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Abstract: PO1592

Spectrum of Mutations in 106 Chinese Patients with Gitelman Syndrome

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Mou, Lijun, Nephrology Department. Zhejiang University School of Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
  • Chen, Xujiao, Nephrology Department. Zhejiang University School of Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
  • Hu, Ying, Nephrology Department. Zhejiang University School of Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
Background

Gitelman’s syndrome (GS) is an rare, autosomal recessively inherited salt-losing tubulopathy(SLT) characterized by hypokalemic metabolic alkalosis. GS is caused by the mutations in SLC12A3 gene encoding for the thiazide-sensitive NaCl cotransporter (NCC). However, the sensitivity of genetic sequencing was low. No large genomic rearrangements in Chinese patients with GS was previously identified.

Methods


Targeted gene sequencing (TES) by next generation sequencing associated with SLTs was performed for patients suspected of GS. Then, a search for large genomic rearrangements by ligation-dependent probe amplification(MLPA) assay was performed in patients with heterozygous for point mutations and patients with homozygous mutations without consanguinity history.

Results

Fifty-nine patients(55.67%) were female, the age was( 34.87±15.36)years, serum potassium level was (2.68±0.36)mmol/L, serum magnesium level was (0.58±0.13)mmol/L, ninty-four patients(88.68%) had hypomagnesemia, seventy-nine patients(81.44%,79/97) had hypocalciuria. Eighty-three different mutations in SLC12A3 were identified within these 106 GS patients, including 32 novel mutations and 4 recurrent ones,5 large genomic rearrangements. Recurrent mutations were p.T60M (22.86%),c.965-1_976delGCGGACATTTTTGinsACCGAAAATTTT(6.19%),p.D486N(4.76%) , p.N359K(4.76%). Triple mutations was identified in 8 patients, compound heterozygous mutations were identified in 70 patients, homozygous mutations were identified in 18 patients, whereas 10 patients had only one heterozygous mutation. The 5 large genomic rearrangements were exon deletion, including E7,E8 deletion, E8,E23 deletion, E20-E24 deletion, E8 deletion,E4-E6 deletion.The sensitivity of genetic testing sequencing was 90.57%.

Conclusion

We identified 83 mutations related to GS, containing 32 novel variants and 4 high-frequency ones, 5 large genomic rearrangements. TES combined with MLPA significantly increased the sensitivity of genetic sequencing and facilitate more accurate diagnosis of GS.

Schematic diagram of mutations in 106 Chinese
GS patients

Funding

  • Government Support - Non-U.S.