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目的通过儿童散发性肾病综合征(NS)致病基因及其突变特点,探讨儿童NS致病基因的筛查策略。方法收集复旦大学附属儿科医院肾脏风湿科2011年1月1日至2013年12月31日的所有住院NS患儿的临床资料,依据发病年龄分为先天性NS(3月龄内)、婴儿型NS(~12月龄)、儿童早发型NS(~5岁)和儿童迟发型NS(~14岁);对儿童早发型和迟发型NS再依据对糖皮质激素(GC)治疗反应分为GC敏感(SSNS)和GC耐药(SRNS),SRNS又分为初发型和迟发型SRNS。先天性NS行NPHS1、NPHS2、PLCE1、LAMB2、LMX1B、COQ2基因所有外显子和WT1基因8、9外显子直接测序;婴儿型NS行NPHS1、NPHS2、PLCE1基因所有外显子和WT1基因8、9外显子直接测序;儿童早发型和迟发型NS行NPHS2基因所有外显子和WT1基因8、9外显子直接测序,以及NPHS1等8个基因42个常见突变位点的Snap Shot分析。结果238例NS患儿进入本文分析,男139例。18/10例(80%)先天性NS患儿检出NPHS1基因致病性突变;212例婴儿型NS患儿检出3例WT1(25.0%)、2例NPHS2(16.7%)和1例NPHS1(8.3%)基因突变;38/132例(6.1%)早发型NS患儿检出基因突变,均属于初发型SRNS(8/32,25.0%),其中WT1 3例(9.4%)、NPHS2 2例(6.3%)、NPHS1 2例(6.3%)和INF21例(3.1%),19例迟发型SRNS和81例SSNS患儿均未检出相关基因突变;484例儿童迟发型NS中未检出基因致病性突变。结论先天性NS、婴儿型NS和儿童早发型NS中的初发型SRNS患儿应是临床基因筛查的对象。NPHS1是本文先天性NS患儿的主要致病基因,推荐在先天性NS患儿行NPHS1基因检测。NPHS1、NPHS2和WT1基因突变频率在婴儿型NS和儿童早发型NS中的初发型SRNS患儿中较高,推荐这些人群中优先选择这3个基因作为目标基因进行筛查。不推荐常规在SSNS和迟发型SRNS患儿中行基因检测。
Objective To explore the screening strategies of children’s NS pathogenicity genes through the pathogenic genes of children with sporadic nephrotic syndrome (NS) and their mutations. Methods The clinical data of all hospitalized children with NS who were admitted to Department of Pediatrics, Fudan University Pediatric Hospital from January 1, 2011 to December 31, 2013 were collected and classified into congenital NS (3 months old), infants NS (~12 months of age), children with early-onset NS (~ 5 years) and children with late-onset NS (~14 years of age); children with early- and late- Sensitive (SSNS) and GC resistant (SRNS), SRNS is divided into primary and delayed SRNS. All exons of NPHS1, NPHS2, PLCE1, LAMB2, LMX1B and COQ2 genes and exons 8 and 9 of WT1 gene were directly sequenced in congenital NS patients. All exons of NPHS1, NPHS2 and PLCE1 genes and WT1 gene 8 , 9 exon direct sequencing; direct sequencing of all exons of NPHS2 gene and exons 8,9 of WT1 gene in children with early-onset and late-onset NS, and Snap Shot analysis of 42 common mutation sites of NPHS1 and other 8 genes . Results 238 cases of NS children entered the analysis of this article, 139 males. The pathogenic mutation of NPHS1 gene was detected in 18/10 children (80%) with congenital NS; three cases of WT1 (25.0%), two cases of NPHS2 (16.7%) and one case of NPHS1 (8.3%). 38/132 (6.1%) patients with early-onset NS were all detected as early onset SRNS (8 / 32,25.0%), including 3 cases of WT1 (9.4%), NPHS2 2 No gene mutation was detected in 6 cases (6.3%), NPHS1 (6.3%), INF21 (3.1%), 19 late-onset SRNS and 81 SSNS children Gene mutation. Conclusions Children with early onset SRNS in congenital NS, infant NS and early childhood NS should be the target of clinical gene screening. NPHS1 is the main causative gene of children with congenital NS in this paper, NPHS1 gene detection is recommended in children with congenital NS. The frequency of NPHS1, NPHS2, and WT1 gene mutations is higher in infants with early-onset SRNS in infants with NS and children with early-onset NS, and it is recommended that these 3 genes be selected as the target genes for screening in these populations. It is not recommended to routinely perform genetic testing in children with SSNS and late-onset SRNS.