Genetic Insights into Persistent Hypouricemia in Adults: Novel Findings from an Adult Nephrogenetic Clinic
Source: PubMed Central Open Access, NCBI / U.S. National Library of Medicine
Abstract Introduction 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: 1 patient with homozygous, one with homozygous, five with heterozygous(1 patient carried two variants; compound heterozygosity could not be confirmed), one with heterozygous, one with homozygous, two with homozygous, one with heterozygous, and one with two heterozygousvariants. 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
Abstract
Abstract Introduction 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: 1 patient with homozygous, one with homozygous, five with heterozygous(1 patient carried two variants; compound heterozygosity could not be confirmed), one with heterozygous, one with homozygous, two with homozygous, one with heterozygous, and one with two heterozygousvariants. 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 2 patients. Finally, 1 female patient with hyperuricosuric hypouricemia carried a likely pathogenicvariant 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.