Phenotypic variability of retinal dystrophies associated with mutations in CRX: with report of a novel macular dystrophy phenotype

Abstract

Purpose: To present the detailed clinical and molecular features of a series of patients with retinal dystrophies consequent upon mutations in the cone-rod homeobox (CRX) gene.

Methods: Eighteen patients from 11 families with retinal dystrophies and CRX mutations were identified; 7 from a large genetics database, 3 from results of exome analysis and 8 by direct sequencing of CRX in a selected panel of 65 cases. Detailed phenotyping included full clinical evaluation, electrophysiological testing, fundus photography, fundus autofluorescence imaging and optical coherence tomography. Bi-directional Sanger sequencing of all exons and intron-exon boundaries of CRX was performed on all 18 patients and available relatives.

Results: Eleven of 18 patients had generalized photoreceptor dysfunction and 7 had late onset macular dystrophy. Five families had more than 1 affected family member and within 3 families, significant phenotypic heterogeneity was found. Four patients presented in infancy with severe visual loss, featureless fundi, macular atrophy in 2 cases, and an undetectable ERG. Two patients presented aged 3 and 6 with reduced vision, evidence of severe retinal dysfunction rod more than cone on electroretinogram (ERG) and progressive deterioration to severe loss of vision by their mid-teens. Five patients presented 11-25 years old with reduced central vision and cone dysfunction greater than rod on ERG. Seven patients from 5 families presented with a bulls eye macular dystrophy at age 35-50 years. Electrophysiology showed an abnormal pattern ERG in all cases. The full field ERG showed reduced cone responses in 1 case and mild rod and cone dysfunction in 2 cases. Visual acuities at last review ranged from 0.2 to 1.3 logMAR. All 18 patients were heterozygous for a rare, likely disease-causing variant in CRX. Eight novel mutations were identified. A de novo mutation was confirmed in 3 families. There was no clear association between the severity, or age of onset and the type or position of CRX mutation.

Conclusions: Mutations in CRX demonstrate significant phenotypic heterogeneity both between and within pedigrees. A novel, late onset, predominantly macular dystrophy is described, extending the phenotypic spectrum associated with mutations in CRX.

Keywords: 696 retinal degenerations: hereditary • 537 gene screening