A Tyr368His RPE65 Founder Mutation is Associated with a Variably Expressed Early-onset Retinal Dystrophy in 10 Families of a Genetically Isolated Population

Abstract

Abstract: : Purpose: To investigate the clinical appearance and molecular cause of early onset retinal dystrophy in a genetic isolate. Methods: Fourteen patients from 10 families were examined clinically, with a mean follow-up of 9 years. Based on the observed ophthalmologic features, involvement of the RPE65 gene was suspected. Homozygosity-by-descent analysis was performed using marker D1S2803 located very near the RPE65 gene. Exons of the RPE65 gene were sequenced. Results: All patients showed moderate to severe visual acuity (VA) loss since birth indicative of an early-onset retinal dystrophy. Twelve patients of nine families are homozygous for a RPE65 1156T→C nucleotide change resulting in a Tyr368His mutation. One patient is compound heterozygous for this mutation and an IVS1+5g→a splice site mutation. One-third of patients homozygous for the Tyr368His mutation on follow-up showed a relatively stable VA, in one-third of patients VA had deteriorated, and in the remaining patients VA had improved. Three out of 96 healthy individuals from the genetic isolate and none of 92 controls from the general Dutch population were heterozygous for the Tyr368His mutation. Conclusions: Homozygosity of the Tyr368His RPE65 founder mutation is associated with congenital rod-cone dystrophy with a variable visual acuity prognosis. Based on mutation analysis and theoretical considerations, we estimate the carrier frequency in this population to be ~1 in 20 individuals rendering a significant risk of blindness in offspring of patients, their heterozygous siblings and other heterozygous individuals of the genetic isolate.

Keywords: retinal degenerations: hereditary • linkage analysis