Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Comprehensive genetic analysis using next-generation sequencing for the diagnosis of nephronophthisis-related ciliopathies in the Japanese population


Nephronophthisis is an autosomal-recessive kidney disease that is caused by abnormalities in primary cilia. Nephronophthisis-related ciliopathies (NPHP-RCs) are a common cause of end-stage kidney disease (ESKD) in children and adolescents. NPHP-RCs are often accompanied by extrarenal manifestations, including intellectual disability, retinitis pigmentosa, or polydactyly. Although more than 100 causative genes have been identified, its diagnosis is difficult because the clinical features of each mutation often overlap. From September 2010 to August 2021, we performed genetic analysis, including next-generation sequencing (NGS), in 574 probands with kidney dysfunction and retrospectively studied cases genetically diagnosed with NPHP-RCs.


We detected mutations related to NPHP-RCs in 93 patients from 83 families. Members of 60 families were diagnosed using NGS, and the mutations and the corresponding number of families are as follows: NPHP1 (24), NPHP3 (10), OFD1 (7), WDR35 (5), SDCCAG8 (4), BBS10 (3), TMEM67 (3), WDR19 (3), BBS1 (2), BBS2 (2), IFT122 (2), IFT140 (2), IQCB1 (2), MKKS (2), SCLT1 (2), TTC21B (2), ALMS1 (1), ANKS6 (1), BBS4 (1), BBS12 (1), CC2D2A (1), DYNC2H1 (1), IFT172 (1), and MAPKBP1 (1). A total of 39 cases (41.9%) progressed to ESKD at the time of genetic analysis, whereas 58 cases (62.3%) showed extrarenal manifestations, the most common being developmental delay, intellectual disability, and autism spectrum disorder in 44 patients. Comprehensive genetic analysis using NGS is useful for diagnosing patients with NPHP-RCs.

This is a preview of subscription content, access via your institution

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1


  1. Wolf MT, Hildebrandt F. Nephronophthisis. Pediatr Nephrol. 2011;26:181–94.

    Article  Google Scholar 

  2. Hildebrandt F, Otto E. Molecular genetics of nephronophthisis and medullary cystic kidney disease. J Am Soc Nephrol. 2000;11:1753–61.

    Article  CAS  Google Scholar 

  3. Hildebrandt F, Waldherr R, Kutt R, Brandis M. The nephronophthisis complex: clinical and genetic aspects. Clin Investig. 1992;70:802–8.

    Article  CAS  Google Scholar 

  4. Simms RJ, Hynes AM, Eley L, Sayer JA. Nephronophthisis: a genetically diverse ciliopathy. Int J Nephrol. 2011;2011:527137.

    Article  Google Scholar 

  5. Srivastava S, Sayer JA. Nephronophthisis. J Pediatr Genet. 2014;3:103–14.

    Article  CAS  Google Scholar 

  6. Stokman M, Lilien M, Knoers N. Nephronophthisis. In: Adam MP, Ardinger HH, Pagon RA, et al. ed. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 2016; 1993–2021. Available from:

  7. Halbritter J, Porath JD, Diaz KA, Braun DA, Kohl S, Chaki M, et al. Identification of 99 novel mutations in a worldwide cohort of 1,056 patients with a nephronophthisis-related ciliopathy. Hum Genet. 2013;132:865–84.

    Article  CAS  Google Scholar 

  8. Braun DA, Schueler M, Halbritter J, Gee HY, Porath JD, Lawson JA, et al. Whole exome sequencing identifies causative mutations in the majority of consanguineous or familial cases with childhood-onset increased renal echogenicity. Kidney Int. 2016;89:468–75.

    Article  CAS  Google Scholar 

  9. Gee HY, Otto EA, Hurd TW, Ashraf S, Chaki M, Cluckey A, et al. Whole-exome resequencing distinguishes cystic kidney diseases from phenocopies in renal ciliopathies. Kidney Int. 2014;85:880–7.

    Article  CAS  Google Scholar 

  10. Kang HG, Lee HK, Ahn YH, Joung JG, Nam J, Kim NDK, et al. Targeted exome sequencing resolves allelic and the genetic heterogeneity in the genetic diagnosis of nephronophthisis-related ciliopathy. Exp Mol Med. 2016;48:e251.

    Article  Google Scholar 

  11. Schueler M, Halbritter J, Phelps IG, Braun DA, Otto EA, Porath JD, et al. Large-scale targeted sequencing comparison highlights extreme genetic heterogeneity in nephronophthisis-related ciliopathies. J Med Genet. 2016;53:208–14.

    Article  CAS  Google Scholar 

  12. Blowey DL, Querfeld U, Geary D, Warady BA, Alon U. Ultrasound findings in juvenile nephronophthisis. Pediatr Nephrol. 1996;10:22–24.

    Article  CAS  Google Scholar 

  13. König J, Kranz B, König S, Schlingmann KP, Titieni A, Tönshoff B, et al. Phenotypic spectrum of children with nephronophthisis and related ciliopathies. Clin J Am Soc Nephrol. 2017;12:1974–83.

    Article  Google Scholar 

  14. Stokman MF, van der Zwaag B, van de Kar NCA, van Haelst MM, van Eerde AM, van der Heijden JW, et al. Clinical and genetic analyses of a Dutch cohort of 40 patients with a nephronophthisis-related ciliopathy. Pediatr Nephrol. 2018;33:1701–12.

    Article  Google Scholar 

  15. Srivastava S, Molinari E, Raman S, Sayer JA. Many genes-one disease? genetics of nephronophthisis (NPHP) and NPHP-associated disorders. Front Pediatr. 2017;5:287.

