Submission Details

PCARE (photoreceptor cilium actin regulator, previously known as c2orf71) was first reported in relation to autosomal recessive retinopathy in published research articles in 2010 (Collin et al, PMID: 20398884; Nishimura et al, PMID: 20398886). The disease entity associated with PCARE was initially named retinitis pigmentosa 54 (MIM# 613428). However, to accommodate the variability in retinal phenotypes observed in patients with variants in this gene, the disease entity used for this curation is “PCARE-related retinopathy” (MONDO:0800404).

Thirteen probands with 14 unique variants (8 nonsense, 5 frameshift, 1 missense) reported in three publications were curated (Collin et al, 2010, PMID: 20398884; Nishimura et al, 2010, PMID: 20398886; Gerth-Kahlert et al, 2017, PMID: 28763557). In addition, segregation evidence based on published LOD scores from 4 large families was included (Collin et al, 2010, PMID: 20398884; Nishimura et al, 2010, PMID: 20398886). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of function.

This gene-disease relationship is also supported by experimental evidence including the biochemical function of PCARE, protein interaction with the products of other genes known to be involved in retinopathy, its expression in the photoreceptor layer of the retina, and the phenotype observed in non-human model organisms. Evidence supports that PCARE plays an important role in delivering actin associated components to the base of the photoreceptor outer segments to regulate the initial development of OS disks (Corral-Serrano et al 2020, PMID: 32312818). It has been shown to be expressed in retina in human and mice (Collin et al, 2010, PMID: 20398884; Nishimura et al, 2010, PMID: 20398886; Kevany et al, 2015, PMID: 25616964). Yest two-hybrid experiments show interaction with OFD1, CEP290 and CEP 250 (Corral-Serrano et al 2020, PMID: 32312818). Evidence in non-human organisms include the phenotype observed in a zebrafish morpholino knockdown (Nishimura et al, 2010, PMID: 20398886); a mouse knock out with severe retinal degeneration (Kevany ey al, 2015, PMID: 25616964); a zebrafish with CRISPR/Cas9-mediated disruption of pcare1, abnormal photoreceptor outer segments, and reduced behavioral and electrophysiological response to light (Corral-Serrano et al 2018, PMID: 29946172); and the identification of a homozygous frameshift variant in PCARE in Gordon Setter and Irish Setter dogs with progressive retinal atrophy (Downs et al, 2013, PMID: 22686255).

In summary, PCARE (c2orf71) is definitively associated with autosomal recessive PCARE-related retinopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification has been approved by the ClinGen Retina GCEP on October 6th, 2022 (SOP Version 9).