目的 · 通过大组测序研究分析汉族成人局灶性节段性肾小球肾炎（FSGS）患者中 NPHS2 基因突变致病情况。方法 · 纳入上海 交通大学医学院附属瑞金医院肾脏科的 FSGS 患者（起病年龄≥ 14 岁），所有 FSGS 均经肾活检证实，并排除全身性疾病继发 FSGS 和其他遗传性肾脏病。抽提外周血基因组DNA，采用 Sanger 测序对NPHS2 编码区和内含子交界区进行深度测序或进行高通量测序 （包括全外显子组测序和 Panel 候选基因测序，所获突变 Sanger 测序验证）。在 100 名健康人中验证所得突变。结果 · 研究共纳入 204 例 FSGS 患者，家族性患者 52 例（25.5%），散发性患者 152 例（74.5%），其中散发患者中激素抵抗性 FSGS 患者占 30.3％（46/152）。 61 例患者采用Sanger 测序，143 例采用高通量测序，共发现2 个新的NPHS2 保守区突变，其中在散发激素抵抗性FSGS 患者中发 现 1 个纯合突变位点，p.N199I；家族性 FSGS 中发现 1 个杂合突变，p.L321fx346。对 100 名健康人进行测序未发现同样突变。SIFT、 Polyphen 和 Mutation Taster 评分提示突变可能致病。在本队列中 FSGS 患者的 NPHS2 突变检出率为 1%。结论 · 汉族成人 FSGS 患者 中 NPHS2 基因突变率较低，NPHS2 突变并非汉族成人 FSGS 的主要致病基因。

Objective · To screen NPHS2 mutations in adult focal segmental glomerulosclerosis(FSGS) patients based on a large Chinese FSGS cohort.  Methods · All patients were biopsy determined FSGS by the Department of Nephrology at Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine. FSGS secondary to systemic disease and other hereditary kidney disease were excluded. After extraction of genomic DNA of peripheral blood, NPHS2 was screened by directly sequencing the exon/intron junction or high-throughput sequencing, including whole exon sequencing and Panel sequencing, and then verified by Sanger sequencing. One hundred  healthy controls were enrolled to validate candidate mutations.  Results · Two hundred and four FSGS patients were enrolled，including 52 familial(25.5%) and 152 sporadic patients(74.5%)，of which steroid-resistant FSGS patients accounted for 30.3%(46/152). By sequencing NPHS2 in all patients of the cohort (Sanger sequencing in 61 patients and high-throughput sequencing in 143 patients), 2 novel conserved mutations were identified, one homozygous mutation in sporadic steroid-resistant FSGS, p.N199I and one heterozygous mutation in familial FSGS, p.L321fx346. Both of them were not detected in 100 healthy controls. These two variants were predicted to be damaging by Polyphen, SIFT and Mutation Taster. Totally, the mutation rate of NPHS2 in the FSGS cohort was 1%.  Conclusion · Since the overall frequency of NPHS2 mutations is considerably low in Chinese adult-onset FSGS, NPHS2 is not the main disease-causing gene of this group of people.