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
Eye Genetics Research Unit, The Children's Hospital at Westmead, Save Sight Institute, Children's Medical Research Institute, University of Sydney, Sydney, NSW, Australia.
Disciplines of Genomic Medicine and Child and Adolescent Health, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.
Eur J Hum Genet. 2021 May;29(5):881-886. doi: 10.1038/s41431-021-00820-1. Epub 2021 Feb 25.
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.
COL9A3基因编码IX型胶原蛋白三条α链之一，据报道杂合变异会导致多发性骨骺发育不良，并且在一些感音神经性听力损失病例中被认为有促成作用。纯合变异患者有面中部发育不全、近视、感音神经性听力损失、骨骺改变，并被诊断为斯-韦二氏综合征。此前尚未报道COL9A3基因变异会导致玻璃体视网膜变性和/或视网膜脱离。本报告描述了两个具有常染色体显性遗传的家族，其主要特征为周边玻璃体视网膜格子样变性和视网膜脱离。基因组测序显示，家族1中COL9A3基因有一个杂合剪接变异[NG_016353.1(NM_001853.4):c.1107+1G>C，NC_000020.10(NM_001853.4):c.1107+1G>C，LRG1253t1]，家族2中有一个杂合错义变异[NG_016353.1(NM_001853.4):c.388G>A p.(Gly130Ser)]，二者均与疾病共分离。对剪接变异的cDNA研究显示COL2结构域存在框内缺失，错义变异发生在COL3结构域，二者均表明IX型胶原蛋白在眼玻璃体基底部起关键作用。
