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Original research
Phenotype and genotype spectra of a Chinese cohort with nephronophthisis-related ciliopathy
  1. Xiaoshan Tang1,2,
  2. Cuihua Liu3,
  3. Xiaorong Liu4,5,
  4. Jing Chen1,2,
  5. Xiaoyan Fan1,2,
  6. Jialu Liu1,2,
  7. Duan Ma6,
  8. Guanghai Cao3,
  9. Zhi Chen4,5,
  10. Daliang Xu7,
  11. Ying Zhu7,
  12. Xiaoyun Jiang8,
  13. Lizhi Cheng8,
  14. Yubing Wu9,
  15. Ling Hou9,
  16. Yuhong Li10,
  17. Xiaoshan Shao10,
  18. Shasha Zheng10,
  19. Aihua Zhang11,
  20. Bixia Zheng12,
  21. Shan Jian13,
  22. Zanhua Rong14,
  23. Qingxiao Su14,
  24. Xia Gao15,
  25. Jia Rao1,16,17,
  26. Qian Shen1,2,
  27. Hong Xu1,2,17,
  28. Chinese Children Genetic Kidney Disease Database (CCGKDD)
  29. “Internet Plus” Nephrology Alliance of the National Center for Children’s Care
  1. 1Department of Nephrology, Children's Hospital of Fudan University, Shanghai, China
  2. 2Shanghai Kidney Development and Pediatric Kidney Disease Research Center, Children's Hospital of Fudan University, Shanghai, China
  3. 3Nephrology and Rheumatology, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, China
  4. 4Nephrology, Bejing Children's Hospital, Beijing, China
  5. 5Beijing Children's Key Laboratory of Chronic Kidney Disease and Blood Purification, Beijing Children's Hospital, Beijing, China
  6. 6Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, Institutes of Biomedical Sciences, Fudan University School of Basic Medical Sciences, Shanghai, China
  7. 7Nephrology, Anhui Provincial Children's Hospital, Hefei, China
  8. 8Pediatric, Sun Yat-sen University First Affiliated Hospital, Guangzhou, Guangdong, China
  9. 9Pediatric Nephrology and Rheumatology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
  10. 10Nephrology and Rheumatology, Guiyang Children's Hospital, Guiyang, China
  11. 11Nephrology, Nanjing Medical University Affiliated Nanjing Children's Hospital, Nanjing, China
  12. 12Nanjing Key Laboratory of Pediatrics, Nanjing Medical University Affiliated Nanjing Children's Hospital, Nanjing, Jiangsu, China
  13. 13Pediatrics, Peking Union Medical College Hospital, Beijing, China
  14. 14Pediatrics, Second Hospital of Hebei Medical University, Shijiazhuang, China
  15. 15Nephrology, Guangzhou Children's Hospital, Guangzhou, China
  16. 16State Key Laboratory of Medical Neurobiology, Institutes of Brain Science and School of Basic Medical Science,Fudan University, Shanghai, China
  17. 17Shanghai Key Lab of Birth Defect, Children's Hospital of Fudan University, Shanghai, China, Shanghai, China
  1. Correspondence to Professor Hong Xu, Department of Nephrology, Children's Hospital of Fudan University, Shanghai, China; hxu{at}; Dr Jia Rao; jiarao{at}; Dr Qian Shen; shenqian{at}


Background Nephronophthisis-related ciliopathies (NPHP-RC) account for the majority of cases of monogenetically caused end-stage renal disease (ESRD) in children. Exploring the correlation between the phenotype and genotype of NPHP-RC is helpful for early diagnosis and management. We investigated the phenotype and genotype spectra of NPHP-RC in a Chinese multicentre cohort.

Methods Crosss-ectional and longitudinal data of 60 patients from 57 families with pathogenic NPHP-RC gene mutations distributed in 22 regions of China were collected into a unified, anonymous database. The mean observation time of this cohort was 3.5±3.1 years.

Results Mutations in NPHP1 and NPHP3 were the most common genetic defects. Overall, 45% of patients presented with isolated nephronophthisis (NPH), and 55% exhibited the extrarenal phenotype, which frequently involved the liver (41.7%, n=25), central nervous system (26.7%, n=16), eyes (26.7%, n=16) and skeletal system (11.7%, n=7). Accidental detection of elevated serum creatinine and non-specific symptoms caused by chronic kidney disease occurred in 65% of patients. Patients carrying NPHP1 mutations mainly presented with isolated NPH (90%, 18/20) and progressed to ESRD at a mean age of 12.9±0.5 years. The mean age of ESRD onset in the non-NPHP1 group was lower than that in the NPHP1 group (6.2±1.4 years, p<0.001), especially for patients carrying NPHP3 mutations (3.1±1.2 years), showing a heterogeneous phenotype characterised by Bardet-Biedl syndrome (12.5%, n=5), Joubert syndrome (7.5%, n=3), COACH syndrome (2.5%, n=1), Mainzer-Saldino syndrome (2.5%, n=1), short-rib thoracic dysplasia (2.5%, n=1) and unclassified symptoms (32.5%, n=13).

Conclusions The Chinese Children Genetic Kidney Disease Database registry characterised the spectrum of the phenotype and genotype of NPHP-RC in the Chinese population. NPHP1 and NPHP3 were the most common pathogenic genes. Rapid progression to ESRD and liver involvement were noted in patients with NPHP3 mutations.

  • genetics
  • medical
  • nephrology
  • child health
  • phenotype

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  • XT, CL and XL contributed equally.

  • Contributors XT, CL and XL contributed equally to this work. JR, QS and HX are co-corresponding authors. HX, CL and XL conceived and designed the study. JC, XF, JL, GC, ZC, YZ, LC, LH, SZ, BZ, SJ and XG collected the blood sample and clinical data. DM, YW, DX and XJ performed gene sequencing. YL, JR, AZ and ZR analysed clinical data. XT and QS wrote the manuscript. All authors reviewed and approved the manuscript.

  • Funding This work was supported by grant NSFC-81801545 from National Natural Science Foundation of China (XT); grant 2017ZZ01008 from Shanghai Municipal Health Commission (HX), grant 2018YFA0801102 from National Key Research and Development Project, grant NSFC-8182207 from National Natural Science Foundation of China (JR), grant 19XD1420600 from Program of Shanghai Academic/Technology Research Leader (JR), and grant 2019-RC-HL_020 from Chinese Academy of Medical Sciences (JR) and grant LHGJ20190923 from Henan Municipal Health Commission.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval The Institutional Review Board of the Children’s Hospital of Fudan University approved and monitored this study involving the 10 participating centres. All participants provided written informed consent.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available on reasonable request. The data that support the findings of this study are available from the corresponding author on reasonable request.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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