Eight novel KCNJ1 variants and parathyroid hormone overaction or resistance in 5 probands with Bartter syndrome type 2.

Purpose: Bartter syndrome type 2 (BS2) is an autosomal recessive renal tubular disorder, which is caused by the mutations in KCNJ1. This study was designed to analyze and describe the genotype and clinical features of five Chinese probands with BS2.

Methods: Identify KCNJ1 gene variants by the next generation sequencing and evaluate their mutation effects according to 2015 American College of Medical Genetics and Genomics (ACMG) standards and guidelines.

Results: Ten variants including eight novel ones of KCNJ1 gene were found, the most common type was missense variant. The common symptoms and signs from high to low incidence were: polydipsia and polyuria (5/5), one of them (1/5) presented with diabetes insipidus; maternal polyhydramnios and premature delivery (4/5); growth retardation (3/5). Two patients presented with hypochloremic metabolic alkalosis and hypokalemia; whereas the acid-base disturbance was absent in the others. One patient had evident parathyroid hormone (PTH) resistance (hypocalcemia, hyperphosphatemia and markedly elevated PTH levels), three presented with PTH overacting (hypercalcemia, hypophosphatemia and mild elevated PTH levels), and one showed normal blood calcium and phosphorus concentrations with high-normal PTH levels. All patients had nephrocalcinosis and/or hypercalciuria, and one of them complicated with nephrolithiasis. Indomethacin has significant therapeutic effect on the growth retardation, polydipsia and polyuria and treatment was associated with a decrease in urine calcium excretion, normalization of electrolyte disturbance and PTH parameters.

Conclusions: Ten variants of KCNJ1 gene were identified in five Chinese probands. These patients had atypical BS phenotype lacking evident metabolic alkalosis and/or manifesting with PTH overaction/resistance, which reminds clinicians to carefully differentiate BS2 with other parathyroid disorders. This is the first report of BS2 from Chinese populations.