Genetic Characterization Of Congenital And Early-Onset Glaucoma In A Jordanian Cohort Using Whole Exome Sequencing And Family-Based Pcr Analysis

To investigate the genetic basis of congenital and early-onset glaucoma in Jordanian patients using whole exome sequencing and to confirm variant segregation within affected families using PCR-based testing.

This study was conducted on Jordanian patients with congenital or early-onset glaucoma referred for genetic evaluation. Clinical assessment, whole exome sequencing, and molecular confirmation were performed through collaboration between ophthalmology department and a clinical genetics laboratory.

Seven patients diagnosed with congenital or early-onset glaucoma underwent detailed clinical evaluation, including age at diagnosis, intraocular pressure, and visual acuity. Clinical whole exome sequencing was performed using a phenotype-driven approach targeting glaucoma-associated genes. Identified pathogenic variants were interpreted according to ACMG/AMP guidelines. Targeted PCR-based testing was subsequently performed for available family members to assess variant segregation and carrier status.

Variants in the CYP1B1 gene were detected in all cases,including homozygous and compound heterozygous pathogenic mutations: c.869_870insC (p.Arg290ProfsTer37), c.1405C>T (p.Arg469Trp),and c.1310C>T (p.Pro437Leu).Most patients exhibited severe clinical manifestations,including elevated intraocular pressure and significant visual impairment,consistent with autosomal recessive primary congenital glaucoma.Additional variants of uncertain or likely pathogenic significance were identified in ASB10 and PEX13 in one patient,without clear phenotypic correlation.PCR-based family testing confirmed segregation of pathogenic CYP1B1 variants with disease status and identified heterozygous carrier parents and relatives,supporting AR inheritance.

CYP1B1 is the predominant genetic cause of congenital and early-onset glaucoma in this Jordanian cohort. The combination of whole exome sequencing and targeted PCR-based family testing provides robust molecular confirmation, facilitates accurate genetic counseling, and enables identification of carriers within affected families. This integrated approach supports early diagnosis and informed clinical management in populations with a high prevalence of autosomal recessive disease.