Background

Gitelman syndrome (GS) is a tubulopathy characterized by hypokalemia, hypomagnesemia, hypocalciuria and metabolic alkalosis, which is caused by mutations in SLC12A3 gene.

Objective

The objective of this study was to investigate the mutation of SLC12A3 gene in a pedigree with GS and analyzed the clinical manifestations.

Methods

Next-generation sequencing and Sanger sequencing were performed to explore the mutations of SLC12A3 gene in a GS pedigree that included a 59-year-old male GS patient and a total of 11 family members within three generations.

Results

A novel compound heterozygous mutation of SLC12A3 gene (c.1712T > C in exon14 and c.2986_2987ins GCT in exon26) was identified by genetic testing in the proband. Moreover, we demonstrated that two brothers shared the same heterozygous mutation with the proband, but only one brother had the GS related symptoms. His nephew was the carrier of one mutation (c.1712T > C), and one of his brother, his sister and niece were carriers of the other (c.2986_2987ins GCT).

Conclusions

This is the first study to report the novel pathogenic compound heterozygous mutation of SLC12A3 gene in GS. Our result further supports the lack of phenotype–genotype correlations in GS. Further functional studies are required to investigate pathophysiologic mechanisms of GS.

中文翻译：

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具有吉特曼综合征的家系中SLC12A3基因的新型复合杂合突变和文献综述。

背景

Gitelman综合征（GS）是一种以SLC12A3基因突变引起的低钾血症，低镁血症，低钙尿症和代谢性碱中毒为特征的肾小管病。

目的

这项研究的目的是调查与GS系谱中的SLC12A3基因突变并分析其临床表现。

方法

进行了下一代测序和Sanger测序，以探索GS家谱中SLC12A3基因的突变，该谱系包括59岁的男性GS患者和三代内总共11位家庭成员。

结果

通过在先证者中进行基因检测，鉴定出一种新的SLC12A3基因复合杂合突变（外显子14中为c.1712T> C，外显子26中为GCT中的c.2986_2987ins）。此外，我们证明了两个兄弟与先证者共享相同的杂合突变，但只有一个兄弟具有GS相关症状。他的侄子是一个突变的携带者（c.1712T> C），而他的兄弟，妹妹和侄女是另一个突变的携带者（c.2986_2987ins GCT）。

结论

这是首次报道GS中SLC12A3基因的新型致病性化合物杂合突变的研究。我们的结果进一步支持了GS中缺乏表型与基因型的相关性。需要进一步的功能研究来研究GS的病理生理机制。