Long term follow-up on a juvenile open angle glaucoma pedigree with a novel EFEMP1 mutation (c.1313, p.Tyr438Cys).

Purpose: Determine the genetic cause of glaucoma in a JOAG pedigree of European ancestry.

Design: Case series / pedigree analysis PARTICIPANTS: A three-generation JOAG pedigree METHODS: We obtained clinical data and tested DNA for mutations in known JOAG-causing genes with Sanger sequencing for MYOC and whole exome sequencing for EFEMP1. We assessed Identified mutations for pathogenicity by 1) frequency in control databases; 2) mutation analysis algorithms; 3) homology analyses; and 4) structural modeling of mutational effects on encoded proteins.

Main Outcome Measures: Detection of a mutation that is co-inherited with glaucoma in the JOAG pedigree. Secondary measures include descriptions of glaucoma phenotype (age at presentation, maximum intraocular pressure (IOP), progression rate, and response to therapy).

Results: Clinical data from an average follow-up of 11.5 ± 7.05 years was available from four family members with JOAG. Members of this pedigree had a mean age of diagnosis of 32.5 ± 8.6 years (range 25 to 43 years) and a mean maximum treated IOP of 32.3 ± 12.0 (range 20 to 50) mm Hg. Family members had visual field progression ranging from -0.25 to -1.1 dB / year and required an average of 1.8 ± 1.0 incisional glaucoma surgeries per eye for IOP control. No MYOC mutations were detected. A heterozygous missense mutation (c.1313A>G, p.Tyr438Cys) was detected in the EFEMP1 gene in all four family members with JOAG and is absent from control subjects. The p.Tyr438Cys mutation altered a highly conserved amino acid and was predicted to be pathogenic by 6 mutation analysis algorithms. Modeling of the p.Tyr438Cys mutation indicated it causes structural changes to EFEMP1 protein that are likely detrimental to its function.

Conclusions: This study identifies a novel mutation, p.Tyr438Cys, as the first known glaucoma-causing EFEMP1 mutation in a JOAG pedigree of European ancestry. Patients with the EFEMP1 mutation p.Tyr438Cys have an early-onset, severe glaucoma phenotype with high maximum IOPs that require surgical interventions and may have rapid progression. These data underscore the severity of this type of JOAG and the need for further research into its pathogenic mechanisms and therapeutic management.