State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
Mol Vis. 2021 May 13;27:309-322. eCollection 2021.
Oculodentodigital dysplasia (ODDD) is a group disorder caused by variants, of which glaucoma leading to blindness is a frequent complication of the ocular phenotype. In this study, the correlation of the genotype with the ocular phenotype was analyzed systematically.
variants were collected from in-house whole-exome sequencing data of 5,307 individuals. Potentially pathogenic variants (PPVs) were defined based on prediction of multiple in silico tools, related phenotypes, and previously established evidence. The characteristics of PPVs were evaluated based on our data, gnomAD, and HGMD.
In total, 21 rare variants in were detected in 32 subjects from the study cohort. Four of the 21 variants were classified as PPVs, including two frameshift, one missense, and one in-frame deletion. The four PPVs were detected in four probands with microcornea or high hyperopia; two developed glaucoma. A systematic review of variants in literature suggested that most heterozygous missense PPVs are located inside the connexin domain. All truncations downstream of the connexin domain are associated with autosomal dominant disease, while most truncations within the domain are associated with autosomal recessive ODDD. Ocular signs were present in 80.0% (116/145) of patients with PPVs. Of the 116 patients, glaucoma was observed in 26.7% (31/116), among whom 77.4% (24/31) of cases occurred in patients ≥10 years old.
Eye abnormalities are the most common signs associated with PPVs, and they carry a high risk of developing glaucoma. The identification of PPVs needs further attention and clarification.
眼牙指发育不良（ODDD）是一种由 变异引起的综合征，其中青光眼导致失明是眼部表型的常见并发症。本研究系统分析了 基因型与眼部表型的相关性。
从 5307 名个体的内部全外显子组测序数据中收集 变异。根据多种计算机预测工具、相关表型和已建立的证据，定义潜在致病性变异（PPV）。根据我们的数据、gnomAD 和 HGMD 评估 PPV 的特征。
在研究队列的 32 名受试者中，共检测到 21 个 的罕见变异。21 个变异中有 4 个被归类为 PPV，包括 2 个移码、1 个错义和 1 个框内缺失。这 4 个 PPV 是在 4 名有小角膜或高度远视的先证者中发现的；其中 2 人发展为青光眼。对文献中 变异的系统综述表明，大多数杂合错义 PPV 位于连接蛋白结构域内。连接蛋白结构域外的所有截断与常染色体显性疾病相关，而结构域内的大多数截断与常染色体隐性 ODDD 相关。80.0%（116/145）的 PPV 患者存在眼部体征。在 116 名患者中，有 26.7%（31/116）观察到青光眼，其中 77.4%（24/31）的病例发生在≥10 岁的患者中。
眼部异常是与 PPV 最常见的相关体征，且发生青光眼的风险较高。需要进一步关注和阐明 PPV 的识别。
