Genotype-phenotype associations in a large PRPH2-related retinopathy cohort

Abstract

Purpose : PRPH2 is associated with various retinopathies including macular dystrophy, cone-rod dystrophy, and retinitis pigmentosa. To better understand the phenotypic range and molecular etiology of PRPH2-related retinopathies, we reviewed genotype and phenotype information obtained from 187 eyeGENE^® participants from 161 families.

Methods : A blood sample was obtained from each participant for DNA extraction. Clinical details were provided by referring clinicians participating in the eyeGENE^® Network. The cohort was sequenced for variants in PRPH2. Variant cohort frequency was compared to healthy population frequencies in public databases to help determine pathogenicity.

Results : Average reported age of onset was 40 years of age. Stargardt disease was the most common provider-reported diagnosis in this cohort. Missense variants accounted for the most prevalent variant type, followed by truncating variants. The c.828+3A>T was the most frequent variant (28 families, 17.4%) in this cohort, of which 19 (67.9%) were diagnosed with Stargardt disease. Missense variants clustered in the D2 intracellular loop of the Peripherin-2 protein. Cone rod dystrophy was the most common diagnosis related to the p.Arg172Trp missense allele and was found to be associated with a younger age of onset.

Conclusions : To our knowledge, this is the largest patient cohort review of PRPH2-related retinopathy. As described in other studies, high variability among reported clinical diagnoses was noted within and between families. Missense alleles clustered in a functional domain important for protein-protein interaction. While variant class did not correlate with reported visual acuity, abnormal electroretinography, or age of onset, we found a significantly lower reported age of first symptoms for the p.Arg172Trp variant.

This is a 2020 ARVO Annual Meeting abstract.