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

Abstract 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.