Genetic Architecture of Childhood Kidney and Urological Diseases in China

Ye Fang; Hua Shi; Tianchao Xiang; Jiaojiao Liu; Jialu Liu; Xiaoshan Tang; Xiaoyan Fang; Jing Chen; Yihui Zhai; Qian Shen; Guomin Li; Li Sun; Yunli Bi; Xiang Wang; Yanyan Qian; Bingbing Wu; Huijun Wang; Wenhao Zhou; Duan Ma; Jianhua Mao; Xiaoyun Jiang; Shuzhen Sun; Ying Shen; Xiaorong Liu; Aihua Zhang; Xiaowen Wang; Wenyan Huang; Qiu Li; Mo Wang; Xiaojie Gao; Yubin Wu; Fang Deng; Ruifeng Zhang; Cuihua Liu; Li Yu; Jieqiu Zhuang; Qing Sun; Xiqiang Dang; Haitao Bai; Ying Zhu; Siguang Lu; Bili Zhang; Xiaoshan Shao; Xuemei Liu; Mei Han; Lijun Zhao; Yuling Liu; Jian Gao; Ying Bao; Dongfeng Zhang; Qingshan Ma; Liping Zhao; Zhengkun Xia; Biao Lu; Yulong Wang; Mengzhun Zhao; Jianjiang Zhang; Shan Jian; Guohua He; Huifeng Zhang; Bo Zhao; Xiaohua Li; Feiyan Wang; Yufeng Li; Hongtao Zhu; Xinhui Luo; Jinghai Li; Jia Rao; Hong Xu

doi:10.1007/s43657-021-00014-1

Genetic Architecture of Childhood Kidney and Urological Diseases in China

Phenomics. 2021 Jul 15;1(3):91-104. doi: 10.1007/s43657-021-00014-1. eCollection 2021 Jun.

Authors

Ye Fang^{1

2

3}, Hua Shi^#^{1

2

3}, Tianchao Xiang^#^{1

2

3}, Jiaojiao Liu^{1

2

3}, Jialu Liu^{1

2

3}, Xiaoshan Tang^{1

2

3}, Xiaoyan Fang^{1

2

3}, Jing Chen^{1

2

3}, Yihui Zhai^{1

2

3}, Qian Shen^{1

2

3}, Guomin Li⁴, Li Sun⁴, Yunli Bi⁵, Xiang Wang⁵, Yanyan Qian⁶, Bingbing Wu⁶, Huijun Wang⁶, Wenhao Zhou⁶, Duan Ma^{3

7}, Jianhua Mao⁸, Xiaoyun Jiang⁹, Shuzhen Sun¹⁰, Ying Shen¹¹, Xiaorong Liu¹¹, Aihua Zhang¹², Xiaowen Wang¹³, Wenyan Huang¹⁴, Qiu Li¹⁵, Mo Wang¹⁵, Xiaojie Gao¹⁶, Yubin Wu¹⁷, Fang Deng¹⁸, Ruifeng Zhang¹⁹, Cuihua Liu²⁰, Li Yu²¹, Jieqiu Zhuang²², Qing Sun²³, Xiqiang Dang²⁴, Haitao Bai²⁵, Ying Zhu²⁶, Siguang Lu²⁷, Bili Zhang²⁸, Xiaoshan Shao²⁹, Xuemei Liu³⁰, Mei Han³¹, Lijun Zhao³², Yuling Liu³³, Jian Gao³⁴, Ying Bao³⁵, Dongfeng Zhang³⁶, Qingshan Ma³⁷, Liping Zhao³⁸, Zhengkun Xia³⁹, Biao Lu⁴⁰, Yulong Wang⁴¹, Mengzhun Zhao⁴², Jianjiang Zhang⁴³, Shan Jian⁴⁴, Guohua He⁴⁵, Huifeng Zhang⁴⁶, Bo Zhao⁴⁷, Xiaohua Li⁴⁸, Feiyan Wang⁴⁹, Yufeng Li⁵⁰, Hongtao Zhu⁵¹, Xinhui Luo⁵², Jinghai Li⁵³, Jia Rao^{1

