摘要
目的 探讨1型肾单位消耗病(nephronophthisis,NPH)的临床表型及NPHP1基因突变特点.方法 本研究为病例系列分析,回顾性收集初步诊断1型NPH患者及其父母的外周血标本、临床、影像和病理资料.通过二代测序或微卫星标记检测NPHP1基因变异.结果 (1)本研究中,16个家系20例患者确诊为1型NPH.起病中位年龄为9.5岁(3.0～21.0岁),发病至确诊的平均时间为2.1年(0.1～6.5年).首诊表现方面,肾功能不全7例(35.0％),多饮、多尿或夜尿增多8例(40.0％),贫血4例(20.0％),生长迟缓7例(35.0％),其中1例以生长迟缓及胸廓畸形为首诊表现.肾脏表现方面,10例(50.0％)尿常规检查尿蛋白阴性,10例(50.0％)有少量蛋白尿,均无血尿;首诊时18例(90.0％)患者有不同程度的肾功能损害,进展至慢性肾脏病5期的中位年龄为12岁(9.1～16.5岁).17例接受尿蛋白成分分析患者中,15例存在a1微球蛋白和β2微球蛋白升高,包括6例尿常规检查尿蛋白阴性患者.11例(55.0％)患者双肾体积正常,9例(45.0％)肾脏体积缩小,其中7例双肾体积缩小,2例单个肾脏体积缩小.B超及磁共振水成像检查显示,12例(60.0％)患者皮髓质交接处和/或肾髓质处有单发或多发肾囊肿,8例(40.0％)未见囊肿.9例患者完成了肾活检,均可见肾小管萎缩及管腔扩张、肾小管基底膜增厚或分层、间质纤维化及炎性细胞浸润.5例存在肾外表现,如Senior-Loken综合征、弱视或屈光不正、Cogan综合征、肝囊肿等.16个家系20例确诊患者中,NPHP1外显子(exon 1～20)纯合缺失发生在8个家系10例患者,杂合缺失伴点突变发生在5个家系7例患者,复合杂合点突变发生在3个家系3例患者,不同基因突变类型患者的临床表型(性别、肾脏体积、囊肿形成、尿蛋白)的差异均无统计学意义(均P＞0.05).16例进行了基因二代测序(靶向外显子组测序和全外显子组测序),其中8例合并其他纤毛病致病基因变异;而与无合并其他纤毛病致病基因变异的8例患者相比,合并其他纤毛病致病基因变异的8例患者在性别构成、发病年龄、就诊前病程、肾脏表型(包括肾脏大小改变及囊肿形成、尿蛋白)、进展至慢性肾脏病5期的年龄无明显改变(均P＞0.05).(2)本研究另4个家系4例患者仅有NPHP1单杂合突变,且无其他囊肿性肾病和/或纤毛病致病基因变异可以解释,经临床诊断为NPH.(3)本研究共发现点突变12个,其中新发现8个(c.728+1G＞A,c.1630delA,c.1122+1G＞T,c.2081A＞G,c.1333C＞G,c.625-2A＞T,c.1374G＞T,c.968C＞T).结论 本系列患者NPHP1基因突变类型与国外报道存在较大差异,新突变比例较高,遗传背景差异较大.不同突变类型患者的临床表型无明显差异.
Abstract
Objective To explore the clinical features and genotypes of patients with nephronophthisis type 1(NPH1)associated with NPHP1 gene defect.Methods It was a case series analysis.Clinical data and blood samples of patients who were suspected of NPH1 were collected retrospectively.Next generation sequencing(NGS)or microsatellite markers(MMS)were used to detect the variations and homozygous deletion of NPHP1.Results(1)In this study,a total of 20 patients from 16 families were diagnosed as NPH1 with NPHP1 variations and/or homozygous deletions.The median onset age of the patients was 9.5 years old(ranging from 3.0 to 21 years old),and the mean time from onset to diagnosis was 2.1 years(ranging from 0.1 to 6.5 years).The clinical manifestations of the first diagnosis were renal insufficiency in 7 cases(35.0％),polydipsia,polyuria or nocturia in 8 cases(40.0％),anemia in 4 cases(20.0％),and growth retardation in 7 cases(35.0％),of which 1 case was first diagnosed with growth retardation and thoracic malformation.In terms of renal manifestations,10 patients(50.0％)exhibited negative urinary protein by urine routine test,while 10 patients(50.0％)presented with a small amount of proteinuria.Notably,none of the patients displayed hematuria.At first diagnosis,18 patients(90.0％)exhibited varying degrees of renal impairment,and the median age of progression to stage 5 chronic kidney disease was 12 years(ranging from 9.1 to 16.5 years).Of the 17 patients who underwent urine protein composition analysis,15 had elevated α1 microglobulin and β2 microglobulin,including 6 patients with negative urine routine test.The volume of the kidney was normal in 11 patients(55.0％)and decreased in 9 patients(45.0％),including 7 patients with both kidneys affected and 2 patients with a single kidney affected.B-ultrasonography and magnetic resonance hydrography showed that 12 patients(60.0％)presented with single or multiple renal cysts located at the cortical medullary junction and/or renal medulla,and 8 patients(40.0％)had no cyst.Renal biopsy performed on 9 patients consistently revealed tubular atrophy and lumen dilation,tubular basement membrane thickening or stratification,interstitial fibrosis and inflammatory cell infiltration.A total of 5 cases exhibited extrarenal manifestations,including Senior-Loken syndrome,amblyopia or ametropia,Cogan syndrome,liver cyst,etc.Among the 20 confirmed patients from 16 families,homozygous deletion of NPHP1 exon(exon 1-20)occurred in 10 patients from 8 families,heterozygous deletion accompanied by point mutation occurred in 7 patients from 5 families,and complex heterozygous point mutation occurred in 3 patients from 3 families.No statistically significant differences were found in clinical phenotypes(gender,kidney volume,cyst formation,urinary protein)among patients with different mutation types(all P＞0.05).Of the 16 patients who underwent NGS(targeted exome sequencing and whole exome sequencing),8 had pathogenic gene variants related to other ciliopathies.When compared to the 8 patients without other ciliopathy-related pathogenic gene variants,no significant differences were found in gender,age of onset,disease duration before treatment,kidney phenotype(including kidney size,cyst formation,urinary protein),and age of progression to stage 5 chronic kidney disease(all P＞0.05).(2)In addition,4 patients from 4 other families were found to have only a single heterozygous mutation in NPHP1,and lacked any other genetic variants that could explain cystic nephropathy and/or ciliopathy.Based on clinical findings,these patients were diagnosed as NPH.(3)Totally,12 point mutations were found in this study,of which 8 novel point mutations(c.728+1G＞A,c.1630delA,c.1122+1G＞T,c.2081A＞G,c.1333C＞G,c.625-2A＞T,c.1374G＞T,c.968C＞T)were identified.Conclusions The genotype of NPHP1 in this series of patients is significantly different from those reported abroad,with a higher proportion of novel mutation and greater genetic background diversity.There is no significant difference in clinical manifestation among patients with different genotypes.
基金项目
国家自然科学基金面上项目(81670610)
广东省自然科学基金(2022A1515012307)
广东省自然科学基金(2020A1515010286)
NETL
NSTL
万方数据