Influence of CYP1B1 Variants on Phenotypic Characteristics and Therapeutic Outcomes in Primary Congenital Glaucoma

IF 3.2 Q1 OPHTHALMOLOGY

Ophthalmology. Glaucoma Pub Date : 2025-09-01 DOI:10.1016/j.ogla.2025.04.012

Rita Rodrigues MD , David Alves MD , João Esteves-Leandro MD , Marta Silva MD , João Barbosa-Breda MD, PhD , João Tavares-Ferreira MD , Joana Araújo MD , Susana Fernandes PhD , Renata Oliveira MD , António Melo MD , Flávio Alves MD , Augusto Magalhães MD , José Cotta MD , Sérgio Estrela-Silva MD

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引用次数: 0

Abstract

Purpose

To identify CYP1B1 variants in primary congenital glaucoma (PCG) patients from Northern Portugal and examine genotype–phenotype correlations.

Design

Cross sectional observational study.

Participants

Seventy-one patients diagnosed and treated for PCG at ULS São João, Porto, Portugal, were included. These patients met the following criteria: available genetic testing data, a minimum follow-up period of 1 year, and the last appointment between January 2022 and January 2024.

Methods

Demographic and clinical data were collected. CYP1B1 variants were screened using DNA sequencing. A next-generation sequencing (NGS) glaucoma panel was performed in patients with heterozygous or absent CYP1B1 variants in the screening. Genotype–phenotype correlations were assessed by comparing clinical characteristics between patients with identified biallelic plausible disease-causing variants in CYP1B1 variants and those with negative genetic testing results.

Main Outcome Measures

CYP1B1 variants, sex, laterality, age at diagnosis, age at first surgery, number of surgical procedures, number of intraocular pressure (IOP)-lowering medications, IOP at last follow-up, and final best-corrected visual acuity (BCVA).

Results

Sixty-six unrelated probands and 5 affected relatives (133 eyes) were analyzed. Two plausible disease-causing CYP1B1 variants were identified in 60.6% (43/71) of patients. Nineteen distinct CYP1B1 variants were identified, including 4 novel variants. The most frequent variants were c.535del (43.5%) and c.1200_1209dup (28.2%). Compared with negative genetic testing group (n = 22), patients with CYP1B1 variants (n = 43) showed significantly higher rates of bilateral disease (100% vs. 68%, P < 0.001), earlier disease onset (median 0 vs. 5.5 months, P < 0.001), poorer final BCVA (median 0.5 vs. 0.25 logarithm of the minimum angle of resolution, P = 0.025), higher IOP at last follow-up (median 16 vs. 12 mmHg, P < 0.001), and greater need for surgical interventions (median 2 vs. 1, P = 0.014) and IOP-lowering medications (median 2 vs. 0, P = 0.005). Next-generation sequencing testing in CYP1B1-negative patients identified 3 novel heterozygous variants of uncertain significance in the TEK gene.

Conclusions

Primary congenital glaucoma patients from Northern Portugal with CYP1B1 variants are more likely to present with bilateral disease, earlier onset, and a more severe clinical phenotype, suggesting a strong genotype–phenotype correlation.

Financial Disclosure(s)

The authors have no proprietary or commercial interest in any materials discussed in this article.

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CYP1B1变异对原发性先天性青光眼表型特征和治疗结果的影响

目的：鉴定葡萄牙北部原发性先天性青光眼（PCG）患者的CYP1B1变异，并检查基因型与表型的相关性。设计：横断面观察性研究。参与者：71例在葡萄牙波尔图的 o jo s诊断和治疗的PCG患者。这些患者符合以下标准：可获得基因检测数据，至少随访1年，最后一次预约时间为2022年1月至2024年1月。方法：收集人口学和临床资料。使用DNA测序筛选CYP1B1变异体。下一代测序（NGS）青光眼小组在筛选中杂合或缺失CYP1B1变异的患者中进行。通过比较在CYP1B1变异中确定的双等位基因似是而非的致病变异的患者与基因检测结果为阴性的患者的临床特征，评估基因型-表型相关性。主要观察指标：CYP1B1变异、性别、侧边、诊断时年龄、首次手术年龄、手术次数、降眼压药物次数、最后随访时眼压、最终最佳矫正视力（BCVA）。结果：对66例无血缘关系先证者和5例患病亲属（133眼）进行分析。60.6%（43/71）的患者发现了两种可能致病的CYP1B1变异。鉴定出19种不同的CYP1B1变异，包括4种新的变异。最常见的变异是c.535del（43.5%）和c.1200_1209dup（28.2%）。与基因检测阴性组（n=22）相比，CYP1B1变异患者（n=43）的双侧疾病发生率明显更高(100% vs 68%， p结论：来自葡萄牙北部的CYP1B1变异的PCG患者更容易出现双侧疾病，发病更早，临床表型更严重，提示基因型-表型相关性强。

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