a State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center , Sun Yat-Sen University , Guangzhou , China.
Curr Eye Res. 2018 Nov;43(11):1334-1341. doi: 10.1080/02713683.2018.1493129. Epub 2018 Jul 17.
Purpose/aim of the study: To conduct a survey spectrum of the PITX2, FOXC1, and PRDM5 genes to reveal genotype-phenotype correlations in a cohort of Southeastern Chinese patients with Axenfeld-Rieger syndrome (ARS).
A total of 20 probands with ARS were recruited in Southeast China. All patients underwent full ocular and systemic examinations. Sanger sequencing was used to analyze all coding regions of and regions adjacent to PITX2, FOXC1, and PRDM5 and 13 upstream regulatory elements of PITX2. Multiplex ligation-dependent probe amplification was performed to detect gross insertions and deletions in PITX2 and FOXC1. Quantitative polymerase chain reaction was used to detect copy number variations in regulatory elements of PITX2. A bioinformatics analysis was conducted to evaluate the pathogenicity of variants.
Eleven mutations, including eight novel mutations, were identified in PITX2. Seven of the mutations were truncations. A genotype-phenotype correlation analysis showed that 81.8% (9/11) of patients with mutations in PITX2 developed glaucoma before reaching 10 years old. The proportion of patients without detected mutations was only 33.3% (3/9, P = 0.0399). In patient G1399, ultrasound biomicroscopy revealed that the left eye exhibited a phenotype similar to aniridia with complete angle closure and a remaining stub of iris tissue.
This is the first genetic study of a cohort of Southeastern Chinese patients with ARS. Eight novel mutations were detected, expanding the mutation spectrum of PITX2. PITX2 may be a major candidate gene for ARS in Southeastern Chinese patients. Truncations may be the primary mutation type in PITX2. Glaucoma onset may be earlier in patients with mutations in PITX2 than in those without mutations in PITX2 and FOXC1. A block of the anterior chamber angle by the end of the iris might represent the main factor influencing the development of glaucoma in ARS patients with an asymmetric aniridia phenotype.
目的/研究目的：对东南中国 Axenfeld-Rieger 综合征（ARS）患者的 PITX2、FOXC1 和 PRDM5 基因进行调查，揭示基因型-表型相关性。
在中国东南地区共招募了 20 名 ARS 患者。所有患者均接受了全面的眼部和全身检查。使用 Sanger 测序分析 PITX2、FOXC1 和 PRDM5 的所有编码区和邻近区域以及 PITX2 的 13 个上游调控元件。使用多重连接依赖性探针扩增检测 PITX2 和 FOXC1 中的大片段插入和缺失。使用定量聚合酶链反应检测 PITX2 调控元件的拷贝数变异。进行生物信息学分析以评估变异的致病性。
在 PITX2 中发现了 11 个突变，包括 8 个新突变。7 个突变是截断突变。基因型-表型相关性分析表明，在 10 岁之前患有 PITX2 突变的患者中有 81.8%（9/11）患有青光眼。未检测到突变的患者比例仅为 33.3%（3/9，P=0.0399）。在患者 G1399 中，超声生物显微镜显示左眼表现出类似于无虹膜的表型，完全角关闭，虹膜组织残留一小段。
这是东南中国 ARS 患者队列的第一项遗传研究。检测到 8 个新突变，扩大了 PITX2 的突变谱。PITX2 可能是东南中国患者 ARS 的主要候选基因。截断可能是 PITX2 中的主要突变类型。与 PITX2 和 FOXC1 无突变的患者相比，PITX2 突变的患者发病年龄更早。虹膜末端对前房角的阻塞可能是影响 ARS 患者不对称无虹膜表型发展为青光眼的主要因素。
