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Clinical and genetic variability of PAX2-related disorder in the Japanese population

Journal of Human Genetics volume 65, pages 541–549 (2020)Cite this article

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Abstract

Pathogenic variants of paired box gene 2 (PAX2) cause autosomal-dominant PAX2-related disorder, which includes renal coloboma syndrome (RCS). Patients with PAX2-related disorder present with renal and ophthalmological pathologies, as well as with other abnormalities, including developmental problems and hearing loss. We sequenced PAX2 in 457 patients with congenital anomalies of the kidney and urinary tract or with renal dysfunction of unknown cause and identified 19 different pathogenic variants in 38 patients from 30 families (6.5%). Thirty-four patients had renal hypodysplasia or chronic kidney disease of unknown cause, and three had focal segmental glomerulosclerosis. Although no obvious genotype–phenotype correlation was observed, six of the seven patients who developed end-stage renal disease in childhood had truncating variants. Twenty-three patients had ocular disabilities, mostly optic disc coloboma. Non-renal and non-ophthalmological manifestations included developmental disorder, electrolyte abnormality, and gonadal abnormalities. Two unrelated patients had congenital cystic adenomatoid malformations in their lungs. Six of ten probands with PAX2 mutation identified by next-generation sequencing did not show typical RCS manifestations. We conclude that PAX2-related disorder has a variable clinical presentation and can be diagnosed by next-generation sequencing even in the absence of typical RCS manifestations.

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Acknowledgements

The authors wish to thank all the patients, their social guardians, and primary doctors. We are profoundly grateful to Ms. Akemi Shono, Mrs. Tetsuko Yamanouchi, Mrs. Yoshimi Nozu, and Mrs. Ming Juan Ye (Kobe University) for their excellent technical assistance. Data for patients SC10, SC56, SC111, SC390, and SC456 were published elsewhere [14, 24,25,26,27]. Data for patients SC239, SC274, and SC468 have been reported in Japanese journals [28,29,30]. The following doctors provided patient samples for this study: Takeshi Futatani (Toyama Prefectural Central Hospital), Yoshimitsu Gotoh (Japanese Red Cross Nagoya Daini hospital), Yuko Hamasaki (Toho University), Ken Hatae (Japanese Red Cross Fukuoka Hospital), Atsuko Iida (Tokyo Women’s Medical University Medical Center East), Yoichi Iwafuchi (Niigata Koseiren Sanjo General Hospital), Yuko Kajiho (The University of Tokyo), Chieko Matsumura (National Chiba Higashi Hospital), Koji Nagatani (Uwajima City Hospital), Tomoka Hase (Wakayama Medical University), Masashi Nishida (Kyoto Prefectural University of Medicine), Shunsuke Noda (Nagano Red Cross Hospital), Akifumi Ohtsuka (Saga University), Shin-ichi Okada (Tottori University), Mika Okutsu (National Center for Child and Development), Koji Sakuraya, Shuichiro Fujinaga (Saitama Children’s Medical Center), Noriko Sugawara (Tohoku University), Hironori Takahashi (Asahikawa Medical University), Masaki Yamamoto (Seirei Hamamatsu Hospital), and Masato Yasui (Fukuyama City Hospital). This work was supported by the Health Labor Sciences Research Grant for the Research on Measures for Intractable Diseases (H24-nanchi-ippan-041 to KI; H29-nanchi-ippan-039 to NM) and Japan Society for the Promotion of Science (KAKENHI Grant Nos. JP15K09261 and 18K08243 to NM).

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Authors and Affiliations

  1. Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan

    Rini Rossanti, Naoya Morisada, Kandai Nozu, Tomoko Horinouchi, Tomohiko Yamamura, Shogo Minamikawa, Junya Fujimura, China Nagano, Nana Sakakibara, Takeshi Ninchoji, Hiroshi Kaito & Kazumoto Iijima

  2. Department of Clinical Genetics, Hyogo Prefectural Kobe Children’s Hospital, 1-6-7, Minatojimaminami-machi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan

    Naoya Morisada

  3. Division of Nephrology and Rheumatology, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan

    Koichi Kamei & Shuichi Ito

  4. Department of Emergency and General Medicine, Hyogo Prefectural Kobe Children’s Hospital, 1-6-7, Minatojim aminami-machi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan

    Shogo Minamikawa & Ryojiro Tanaka

  5. Department of Pediatrics, Kakogawa City Hospital, Kakogawa, 439, Honmachi, Kakogawa, Hyogo, 675-8611, Japan

    Junya Fujimura

  6. Department of Nephrology, Hyogo Prefectural Kobe Children’s Hospital, 1-6-7, Minatojimaminami-machi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan

    Hiroshi Kaito & Ryojiro Tanaka

  7. Department of Pediatrics, Yokohama City University, 3-9, Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan

    Shuichi Ito

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  1. Rini Rossanti
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  9. China Nagano
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  14. Ryojiro Tanaka
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  15. Kazumoto Iijima
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Corresponding author

Correspondence to Naoya Morisada.

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Conflict of interest

KI has received grant support from Daiichi Sankyo Co., Ltd and Zenyaku Kogyo Co., Ltd.

Ethical approval

All procedures involving human participants performed in this study were in accordance with the ethical standards of the Institutional Review Board of the Kobe University Graduate School of Medicine (IRB approvals no. 65 and no. 301) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from the patients or their parents.

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Rossanti, R., Morisada, N., Nozu, K. et al. Clinical and genetic variability of PAX2-related disorder in the Japanese population. J Hum Genet 65, 541–549 (2020). https://doi.org/10.1038/s10038-020-0741-y

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