Work

Genotype-Phenotype Correlations Reveal Positive Inheritance and Phenotype Associations for PROM1 -Associated Inherited Retinal Degenerations

Year: 2026

Type: preprint

Abstract: Objective We analyzed 190 PROM1 variants to determine whether we could identify genotype-phenotype correlations with predictive value for patient outcomes. We present a case-series of 7 patients with rare, under-reported, or unique forms of PROM1 -associated retinal dystrophies. Design We performed a retrospective database study by searching for human PROM1 variants reported to be pathogenic, likely pathogenic, or disease-causing in two online databases: ClinVar and Human Gene Mutation Database. Contingency tables were constructed variable pairs – inheritance pattern vs. variant type, inheritance pattern vs. reported phenotype, inheritance pattern vs. protein domain, phenotype vs. variant type, phenotype vs. protein domain, and variant type vs. protein domain – and were then analyzed using a Monte Carlo chi-square test of independence with adjusted standardized residuals. Cells with absolute standardized residuals ≤ -1.96 and ≥ 1.96 were interpreted as under- or over-represented relative to expectation (p < 0.05). Participants Seven participants with PROM1 -associated retinal degeneration were contacted from our ocular genetics clinical practice; all contacted patients or legal guardians consented to be included in this case-series. Main Outcome(s) and Measure(s) The primary study outcome was to determine whether there were any meaningful genotype-phenotype relationships for disease-causing PROM1 variants by chi-square correlation analysis. Patient case-series were included to enrich statistical findings. Results We found a meaningful increase in observed counts of autosomal dominant missense variants associated with macular dystrophy. Of 7 patients, 3 were women (43%) and ages ranged from 4-58 years. Four of the seven patients had dominantly inherited missense variants (c.1117C>T, c.1557C>A, c.2110C>T, c.1655T>C). Recessive patient variants were all predicted to generate a truncated protein, including two patients with the same variant (c.1423_1424del), and a patient with a c.1354dup variant and compound heterozygous ABCA4 variants of unknown significance (c.2382+95A, c.-79C>T). All patient phenotypes were in agreement with predicted phenotypic outcomes from our statistical analysis. Conclusions We provided statistical outcomes and patient case-series data that support predictive value for dominant and recessive forms of PROM1 -associated inherited retinal degeneration. These data could inform expected outcomes for patients with PROM1- associated blindness, lessoning anxiety about unknown outcomes, and provide a framework to inform best-practices for patient follow-up.

Source: medRxiv

DOI: 10.64898/2026.09.03.26361572