Genetic Insights into Persistent Hypouricemia in Adults: Novel Findings from an Adult Nephrogenetic Clinic

Background: Hypouricemia is an often-overlooked condition. Isolated persistent hypouricemia is rare and may be associated with uncommon genetic disorders, such as familial renal hypouricemia or xanthinuria. Methods: Fifteen non-consanguineous adult patients were included in this single-center study. Secondary causes of hypouricemia, including malnutrition, SIADH, cirrhosis, uricosuric drug use, and full-blown Fanconi syndrome, were excluded. Patients were classified as hyperuricosuric or hypouricosuric based on urinary uric acid levels. Clinical or whole-exome sequencing was performed, and variant pathogenicity was assessed using in silico prediction tools. Results: Ten patients were female (66.7%), and four were hypouricosuric (26.7%). Three patients (20%) had also glucosuria without diabetes mellitus and full-blown Fanconi syndrome. Thirteen patients (86.7%) carried at least one rare variant (variant of unknown significance, likely pathogenic, or pathogenic) in genes associated with hypouricemia: one patient with homozygous SLC2A9, one with homozygous SLC22A12, five with heterozygous SLC22A12 (one patient carried two variants; compound heterozygosity could not be confirmed), one with heterozygous CLCN5, one with homozygous XDH, two with homozygous MOCOS, one with heterozygous MOCS1, and one with two heterozygous SLC5A2 variants. This study reports, for the first time, the co-occurrence of familial renal glucosuria and familial renal hypouricemia, as well as the coexistence of xanthinuria type 2 and familial renal glucosuria in two patients. Finally, one female patient with hyperuricosuric hypouricemia carried a likely pathogenic FTL variant and a mitochondrial DNA variant of unknown significance, which may represent candidate genes, and require confirmation in larger cohorts and functional studies. Conclusion: Our study expands the clinical and genetic spectrum of persistent hypouricemia. Genetic testing has a high diagnostic yield and should be considered in patients with unexplained persistent hypouricemia.