Early diagnosis of WT1 nephropathy and follow up in a Chinese multicenter cohort

Shuzhen Sun; Linan Xu; Yunli Bi; Jing Wang; Zhiqing Zhang; Xiaoshan Tang; Qi Cao; Yihui Zhai; Jing Chen; Xiaoyan Fang; Jialu Liu; Ye Fang; Tianchao Xiang; Yanyan Qian; Bingbing Wu; Huijun Wang; Wenhao Zhou; Jian Shen; Kuiran Dong; Xiaorong Liu; Bixia Zheng; Aihua Zhang; Xiaowen Wang; Yubing Wu; Duan Ma; Qian Shen; Jia Rao; Hong Xu

doi:10.1016/j.ejmg.2020.104047

Early diagnosis of WT1 nephropathy and follow up in a Chinese multicenter cohort

Eur J Med Genet. 2020 Nov;63(11):104047. doi: 10.1016/j.ejmg.2020.104047. Epub 2020 Sep 4.

Authors

Shuzhen Sun¹, Linan Xu², Yunli Bi³, Jing Wang¹, Zhiqing Zhang², Xiaoshan Tang², Qi Cao², Yihui Zhai², Jing Chen², Xiaoyan Fang², Jialu Liu², Ye Fang², Tianchao Xiang², Yanyan Qian⁴, Bingbing Wu⁴, Huijun Wang⁴, Wenhao Zhou⁴, Jian Shen³, Kuiran Dong⁵, Xiaorong Liu⁶, Bixia Zheng⁷, Aihua Zhang⁸, Xiaowen Wang⁹, Yubing Wu¹⁰, Duan Ma¹¹, Qian Shen², Jia Rao¹², Hong Xu¹³

Affiliations

¹ Department of Pediatric Nephrology, Rheumatism and Immunology, Shandong Provincial Hospital Affiliated to Shandong University, Shandong, China.
² Department of Nephrology, Children's Hospital of Fudan University, National Pediatric Medical Center of CHINA, Shanghai, China; Shanghai Kidney Development and Pediatric Kidney Disease Research Center, Shanghai, China; Shanghai Key Lab of Birth Defect, Children's Hospital of Fudan University, Shanghai, China.
³ Department of Nephrology, Children's Hospital of Fudan University, National Pediatric Medical Center of CHINA, Shanghai, China; Shanghai Kidney Development and Pediatric Kidney Disease Research Center, Shanghai, China; Department of Urology, Children's Hospital of Fudan University, Shanghai, China.
⁴ Clinical Genetic Center, Children's Hospital of Fudan University, Shanghai, China.
⁵ Department of Pediatric Surgery, Children's Hospital of Fudan University, National Pediatric Medical Center of CHINA, Shanghai, China.
⁶ Department of Nephrology, Beijing Children's Hospital Affiliated to Capital University of Medical Science, Beijing, China.
⁷ Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, China.
⁸ Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, China.
⁹ Department of Nephrology and Rheumatology, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China.
¹⁰ Department of Pediatric Renal Rheumatism Immunology, Shengjing Hospital Affiliated to China Medical University, Shenyang, China.
¹¹ 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.
¹² Department of Nephrology, Children's Hospital of Fudan University, National Pediatric Medical Center of CHINA, Shanghai, China; Shanghai Key Lab of Birth Defect, Children's Hospital of Fudan University, Shanghai, China; State Key Laboratory of Medical Neurobiology, Institutes of Brain Science and School of Basic Medical Science, Fudan University, China. Electronic address: jiarao@fudan.edu.cn.
¹³ Department of Nephrology, Children's Hospital of Fudan University, National Pediatric Medical Center of CHINA, Shanghai, China; Shanghai Kidney Development and Pediatric Kidney Disease Research Center, Shanghai, China; Shanghai Key Lab of Birth Defect, Children's Hospital of Fudan University, Shanghai, China. Electronic address: hxu@shmu.edu.cn.

PMID: 32891756
DOI: 10.1016/j.ejmg.2020.104047

Abstract

Background: WT1 mutations cause a wide spectrum of renal and extrarenal manifestations concerning urogenital development and the development of tumors.

Methods: We retrospectively collected the information on the genotype and phenotype of WT1 nephropathy from the multicenter registry since 2014 to 2019. All patients were stratified by renal function decline status or by sequence timing. Rapid progressive group was defined as rapidly developing into ERSD within 12 months since disease onset. Early sequencing group was defined as gene mutation identified before ERSD.

Results: Thirty-three (3.5%) cases were identified with a WT1 mutation in patients with steroid resistant nephrotic syndrome (SRNS), proteinuria and chronic kidney disease (CKD) 3-5 stage of unknown origin. ESRD developed in twenty patients at a median age of 4.3 years old. Comparing study between the rapid progressive group (n = 8) and non-rapid progressive group (n = 25) showed no significant difference in age of onset, gender, syndrome phenotype, genotype and proteinuria except for initial estimated glomerular filtration rate (eGFR) (p = 0.021) or sequencing timing (p = 0.003). In multivariable logistic regression analysis, the delayed sequencing was associated with rapid renal function decline, even after adjusting for established clinical factors including syndromic phenotype, genotype, age onset and eGFR at initial stage (p = 0.019). The renal survival analysis did not show a significantly better outcome in early sequencing group than in delayed sequencing group (p > 0.05).

Conclusion: Screening for WT1 mutations should be performed in children with Wilms' tumor, proteinuria/SRNS or CKD. Early diagnosis of WT1 nephropathy through clinical and genetic findings is warranted.

Keywords: Chronic kidney disease (CKD); Denys-drash syndrome (DDS); End stage renal disease (ESRD); Fraiser syndrome (FS); Steroid resistant nephrotic syndrome (SRNS); WT1; Wilms' tumor.

Publication types

Evaluation Study

MeSH terms

Child, Preschool
Cohort Studies
Early Diagnosis
Female
Genetic Testing / methods
Genetic Testing / standards*
Humans
Infant
Male
Multicenter Studies as Topic
Nephrotic Syndrome / diagnosis*
Nephrotic Syndrome / genetics
Proteinuria / diagnosis*
Proteinuria / genetics
Renal Insufficiency, Chronic / diagnosis*
Renal Insufficiency, Chronic / genetics
WT1 Proteins / genetics*
Wilms Tumor / diagnosis*
Wilms Tumor / genetics

Substances

WT1 Proteins
WT1 protein, human