A frequent variant in the Japanese population determines quasi-Mendelian inheritance of rare retinal ciliopathy

Konstantinos Nikopoulos, Katarina Cisarova, Mathieu Quinodoz, Hanna Koskiniemi-Kuendig, Noriko Miyake, Pietro Farinelli, Atta Ur Rehman, Muhammad Imran Khan, Andrea Prunotto, Masato Akiyama, Yoichiro Kamatani, Chikashi Terao, Fuyuki Miya, Yasuhiro Ikeda, Shinji Ueno, Nobuo Fuse, Akira Murakami, Yuko Wada, Hiroko Terasaki, Koh Hei SonodaTatsuro Ishibashi, Michiaki Kubo, Frans P.M. Cremers, Zoltán Kutalik, Naomichi Matsumoto, Koji M. Nishiguchi, Toru Nakazawa, Carlo Rivolta

研究成果: ジャーナルへの寄稿記事

抄録

Hereditary retinal degenerations (HRDs) are Mendelian diseases characterized by progressive blindness and caused by ultra-rare mutations. In a genomic screen of 331 unrelated Japanese patients, we identify a disruptive Alu insertion and a nonsense variant (p.Arg1933*) in the ciliary gene RP1, neither of which are rare alleles in Japan. p.Arg1933* is almost polymorphic (frequency = 0.6%, amongst 12,000 individuals), does not cause disease in homozygosis or heterozygosis, and yet is significantly enriched in HRD patients (frequency = 2.1%, i.e., a 3.5-fold enrichment; p-value = 9.2 × 10−5). Familial co-segregation and association analyses show that p.Arg1933* can act as a Mendelian mutation in trans with the Alu insertion, but might also associate with disease in combination with two alleles in the EYS gene in a non-Mendelian pattern of heredity. Our results suggest that rare conditions such as HRDs can be paradoxically determined by relatively common variants, following a quasi-Mendelian model linking monogenic and complex inheritance.

元の言語英語
記事番号2884
ジャーナルNature communications
10
発行部数1
DOI
出版物ステータス出版済み - 12 1 2019

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Retinal Degeneration
degeneration
mutations
genes
insertion
heredity
Genes
Alleles
blindness
Population
Mutation
Heredity
Blindness
Japan
causes
Ciliopathies

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

これを引用

Nikopoulos, K., Cisarova, K., Quinodoz, M., Koskiniemi-Kuendig, H., Miyake, N., Farinelli, P., ... Rivolta, C. (2019). A frequent variant in the Japanese population determines quasi-Mendelian inheritance of rare retinal ciliopathy. Nature communications, 10(1), [2884]. https://doi.org/10.1038/s41467-019-10746-4

A frequent variant in the Japanese population determines quasi-Mendelian inheritance of rare retinal ciliopathy. / Nikopoulos, Konstantinos; Cisarova, Katarina; Quinodoz, Mathieu; Koskiniemi-Kuendig, Hanna; Miyake, Noriko; Farinelli, Pietro; Rehman, Atta Ur; Khan, Muhammad Imran; Prunotto, Andrea; Akiyama, Masato; Kamatani, Yoichiro; Terao, Chikashi; Miya, Fuyuki; Ikeda, Yasuhiro; Ueno, Shinji; Fuse, Nobuo; Murakami, Akira; Wada, Yuko; Terasaki, Hiroko; Sonoda, Koh Hei; Ishibashi, Tatsuro; Kubo, Michiaki; Cremers, Frans P.M.; Kutalik, Zoltán; Matsumoto, Naomichi; Nishiguchi, Koji M.; Nakazawa, Toru; Rivolta, Carlo.

:: Nature communications, 巻 10, 番号 1, 2884, 01.12.2019.

