Clinical characterization and genotype-phenotype correlation in RPGRIP1 patients with autosomal recessive early onset retinal degeneration

Abstract

Purpose : RPGRIP1 encodes a ciliary protein expressed in photoreceptor cilia. It contains a C-terminal RPGR interacting domain and two C2 domains, which are known to be involved in signal transduction or membrane trafficking. Mutations in this gene are known to cause ~5% of Leber congenital amaurosis (LCA) worldwide, but are also associated with cone-rod dystrophy (CRD) and retinitis pigmentosa (RP) phenotypes. Our purpose was to clinically characterize RPGRIP1 patients in the Israeli and Palestinian populations, perform an extensive literature search to collect clinical data of additional RPGRIP1 patients. From this combined data set we attempted to identify common clinical features and sought genotype-phenotype correlations.

Methods : Clinical data from 16 patients from our cohort and 175 RPGRIP1 patients previously reported by other groups was collected including (when available) family history, best corrected visual acuity (BCVA), refraction, full ocular examination, ocular coherence tomography (OCT) imaging, visual fields (VF) and full-field electroretinography (ffERG).

Results : Out of 191 patients, the majority (158, 83%) were diagnosed with LCA, 9% with CRD, and 8% with RP. Age of onset in all patients for whom this data was reported was during childhood (n=121), all had moderate myopia (n=49, Mean of -4.8D), and average BCVA was 0.06 Snellen (n=116; only 10 patients had VA>0.1). On funduscopy, narrowing of blood vessels was noted early in life. Most patients had mild bone spicule-like pigmentation starting in the midperiphery and later encroaching upon the posterior pole. OCT shows thinning of the ONL, while cystoid changes and edema are relatively rare. VF are usually very constricted from early-on. FFERG responses were non-detectable in the vast majority of cases. Most of the mutations are predicted to be null (297 alleles) and 85 alleles harbored missense mutations. Missense mutations were identified only in two regions: the RPGR interacting domain and the C2 domains. Patients with 2 missense mutations tended to show a milder course of disease (CRD/RP and not LCA).

Conclusions : RPGRIP1 usually causes severe retinal degeneration at an early age, with rapid disease progression. Most patients manifest a LCA phenotype. Missense changes in the conserved domains are usually associated with a less severe disease phenotype (CRD/RP) than null-predicted mutations.

This is a 2021 ARVO Annual Meeting abstract.