LTBP2 Sequence Variants in Patients with Congenital Glaucoma

Abstract

Primary congenital glaucoma is a genetically and phenotypically heterogeneous condition that can cause irreversible blindness in children. Recently null mutations in LTBP2 have been shown to be responsible for autosomal recessive congenital glaucoma in Pakistani, Iranian and Gypsy/Roma populations. Null mutations in LTBP2 have also been shown to cause glaucoma associated with other ocular findings of megalocornea and spherophakis. The purpose of this study is to determine if LTBP2 sequence variants are responsible for congenital glaucoma in a US clinic-based population. 37 individuals with congenital glaucoma defined as glaucoma developing before age 3 without evidence of anterior segment dysgenesis were included in this study. 13 patients also had affected family members while the remaining were sporadic cases. The entire coding sequence of the LTBP2 gene including all exons and flanking introns (up to 50 bases) were directly sequenced from genomic DNA using the ABI3100 sequence analyzer and BIGDYE chemistries. Sequence analysis was done using the contig alignment function of Vector NTI. Each exon was sequenced in both the forward and reverse directions. 46 LTBP2 sequence variants were found in this population of patients: 6 nonsynonymous variants, (3 were novel); 1 in-frame duplication (c.782-799dup(agccgccagcaccacagt) p.S267X); 12 synonymous variants (6 were novel), and 27 intronic variants (11 novel). One patient was homozygous for a missense change causing a highly conserved Arginine to be replaced by a Methionine (Arg37Met, rs934996). No patient had a combination of heterozygous changes likely to be disease causing. In this study we have identified probable disease causing mutations in 1/37 US congenital glaucoma patients suggesting that mutations in LTBP2 are a rare cause of this form of glaucoma in ethnically heterogeneous populations. Further analysis of this gene in other populations would be of interest.

Keywords: Genetics, Gene screening, Mutations