8个家系9例 NPHS1变异相关肾病患儿临床表型与基因变异特点分析  

Clinical feature and genetic variation in 9 cases of NPHS1-variant associated nephropathy from 8 Chinese families

作　　者：张旭媚 王海燕[2] 岳智慧[3] 魏海霞 孙良忠 Zhang Xumei;Wang Haiyan;Yue Zhihu;Wei Haixia;Sun Liangzhong(Department of Pediatrics,Nanfang Hospital,Southern Medical University,Guangzhou 510515,China;Department of Pediatrics,Sun Yat-sen Memorial Hospital,Sun Yat-sen University,Guangzhou 510120,China;Department of Pediatrics,the First Affiliated Hospital,Sun Yat-sen University,Guangzhou 510080,China)

机构地区：[1]南方医科大学南方医院儿科,广州510515 [2]中山大学孙逸仙纪念医院儿科,广州510120 [3]中山大学附属第一医院儿科,广州510080

出　　处：《中华肾脏病杂志》2025年第2期99-106,共8页Chinese Journal of Nephrology

基　　金：广东省自然科学基金(2022A1515012307、2024A1515013163)。

摘　　要：目的:探索NPHS1变异相关肾病(NPHS1-variant associated nephropathy,NPHS1-VAN)临床表型与基因变异特点及其关系。方法:该研究为病例系列分析。收集2018—2023年南方医科大学南方医院儿科诊治和随访的NPHS1-VAN病例及其家系资料。分析其临床、病理和基因变异特点及其相关性。结果:共收集8个家系9例患者,男5例,女4例。起病年龄0~3个月7例,3个月以上2例。9例均检测到NPSH1(可能)致病性变异,其中7例为复合杂合变异,2例为纯合变异;包括8种错义变异、3种移码变异和1种剪切位点变异。3个家系4例患者均含c.928G>A错义变异,其中3例患儿出生后1个月内起病,2例分别于1岁、2岁蛋白尿自发缓解;1例患儿蛋白尿持续,11岁进展至终末期肾病;另1例患儿6个月起病,激素初治不敏感,后期部分有效,他克莫司治疗蛋白尿缓解,但频复发。2例患儿死亡,其中1例宫内胎儿水肿,出生3 d后呼吸衰竭死亡,其母前2孕分别为死胎和死产;患儿NPHS1变异为c.1135C>G(R379G)和c.1339G>A(E447K)复合杂合错义变异。本研究1例患儿为c.1339G>A(E447K)纯合点变异,临床表型较轻,21岁尚未进展至终末期肾病,推测E447K致病性较弱,R379G致病性较强。发现5个新变异:3个错义变异(c.1135C>G、c.1157A>T、c.3197T>A)和2个移码变异(c.709_710delCT、c.3193delG)。4例患儿行肾活检,局灶节段性肾小球硬化和微小病变型肾病各2例。结论:NPHS1-VAN有较大的临床异质性和遗传异质性。本组病例发现5种新变异,错义变异是最常见变异类型,以c.928G>A最多见,与既往国内报道一致;含c.928G>A变异患儿,临床表型可能较轻,有自发缓解可能,并可能对激素和钙调磷酸酶抑制剂治疗有效。c.1135C>G(R379G)变异可能有较重的临床表型。Objective:To explore the clinical feature and genetic variation of NPHS1 variant-associated nephropathy(NPHS1-VAN)in Chinese patients.Methods:This study was a case-series analysis.Patients with NPHS1-VAN,who were treated and/or followed in the Department of Pediatrics,Nanfang Hospital,Southern Medical University between 2018 and 2023 were recruited into this study.Genotype,phenotype and their relationship were analyzed.Results:Nine NPHS1-VAN patients from 8 non-consanguineous Chinese families were collected,including 5 males and 4 females.There were 7 cases with an onset age within 3 months and 2 cases with an onset age of 6 months and 13 years,respectively.Seven patients harbored compound heterozygous variants,two had homozygous variants,including 8 missense variations,3 frameshift variants,and 1 splicing site variant.Four patients in 3 families harbored missense variant c.928G>A,two of them experienced spontaneous remission of proteinuria at the age of 1 year and 2 years,respectively,another one had persistent proteinuria and entered end stage renal disease(ESRD)at 11 years old.The other one had an onset age of 6 months with no response to steroids initially.She got complete remission by tacrolimus administered,but relapse frequently and partially responded to steroids later.Two patients of this group died,one of them died of respiratory failure 3 days after birth.Excessive amniotic fluid and fetal edema were acknowledged at 28 weeks of gestational age.He harbored compound heterozygous variants of NPHS1,c.1135C>G(R379G)and c.1339G>A(E447K).His mother previously experienced fetal death at 28 weeks gestational age for her first pregnant and stillborn at 36 weeks of gestational age for her second pregnant,respectively.One patient in this study who harbored homozygous variant of c.1339G>A(E447K)presented with a mild phenotype,onset age was 13 years old and didn't progress to ESRD yet at 21 years.Thus,variant E447K was hypothesized to be weakly pathogenic,while R379G may be strongly pathogenic with a risk of death.F

关 键 词：肾病综合征 突变 遗传变异 表型 基基因型 1 NPHSI NEPHRIN 

分 类 号：R726.9[医药卫生—儿科]