研究成果: ジャーナルへの寄稿記事

Nikopoulos, K, Cisarova, K, Quinodoz, M, Koskiniemi-Kuendig, H, Miyake, N, Farinelli, P, Rehman, AU, Khan, MI, Prunotto, A, Akiyama, M, Kamatani, Y, Terao, C, Miya, F, Ikeda, Y, Ueno, S, Fuse, N, Murakami, A, Wada, Y, Terasaki, H, Sonoda, KH, Ishibashi, T, Kubo, M, Cremers, FPM, Kutalik, Z, Matsumoto, N, Nishiguchi, KM, Nakazawa, T & Rivolta, C 2019, 'A frequent variant in the Japanese population determines quasi-Mendelian inheritance of rare retinal ciliopathy', Nature communications, 巻. 10, 番号 1, 2884. https://doi.org/10.1038/s41467-019-10746-4
Nikopoulos K, Cisarova K, Quinodoz M, Koskiniemi-Kuendig H, Miyake N, Farinelli P その他. A frequent variant in the Japanese population determines quasi-Mendelian inheritance of rare retinal ciliopathy. Nature communications. 2019 12 1;10(1). 2884. https://doi.org/10.1038/s41467-019-10746-4
Nikopoulos, Konstantinos ; Cisarova, Katarina ; Quinodoz, Mathieu ; Koskiniemi-Kuendig, Hanna ; Miyake, Noriko ; Farinelli, Pietro ; Rehman, Atta Ur ; Khan, Muhammad Imran ; Prunotto, Andrea ; Akiyama, Masato ; Kamatani, Yoichiro ; Terao, Chikashi ; Miya, Fuyuki ; Ikeda, Yasuhiro ; Ueno, Shinji ; Fuse, Nobuo ; Murakami, Akira ; Wada, Yuko ; Terasaki, Hiroko ; Sonoda, Koh Hei ; Ishibashi, Tatsuro ; Kubo, Michiaki ; Cremers, Frans P.M. ; Kutalik, Zoltán ; Matsumoto, Naomichi ; Nishiguchi, Koji M. ; Nakazawa, Toru ; Rivolta, Carlo. / A frequent variant in the Japanese population determines quasi-Mendelian inheritance of rare retinal ciliopathy. :: Nature communications. 2019 ; 巻 10, 番号 1.
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AU - Miyake, Noriko

AU - Farinelli, Pietro

AU - Rehman, Atta Ur

AU - Khan, Muhammad Imran

AU - Prunotto, Andrea

AU - Akiyama, Masato

AU - Kamatani, Yoichiro

AU - Terao, Chikashi

AU - Miya, Fuyuki

AU - Ikeda, Yasuhiro

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AU - Fuse, Nobuo

AU - Murakami, Akira

AU - Wada, Yuko

AU - Terasaki, Hiroko

AU - Sonoda, Koh Hei

AU - Ishibashi, Tatsuro

AU - Kubo, Michiaki

AU - Cremers, Frans P.M.

AU - Kutalik, Zoltán

AU - Matsumoto, Naomichi

AU - Nishiguchi, Koji M.

AU - Nakazawa, Toru

AU - Rivolta, Carlo

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N2 - Hereditary retinal degenerations (HRDs) are Mendelian diseases characterized by progressive blindness and caused by ultra-rare mutations. In a genomic screen of 331 unrelated Japanese patients, we identify a disruptive Alu insertion and a nonsense variant (p.Arg1933*) in the ciliary gene RP1, neither of which are rare alleles in Japan. p.Arg1933* is almost polymorphic (frequency = 0.6%, amongst 12,000 individuals), does not cause disease in homozygosis or heterozygosis, and yet is significantly enriched in HRD patients (frequency = 2.1%, i.e., a 3.5-fold enrichment; p-value = 9.2 × 10−5). Familial co-segregation and association analyses show that p.Arg1933* can act as a Mendelian mutation in trans with the Alu insertion, but might also associate with disease in combination with two alleles in the EYS gene in a non-Mendelian pattern of heredity. Our results suggest that rare conditions such as HRDs can be paradoxically determined by relatively common variants, following a quasi-Mendelian model linking monogenic and complex inheritance.

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