#2568 LONG-READ SEQUENCING IDENTIFIES NOVEL PATHOGENIC INTRONIC VARIANTS IN GITELMAN SYNDROME

Abstract Background and Aims Gitelman syndrome is a salt-losing tubulopathy characterized by hypokalemic alkalosis hypomagnesemia. It caused homozygous recessive or compound heterozygous pathogenic variants in SLC12A3, which encodes the Na+-Cl− cotransporter (NCC). In up to 10% of patients with syndrome, current genetic techniques detect only one specific variant. This study aimed identify second variant introns, splice sites, promoters increase diagnostic yield. Method Long-read sequencing SLC12A3 was performed 67 DNA samples from individuals suspected whom single likely previously detected. addition, we sequenced 28 uncertain significance no candidate Midigene assays assessed pathogenicity novel intronic variants. Results A pathogenic/pathogenic identified 45 (67%) patients. Those two had more severe electrolyte phenotype than other Of patients, 16 outside canonic sites (nine variants, mostly deep intronic, six novel), whereas 29 an exonic site known c.1670-191C>T demonstrated aberrant splicing patterns. Conclusion Intronic explain important part missing heritability syndrome. should be considered workflows for especially