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

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Version: Final published version
License: CC BY 4.0
Serval ID
serval:BIB_5CE00AD41EAE
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
A frequent variant in the Japanese population determines quasi-Mendelian inheritance of rare retinal ciliopathy.
Journal
Nature communications
Author(s)
Nikopoulos K., Cisarova K., Quinodoz M., Koskiniemi-Kuendig H., Miyake N., Farinelli P., Rehman A.U., Khan M.I., Prunotto A., Akiyama M., Kamatani Y., Terao C., Miya F., Ikeda Y., Ueno S., Fuse N., Murakami A., Wada Y., Terasaki H., Sonoda K.H., Ishibashi T., Kubo M., Cremers FPM, Kutalik Z., Matsumoto N., Nishiguchi K.M., Nakazawa T., Rivolta C.
ISSN
2041-1723 (Electronic)
ISSN-L
2041-1723
Publication state
Published
Issued date
28/06/2019
Peer-reviewed
Oui
Volume
10
Number
1
Pages
2884
Language
english
Notes
Publication types: Journal Article
Publication Status: epublish
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 <sup>-5</sup> ). 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.
Pubmed
Web of science
Open Access
Yes
Create date
12/07/2019 15:29
Last modification date
20/08/2019 14:15
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