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

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, gender, laterality, age at diagnosis, age at first surgery, number of surgical procedures, number of 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 four 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 logMAR, p = 0.025), higher IOP at last follow-up (median 16 vs 12 mmHg, p < 0.001), greater need for surgical interventions (median 2 vs 1, p = 0.014) and IOP-lowering medications (median 2 vs 0, p = 0.005). NGS testing in CYP1B1-negative patients identified three novel heterozygous variants of uncertain significance in the TEK gene.

Conclusions: PCG 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.