A novel indel CYP1B1 variant in a large multigenerational Pakistani family expands the mutation spectrum of primary congenital glaucoma

Background: Primary congenital glaucoma (PCG) is a rare genetic disorder affecting the ocular drainage system, accounting for only 0.01–0.04% blindness related cases. However, its prevalence varies significantly in ethnicities, being higher in populations that practice consanguinity, such as Pakistan where approximately 70% of marriages are consanguineous. This study aimed to investigate the genetic cause of PCG in a large Pakistani family with autosomal recessive inheritance. Methods: A large multigenerational family having multiple consanguineous marriages resulting in fifteen affected individuals was recruited for the current study. All relevant clinical information was collected and venous blood drawn for further genetic analysis. The family was subjected to direct sequencing of CYP1B1 which is the most plausible candidate of PCG. The resulting candidate variant was further confirmed using BanII restriction enzyme analysis. Results: The sequence analysis revealed a novel indel (c.862delinsCC) in exon 2 of the CYP1B1 gene, resulting in a frameshift mutation (p.Ala288Profs*39) thereby creating a premature stop codon 39 amino acids downstream. BanII restriction enzyme analysis further confirmed this putative null mutation co-segregating with the disease trait in all the family members of the pedigree. Conclusion: The novel indel, putative null mutation causes PCG related disease phenotypes. This genetic variant has a high penetrance but shows variable expressivity among the affected members of the family. This putative null mutation enhances the mutation spectrum of CYP1B1 globally and from Pakistan in particular.