Uncovering the Novel Genetic Determinants of Primary Congenital Glaucoma in Pakistani Families

Primary congenital glaucoma (PCG) is an early-onset eye disorder, particularly prevalent in populations with high consanguinity rates. In Pakistan, approximately 63% of marriages are reported to be consanguineous, contributing to an increased burden of autosomal-recessive disorders. The genetic basis of PCG in the highly consanguineous Pakistani population is largely unexplored. This study was conducted to broaden the genetic landscape of PCG in families of Pakistani origin. PCG families identified through clinical characterization were recruited in the study. All probands were initially investigated for CYP1B1 mutations by targeted Sanger sequencing, followed by segregation analysis of the identified variants. Moreover, one family (PCG02) not linked to CYP1B1 was further subjected to a 250K SNP microarray and whole-exome sequencing (WES). The study participants comprised nine large, unrelated consanguineous and three PCG trio families collected from Pakistan. Nine identified variants were recurrent, whereas one previously unreported variant, CYP1B1 (NM_000104.4: c.1390T>C; p.Ser464Pro), was not found in any of the online databases such as gnomAD, ClinVar, and dbSNP, and was predicted to be deleterious by all the pathogenicity predicting tools. Furthermore, a plausible 2-Mb novel locus was identified on Chromosome 7q34 (139,681,371-141,507,822) (GRCh38/hg38) in family PCG02. The current study expands the mutation spectrum of CYP1B1 in the Pakistani population and highlights the genetic heterogeneity of the disease in this population.