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, Kohei Sonoda & 8 others Tatsuro Ishibashi, Michiaki Kubo, Frans P.M. Cremers, Zoltán Kutalik, Naomichi Matsumoto, Koji M. Nishiguchi, Toru Nakazawa, Carlo Rivolta

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Article number2884
JournalNature communications
Volume10
Issue number1
DOIs
Publication statusPublished - Dec 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)

Cite this

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, Kohei; Ishibashi, Tatsuro; Kubo, Michiaki; Cremers, Frans P.M.; Kutalik, Zoltán; Matsumoto, Naomichi; Nishiguchi, Koji M.; Nakazawa, Toru; Rivolta, Carlo.

In: Nature communications, Vol. 10, No. 1, 2884, 01.12.2019.

Research output: Contribution to journalArticle

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, K, 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, vol. 10, no. 1, 2884. https://doi.org/10.1038/s41467-019-10746-4
Nikopoulos K, Cisarova K, Quinodoz M, Koskiniemi-Kuendig H, Miyake N, Farinelli P et al. A frequent variant in the Japanese population determines quasi-Mendelian inheritance of rare retinal ciliopathy. Nature communications. 2019 Dec 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, Kohei ; 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. In: Nature communications. 2019 ; Vol. 10, No. 1.
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