Genetic Architecture of Childhood Kidney and Urological Diseases in China.

中国儿童肾脏和泌尿外科疾病的遗传结构。

• 发表时间: Jun 2021
• 来源期刊: Phenomics
• DOI: 10.1007/s43657-021-00014-1
• PMID: 36939782
• 文章类型: Journal Article
• 作者列表: Fang Y,Shi H,Xiang T,Liu J,Liu J,Tang X,Fang X,Chen J,Zhai Y,Shen Q,Li G,Sun L,Bi Y,Wang X,Qian Y,Wu B,Wang H,Zhou W,Ma D,Mao J,Jiang X,Sun S,Shen Y,Liu X,Zhang A,Wang X,Huang W,Li Q,Wang M,Gao X,Wu Y,Deng F,Zhang R,Liu C,Yu L,Zhuang J,Sun Q,Dang X,Bai H,Zhu Y,Lu S,Zhang B,Shao X,Liu X,Han M,Zhao L,Liu Y,Gao J,Bao Y,Zhang D,Ma Q,Zhao L,Xia Z,Lu B,Wang Y,Zhao M,Zhang J,Jian S,He G,Zhang H,Zhao B,Li X,Wang F,Li Y,Zhu H,Luo X,Li J,Rao J,Xu H

关键词: Chronic kidney disease (CKD); Congenital anomalies of the kidney and urinary tract (CAKUT); Exome sequencing (ES); Nephronophthisis (NPHP); Polycystic kidney disease (PKD); Steroid-resistant nephrotic syndrome (SRNS)

Abstract

Kidney disease is manifested in a wide variety of phenotypes, many of which have an important hereditary component. To delineate the genotypic and phenotypic spectrum of pediatric nephropathy, a multicenter registration system is being implemented based on the Chinese Children Genetic Kidney Disease Database (CCGKDD). In this study, all the patients with kidney and urological diseases were recruited from 2014 to 2020. Genetic analysis was conducted using exome sequencing for families with multiple affected individuals with nephropathy or clinical suspicion of a genetic kidney disease owing to early-onset or extrarenal features. The genetic diagnosis was confirmed in 883 of 2256 (39.1%) patients from 23 provinces in China. Phenotypic profiles showed that the primary diagnosis included steroid-resistant nephrotic syndrome (SRNS, 23.5%), glomerulonephritis (GN, 32.2%), congenital anomalies of the kidney and urinary tract (CAKUT, 21.2%), cystic renal disease (3.9%), renal calcinosis/stone (3.6%), tubulopathy (9.7%), and chronic kidney disease of unknown etiology (CKDu, 5.8%). The pathogenic variants of 105 monogenetic disorders were identified. Ten distinct genomic disorders were identified as pathogenic copy number variants (CNVs) in 11 patients. The diagnostic yield differed by subgroups, and was highest in those with cystic renal disease (66.3%), followed by tubulopathy (58.4%), GN (57.7%), CKDu (43.5%), SRNS (29.2%), renal calcinosis /stone (29.3%) and CAKUT (8.6%). Reverse phenotyping permitted correct identification in 40 cases with clinical reassessment and unexpected genetic conditions. We present the results of the largest cohort of children with kidney disease in China where diagnostic exome sequencing was performed. Our data demonstrate the utility of family-based exome sequencing, and indicate that the combined analysis of genotype and phenotype based on the national patient registry is pivotal to the genetic diagnosis of kidney disease.
UNASSIGNED: The online version contains supplementary material available at 10.1007/s43657-021-00014-1.

摘要

肾脏疾病表现为各种各样的表型，其中许多都有重要的遗传成分。描绘小儿肾病的基因型和表型谱，正在基于中国儿童遗传性肾脏病数据库(CCGKDD)实施多中心登记系统.在这项研究中,纳入了2014年至2020年的所有肾脏和泌尿系统疾病患者.使用外显子组测序对患有肾病或由于早发性或肾外特征而临床怀疑遗传性肾病的多个受影响个体的家庭进行遗传分析。在中国23个省的2256例患者中，有883例（39.1％）得到了基因诊断。表型图谱显示，主要诊断包括类固醇抗性肾病综合征(SRNS，23.5%），肾小球肾炎（GN，32.2%)，先天性肾脏和泌尿道异常（CAKUT，21.2%），囊性肾病(3.9%)，肾钙质沉着/结石(3.6%)，肾小管病(9.7%)，和病因不明的慢性肾脏病(CKDu，5.8%）。确定了105种单基因疾病的致病变体。在11名患者中，10种不同的基因组疾病被鉴定为致病性拷贝数变异（CNV）。诊断结果因亚组而异，在患有囊性肾病的患者中最高（66.3％），其次是肾小管病(58.4%)，GN（57.7%），CKDu（43.5%），SRNS（29.2%），肾钙质沉着/结石(29.3%)和CAKUT(8.6%)。反向表型允许在40例具有临床重新评估和意外遗传条件的病例中正确鉴定。我们介绍了中国最大的肾脏疾病儿童队列的结果，其中进行了诊断外显子组测序。我们的数据证明了基于家族的外显子组测序的实用性，并表明基于国家患者注册的基因型和表型的联合分析对于肾脏疾病的基因诊断至关重要。
UNASSIGNED：在线版本包含补充材料，可在10.1007/s43657-021-00014-1获得。