NPHS1基因Fin-minor突变致中国先天性肾病综合征2例报道并文献复习

Two Chinese cases with congenital nephrotic syndrome caused by Fin-minor mutation of NPHS1 gene and literature review

目的总结2例先天性肾病综合征芬兰型NPHS1基因Fin-minor突变患儿临床资料,提高对该病的认识。方法报道2例先天性肾病综合征患儿的临床特点。对可能致病基因NPHS1、NPHS2、PLCε1、LAMB2、COQ2和LMX1B外显子和WT1基因第8、9外显子,以及外显子相邻附近区域进行直接测序。对该家系相关成员进行NPHS1基因外显子及附近调控区域直接测序,分析突变位点,并文献综述。结果 2例患儿均于出生后1个月内起病,临床表现为肾病综合征。血清病原学检查均为阴性。家系调查未发现家族中有类似疾病的成员。NPHS1、NPHS2、PLCε1、LAMB2、COQ2、LMX1B和WT1基因分析发现,2例患儿存在双NPHS1基因杂合突变,未发现其他基因有致病性突变。1例患儿为NPHS1基因的p.R1109X(c.3325C>T,Fin-minor)和IVS26DS-2A>T杂合突变,IVS26DS-2A>T剪切突变为首次报道,其父亲携带IVS26DS-2A>T,其母亲携带p.R1109X。1例患儿为NPHS1基因的p.R1109X(c.3325C>T)和p.A1160X(c.3478C>T)杂合突变,其母亲携带p.R1109X突变,未发现p.A1160X突变,其父亲拒绝行NPHS1基因分析。以上发现的突变在100例正常人群中未发现。结论中国先天性肾病综合征儿童不仅有NPHS1基因突变,而且有经典的Fin-minor突变,为国内首报。本研究新发现的IVS26DS-2A>T剪切突变丰富了NPHS1基因突变谱。

Objective To summarize and review the clinical data of two Chinese cases with congenital nephrotic syndrome( CNS) caused by Fin-minor mutation of NPHS1 gene. Methods Clinical data of two cases with CNS were summarized,including clinical manifestations,laboratory findings and family investigation. All exons and flanking regions of NPHS1,NPHS2,PLCε1,LAMB2, COQ2,LXM1B gene,and exon 8 and 9 of WT1 gene were sequenced for the two cases,and NPHS1 gene was sequenced in his family. And related literatures were reviewed also. Results Two cases presented nephrotic syndrome within the first month after birth. Screening of blood serum from the patient was performed to exclud the presence of antibodies for toxoplasma,syphilis, rubella virus,cytomegalovirus and herpes simplex virus. Serum etiology examination was negative. No additional patient was identified in their families. No pathogenic mutations were found in NPHS2,PLCε1,LAMB2,COQ2,LXM1B and WT1 genes in two cases,mutations in NPHS1 were detected in two cases,both being heterozygous. One case had p. R1109X( c. 3325C > T,Finminor) and IVS26DS-2A > T heterozygous mutations in NPHS1 gene. These two mutations were identified by analysis of NPHS1gene in her parents. IVS26DS-2A > T mutation was first reported in this study. Another case had p. R1109X( c. 3325C > T) and p. A1160X( c. 3478C > T) heterozygous mutations in NPHS1 gene. p. R1109X mutation was detected in his mother,but p. A1160X was absent. His father refused analysis of NPHS1 gene. The above NPHS1 mutations were not found in 100 normal people. Conclusion Chinese patients with CNS not only carry NPHS1 mutations,also carry typical Fin-minor mutation of NPHS1. The novel IVS26DS-2A > T mutations was a pathogenic mutation in our study. And it extended the spectrum of NPHS1 gene mutations.