Identification of Rare Variants Causing Early-Onset Bartter Syndrome: a Clinical, Genetic, and Biophysical Study

Objective: Bartter syndrome (BS) is a rare congenital renal tubular disease. 2 children with BS were recruited and experienced a series of ultrasound, biochemical, genetic investigation. Methods: Genomic DNA was obtained from the probands and family members for trio-whole-exome sequencing, copy number variation analysis and Sanger Sequencing Results: Four variants were detected from the 2 probands. Patient I was diagnosed as BS typeⅡ, since she carried two novel variations in KCNJ1 gene, which are c.504delA, p.Lys168Asnfs*13 and c.406_407insA, p.Thr136Asnfs*61, inherited from her parents. Patient Ⅱ was diagnosed as BS type Ⅲ because he carried a known pathogenic variant, c.1313G > A ,p. Arg 438 His in CLCNKB gene, which was inherited from his mother,another novel variant inherited from his father was (loss exon2-20) in CLCNKB gene. The three novel variations have not been reported in ClinVar, HGMD, and public databases. According to ACMG guidelines, these variations were likely pathogenic (PVS1 + PM2). By protein structure and molecular analysis: the protein coded by KCNJ1 gene contains inward rectifier potassium channel transmembrane domain (IRK) and inward rectifier potassium channel C-terminal domain (IRK_C). The two altered amino acids located on the IRK and IRK_C domain, may affect conserved protein domains, resulting in premature stop codons and truncated protein, thereby affecting protein function. The variant (loss exon2-20) in CLCNKB gene resulted in a loss of protein function. PatientⅡ’s old sister carried the variation c.1313G > A in CLCNKB gene. The fetus in his mother's womb carried the same variations as the proband, and the mother finally underwent an induced abortion. Conclusion: Our findings expand the gene spectrum of KCNJ1 and CLCNKB associated with BS.