    Article  Google Scholar 

  16. Wolf MT. Nephronophthisis and related syndromes. Curr Opin Pediatr. 2015;27:201–11.

    Article  CAS  Google Scholar 

  17. Hildebrandt F, Rensing C, Betz RC, Sommer U, Brinbaum S, Imm A, et al. Establishing an algorithm for molecular genetic diagnostics in 127 families with juvenile nephronophthisis. Kidney Int. 2001;59:434–45.

    Article  CAS  Google Scholar 

  18. Snoek R, Van Setten J, Keating BJ, Israni AK, Jacobsen PA, Oetting WS, et al. NPHP1 (Nephrocystin-1) gene deletions cause adult-onset ESRD. J Am Soc Nephrol. 2018;29:1772–9.

    Article  CAS  Google Scholar 

  19. Macferran KM, Buchmann RF, Ramakrishnaiah R, Griebel ML, Sanger WG, Saronwala A, et al. Pontine tegmental cap dysplasia with a 2q13 microdeletion involving the NPHP1 gene: insights into malformations of the mid-hindbrain. Semin Pediatr Neurol. 2010;17:69–74.

    Article  Google Scholar 

  20. Inaguma Y, Kaito H, Morisada N, Iijima K, Tanaka R. Renal-hepatic-pancreatic dysplasia-1 diagnosed on comprehensive gene analysis. Pediatr Int. 2019;61:210–2.

    Article  Google Scholar 

  21. Sakakibara N, Morisada N, Nozu K, Nagatani K, Ohta T, Shimizu J, et al. Clinical spectrum of male patients with OFD1 mutations. J Hum Genet. 2019;64:3–9.

    Article  CAS  Google Scholar 

Download references


We thank all the patients, their social guardians, and primary doctors. We are grateful to Ms. Yoshimi Nozu, Ms. Yuko Noguchi, and Ms. Tetsuko Yamanouchi (Kobe University) for their excellent technical assistance. The following doctors provided patient samples for the study: Takayuki Okamoto (Hokkaido University), Tomomi Aizawa (Hirosaki University), Akira Ashida (Osaka Medical University), Shunsuke Goto, Hideki Fujii (Kobe University Graduate School of Medicine), Kouki Tomari (Tokyo Metropolitan Children’s Hospital), Satoshi Hibino (Aichi Children’s Health and Medical Center), Takashi Iijima, Yoshifumi Ubara (Toranomon Hospital), Marie Ito, Shunsuke Sakurai (Showa University Fujigaoka Hospital), Hidefumi Kishikawa (Hyogo Prefectural Nishinomiya Hospital), Koichi Kamei, Mika Okutsu, Ryutaro Suzuki, Mai Sato, Toru Kanamori (National Center for Child Health and Development), Rie Kawakita, Rika Fujimaru, Ichiro Kuki (Osaka City General Hospital), Takayuki Miyai (Okayama University), Kazuetsu Mori (Seirei Sakura Citizen Hospital), Masayuki Nakazawa (Sasebo Chuo Hospital), Ayumi Nogi (Ome Municipal Hospital), Katsusuke Yamamoto (Osaka Women’s and Children’s Hospital), Ken Saida (Yokohama City University), Takayuki Shibano (Hyogo College of Medicine), Junya Shimizu (NHO Okayama Medical Center), Ryojiro Tanaka (Hyogo Prefectural Kobe Children’s Hospital), Emi Utsuno (Chiba University), Takuzo Wada (Kinan Hospital), Masato Yasui (Fukuyama City Hospital), Shuichiro Fujinaga, Yoshitaka Watanabe, Shota Endo (Saitama Prefectural Children’s Medical Center), Tetsuji Inagaki (Miyagi Children’s Hospital), Masaki Takahashi (Tokyo Metropolitan Bokutoh Hospital), Tadashi Sofue (Kagawa University), Takeshi Yamada, Keisuke Nagasaki, Hiroya Hasegawa (Niigata University), Ayako Saito (Ibaraki Children’s Hopital), Ichiro Hada, Eriko Tanaka (Kyorin University), Yoshinobu Nagaoka (Sapporo Medical University), Tomo Suzuki (Kameda Medical Center), Takashi Uzu (Nippon Life Hospital), Masayuki Iwano (Fukui University), Toshihiko Shirakawa (Nagasaki University), Tomoko Nakamura (Odawara Municipal Hospital), Ryoichi Kitagata (Hamamatsu University School of Medicine), Daisuke Ichikawa (St. Marianna University School of Medicine), Masaki Yamamoto (Seirei Hamamatsu Hospital), Hisatsugu Takahara (Juntendo University Urayasu Hospital), Takashi Ohmae (Nara Prefectural Medical University), Kenichiro Miura (Tokyo Women’s Medical University).


This work was supported by the Health Labor Sciences Research Grant for the Research on Measures for Intractable Diseases (H24-nanchi-ippan-041 to K.I.; H29-nanchi-ippan-039 to NM) and the Japan Society for the Promotion of Science (KAKENHI Grant Numbers JP15K09261 and 18K08243 to NM)

Author information

Authors and Affiliations


Corresponding author

Correspondence to Naoya Morisada.

Ethics declarations

Competing interests

MM reports the following: Current Employer: Kobe Gakuin University which is financially supported by KNC Laboratories Co. Ltd. Inc. Japan. Consultancy Agreements: JCR Pharma Co., Ltd., Japan; Daiichi Sankyo Co., Ltd., Japan. Research Funding: Daiichi Sankyo Co., Ltd., Japan.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Sakakibara, N., Nozu, K., Yamamura, T. et al. Comprehensive genetic analysis using next-generation sequencing for the diagnosis of nephronophthisis-related ciliopathies in the Japanese population. J Hum Genet 67, 427–440 (2022).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


Quick links