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 Sonoda, Tatsuro Ishibashi, Michiaki Kubo, Frans P. M. Cremers, Zoltán Kutalik, Naomichi Matsumoto, Koji M. Nishiguchi, Toru Nakazawa and Carlo Rivolta ()
Additional contact information
Konstantinos Nikopoulos: University of Lausanne
Katarina Cisarova: University of Lausanne
Mathieu Quinodoz: University of Lausanne
Hanna Koskiniemi-Kuendig: University of Lausanne
Noriko Miyake: Yokohama City University Graduate School of Medicine
Pietro Farinelli: University of Lausanne
Atta Ur Rehman: University of Lausanne
Muhammad Imran Khan: Radboud University Medical Center
Andrea Prunotto: University of Lausanne
Masato Akiyama: RIKEN Center for Integrative Medical Sciences
Yoichiro Kamatani: RIKEN Center for Integrative Medical Sciences
Chikashi Terao: RIKEN Center for Integrative Medical Sciences
Fuyuki Miya: Tokyo Medical and Dental University
Yasuhiro Ikeda: Kyushu University
Shinji Ueno: Nagoya University Graduate School of Medicine
Nobuo Fuse: Tohoku Medical Megabank Organization
Akira Murakami: Juntendo University School of Medicine
Yuko Wada: Yuko Wada Eye Clinic
Hiroko Terasaki: Nagoya University Graduate School of Medicine
Koh-Hei Sonoda: Kyushu University
Tatsuro Ishibashi: Kyushu University
Michiaki Kubo: RIKEN Center for Integrative Medical Sciences
Frans P. M. Cremers: Radboud University Medical Center
Zoltán Kutalik: Lausanne University Hospital
Naomichi Matsumoto: Yokohama City University Graduate School of Medicine
Koji M. Nishiguchi: Tohoku University Graduate School of Medicine
Toru Nakazawa: Tohoku University Graduate School of Medicine
Carlo Rivolta: University of Lausanne

Nature Communications, 2019, vol. 10, issue 1, 1-7

Abstract: 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.

Date: 2019
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-019-10746-4 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10746-4

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-019-10746-4

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().