec L, Loi, To Ha, Bennetts, Bruce, Jelovic, Diana, Polkinghorne, Philip J, Gorbatov, Mark, Grigg, John R, Vincent, Andrea L, Jamieson, Robyn V
• Format: Article
• Language: English
• Subjects: Adult; Alternative splicing; Autosomal dominant inheritance; Brief Communication; Collagen; Collagen (type IX); Collagen Type IX - genetics; Degeneration; Dysplasia; Female; Gene deletion; Genes, Dominant; Hearing loss; Heredity; Heterozygote; Humans; Hypoplasia; Male; Middle Aged; Mutation, Missense; Myopia; Pedigree; Retina; Retinal Degeneration - genetics; Retinal Degeneration - pathology; Retinal detachment; Retinal Detachment - genetics; Retinal Detachment - pathology; Vitreous Body - pathology
• ISSN: 1018-4813; 1476-5438
• DOI: 10.1038/s41431-021-00820-1

The COL9A3 gene encodes one of the three alpha chains of Type IX collagen, with heterozygous variants reported to cause multiple epiphyseal dysplasia, and suggested as contributory in some cases of sensorineural hearing loss. Patients with homozygous variants have midface hypoplasia, myopia, sensorineural hearing loss, epiphyseal changes and carry a diagnosis of Stickler syndrome. Variants in COL9A3 have not previously been reported to cause vitreoretinal degeneration and/or retinal detachments. This report describes two families with autosomal dominant inheritance and predominant features of peripheral vitreoretinal lattice degeneration and retinal detachment. Genomic sequencing revealed a heterozygous splice variant in COL9A3 [NG_016353.1(NM_001853.4):c.1107 + 1G>C, NC_000020.10(NM_001853.4):c.1107 + 1G>C, LRG1253t1] in Family 1, and a heterozygous missense variant [NG_016353.1(NM_001853.4):c.388G>A p.(Gly130Ser)] in Family 2, each segregating with disease. cDNA studies of the splice variant demonstrated an in-frame deletion in the COL2 domain, and the missense variant occurred in the COL3 domain, both indicating the critical role of Type IX collagen in the vitreous base of the eye.