Characterization of PROM1 p.Arg373Cys Variant in a Cohort of Chinese Patients: Macular Dystrophy Plus Peripheral Bone-Spicule Degeneration

Abstract

The PROM1 p.Arg373Cys variant has been reported to cause dominant Stargardt disease, cone-rod dystrophy, and occasionally retinitis pigmentosa. This study aimed to evaluate the common phenotype associated with this variant in Chinese patients. METHODS.Variants in PROM1 were collected from in-house exome data. Potential pathogenic variants were selected, verified, and then confirmed by Sanger sequencing and co-segregation analysis. Ocular phenotypes were reviewed and further clarified by ophthalmologic examinations. RESULTS.The heterozygous c.1117C>T (p.Arg373Cys) variant was identified in four unrelated families, and biallelic variants were detected in three families. Of the 10 patients from four families with the p.Arg373Cys variant, six patients from three families who underwent full fundus examination demonstrated various degrees of macular dystrophy, as well as typical bone-spicule pigment deposits in the peripheral retina. The remaining four patients did not undergo a full dilated fundus examination. A relatively preserved zone was observed between the macular and peripheral lesions. Electroretinography results showed cone and rod involvement in three patients. CONCLUSIONS.Unlike Stargardt disease alone, which was considered to be the main phenotype of the p.Arg373Cys variant, all patients with full-field fundus examination in our study presented with macular dystrophy plus peripheral retinopathy resembling retinitis pigmentosa. Different phenotypes associated with the p.Arg373Cys variant may actually reflect different stages of the same disease: a predominant central cone phenotype at an early stage and peripheral rod involvement as degeneration progresses. Evaluation of the full fundus, especially the peripheral region in additional patients, is expected to confirm our findings.

Genetic and clinical characteristics of PROM1-related retinal degeneration in Korean

“…These findings indicate a considerable prevalence of autosomal dominant PROM1 p.R373C variants within Korean patients of PROM1-related IRD. Interestingly, according to previous reports, the p.R373C variant was found in six out of eight Japanese families with PROM1-related IRD 18 and in four out of seven Chinese families with PROM1-related IRD 19 , which closely aligns with the results of the present study. These findings suggest a higher proportion of autosomal dominant PROM1 p.R373C variants in Asian populations than in Western populations.…”

“…Although studies have investigated PROM1-related retinal degeneration in various populations, few have focused on the genetic variants and clinical characteristics of PROM1-associated retinal degeneration within the Asian population 18 , 19 . Asian populations have a distinct genetic architecture influenced by unique ancestral lineages; therefore, it is crucial to understand the distribution of the variants and their effect on the clinical manifestation of IRDs within this population.…”

Landscape of pathogenic variants in six pre‐mRNA processing factor genes for retinitis pigmentosa based on large in‐house data sets and database comparisons

“…2018; Luo et al. 2021; 2021a, b, c). However, the findings of this study showed that patients with PRPF gene‐related ADRP had more severe macular involvement (Fig.…”

“…2). In the studies of Witkin et al (2006) and Birch et al (2013), it was found that the thickness of the outer retinal and the width of EZ could related RP are mainly distributed in the far-peripheral retina (Wang et al 2021c). In the current study, through a wide-field SLO examination, it was found that bone spicule-like pigmentation in patients with ADRP related to PRPF8 and PRPF31 was observed from the mid-to the farperipheral retina (Figs.…”

Clinical and Genetic Analysis ofRDH12-Associated Retinopathy in 27 Chinese Families: A Hypomorphic Allele Leads to Cone-Rod Dystrophy

“…Reports suggest that a single heterozygous variant of the autosomal recessive genes may cause ad-related retinopathy, such as, the heterozygous p.(Arg373Cys) variant in PROM1 , 42 – 44 heterozygous p.(Asp477Gly) variant in RPE65 , 45 – 47 and heterozygous substitution of p.Arg838 in GUCY2D . 48 – 51 Similarly, heterozygous frameshift variants of RDH12 have been identified in patients with adRP.…”