Frequent variants in the Japanese population determine quasi-Mendelian inheritance of rare retinal ciliopathy

Nikopoulos, K.; Cisarova, K.; Koskiniemi-Kuendig, H.; Miyake, N.; Farinelli, P.; Quinodoz, M.; Imran, M.; Prunotto, A.; Akiyama, M.; Kamatani, Y.; Terao, C.; Miya, F.; Ikeda, Y.; Ueno, S.; Fuse, N.; Murakami, A.; Terasaki, H.; Sonoda, K.-H.; Ishibashi, T.; Kubo, M.; Cremers, F. P. M.; Matsumoto, N.; Nishiguchi, K. M.; Nakazawa, T.; Rivolta, C.

doi:10.1101/257634

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bioRxiv · 10.1101/257634

Frequent variants in the Japanese population determine quasi-Mendelian inheritance of rare retinal ciliopathy

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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 = 9.2x10-5). 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 cause disease in association 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.

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Nikopoulos, K., Cisarova, K., Koskiniemi-Kuendig, H., Miyake, N., Farinelli, P., Quinodoz, M., Imran, M., Prunotto, A., Akiyama, M., Kamatani, Y., Terao, C., Miya, F., Ikeda, Y., Ueno, S., Fuse, N., Murakami, A., Terasaki, H., Sonoda, K.-H., Ishibashi, T., Kubo, M., Cremers, F. P. M., Matsumoto, N., Nishiguchi, K. M., Nakazawa, T., Rivolta, C.. 2018-01-31. Frequent variants in the Japanese population determine quasi-Mendelian inheritance of rare retinal ciliopathy. https://doi.org/10.1101/257634

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