The distinct clinical features of adult-onset retinal dystrophy associated with carboxyl mutations in the RPGR-ORF15 gene

Abstract

Purpose: Mutations in the carboxyl end of the retinitis pigmentosa GTPase regulator (RPGR) exon 15 (ORF15) gene are usually associated with severe rod-cone dystrophy. This observational case series describes the distinct cone and cone-rod dystrophy phenotype associated with mutations in the carboxyl end of RPGR-ORF15.

Methods: Probands who presented with signs and symptoms in keeping with macular or cone/cone-rod dystrophy, and a recessive inheritance pattern were included. Clinical assessment included fundus autofluorescence (AF); optical coherence tomography (OCT); and pattern (PERG) and full-field electroretinography (ERG). Leukocyte DNA from 2 simplex males was analyzed using high-throughput sequencing (exon capture by SureSelectXT Human All Exon V5, Agilent; sequencing by HiSeq2000, Illumina). Six further males with similar clinical features and 2 female carriers were analysed following PCR of the 3’ end of ORF15 using dideoxynucleotide Sanger sequencing.

Results: Seven unrelated probands, and 1 related hemizygous male, were found to have 5 putative mutations in the carboxyl end of ORF15: (c.3092delA; c.3096_3097delGG; c.3178_3179delAG; c.3317dupA; c.3320_3323delCAGT). All were myopic and presented with adult-onset reduction of visual acuity (age 32-44, median 37 years; 20/30-20/600) and defective color vision. Fundus examination showed variable degrees of macular atrophy. There were bilateral paracentral rings of increased macular AF. The OCT showed loss of outer retinal bands within the AF rings. PERG and ERG showed macular and generalized cone dysfunction in all 8 patients, with additional rod dysfunction in 7 patients. Both carriers did not show significant fundus or ERG abnormalities.

Conclusions: Male patients with retinal dystrophy associated with RPGR mutations usually manifest severe rod-cone dystrophy. However, those with mutations close to the 3' end of ORF15 can have a less severe adult-onset cone or cone-rod dystrophy. This phenotype appears to occur with frameshifting mutations at or 3’ to c.3092 of the retinal transcript (NM_001034853), consistent with previous reports. This suggests that normal photoreceptor function, particularly in the cones, requires an intact sequence carboxyl to the polyglutamate repeat. Such cases are good candidates for gene-replacement therapy as early intervention may arrest progression before the onset of significant visual loss.