No abstract

Refractive errors, in particular myopia, are common in IRD. The bipolar synapse and the inner and outer segments of the photoreceptor may serve as critical sites for myopia development.

Purpose To identify the genetic cause and describe the phenotype in four families with autosomal recessive retinitis pigmentosa (arRP) that can be associated with pseudocoloboma. Design Case series. Subjects Seven patients from four unrelated families with arRP of which three patients had bilateral early-onset macular pseudocoloboma. Methods We performed homozygosity mapping and whole-exome sequencing (WES) in five probands and two unaffected family members of four unrelated families. Subsequently, Sanger sequencing and segregation analysis were done in additional family members. We reviewed the medical history of individuals carrying IDH3A variants and performed additional ophthalmic examinations, including full-field electroretinography (ffERG), fundus photography, fundus autofluorescence imaging and optical coherence tomography. Main Outcome Measures IDH3A variants, age at diagnosis, visual acuity, fundus appearance, visual field, ffERG, fundus autofluorescence and OCT findings. Results We identified seven different variants in IDH3A in four unrelated families, i.e. five missense, one nonsense and one frameshift variant. All subjects developed symptoms early in life ranging from night blindness to decreased visual acuity and were diagnosed between the ages of one and 11 years. Four subjects with biallelic IDH3A variants displayed a typical arRP phenotype and three subjects were diagnosed with arRP and pseudocoloboma of the macula. Conclusions IDH3A variants were identified as a novel cause of typical arRP, in some individuals associated with macular pseudocoloboma. We observed both phenotypes in two siblings carrying the same compound heterozygous variants, which could be explained by variable disease expression and warrants caution when making assertions about genotype-phenotype correlations.