Genotype-Informed Characterization of Mild Renal Hypouricemia

Renal hypouricemia is caused by pathogenic variants in SLC22A12 and SLC2A9. Current diagnostic thresholds based on serum uric acid (UA) (SUA < 2 mg/dl) and fractional excretion of UA (FEUA > 10%) may overlook individuals with monoallelic variants and mild hypouricemia, whose clinical implications remain incompletely defined. This study evaluated genotype-phenotype correlations across individuals with 0, 1, or 2 pathogenic alleles in a referral-based genetic testing cohort from Galicia (Western Europe).

We analyzed probands referred for suspected renal hypouricemia, their relatives, and additional carriers not previously suspected of the condition. Genetic, biochemical, and clinical data were integrated to characterize SUA and FEUA distributions by genotype and to identify overlooked cases.

Among 21 probands, 15 carried pathogenic or likely pathogenic variants (71% diagnostic yield), including 3 variants not previously linked to renal hypouricemia. Monoallelic carriers frequently showed mild hypouricemia (SUA: 2-3.3 mg/dl), whereas biallelic carriers had SUA < 2 mg/dl. SUA and FEUA showed an allele-dose pattern, although FEUA availability was limited. Additional carriers identified outside renal hypouricemia suspicion had compatible biochemical profiles when data were available, suggesting underrecognition in clinical practice.

In this referral-based cohort, monoallelic pathogenic or likely pathogenic variants in SLC22A12 and SLC2A9 were frequently associated with mild hypouricemia, supporting FEUA assessment and follow-up when low SUA is persistent or clinically suggestive. Current diagnostic thresholds may miss some of these individuals, supporting genotype-informed refinement of serum urate criteria to improve detection and monitoring.