少年型肾单位肾痨13例临床特点和基因突变分析

Clinical features and gene mutation analysis of 13 Chinese juvenile patients with nephronophthisis

目的 探讨少年型肾单位肾痨（NPHP）临床和基因突变特点.方法 收集2010年1月至2016年7月广东省6家医院临床拟诊或病理确诊来自25个家系的27例少年型NPHP患儿的临床资料和外周血标本.所有患儿均行NPHP1基因纯合片段缺失检测,无片段缺失且无眼部受累患儿进一步行NPHP1基因外显子测序;合并眼部受累者先行NPHP5基因外显子测序,无突变者再依次行NPHP10基因和NPHP1基因外显子测序.结果 27例患儿中通过病理和（或）基因检测确诊13例,男4例,女9例.起病年龄8.5（0.1 ～12.8）岁.7例尿常规无异常,6例有少至中量蛋白尿,无持续血尿患儿.就诊时估算肾小球滤过率为（12.7＆#177;10.7）ml/（min＆#183;1.73 m2）.影像学检查：5例患儿见单发或多发肾囊肿,8例未见囊肿;双肾体积缩小9例,正常4例.5例肾活检患儿肾皮髓质交界处见肾小管囊肿形成及小管基底膜增厚分层.2例患儿合并眼部损害,1例有肝功能损害.7例（25.9％）患儿检测到NPHP1基因突变,其中3例为大片段纯合缺失（del2、804/6、del-10,del2、804/6、del-10、del-5、del-9及804/6、del-10、del-5）;点突变4例,均为新突变,预测均可导致NPHP1蛋白结构和功能改变：1例双重杂合突变[c.13 C ＞T （p.Arg5Term）及c.1520 ＋5 G＞A];3例为纯合突变,其中2例来自同一家系[c.1756 C ＞T（p.Arg586Term）],另1例检测到c.1298delA（p.Lys433fs）.1个家系检测到NPHP5基因突变,该家系有2例合并先天性视网膜病患儿.结论 少年NPHP起病隐匿,尿液改变轻微或无改变,肾脏大小正常或缩小,肾囊肿仅见于部分患儿.7例患儿检测到NPHP1基因突变.

Objective To explore the clinical features and pathogenic gene mutation of juvenile nephronophthisis （NPHP） in Chinese patients.Method Clinical data and blood samples of 27 juvenile NPHP patients from 25 families who were initially clinically diagnosed in six hospitals in Guangdong province were collected.NPHP1 homozygous deletions were detected in all patients.Sequencing of NPHP1 gene was performed when homozygous deletions were not found in patients without eye involvement.In patients with eye involvement,NPHP5 sequencing was carried out initially and subsequendy NPHP10 gene and NPHP1 when there were no NPHP5 gene mutation found.Result Diagnosis was confirmed in 13 patients by renal pathology and （or） gene sequencing,including four boys and nine girls with a median onset age of 8.5 （0.1-12.8） years.Seven of the 13 patients had a normal routine urine test and six patients had mild to moderate proteinuria.None had persistent hematuria.The estimated glomerular filtration rate of the 13 patients was （12.7 ＆#177; 10.7） ml/（min ＆#183; 1.73 m2） at the time of diagnosis.Renal cysts were found in only five patients by iconography.Decreased renal size was observed in nine cases and normal renal size in four patients.Renal pathology was available in five patients,renal cysts formation at the cortical-medullar area,thickening and laying tubular basement membrane,were observed.Two of the thirteen children had eye involvement,one had liver impairment and one had growth retardation.NPHP1 gene defects were detected in seven patients with a mutation rate of 25.9%,and large homozygous deletions were observed in three patients.Four patients had single point mutations,i.e.compound heterozygous mutations （c.13 C 〉 T and c.1520 ＋5 G 〉 A） in one patient;homozygous mutation in three patients,two patients were siblings from the same pedigree harbored c.1756 C 〉 T and the other one harbored c.1298delA.NPHP5 gene homozygous mutation was found in one pedigree.The fourteen children without renal pathology and whose genetic tests were negative shared similar clinical features with the thirteen patients whose diagnosis were confirmed by gene mutation and （or） renal pathology.Conclusion The onset of juvenile NPHP is insidious.Urine and renal iconography changes are mild or negative.The ratio of NPHP1 mutant patient is similar with previous reports,but the proportion of NPHP1 gene homozygous deletions is much lower and all of the NPHP1 gene single point mutations detected in this research were novel,which indicates a genetic discrepancy existed between Chinese NPHP patients and the western ones.