[Analysis of variants in complement genes in Han Chinese children with atypical hemolytic uremic syndrome].

Objective: To investigate the prevalence and characteristics of pathogenic variants in complement genes in Han Chinese children with atypical hemolytic uremic syndrome (aHUS). Method: Eleven Han Chinese children with aHUS, including 9 boys and 2 girls aged between 1 year and 4 months and 13 years, were investigated in Department of Pediatrics, Fuzhou General Hospital, from November 1998 to February 2014. Analysis of variants of all the exons of 10 complement genes (CFH, MCP, CFI, C3, CFB, CFHR1, CFHR2, CFHR3, CFHR4 and CFHR5), including 25 bases from 3' end and 25 bases from 5' end, was performed in the 11 cases by targeted sequence capture and next generation sequencing. Significant variants detected by next generation sequencing were confirmed by Sanger sequencing. To understand pathogenicity of variants found in the captured genes, we investigated genetic conservation by multiple protein sequence alignment among different species, and analyzed whether the variants were located in protein domains or not, and investigated functional significance by functional computational prediction methods. Result: Twenty-seven percent of Han Chinese children with aHUS carried pathogenic variants in the 10 complement genes. Pathogenic variant CFB 221G>A (R74H) was detected in Patient 3 and Patient 9, which was not found in parents of Patient 3' , and was found in healthy father of patient 9. Pathogenic variant CFHR5 242C>T (P81L) was found in Patient 2, and was found in healthy father of patient 2. However, no pathogenic variants in genes CFH, MCP, CFI, C3, CFHR1, CFHR2, CFHR3 and CFHR4 were identified. Conclusion: Pathogenic variants in the 10 complement genes were identified in 3/11 of Han Chinese children with aHUS in our study and CFB was the most frequently mutated gene.目的： 探讨非典型溶血尿毒综合征(aHUS)汉族儿童补体基因致病变异检出率及其特点。 方法： 收集自1998年11月至2014年2月就诊于解放军福州总医院儿科的aHUS患儿11例，均为汉族，男9例，女2例，年龄为1岁4月龄至13岁。应用靶序列捕获和二代测序法对11例aHUS患儿10个补体基因(CFH、MCP、CFI、CFB、C3、CFHR1、CFHR2、CFHR3、CFHR4和CFHR5)所有外显子及每个外显子5′端及3′端各25 bp序列进行捕获测序；筛选基因变异后应用PCR和Sanger测序法进行验证；根据氨基酸保守性、蛋白质的结构功能和6种功能预测软件对基因变异的致病性进行分析。 结果： 11例aHUS患儿中有3例检测到2个致病变异：CFB 221G>A (R74H)及CFHR5 242C>T (P81L)，其中例3、例9检出CFB基因致病变异，例3父母未检测出该变异，例9父亲尿检正常，携带CFB 221G>A杂合变异；例2检出CFHR5基因致病变异，其父亲尿检正常，携带CFHR5 242C>T杂合变异；CFH、MCP、CFI、C3、CFHR1、CFHR2、CFHR3和CFHR4基因致病变异检出率为0。 结论： 1998年11月至2014年2月就诊于解放军福州总医院儿科的aHUS汉族儿童补体基因致病变异检出率为3/11，CFB是致病变异检出率最高的基因。.