Identification of novel variants in CYP1B1, PITX2, FOXC1, and PAX6 in congenital glaucoma and anterior segment dysgenesis

Abstract

Purpose : The current study was undertaken to identify the pathogenic mutations in the CYP1B1, PAX6, PITX2 and FOXC1 among the families and sporadic patients with primary congenital glaucoma and anterior segment dysgenesis which includes Axenfeld Rieger syndrome and aniridia.

Methods : The study included a cohort of probands of Pakistani families (n=80) diagnosed with PCG. A European cohort included PCG; (n=97; 4 families, 93 sporadic), Axenfeld Rieger syndrome (ARS; n=50) and aniridia (n=42; 11 families, 31 sporadic patients). Complete ophthalmic examination was performed for all the affected and unaffected family members and sporadic patients. Total genomic DNA was isolated from the peripheral blood and was used for the genetic analysis. PCR and Sanger sequencing were performed for the exons and intron-exon boundaries of the associated genes. In addition, MLPA was used to identify the deletions in the PAX6 in patients with aniridia.

Results : A total of 12 pathogenic CYP1B1 variants (including two novel mutations c.1044-1G>C & p.Ser464Thr) have been identified which co-segregated with the disease in the 25 Pakistani families. In two families, compound heterozygous mutations (p.Arg368His/p.Arg444*; p.Arg390His/p.Ser464Thr) were identified. In the European cohort, 15 CYP1B1 mutations have been identified, that included one novel variant (c.475C>T:p.Gln159*). In total CYP1B1 explains 31.25% of Pakistani and 27.8% of the European cohort however, 7.2% of the European cases revealed only single mutated allele and the other variant remained undetermined.

The FOXC1 & PITX2 genes explains 10% and 6% ARS cases respectively. Identified variants include 4 novel FOXC1 mutations (p.Gln200Argfs*109, p. Arg127Cys, P.Arg169Gln and p.Gly378_Gly380del) and three PITX2 novel mutations (p.Tyr109*, p.Thr122Pro and c.391-11A>G). In total 27 mutations were identified in the PAX6 gene (18 unique and 9 known) in the families and the sporadic patients with aniridia. Eleven families and 24 of 31 (77.4%) sporadic patients were solved with PAX6. Several mutations identified in the PAX6 among the families were de novo.

Conclusions : In summary, the identification of novel mutations in the current study expands the mutational spectrum of the CYP1B1 gene in the PCG patients and PITX2, FOXC1 and PAX6 in patients with ARS and aniridia respectively.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.