Abstract Bartter syndrome (BS) and Gitelman syndrome (GS) are renal tubular disorders affecting sodium, potassium and chloride reabsorption. Clinical features include muscle cramps and weakness, in association with hypokalaemia, hypochloraemic metabolic alkalosis and hyperreninemic hyperaldosteronism. Hypomagnesaemia and hypocalciuria are typical of GS, whilst juxtaglomerular hyperplasia is characteristic of BS. GS is due to SLC12A3 variants, whereas BS is due to variants in SLC12A1, KCNJ1, CLCNKA, CLCNKB, BSND, MAGED2 or CASR. We had the opportunity to follow-up one of the first reported cases of a salt-wasting tubulopathy, who based on clinical features was diagnosed with GS. The patient had presented at 10 years of age with tetany precipitated by vomiting or diarrhoea. She had hypokalaemia, a hypochloraemic metabolic alkalosis, hyponatraemia, mild hypercalcaemia, and normomagnesaemia, and subsequently developed hypocalciuria and hypomagnesaemia. A renal biopsy showed no evidence for juxta-glomerular hyperplasia. She developed chronic kidney failure aged 55 years, and ocular sclerochoroidal calcification, associated with BS and GS, aged >65 years. Our aim was therefore to establish the genetic diagnosis in this patient using whole genome sequencing (WGS). Leukocyte DNA was utilised for WGS analysis, and this revealed a homozygous c.226C>T (p.Arg76Ter) nonsense CLCNKB mutation, thereby establishing a diagnosis of BS type-3. WGS also identified two >5Mb regions of homozygosity, that suggested likely mutational heterozygosity in her parents, who originated from a Greek island with <1500 inhabitants and may therefore have shared a common ancestor. Our results demonstrate the utility of WGS in establishing the correct diagnosis in renal tubular disorders with overlapping phenotypes.
Journal of the Endocrine Society
The Endocrine Society