Supplementary Material for: Genetic Features of Chinese Patients with Gitelman Syndrome: Sixteen Novel SLC12A3 Mutations Identified in a New Cohort

<i>Background:</i> Gitelman syndrome (GS) is an autosomal recessive renal tubulopathy caused by inactivating mutations in the <i>SLC12A3</i> gene. Although hundreds of different mutations across the <i>SLC12A3</i> gene have been reported worldwide, data from mainland China are limited. We investigated the clinical manifestations and genetic features of Chinese patients with GS. <i>Methods:</i> Fifty-four unrelated Chinese patients with clinically diagnosed GS were included. Clinical manifestations and biochemical parameters were collected and analyzed. All exons and flanking regions of the <i>SLC12A3</i> and <i>CLCNKB</i> genes were screened by direct sequencing. <i>Results:</i>Weakness was the most commonly reported symptom in this cohort of patients with GS. In gender-based analyses, higher systolic blood pressure and urine protein excretion were observed in male patients. For genetic screening, 2 pathogenic<i>SLC12A3</i> mutations were identified in 38 patients (70.4%), 1 mutation in 11 patients (20.4%) and no mutation in 5 patients (9.3%). In total, 42 distinct pathogenic mutations throughout <i>SLC12A3</i> were identified; 16 were novel, including 9 missense, 1 deletion, 1 insertion, 3 splice site and 2 nonsense mutations. Eleven mutations were recurrently found in different patients. Among them, T60M and D486N were identified in 11 individuals. No <i>CLCNKB</i> mutations were found. <i>Conclusion:</i> Sixteen novel <i>SLC12A3</i> pathogenic mutations were identified in a cohort of Chinese patients with GS. T60M and D486N were most frequent and appear to be important candidate alleles in Chinese patients with GS.

背景：吉特曼综合征（Gitelman syndrome, GS）是一种由SLC12A3基因失活性突变引发的常染色体隐性遗传性肾小管疾病。尽管全球范围内已报道SLC12A3基因存在数百种不同突变，但中国大陆地区的相关研究数据仍较为有限。本研究旨在探讨中国GS患者的临床表型与遗传学特征。
方法：本研究纳入54例经临床确诊的非亲缘性中国GS患者，收集并分析其临床表型与生化指标。采用直接测序法对SLC12A3及CLCNKB基因的全部外显子与侧翼区域进行筛查。
结果：肌无力是本研究队列中GS患者最常见的临床表现。性别亚组分析显示，男性患者的收缩压及尿蛋白排泄量更高。遗传学筛查结果显示，38例患者（70.4%）检出2个致病性SLC12A3突变，11例（20.4%）检出1个致病性突变，剩余5例（9.3%）未检出致病性突变。本研究共鉴定出42种不同的SLC12A3致病性突变，其中16种为新发突变，包括9种错义突变、1种缺失突变、1种插入突变、3种剪接位点突变及2种无义突变。有11种突变在不同患者中反复被检出，其中T60M与D486N分别在11例个体中被鉴定到。本研究未检出CLCNKB基因的致病性突变。
结论：本研究在中国GS患者队列中鉴定出16种全新的SLC12A3致病性突变。T60M与D486N为最常见的突变位点，可能是中国GS患者的重要致病候选等位基因。