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

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

Cross sectional observational study.

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.

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.

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).

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.

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.

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