Autosomal dominant retinitis pigmentosa with intrafamilial variability and incomplete penetrance in two families carrying mutations in PRPF8.

PURPOSE: The aim of this study was to report detailed genotype/phenotype correlation in two British autosomal dominant retinitis pigmentosa (adRP) families with recently described mutations in PRPF8.

METHODS: Ten affected members from the two families (excluded for PRPF31 mutations) were assessed clinically. Seven subjects had fundus photography; some had electrophysiology, autofluorescence imaging, and visual field testing. Linkage analysis was performed from genomic DNA in one family. RNA was extracted from lymphocytes of the proband from both families, reverse transcribed into cDNA and subsequently screened for mutations in PRPF8. Segregation of mutations in each family was tested by direct genomic sequencing of the specific exons carrying the mutation.

RESULTS: All affected members complained of nyctalopia with variable age of onset. In the first family, there was marked variation in the clinical phenotype among affected individuals ranging from severe rod-cone dystrophy to a 67-year-old patient with a normal retinal appearance and mild rod dysfunction on scotopic electroretinography (ERG). The second family demonstrated similar variability and a history of a nonpenetrant individual. Linkage analysis in the first family showed strong evidence for linkage to markers on chromosome 17p implicating PRPF8 as a candidate gene. A c.6353 C>T change causing a nonconservative missense mutation p.S2118F was found in exon 38 of PRPF8 by direct sequencing of the cDNA. The mutation c.6930G>C (p.R2310S) was found in the second family.

CONCLUSIONS: This is the first report of marked intrafamilial variability associated with mutations in the PRPF8 gene, including incomplete penetrance. PRPF8 mutations should be suspected in patients with adRP and variable expressivity.