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Abstract: SA-PO410

More Than Half of Patients Clinically Diagnosed as Gitelman Syndrome in Adulthood Do Not Have Causal Mutations in Known Pathogenic Genes

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Mori, Takayasu, Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
  • Chiga, Motoko, Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
  • Fujimaru, Takuya, Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
  • Mandai, Shintaro, Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
  • Nanamatsu, Azuma, Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
  • Sohara, Eisei, Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
  • Rai, Tatemitsu, Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
  • Uchida, Shinichi, Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
Background

Gitelman syndrome (GS) is an autosomal recessive kidney disorder characterized by hypokalemia, hypomagnesemia, hypocalciuria, and metabolic alkalosis. GS is caused by loss of function mutations in SLC12A3 encoding Na-Cl cotransporters (NCC). Most of previous reports includes child-onset GS cases, and thus etiological profiles in adult GS have not been fully elucidated. The purpose of this study is to clarify mutation profiles of clinically diagnosed GS cases in adulthood, and to investigate the phenotypic difference between cases in which their genetic diagnoses were established or not.

Methods

A total of 84 genetically independent individuals who were referred to our institute with a clinical diagnosis of GS during 2012 to 2018 were retrospectively reviewed. Individuals who have any episodes of using loop or thiazide diuretics, or laxatives were not included. All of them received comprehensive genetic screening for known genes responsible for GS, Bartter syndrome, and hypomagnesemia (SLC12A3, SLC12A1, KCNJ1, CLCNKB, BSND, CLCNKA, CASR, MAGED2, TRPM6, CLDN16, KCNJ10, etc.). Twenty individuals were excluded because of the following reasons; 9 with insufficient clinical information, 5 under 18 years, 2 with only single heterozygous variant in SLC12A3, 3 with responsible mutations in CLCNKB, 1 with variants in BSND.

Results

Of the remaining 64 cases, 27 (42.1%) were genetically diagnosed as GS (solved cases). Thirty-seven (57.9%) did not have any responsible variants (unsolved cases). Unsolved cases were older (47.1 ± 15.2 vs. 37.3 ± 13.1 years, P = 0.01). Interestingly, most of unsolved cases were female (83.8% vs. 59.3%). Serum Mg was higher in unsolved cases (1.95 ± 0.47 vs. 1.67 ± 0.34, P = 0.02). There were no differences in serum K, HCO3-, FEK, urine Ca/Cr ratio between the groups. Regarding the causal mutations in SLC12A3, L858H (33.3%) and T180K (25.9%) were major, which are reported as hotspots in Japanese GS. In this study, R399C was also found in 11.1% cases.

Conclusion

More than half of the adult cases with GS phenotype were mutation-negative for known pathogenic genes. Phenotypic difference of the two was not evident other than age and serum Mg. Unsolved adult cases might have novel pathogenic genes responsible for their GS phenotype.

Funding

  • Government Support - Non-U.S.