Genotype-Phenotype Correlations Reveal Positive Inheritance and Phenotype Associations for PROM1-Associated Inherited Retinal Degenerations
- 1University of Alberta
Abstract
ObjectiveWe 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.
DesignWe 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).
ParticipantsSeven 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.
ResultsWe 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.
ConclusionsWe 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.
Related
- Inheritance of the epigenetic signature and reduced intermuscular bone phenotype acquired via DNA methylation editing of the runx2b promoter in zebrafish
- Inheritance of a Single Edited CD46 Allele Is Associated with Reduced Ex Vivo Susceptibility to Bovine Viral Diarrhea Virus
- Hereditary Breast Cancer in a Brazilian Referral Cohort: Germline Diversity and Genotype–Phenotype Associations
- Senomorphic miR-3155b suppresses the senescence-associated secretory phenotype in therapy-induced senescence
- Native American Ancestry Is Associated with NAT2 Haplotype and Inferred Metabolizer Phenotype Variation in Latin American Populations
BibTeX
@misc{shoukat2026genotypephenotype,
title = {{Genotype-Phenotype Correlations Reveal Positive Inheritance and Phenotype Associations for PROM1-Associated Inherited Retinal Degenerations}},
author = {M. Shoukat and K. M. Papp and E. Misaghi and D. J. Kalra and I. M. MacDonald and M. D. Benson and B. J. Carr},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.03.26361572},
url = {https://www.medrxiv.org/content/10.64898/2026.09.03.26361572v1},
note = {CC BY-ND},
}
RIS
TY - UNPB
TI - Genotype-Phenotype Correlations Reveal Positive Inheritance and Phenotype Associations for PROM1-Associated Inherited Retinal Degenerations
AU - M. Shoukat
AU - K. M. Papp
AU - E. Misaghi
AU - D. J. Kalra
AU - I. M. MacDonald
AU - M. D. Benson
AU - B. J. Carr
PY - 2026
DA - 2026/09/03
PB - medRxiv
DO - 10.64898/2026.09.03.26361572
UR - https://www.medrxiv.org/content/10.64898/2026.09.03.26361572v1
AB - ObjectiveWe 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. DesignWe 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). ParticipantsSeven 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. ResultsWe 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. ConclusionsWe 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.
ER -