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.
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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)
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.
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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). https://doi.org/10.1038/s10038-022-01020-5