Endocrine Abstracts (2018) 59 OC1.4 | DOI: 10.1530/endoabs.59.OC1.4

Whole genome sequence analysis establishes correct diagnosis for a syndromic form of hyperuricaemia

Mark Stevenson1, Alistair T Pagnamenta2, Silvia Reichart3, Stefan Mennel3, Charlotte Philpott1, Kate E Lines1, Caroline M Gorvin1, Karl Lhotta4, Jenny C Taylor2 & Rajesh V Thakker1


1Academic Endocrine Unit, OCDEM, University of Oxford, Oxford, UK; 2Oxford BRC, WCHG, University of Oxford, Oxford, UK; 3Department of Ophthalmology, Akademisches Lehrkrankenhaus, Feldkirch, Austria; 4Innere Medizin III (Nephrologie und Dialyse), Akademisches Lehrkrankenhaus, Feldkirch, Austria.


Whole genome sequencing (WGS) has the potential to identify nearly all forms of genetic variation. In complex disorders with multiple manifestations WGS can establish a definitive diagnosis that may change clinical management (Stavropoulos et al. 2016 Genomic Med). Here, we report on the utility of WGS in establishing the correct diagnosis in a family with hyperuricaemia. Hyperuricaemia may occur as: part of a syndromic disorder (e.g. Lowe syndrome, renal coloboma syndrome (RCS), and familial juvenile hyperuricaemic nephropathy (FJHN)); or as an isolated non-syndromic disease. The proband, presented with gout and had hyperuricaemia, with reduced fractional excretion of uric acid (FEUA), and later developed chronic kidney disease and secondary hyperparathyroidism, consistent with FJHN. The proband’s brother had gout, hyperuricaemia and reduced FEUA, and father had chronic renal failure. Genetic studies had not detected mutations in the UMOD or REN genes, which cause FJHN. WGS was therefore undertaken in the two siblings after obtaining informed consent. This identified a heterozygous c.226G>C variant in the paired box 2 gene (PAX2), that predicted a missense mutation pGly76Arg. This mutation co-segregated with hyperuricaemia and disrupts an evolutionarily conserved amino acid. A different missense change at this same residue (p.Gly76Ser) has been reported in RCS patients (Devriendt et al. 1998 Human Genet). RCS is characterized by abnormalities in renal structure and function in >90% of patients, and anomalies of the optic nerve and retina in >75% of patients, while hyperuricaemia is reported in only <1% of patients. These genetic findings prompted ophthalmological examination of the hyperuricaemic patients that revealed the presence of optic pits, consistent with coloboma, in the proband and his affected brother. The diagnosis was therefore revised to RCS, a syndromic form of hyperuricaemia. Thus, our results demonstrate the importance of WGS analysis in establishing diagnosis in disorders that may have multiple aetiologies.