Two novel variants in gene: a major contributor of autosomal recessive primary congenital glaucoma with allelic heterogeneity in Pakistani patients.

Aim: To find the mutations associated with primary congenital glaucoma (PCG) in Pakistani consanguineous pedigrees.

Methods: After getting informed consent, 11 consanguineous pedigrees belonging to different ethnic groups were enrolled. Detailed medical history was recorded and pedigrees were drawn. The standard ophthalmological examination was done to characterize the phenotype. Genomic DNA was extracted from 10 mL whole blood and coding exons and exon intron boundaries of gene were directly sequenced. Bioinformatics tools were used to model the mutant protein and predict the effect of novel variants on protein structure and function.

Results: Sequencing analysis revealed 5 different variants in 7 families (7/11; 64%), including two novel variants. A common mutation, p.R390H was found in four families, whereas p.P437L was found once in a family. Two novel variants, a homozygous non sense variant p.L13* and a compound heterozygous variant, p.P350T along with p.V364M were segregating with PCG in two families. All the patients had the variable onset and severity of the disease. The success rate of early clinical interventions was observed dependent on mutation types and position. Two different haplotypes were associated with frequently found mutation, p.R390H.

Conclusion: Identification of novel variants reassert the genetic heterogeneity of Pakistani PCG patients. The patients with missense mutations show severe phenotypic presentations and poor vision after surgical interventions as compare to patients with null variants. This may help to better understand the role of mutations in the development of PCG and its course of pathogenicity.