Determination of Phenotype Using Genetic Analysis in Hereditary Conditions With Incomplete Penetrance and Variable Expressivity: The Autosomal Dominant Optic Atrophy (ADOA) Story

Abstract

Abstract: : Purpose: Autosomal dominant optic atrophy (ADOA), or Kjer type optic atrophy, is a hereditary disorder associated with variable loss of vision, anomalous color vision and contrast sensitivity, and visual field defects. The penetrance is incomplete and the expressivity variable. One gene and one additional locus have been described for the uncomplicated form of ADOA: OPA1 maps to chromosome 3q28–29, and a second locus maps to chromosome 18q12.2 to 12.3. We describe a family with 5 affected individuals. Electroretinogram (ERG) abnormalities were noted in some family members, some of which also had optic atrophy. The purpose of the study is to identify the causative gene in this family, and to characterize the phenotype in affected members. Methods: The family was ascertained and clinical data collected (including psychophysical and electrodiagnostic testing) on 16 family members. Blood samples were drawn for DNA. Linkage analysis of the two known loci and direct sequencing of the OPA1 gene were performed. Results: A Q217term mutation in the OPA1 gene was identified in 4 of the 5 affected individuals with unambiguous optic atrophy. The mutation did not segregate with the ERG abnormalities in this family. The fifth individual represents a phenocopy of the disease. Conclusions: ADOA in this family is due to an OPA1 mutation that does not segregate with the ERG abnormalities, suggesting that these abnormalities are not associated with ADOA. In conditions demonstrating incomplete penetrance and variable expressivity, the determination of associated features can be difficult. Identification of gene mutations is a critical parameter to accurately describe the phenotype of hereditary conditions. This is essential in making proper diagnoses and counseling of family members.

Keywords: genetics • electroretinography: clinical • neuro-ophthalmology: optic nerve