2

3}, Hong Xu^{1

2

3}

Affiliations

¹ Department of Nephrology, Children's Hospital of Fudan University, National Pediatric Medical Center of CHINA, 399 Wanyuan Road, Shanghai, China.
² Shanghai Kidney Development and Pediatric Kidney Disease Research Center, Shanghai, China.
³ Shanghai Key Lab of Birth Defect, Children's Hospital of Fudan University, Shanghai, 201102 China.
⁴ Department of Rheumatology, Children's Hospital of Fudan University, Shanghai, China.
⁵ Department of Urology, Children's Hospital of Fudan University, Shanghai, China.
⁶ Clinical Genetic Center, Children's Hospital of Fudan University, Shanghai, China.
⁷ Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, Institutes of Biomedical Sciences, School of Basic Medical Sciences, Fudan University, Shanghai, China.
⁸ The Children Hospital of Zhejiang University School of Medicine, Hangzhou, China.
⁹ The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
¹⁰ Shandong Provincial Hospital, Jinan, China.
¹¹ Bejing Children's Hospital Affiliated to Capital University of Medical Science, Beijing, China.
¹² Children's Hospital of Nanjing Medical University, Nanjing, China.
¹³ Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
¹⁴ Shanghai Children's Medical Centre, Shanghai Jiaotong University School of Medicine, Shanghai, China.
¹⁵ Children's Hospital of Chongqing Medical University, Chongqing, China.
¹⁶ Shenzhen Children's Hospital, Shenzheng, China.
¹⁷ Shengjing Hospital of China Medical University, Shenyang, Liaoning China.
¹⁸ Anhui Provincial Children's Hospital, Hefei, China.
¹⁹ Xuzhou Children's Hospital, Xuzhou, China.
²⁰ Henan Children's Hospital, Zhengzhou, China.
²¹ Guangzhou First People's Hospital, Guangzhou, China.
²² The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
²³ Qingdao Women and Children's Hospital, Qingdao, China.
²⁴ Xiangya Hospital Central South University, Changsha, Hunan China.
²⁵ The First Affiliated Hospital of Xiamen University, Xiamen, China.
²⁶ First Affiliated Hospital of Anhui Medical University, Hefei, China.
²⁷ Children's Hospital of Lianyungang, Lianyungang, China.
²⁸ Tianjin Children Hospital, Tianjing, China.
²⁹ The Children's Hospital of Guiyang City, Guiyang, China.
³⁰ Qilu Children's Hospital of Shandong University, Jinan, China.
³¹ Dalian Children's Hospital, Dalian, China.
³² Shanxi Children's Hospital, Taiyuan, China.
³³ Boai Hospital of Zhongshan, Zhongshan, China.
³⁴ Weifang Maternal and Child Health Hospital, Weifang, China.
³⁵ Xi'an Children's Hospital, Xian, China.
³⁶ Children's Hospital of Hebei Province, Shijiazhuang, China.
³⁷ First Affiliated Hospital of Jilin University, Changchun, China.
³⁸ Wuxi Municipal Children's Hospital, Wuxi, China.
³⁹ Department of Pediatrics, Jinling Hospital, Nanjing Medical University, Nanjing, China.
⁴⁰ General Hospital of Ningxia Medical University, Yinchuan, China.
⁴¹ The Second Hospital of Shandong University, Jinan, China.
⁴² Shenzhen Hospital of University of Hong Kong, Shenzhen, China.
⁴³ First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
⁴⁴ Peking Union Medical College Hospital, Beijing, China.
⁴⁵ Child Health Hospital of Foshan, Foshan, Guangdong China.
⁴⁶ The Second Hospital of Hebei Medical University, Shijiazhuang, China.
⁴⁷ Kunming Children's Hospital, Kunming, China.
⁴⁸ Affiliated Hospital of Inner Mongolia Medical University, Hohehot, China.
⁴⁹ Urumqi City Children's Hospital, Urumqi, China.
⁵⁰ Xinhua Hospital Affiliated to Medical College of Shanghai Jiaotong University, Shanghai, China.
⁵¹ Academy of Pediatrics, Xinjiang Medical University, Urumqi, China.
⁵² Xinjiang Uygur Autonomous Region People's Hospital, Urumqi, China.
⁵³ Changchun Children's Hospital, Changchun, China.

^# Contributed equally.

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.

Supplementary information: The online version contains supplementary material available at 10.1007/s43657-021-00014-1.

Keywords: 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).