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
hypokalemia, hypochloremic metabolic
alkalosis, and hyperreninemic
hyperaldosteronism. Hypomagnesemia and hypocalciuria are typical of GS, while 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 age 10 years with
tetany precipitated by
vomiting or
diarrhea. She had
hypokalemia, a hypochloremic metabolic
alkalosis,
hyponatremia, mild
hypercalcemia, and normomagnesemia, and subsequently developed hypocalciuria and hypomagnesemia. A renal biopsy showed no evidence for juxtaglomerular
hyperplasia. She developed
chronic kidney failure at age 55 years, and ocular sclerochoroidal calcification, associated with BS and GS, at older than 65 years. Our aim was therefore to establish the genetic diagnosis in this patient using whole-genome sequencing (WGS). Leukocyte
DNA was used 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 2 greater than 5-Mb regions of homozygosity that suggested likely mutational heterozygosity in her parents, who originated from a Greek island with fewer than 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.