PT  - JOURNAL ARTICLE
AU  - Konstantinos Nikopoulos
AU  - Katarina Cisarova
AU  - Hanna Koskiniemi-Kuending
AU  - Noriko Miyake
AU  - Pietro Farinelli
AU  - Mathieu Quinodoz
AU  - Muhammad Imran Khan
AU  - Andrea Prunotto
AU  - Masato Akiyama
AU  - Yoichiro Kamatani
AU  - Chikashi Terao
AU  - Fuyuki Miya
AU  - Yasuhiro Ikeda
AU  - Shinji Ueno
AU  - Nobuo Fuse
AU  - Akira Murakami
AU  - Hiroko Terasaki
AU  - Koh-Hei Sonoda
AU  - Tatsuro Ishibashi
AU  - Michiaki Kubo
AU  - Frans P. M. Cremers
AU  - Naomichi Matsumoto
AU  - Koji M. Nishiguchi
AU  - Toru Nakazawa
AU  - Carlo Rivolta
TI  - Frequent variants in the Japanese population determine quasi-Mendelian inheritance of rare retinal ciliopathy
AID  - 10.1101/257634
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 257634
4099  - http://biorxiv.org/content/early/2018/05/15/257634.short
4100  - http://biorxiv.org/content/early/2018/05/15/257634.full
AB  - Hereditary retinal degenerations (HRDs) are Mendelian diseases caused by ultra-rare mutations and leading to progressive blindness. Following the genomic screening of 331 unrelated Japanese patients, we identified an Alu insertion and a nonsense variant (p.Arg1933*) in the ciliary gene RP1. Surprisingly, none of these changes were rare alleles in Japan. p.Arg1933* was almost polymorphic (frequency = 0.6%, amongst 12,000 individuals), did not cause disease in homozygosis or heterozygosis, and yet was considerably enriched in patients vs. controls (frequency = 2.1%, i.e. a 3.5-fold enrichment; p-value = 1.29×10-6). Family and population analyses showed that p.Arg1933*could act as a Mendelian mutation, in trans with the Alu insertion and other pathogenic variants, but also cause disease in conjunction with rare alleles in ciliary genes elsewhere in the genome, according to an oligogenic 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.