A frequent variant in the Japanese population determines quasi-Mendelian inheritance of rare retinal ciliopathy.pdf (688.39 kB)
A frequent variant in the Japanese population determines quasi-Mendelian inheritance of rare retinal ciliopathy.
journal contribution
posted on 2019-07-08, 09:01 authored by K Nikopoulos, K Cisarova, M Quinodoz, H Koskiniemi-Kuendig, N Miyake, P Farinelli, AU Rehman, MI Khan, A Prunotto, M Akiyama, Y Kamatani, C Terao, F Miya, Y Ikeda, S Ueno, N Fuse, A Murakami, Y Wada, H Terasaki, K-H Sonoda, T Ishibashi, M Kubo, FPM Cremers, Z Kutalik, N Matsumoto, KM Nishiguchi, T Nakazawa, C RivoltaHereditary 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.
Funding
This work was supported by the following agencies. The Swiss National Science Foundation (grant #176097, to C.R.); the Rotterdamse Stichting Blindenbelangen, the Stichting voor Ooglijders and the Nelly Reef fund (to M.I.K. and F.P.M.C.); the Japan Agency for Medical Research and Development (grant #17ek0109213h0001) and the Japan Society for the Promotion of Science (grant #16K11315, to K.M.N.); Research on Measures for Intractable Diseases, Comprehensive Research on Disability Health and Welfare, the Strategic Research Program for Brain Science, and the Initiative on Rare and Undiagnosed Diseases (all to N.Ma.); the Japanese Agency for Medical Research and Development, Grants-in-Aid for Scientific Research (to N.Ma. and N.Mi.); the BioBank Japan Project, by the Japanese Ministry of Education, Culture, Sport, Science and Technology and the Japanese Agency for Medical Research and Development (to M.K.); the PhD Fellowship in Life Sciences (Faculty of Biology and Medicine, University of Lausanne), to M.Q. Most HRD patients were recruited from the Japanese Retinitis Pigmentosa Registry Project (JRPRP).
History
Citation
Nature Communications, 2019, 10, Article number: 2884Author affiliation
/Organisation/COLLEGE OF LIFE SCIENCES/Biological Sciences/Genetics and Genome BiologyVersion
- VoR (Version of Record)
Published in
Nature CommunicationsPublisher
Nature Research (part of Springer Nature)eissn
2041-1723Acceptance date
2019-05-23Copyright date
2019Available date
2019-07-08Publisher DOI
Publisher version
https://www.nature.com/articles/s41467-019-10746-4Notes
Data availability The data supporting the findings of this study, as a whole, contain information that could compromise the privacy/consent of the participants, therefore we provide the genotypes of the cases analyzed as a summary statistics file containing aggregated data (Supplementary Data 2). Genotypes of control Japanese individuals from the ToMMo Japanese Reference Panel Project (3.5KJPN release, v20181105open) can be accessed at https://jmorp.megabank.tohoku.ac.jp/201905/downloads. Data from the BioBank Japan Project and the Tohoku University School of Medicine and Yokohama City University Graduate School of Medicine is available upon request to the corresponding author, pending authorization of the Centers that generated them and in agreement with their specific IRB approvals. Code availability Processing of raw sequence files, variant calling, variant annotation, as well as all the other analyses described in this work were performed using available and open source software, as detailed in the Methods section. No custom code was therefore used, aside from simple scripts integrating commands for such programs.Language
enAdministrator link
Usage metrics
Categories
No categories selectedKeywords
Licence
Exports
RefWorks
BibTeX
Ref. manager
Endnote
DataCite
NLM
DC