Familial cavitary optic disk anomalies: identification of a novel genetic locus

Abstract

Purpose: To identify the chromosomal location of the gene involved in the pathogenesis of cavitary optic disk anomalies in a large pedigree with autosomal dominant inheritance of disease.

Design: Linkage analysis of a pedigree affected with cavitary optic disk anomalies.

Methods: Optic disk photographs were examined for the presence of cavitary optic disk anomalies. Sixteen affected family members and one obligate carrier were identified and studied with linkage analysis using both microarrays of single nucleotide polymorphisms (SNPs) and short tandem repeat polymorphism (STRP) markers.

Results: Multipoint linkage analysis of SNP genotypes yielded a maximum nonparametric logarithm of the odds (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 is 9.1 cM, which corresponds to 13.5 Mbp. Three candidate genes (GDF-11, NEUROD4, and WIF1) in the chromosome 12q locus were evaluated as possible disease-causing genes. No mutations were detected in the coding sequence of these genes.

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

Figure 1

Pedigree affected with cavitary optic disc anomaly. Individuals found to be clinically affected with cavitary anomalies of the optic nerve including optic pits, optic nerve colobomas, or morning glory disc anomaly are represented by black symbols while unaffected individuals are depicted with open symbols. Family members who are obligate carriers are indicated with grey symbols. These family members were either unavailable for examination or they did not meet clinical criteria for having definite cavitary optic disc anomalies, however, they are obligate carriers by virtue of having offspring with cavitary optic disc anomalies. Individuals that are deceased are marked with a slash. Patients who were examined by the authors are indicated with an “X”.

Figure 2

Appearance of cavitary optic disc anomalies. Affected members of the cavitary optic disc anomaly pedigree have abnormal optic discs with features of optic pits, optic nerve colobomas, and morning glory disc anomaly. A. The left optic disc of patient IV-11 is deeply excavated and exhibits features of an optic nerve coloboma and optic pit. B. The right optic disc of patient IV-8 is anomalous and has some characteristics that are similar to that of the morning glory disc anomaly including abnormal, radial vessels and a central tuft of glial tissue.

Figure 2

Appearance of cavitary optic disc anomalies. Affected members of the cavitary optic disc anomaly pedigree have abnormal optic discs with features of optic pits, optic nerve colobomas, and morning glory disc anomaly. A. The left optic disc of patient IV-11 is deeply excavated and exhibits features of an optic nerve coloboma and optic pit. B. The right optic disc of patient IV-8 is anomalous and has some characteristics that are similar to that of the morning glory disc anomaly including abnormal, radial vessels and a central tuft of glial tissue.

Figure 3

Cavitary optic disc anomalies linkage analysis: Two point linkage data and analysis of recombinant individuals. Sixteen genetic markers from the long arm of chromosome 12 are listed on the left of the figure with the most centromeric marker at the top. The physical position of the STRP markers is based on NCBI Build 36.1 of the human genome and the genetic position of the markers is based on the Marshfield map (http://www.ncbi.nlm.nih.gov/mapview/). The maximum LOD score (Zmax) is given for each marker as well as the recombination frequency at which the Zmax occurred. The patient designations correspond to those in Figure 1. A black box indicates that during the meiosis that gave rise to the individual (or that individual’s ancestor), an informative recombination event occurred between the marker and the disease gene. Parents were not available from any of the recombinant individuals. Consequently, it is not possible to identify those markers in which no recombinations occurred between the disease gene and the markers. The recombination events summarized in this figure suggest that the disease-causing mutations lie within the 9.1 cM (13.5 Mbp) interval bounded by D12S1618 and D12S1702.