Modifier Genes for Glaucoma

Abstract

Purpose: : Open angle glaucoma (OAG) is a complex disease arising from gene-gene and/or gene-environment interactions. As a 1st step towards the characterization of modifier genes for glaucoma (modifier: variant of a gene, or locus, that modulates the expression of a primary target gene), we assessed if age-at-onset (AAO) had a genetic component in 2 huge autosomal dominant glaucoma families in which the primary disease-causing gene was associated with wide variability of the phenotype.

Methods: : More than 90 % of the subjects have been investigated on a yearly basis. Measures were extracted from ophthalmological charts, some going back to the 1950s, and entered in our genotype/phenotype database. Age-at-onset was defined as age at which ocular hypertension (OHT) or OAG was first detected. In the CA family, out of the 152 heterozygotes carrying the MYOC^K423E mutation, 104 were OAG or suspects (+ OHT) with treatment while 11 were suspects untreated. In the BV family, out of 41 FOXC1 duplication carriers, 28 were OAG or suspects with a treatment, 3 suspects untreated and 1 Axenfeld-Rieger anomaly. 12 of those also had iris hypoplasia and/or mesodermic tissue in the angle. Clusters were built using a neighboring approach.

Results: : Phenotypes ranged from OHT, juvenile open-angle glaucoma, primary open-angle glaucoma, to asymptomatic subjects. Age-at-onset ranged from 7 to 63 years old in the CA family and, from 5 to 75 years old in the BV kindred. In the CA family, we detected 7 distinct clusters relative to extreme AAO. Three of those encompassed branches of the pedigree in which the median for AAO calculated for the neighborhood of each one of the heterozygotes was younger than 26 years old (NM: neighborhood’s AAO median). These three clusters contained 35 MYOC^K423E heterozygotes. In the other 4 clusters (56 heterozygotes), at least half of the heterozygotes showed a median for age-at-onset (NM) >= 34 years of age. Five distinct clusters for AAO were detected in the BV pedigree. Three clusters (17 duplication carriers) had NM >= 39 years whereas the other 2 clusters (16 carriers) demonstrated a NM <= 25 years. Within the BV family, age-at-onset also displayed a tendency to decrease in younger generations.

Conclusions: : In the CA, our clustering approach strongly suggests that variability of age-at-onset was caused by a genetic component, supporting the presence of at least 1 modifier gene. In the BV, the wide variation of age-at-onset may be accounted for by a modifier gene and/or anticipation associated with potential de novo copy number variations within the FOXC1 duplicatedregion.

Keywords: gene modifiers • genetics • gene mapping