Dataset Information

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

ABSTRACT:

Purpose

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.

SUBMITTER: Wang Y

PROVIDER: S-EPMC8142721 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ImportanceThe PROM1 gene, commonly associated with cone-rod dystrophies, may have dominant or recessive phenotypes that influence disease onset and severity.ObjectiveTo characterize the clinical phenotype and molecular genetic variations in patients with PROM1 variants.Design, setting, and participantsThis case-series study was conducted at 2 specialist retinal genetics clinics and examined 19 consecutively enrolled patients with PROM1-related retinal degeneration. Data were collected and analyzed from May 2018 to December 2018.Main outcomes and measuresResults of ophthalmic examination, retinal imaging, and molecular genetic analysis by next-generation sequencing.ResultsOf 19 patients, 13 (68%) were women, and age ranged from 11 to 70 years. All patients presented with central visual loss, with or without photophobia. Individuals with recessive variants commonly had severe loss of visual acuity by their 20s, whereas the dominant variant was associated with a milder phenotype, with most patients retaining good vision into late adulthood. The recessive cases were associated with a panretinal dystrophy of cone-rod phenotype with early macular involvement, whereas the dominant variants were associated with a cone-rod phenotype that was restricted to the macula with predominantly cone dysfunction. Next-generation sequencing identified 3 novel and 9 previously reported variants in PROM1. Recessive mutations included 6 truncating variants (3 nonsense and 3 frameshift), 4 splice site variants, and 1 missense variant. All 6 dominant variants were associated with a c.1117C>T missense variant. The variants were distributed throughout the PROM1 genomic sequence with no specific clustering on protein domains.Conclusions and relevanceIn this case-series study, PROM1 recessive variants were associated with early-onset, severe panretinal degeneration. The similar phenotypes observed in patients with homozygous missense variants and splice site variants compared with similarly aged patients with truncating variants suggests that all recessive variants have a null (or loss of function close to null) outcome on PROM1 function. In contrast, the dominant missense cases were associated with a milder, cone-driven phenotype, suggesting that the dominant disease is preferentially associated with cones. This has implications for the development of treatments for this severely blinding disease, and adeno-associated viral vector-based gene therapy and optogenetics could become successful treatment options.