Genotype–phenotype associations in a large PRPH2 ‐related retinopathy cohort

Abstract

Molecular variant interpretation lacks disease gene‐specific cohorts for determining variant enrichment in disease versus healthy populations. To address the molecular etiology of retinal degeneration, specifically the PRPH2‐related retinopathies, we reviewed genotype and phenotype information obtained from 187 eyeGENE® participants from 161 families. Clinical details were provided by referring clinicians participating in the eyeGENE® Network. The cohort was sequenced for variants in PRPH2. Variant complementary DNA clusters and cohort frequency were compared to variants in public databases to help us to determine pathogenicity by current American College of Medical Genetics and Genomics/Association for Molecular Pathology interpretation criteria. The most frequent variant was c.828+3A>T, which affected 28 families (17.4%), and 25 of 79 (31.64%) variants were novel. The majority of missense variants clustered in the D2 intracellular loop of the peripherin‐2 protein, constituting a hotspot. Disease enrichment was noted for 23 (29.1%) of the variants. Hotspot and disease‐enrichment evidence modified variant classification for 16.5% of variants. The missense allele p.Arg172Trp was associated with a younger age of onset. To the best of our knowledge, this is the largest patient cohort review of PRPH2‐related retinopathy. Large disease gene‐specific cohorts permit gene modeling for hotspot and disease‐enrichment analysis, providing novel variant classification evidence, including for novel missense variants.

Genetic and Phenotypic Landscape of PRPH2-Associated Retinal Dystrophy in Japan

“…Previous reports have suggested association between the location of the variant in PRPH2 and clinical phenotype. Specifically, variants are mostly found in the D2 loop [13,43,[46][47][48], which is critical for protein-protein interactions. Variants that cause autosomal dominant RP tend to accumulate between Lys193 and Glu226 [3].…”

“…Particularly, missense mutations in Pro210 to Pro216 cause autosomal dominant RP [3]. Patients diagnosed with CRD, RP, and STGD tend to have variants in exon 1, whereas patients with Best disease and pattern dystrophy tend to have variants in exon 2 [13,43]. Patients with p.Arg172Trp present earlier onset than those with other alleles [43].…”

Childhood-onset genetic cone-rod photoreceptor diseases and underlying pathobiology

“…3 a) [36] . PRPH2 disease has genetic and phenotypic heterogeneity [36 , 37 , 46] . In CORD patients, mutations are most often associated with autosomal dominant inheritance [36 , 46] .…”

“…PRPH2 disease has genetic and phenotypic heterogeneity [36 , 37 , 46] . In CORD patients, mutations are most often associated with autosomal dominant inheritance [36 , 46] . Although genotype-phenotype correlations have been elusive, the majority of PRPH2 -CORD patients have mutations in exon 1, and the D2 loop of the protein, important for mediating protein-protein interactions, is a mutational hotspot in exon 1.…”

“…Although genotype-phenotype correlations have been elusive, the majority of PRPH2 -CORD patients have mutations in exon 1, and the D2 loop of the protein, important for mediating protein-protein interactions, is a mutational hotspot in exon 1. Additionally, p.Arg172Trp, a common mutation in PRPH2 that can cause a disease with early cone involvement, is generally associated with earlier age of onset compared to other PRPH2 variants [46] .…”