Zhou Lin, Wang Xiaoli, An Jingqi, Zhang Yao, He Mengxia, Tang Li
Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, 610041, China.
Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, 610041, China; Department of Ophthalmology, People's Hospital of Jianyang City, No. 180, the Road of Hospital, Jianyang, 641400, China.
Exp Eye Res. 2023 Jan;226:109307. doi: 10.1016/j.exer.2022.109307. Epub 2022 Nov 25.
PITX2 and FOXC1 are the most common pathogenic genes associated with Axenfeld-Rieger syndrome (ARS). In this study, we aimed to explore the variation spectrum of PITX2 and FOXC1 and their associated phenotype based on data from our study and previously reported literatures. Whole exome sequencing was performed on eight probands in our study. Multistep bioinformatic and co-segregation analyses were performed to detect pathogenic variants. Genotype-phenotype correlations of PITX2 and FOXC1 and the differences between them were determined. We detected three variants of FOXC1 and two variants of PITX2 in five unrelated families with ARS. Macular retinoschisis had been observed in AR1 with variant in PITX2 and it is not reported before. Additionally, a review of published literature and our study led to the identification of 593 families with variants of PITX2 or FOXC1, including 316 families with heterozygous variants in FOXC1, 251 families with heterozygous variants in PITX2, 13 families with variants in double genes, seven families with homozygous or compound heterozygous variants in FOXC1, and six families with variants in ADAMTS17, PRDM5, COL4A1 or CYP1B1. Significant differences were observed between the prevalence of missense and in-frame, truncation, and large deletion variants in PITX2 (32.00%, 42.67%, and 25.33%, respectively) and FOXC1 (34.49%, 35.13%, 30.38%, respectively) (p = 1.16E-43). Enrichment and frequency analyses revealed that missense variants were concentrated in the forkhead domain of FOXC1 (76.14%) and homeodomain of PITX2 (87.50%). The percentage of Caucasians with variants in FOXC1 was significantly higher than that of PITX2 (p = 2.00E-2). Significant differences between PITX2 and FOXC1 were observed in glaucoma (p = 3.00E-2), corectopia (p = 3.050E-6), and polycoria (p = 5.21E-08). Additionally, we observed a significant difference in best-corrected visual acuity (BCVA) between FOXC1 and PITX2 (p = 3.80E-2). Among all the family members with PITX2 or FOXC1 variants, the prevalence of systemic abnormalities was significantly higher in PITX2 than in FOXC1 (89.16% vs. 58.77%, p = 5.44E-17). In conclusion, macular retinoschisis as a novel phenotype had been observed in patient with variant in PITX2. Significant differences were detected in phenotypes and genotypes between PITX2 and FOXC1.
PITX2和FOXC1是与阿克森费尔德-里格尔综合征（ARS）相关的最常见致病基因。在本研究中，我们旨在基于我们的研究数据和先前报道的文献，探索PITX2和FOXC1的变异谱及其相关表型。对我们研究中的8名先证者进行了全外显子测序。进行了多步骤生物信息学和共分离分析以检测致病变异。确定了PITX2和FOXC1的基因型-表型相关性及其之间的差异。我们在5个患有ARS的无关家族中检测到3个FOXC1变异和2个PITX2变异。在携带PITX2变异的AR1患者中观察到黄斑视网膜劈裂，此前未见报道。此外，对已发表文献和我们的研究进行回顾后，共鉴定出593个携带PITX2或FOXC1变异的家族，其中包括316个携带FOXC1杂合变异的家族、251个携带PITX2杂合变异的家族、13个携带双基因变异的家族、7个携带FOXC1纯合或复合杂合变异的家族，以及6个携带ADAMTS17、PRDM5、COL4A1或CYP1B1变异的家族。PITX2（分别为32.00%、42.67%和25.33%）和FOXC1（分别为34.49%、35.13%、30.38%）中错义、框内、截短和大片段缺失变异的发生率存在显著差异（p = 1.16E-43）。富集和频率分析显示，错义变异集中在FOXC1的叉头结构域（76.14%）和PITX2的同源结构域（87.50%）。携带FOXC1变异的白种人百分比显著高于携带PITX2变异的白种人（p = 2.00E-2）。在青光眼（p = 3.00E-2）、瞳孔异位（p = 3.050E-6）和多瞳症（p = 5.21E-08）方面，PITX2和FOXC1之间存在显著差异。此外，我们观察到FOXC1和PITX2之间的最佳矫正视力（BCVA）存在显著差异（p = 3.80E-2）。在所有携带PITX2或FOXC1变异的家庭成员中，PITX2患者全身异常的发生率显著高于FOXC1患者（89.16%对58.77%，p = 5.44E-17）。总之 在携带PITX2变异的患者中观察到黄斑视网膜劈裂这一新表型。PITX2和FOXC1在表型和基因型上存在显著差异。
