New Mutations in Bartter Syndrome (BS) Type 1

Introduction: Bartter syndrome type 1 is a rare disorder caused by mutations in the SLC12A1 gene. Overlapping features with other electrolyte-wasting disorders caused diagnosis to be challenging but new diagnostic testing has allowed to identify new pathogenic mutations such as the following. Case Description: We describe a 22-year-old male with a history of severe hypokalemia managed with potassium supplements and amiloride who presented after routine labs revealed severe hypokalemia following missed doses of both medications. His medical history included recurrent episodes of severe hypokalemia, hypocalciuria, nephrocalcinosis and renal potassium wasting since age of 5. At that time, he was tested for Bartter syndrome following an episode of severe hypokalemia and spontaneous rhabdomyolysis; however, genetic testing was inconclusive. Given his clinical presentation, consistent with Bartter syndrome type 1, and advancements in genetic testing technology over last 15 years, repeat testing using next-generation sequencing was done. This revealed two heterozygous mutations in the SLC12A1 gene, specifically c.348dup ( p.Asn117*) and c.737A>G (p.Tyr246Cys) mutation. The first one at DNA position 348, a duplication causes the protein to stop prematurely at amino acid 117 producing a non-functional protein (nonsense) and in the second a single base substitution changes the amino acid at position 246 from tyrosine to cysteine leading to a missense mutation which may affect the protein function. Though testing reported the second mutation as likely pathogenic, his clinically presentation of this autosomal recessive condition makes the mutation pathogenic. These mutations, located on different alleles, establishes compound heterozygosity, confirming a diagnosis of Bartter syndrome type 1. Discussion: The SLC12A1 gene encodes the NKCC2 protein, crucial for sodium, potassium, and chloride reabsorption in the thick ascending limb of the loop of Henle. Prior genetic analyses were limited to sequential single-gene testing, an approach that was time-consuming, costly, and lacked complete diagnostic yield. This case illustrates the value of re-evaluating genetic testing in patients with previous inconclusive results to help identify novel mutations, as advances in technology now allow for the detection of mutations previously undetectable.