Hereditary hyperuricemia may occur as an isolated nonsyndromic disease or as part of a syndromic disorder (Megaw, Lampe, Dhillon, Yoshida, & Wright, 2013 Partington & Hennen, 1967 Sperling, Sarapers, Eilam, & Devries, 1972). Acquired hyperuricemia may be due to: a diet high in purines (e.g., meats, fructose, and beer) drugs (e.g., thiazide diuretics, cytotoxic agents, and low dose aspirin) obesity and metabolic syndrome as a consequence of insulin resistance and the role of insulin reducing urinary urate excretion hypertension resulting in renal vasoconstriction and uric acid retention chronic kidney disease (CKD) and renal failure and low level lead and cadmium intoxication (Choi, Atkinson, Karlson, Willett, & Curhan, 2004 Johnson et al., 2013 Lin, Ho, & Yu, 1999 Messerli, Frohlich, Dreslinski, Suarez, & Aristimuno, 1980 Quinones Galvan et al., 1995 Sharon & Schlesinger, 2016). Hyperuricemia, which may lead to gout, occurs as an acquired or inherited metabolic abnormality. Thus, our results demonstrate the utility of WGS analysis in establishing the correct diagnosis in disorders with multiple etiologies. Ophthalmological examination in two adult brothers affected with hyperuricemia, gout, and CKD revealed the presence of optic disc pits, consistent with optic nerve coloboma, thereby revising the diagnosis from FJHN to RCS. PAX2 mutations are associated with renal coloboma syndrome (RCS), which is characterized by abnormalities in renal structure and function, and anomalies of the optic nerve. WGS was therefore undertaken, and this identified a heterozygous c.226G>C (p.Gly76Arg) missense variant in the paired box gene 2 ( PAX2) gene, which co-segregated with renal tubulopathy in the family.
However, single gene testing had not detected mutations in the uromodulin ( UMOD) or renin ( REN) genes, which cause approximately 30–90% of FJHN. Here, we report the use of whole genome sequencing (WGS) to establish a diagnosis in a family in which individuals were affected with gout, hyperuricemia associated with reduced fractional excretion of uric acid, chronic kidney disease (CKD), and secondary hyperparathyroidism, that are consistent with familial juvenile hyperuricemic nephropathy (FJHN). Hereditary hyperuricemia may occur as part of a syndromic disorder or as an isolated nonsyndromic disease, and over 20 causative genes have been identified.
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