Whole genome sequence analysis identifies a PAX2 mutation to establish a correct diagnosis for a syndromic form of hyperuricemia.

Mark Stevenson,Silvia Reichart,Karl Lhotta,Rajesh V Thakker,Alistair T Pagnamenta,Kate E Lines,Charlotte Philpott,Caroline M Gorvin,Jenny C Taylor

doi:10.1002/ajmg.a.61814

Abstract

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.

Highlights

Members of HICF2 Whole Genome Sequencing and Analysis Consortium (OxClinWGS) listed in the supplementary information (Appendix S2); Chair and Principal Investigator is Jenny C
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)
renal coloboma syndrome (RCS), which is known as papillorenal syndrome (PAPRS) (MIM 120330) (Devriendt et al, 1998), is characterized by renal and ocular anomalies that include renal hypodysplasia and insufficiency progressing to end stage renal disease (ESRD), and optic nerve coloboma

Summary

| INTRODUCTION

Members of HICF2 Whole Genome Sequencing and Analysis Consortium (OxClinWGS) listed in the supplementary information (Appendix S2); Chair and Principal Investigator is Jenny C. Hyperuricemia, which may lead to gout, occurs as an acquired or inherited metabolic abnormality. FJHN, which is a genetically heterogeneous disorder, is characterized by hyperuricemia, reduced fractional excretion of uric acid (FEUA), gout, and progressive end stage renal disease (ESRD) associated with interstitial fibrosis. We report a kindred considered to have FJHN on the basis of hyperuricemia, gout, reduced FEUA, and CKD, but in whom Sanger DNA sequence analysis had not detected mutations of UMOD or REN, which account for approximately 30–90% of cases. Whole genome sequence (WGS) analysis unexpectedly revealed that a mutation of the paired box 2 (PAX2) gene was the likely cause of FJHN in this kindred, which prompted clinical reassessment of the family

| MATERIALS AND METHODS

| RESULTS

| DISCUSSION