Department of Ophthalmology, Flinders University, Adelaide, Australia.
Department of Ophthalmology, Flinders University, Adelaide, Australia.
Ophthalmology. 2020 Jun;127(6):758-766. doi: 10.1016/j.ophtha.2019.12.024. Epub 2020 Jan 7.
Developmental abnormalities of the ocular anterior segment in some cases can lead to ocular hypertension and glaucoma. CPAMD8 is a gene of unknown function recently associated with ocular anterior segment dysgenesis, myopia, and ectopia lentis. We sought to assess the contribution of biallelic CPAMD8 variants to childhood and juvenile open-angle glaucoma.
Retrospective, multicenter case series.
A total of 268 probands and their relatives with a diagnosis of childhood or juvenile open-angle glaucoma.
Developmental abnormalities of the ocular anterior segment in some cases can lead to ocular hypertension and glaucoma. CPAMD8 is a gene of unknown function recently associated with ocular anterior segment dysgenesis, myopia, and ectopia lentis. We sought to assess the contribution of biallelic CPAMD8 variants to childhood and juvenile open-angle glaucoma.
Patients underwent a comprehensive ophthalmic assessment, with DNA from patients and their relatives subjected to genome, exome, or capillary sequencing. CPAMD8 RNA expression analysis was performed on tissues dissected from cadaveric human eyes.
Diagnostic yield within a cohort of childhood and juvenile open-angle glaucoma, prevalence and risk of ophthalmic phenotypes, and relative expression of CPAMD8 in the human eye.
We identified rare (allele frequency < 4×10) biallelic CPAMD8 variants in 5.7% (5/88) of probands with childhood glaucoma and 2.1% (2/96) of probands with juvenile open-angle glaucoma. When including family members, we identified 11 individuals with biallelic variants in CPAMD8 from 7 unrelated families. Nine of these individuals were diagnosed with glaucoma (9/11, 81.8%), with a mean age at diagnosis of 9.22±14.89 years, and all individuals with glaucoma required 1 or more incisional procedures to control high intraocular pressure. Iris abnormalities were observed in 9 of 11 individuals, cataract was observed in 8 of 11 individuals (72.7%), and retinal detachment was observed in 3 of 11 individuals (27.3%). CPAMD8 expression was highest in neural crest-derived tissues of the adult anterior segment, suggesting that CPAMD8 variation may cause malformation or obstruction of key drainage structures.
Biallelic CPAMD8 variation was associated with a highly heterogeneous phenotype and in our cohorts was the second most common inherited cause of childhood glaucoma after CYP1B1 and juvenile open-angle glaucoma after MYOC. CPAMD8 sequencing should be considered in the investigation of both childhood and juvenile open-angle glaucoma, particularly when associated with iris abnormalities, cataract, or retinal detachment.
眼部前段的发育异常在某些情况下可导致眼压升高和青光眼。CPAMD8 是一个功能未知的基因，最近与眼部前段发育不良、近视和晶状体异位有关。我们试图评估双等位 CPAMD8 变体对儿童和青少年开角型青光眼的贡献。
回顾性、多中心病例系列。
共 268 名被诊断为儿童或青少年开角型青光眼的患者及其亲属。
眼部前段的发育异常在某些情况下可导致眼压升高和青光眼。CPAMD8 是一个功能未知的基因，最近与眼部前段发育不良、近视和晶状体异位有关。我们试图评估双等位 CPAMD8 变体对儿童和青少年开角型青光眼的贡献。
对患者进行全面的眼科评估，对患者及其亲属的 DNA 进行基因组、外显子或毛细血管测序。对从尸体人眼中解剖出的组织进行 CPAMD8 RNA 表达分析。
儿童和青少年开角型青光眼队列中的诊断率、眼科表型的患病率和风险，以及 CPAMD8 在人眼中的相对表达。
我们在 5.7%（5/88）的儿童青光眼患者和 2.1%（2/96）的青少年开角型青光眼患者中发现了罕见的（等位基因频率<4×10）双等位 CPAMD8 变体。当包括家庭成员时，我们从 7 个无关家庭中发现了 11 个 CPAMD8 双等位基因变异个体。这 11 个人中有 9 人被诊断为青光眼（9/11，81.8%），诊断时的平均年龄为 9.22±14.89 岁，所有青光眼患者均需要 1 次或多次手术以控制高眼压。11 名个体中有 9 名存在虹膜异常，8 名（72.7%）存在白内障，3 名（27.3%）存在视网膜脱离。CPAMD8 在成人前节神经嵴来源组织中的表达最高，这表明 CPAMD8 变异可能导致关键引流结构的畸形或阻塞。
双等位 CPAMD8 变异与高度异质性表型相关，在我们的队列中，它是继 CYP1B1 之后儿童青光眼的第二大常见遗传性病因，仅次于 MYOC 之后的青少年开角型青光眼。在儿童和青少年开角型青光眼的研究中，特别是当伴有虹膜异常、白内障或视网膜脱离时，应考虑 CPAMD8 测序。
