Hereditary hyperuricemia may occur as part of a syndromic disorder or as an isolated nonsyndromic disease, and over 20 causative genes have been identified. 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). However, single gene testing had not detected mutations in the uromodulin (UMOD) or renin (REN) genes, which cause approximately 30–90% of FJHN. 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. 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. 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. Thus, our results demonstrate the utility of WGS analysis in establishing the correct diagnosis in disorders with multiple etiologies.

中文翻译：

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全基因组序列分析确定了 PAX2 突变，以建立对高尿酸血症综合征形式的正确诊断。

遗传性高尿酸血症可能作为综合征疾病的一部分或作为孤立的非综合征疾病发生，并且已经确定了超过 20 个致病基因。在这里，我们报告了使用全基因组测序 (WGS) 在一个患有痛风、与尿酸排泄分数减少相关的高尿酸血症、慢性肾脏病 (CKD) 和继发性甲状旁腺功能亢进症的家庭中建立诊断，即与家族性幼年高尿酸血症肾病（FJHN）一致。然而，单基因检测未检测到尿调节素 ( UMOD ) 或肾素 ( REN ) 基因突变，这导致大约 30-90% 的 FJHN。因此进行了 WGS，这确定了配对盒基因 2 中的杂合 c.226G>C (p.Gly76Arg) 错义变体（PAX2 ) 基因，在家族中与肾小管病共同分离。PAX2突变与肾缺损综合征 (RCS) 相关，RCS 的特征是肾脏结构和功能异常，以及视神经异常。两名患有高尿酸血症、痛风和 CKD 的成年兄弟的眼科检查显示存在视盘凹陷，符合视神经缺损，从而将诊断从 FJHN 修改为 RCS。因此，我们的结果证明了 WGS 分析在建立具有多种病因的疾病的正确诊断方面的效用。