Two unusual cases of Gitelman's syndrome with a complex inheritance: how the phenotype can help interpret the genotype: lesson for the clinical nephrologist

Bartter’s syndrome (BS) and Gitelman’s syndrome (GS) are autosomal recessive disorders with overlapping features, caused by biallelic variants in six genes encoding proteins involved in renal electrolyte homeostasis in different districts of the nephron. Here we describe two patients with a clinical diagnosis of GS with a complex inheritance whose clinical interpretation and treatment proved challenging. In one patient, compound heterozygosity for two known pathogenic variant in the SLC12A3 gene was associated with an uncommon variant in the KCNJ1 gene (one of the known BS genes). The unusual severity of GS phenotype encountered in this patient led us to hypothesize that the missense variant can act as a genetic modifier by exacerbating the severity of the disease and by inducing BS-like clinical manifestations. In the other patient, two novel likely pathogenic variants in the SLC12A3 gene were coupled with a hitherto unreported rare variant in the SLC4A1 gene; the latter’s disease-causing variants have been associated with both dominant and recessive forms of distal renal tubular acidosis (dRTA). Patient’s medical history (he was clinically diagnosed with incomplete hypokalemic dRTA at 10 years old) supports the hypothesis of a dual molecular diagnosis and hence of a blended phenotype.