Characterization of recurrent UMOD variants (p.C255Y y p.Q316P) in a Galician cohort: genotype-phenotype correlation and clinical implications

Abstract

Background

The UMOD gene encodes the uromodulin protein, which plays a crucial role in renal function. Genetic alterations affecting its correct function are mainly related to Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD), progressive renal failure and hyperuricaemia, among other variable clinical phenotypes. In the Galician population there are recurrent mutations in this gene, this study aims to phenotypically characterize the recurrent variants to improve the prognosis and management strategies of affected patients.

Methods

In a Galician population characterized by high genetic conservation, a retrospective cohort study was conducted with 37 patients from 15 families carrying recurrent variants in UMOD (p.C255Y and p.Q316P, from transcript NM_001008389.3). Clinical data were collected, including renal function, hyperuricemia, hypertension and presence of renal cysts. Genomic analyses were performed by NGS and Sanger sequencing, variant classification were conducted according to ACMG guidelines. Statistical comparisons were performed using Mann-Whitney, Chi-square and Fisher tests, with Benjamini-Hochberg correction for multiple testing.

Results

The cohort included 28 carriers of p.C255Y and 9 of p.Q316P genetic variants. Both variants affect highly conserved domains with low tolerance to amino acid changes, which alters protein function and has clinical effects in patients. Hyperuricemia was observed in 76% of p.C255Y carriers and 50% of p.Q316P carriers, while interestingly only the first variant was associated with episodes of gout. Renal cysts and hypertension were identified in about half of the patients, independently of variant type. Kaplan–Meier curves suggested an earlier progression to hyperuricemia and advanced chronic kidney disease (CKD) in p.C255Y carriers, although without reaching statistical significance.

Conclusions

Recurrent UMOD mutations in a Galician cohort revealed shared clinical features, including hyperuricemia and CKD progression, with phenotypic variability influenced by age and additional genetic modifiers. The findings highlight the prognostic value of genotype-phenotype correlations and the need for tailored clinical management in ADTKD patients.