Identification of a Novel Genetic Locus for Familial Cavitary Optic Disc Anomalies

Abstract

Purpose:: Congenital malformations of the optic disc include optic pits, optic nerve coloboma, and morning glory disc anomaly, which have been collectively referred to as cavitary optic disc anomalies. The purpose of this study was to identify the chromosomal location of the gene involved in the pathogenesis of cavitary optic disc anomaly in one large pedigree with an autosomal dominant pattern of disease.

Methods:: Optic disc photographs were examined for the presence of cavitary optic disc anomalies and affected family members were studied using linkage analysis with single nucleotide polymorphism (SNP) arrays and short tandem repeat polymorphism (STRP) genetic markers. Candidate genes were evaluated by automated sequencing of the coding regions.

Results:: Multipoint linkage analysis of SNP genotypes yielded a maximum nonparametric LOD score of 21.7 with markers located on chromosome 12q. Linkage was confirmed with 16 STRP markers in the 12q region. A maximum two point LOD score of 4.06 (theta=0) was obtained with marker D12S1700. The disease interval defined by observed recombinants was 9.1 cM (13.5 Mbp). Three candidate genes (GDF-11, NEUROD4, and WIF1) that lie within the chromosome 12q locus were evaluated as possible disease-causing genes, however, no mutations were detected in the coding sequence of these genes in affected family members.

Conclusions:: The discovery of the chromosomal location of a gene responsible for cavitary optic disc anomalies is a key step in identifying the genetic basis of this condition and may ultimately provide important insight into the pathogenesis of more common optic nerve diseases such as primary open angle glaucoma (POAG) and normal tension glaucoma.

Keywords: genetics • linkage analysis • optic disc