Renal Phenotype Variations Among Families with Autosomal Alport Syndrome

Background: Alport syndrome (AS) is an inherited disorder characterized by progressive renal disease, hearing deficits, and ocular abnormalities. This study investigates phenotypic variability among individuals with identical autosomal genetic mutations in COL4A3 and explores the potential influence of modifier genes. The study focuses on three families carrying the same COL4A3 mutation ( c.2083G>A, p.Gly695Arg ) but exhibiting differences in phenotype. The objective is to elucidate interfamilial and intrafamilial variations and identify potential genetic modifiers contributing to these differences. Methods: Three families from a cohort at the University of Utah were studied. Clinical data, blood, urine, and tissue samples were collected with informed consent. Whole-exome sequencing (WES) was performed to identify genetic variants, using the SureSelect Human All Exon Target Enrichment System. Variant calling and annotation were conducted with GATK, VEP, and PEDDY. Disease-gene prioritization was achieved using the Variant Annotation, Analysis, and Search Tool (VAAST), pVAAST, and the Phenotype Driven Variant Ontological Re-ranking Tool (PHEVOR). Modifier genes were identified through co-segregation analysis and functional annotation using public databases. Results: The study highlighted significant phenotypic variability within and between families with the same COL4A3 mutation. Individuals with single mutations often presented mild phenotypes, such as isolated hematuria, while compound heterozygotes and digenic cases exhibited severe manifestations, including proteinuria, hearing loss, and chronic kidney disease (CKD). Modifier genes such as GRIP1, CCND1, and CYP3A7 were identified and linked to phenotypic variability, suggesting their potential role in disease progression. Conclusions: The findings underscore the role of genetic modifiers in influencing phenotypic variability in AS. Understanding these modifiers is crucial for personalized therapeutic strategies and genetic counseling. Future research should validate these candidate genes through functional studies and larger cohorts to enhance clinical care and improve prognostic predictions for patients with AS.