Phenotypic differences of mutation‐negative cases in Gitelman syndrome clinically diagnosed in adulthood

Abstract

Gitelman syndrome (GS), an autosomal recessive kidney disorder, is characterized by hypokalemia, hypomagnesemia, hypocalciuria, and metabolic alkalosis. Generally, diagnosis is made in school‐aged children but multiple cases have been diagnosed in adulthood. This study examines the phenotypic differences between genetically confirmed cases and mutation‐negative cases in adults. A comprehensive screening of 168 genes, including GS‐related genes, was performed for 84 independent individuals who were referred to our institute with a clinical diagnosis of GS. The cases of pseudo‐Bartter syndrome (BS)/GS because of diuretic abuse or other causes, which was determined based on patients' medical records, were excluded during registration. Of these 70 eligible cases for analysis, 27 (38.6%) had genetic confirmation of GS, while 37 (52.8%) had no known variants associated with GS and were considered to be unsolved cases. Note that unsolved cases comprised older, mostly female, individuals with decreased kidney function and multiple basic features of GS. The phenotype of unsolved cases is similar to that of pseudo BS/GS cases, although these cases were excluded in advance. However, the genetic and autoimmune profiles of these unsolved cases have not yet been investigated to date. Therefore, these cases may be categorized into new disease groups.

Detecting pathogenic deep intronic variants in Gitelman syndrome

“…Gitelman syndrome (GS) is an inherited tubulopathy caused by defects in the SLC12A3 gene (NM_000339.2), the apical sodium chloride transporter (natrium chloride cotransporter/NCCT) also known as the thiazide sensitive cotransporter in the distal convoluted tubule (Blanchard et al, 2017; Mori et al, 2020; Nozu et al, 2009). Gitelman et al (1966) described a familial disorder characterized by hypokalemia, hypomagnesemia, hypocalciuria, metabolic alkalosis, and hypereninemic hyperaldosteronism.…”

Pseudo-Gitelman Syndrome Presenting with Hypokalemic Metabolic Alkalosis and Hypocalciuria

“…Therefore, our findings are compatible with a diagnosis of pseudo-GS. Interestingly, Mori et al reported that approximately 50% of 70 clinically diagnosed patients with GS were mutation-negative based on gene panel sequencing 8) .…”

Gitelman syndrome with a novel frameshift variant in SLC12A3 gene accompanied by chronic kidney disease and type 2 diabetes mellitus

“…To date, more than 350 pathogenic variants loci associated with Gitelman syndrome have been identified [1]. However, some patients with clinically suspected Gitelman syndrome do not carry variants in SLC12A3 [2]. For example, some patients who carry pathogenic variants in other genes, such as CLCNKB or HNF1B [1], present with a phenotype similar to that of Gitelman syndrome.…”