Pericentral Retinitis Pigmentosa is associated with a high prevalence of USH2A pathogenic variants in an Italian cohort of patients

Purpose : Pericentral Retinitis Pigmentosa (pericentral RP) is an atypical form of RP characterized by bone-spicule pigmentation and/or atrophy confined in the near mid-periphery of the retina. In contrast to classic RP, the far periphery is better preserved. We performed a detailed clinical and molecular analysis of a cohort of Italian subjects with pericentral RP to determine the phenotypic features and genetic bases of the disease. Methods : Fifty-four subjects (from 48 unrelated families) with pericentral RP underwent a complete ophthalmological examination and genetic analysis by clinical exome or retinopathy gene panel sequencing. The cohort included both cases with isolated RP (n = 42) as well as patients presenting syndromic forms (n = 12). Results : The patients had a mean Best Corrected Visual Acuity (BCVA) of 0.7 ± 0.3 decimals, ranging from light perception to 20/20 in both eyes, and the majority (85%) achieved a BCVA of 20/40 or better in at least one eye. Fundus examination revealed a normal-appearing disk and macula, mid-peripheral bone spicule pigmentation and a normal far periphery in all patients. Almost 50% of patients showed a pericentral field loss at Goldman visual field test. Dark-adapted ERG responses were reduced in 39 patients (72%) and were below noise level in 15 subjects (28%). Light-adapted 3.0 and 30Hz responses were subnormal in all patients but one, who showed normal amplitudes. Disease-causative variants were identified in 63% of cases. Fourteen of the 34 likely pathogenic variants were novel. We found a significant enrichment of pathogenic variants in USH2A (41% of cases) and in other genes causing syndromic RP. Following molecular analysis (identification of variants in PEX1), one patient who presented amelogenesis imperfecta and nail abnormalities, in addition to RP and hearing loss, was retrospectively diagnosed with Heimler Syndrome. Conclusions : We conclude that pericentral RP is a rather uncommon, mild RP subtype. A significant percentage of the cases reported herein were identified in the context of syndromic forms, namely Usher Syndrome type 2. In agreement, mutations in USH2A were the most recurrent cause of pericentral RP in the analyzed cohort. The current study extends the spectrum of genes associated with this atypical RP form and provides insights on its clinical presentation.