Extensive Phenotype Analysis in a Familiy With Cone Rod Dystrophy Due to a Novel CRX Gene Mutation

Abstract

Purpose:: Cone and cone-rod dystrophies (CD/CRD) are genetically and clinically heterogeneous retinal dystrophies. An associated gene, the cone rod homeobox (CRX), codes for a retina specific transcription factor important for photoreceptor development and maintenance. Here we describe the detailed phenotypes of mutation carriers in a family with autosomal dominant CRD (adCRD), due to a novel frame-shift mutation in the CRX gene.

Methods:: Fourteen members from three generations of a family with adCRD were recruited and gave their informed consent to genetic testing. Mutation screening of the CRX gene and segregation analysis were performed. Six carriers of the mutation underwent detailed ophthalmologic examination and psychophysical and electrophysiological testing.

Results:: A novel frame-shift mutation in the CRX gene, c.636delC, was identified in a family with adCRD. The predicted truncated form ablates an important site for transactivation activity. Thus, CRX function is expected to be impaired. Family carrier analysis confirmed segregation of the mutation with the disease phenotype, but also identified additional mutation carriers. Detailed clinical phenotyping of 6 available mutation carriers revealed clinical and electrophysiological intrafamilial heterogeneity. In general the younger mutation carriers had no significant visual impairment and a normal fundus appearance. Electrophysiological testing showed reduced cone ERG (family branch A) and a negative ERG (familiy branch B) respectively. In contrast the parent generation suffered from severe visual impairment corresponding to advanced retinal degeneration. Also the parent generation showed heterogeneity of ERGs with reduced cone ERG (family branch A) and a negative ERG (familiy branch B) respectively. Interestingly one brother (branch B) showed a different phenotype. He had no apparent visual problems and only detailed examination of this 48 year old patient revealed a maculopathy.

Conclusions:: We identified a novel disease causing mutation in the CRX gene associated with adCRD. Strong intrafamilial phenotypic variability and potential non-penetrance were observed. Furthermore, we show here for the first time the coexistence of reduced cone and negative ERG in different individuals of the same family, all affected by the same mutation.

Keywords: retinal degenerations: hereditary • electroretinography: clinical • transcription factors