TY - JOUR
T1 - A frequent variant in the Japanese population determines quasi-Mendelian inheritance of rare retinal ciliopathy
AU - Nikopoulos, Konstantinos
AU - Cisarova, Katarina
AU - Quinodoz, Mathieu
AU - Koskiniemi-Kuendig, Hanna
AU - Miyake, Noriko
AU - Farinelli, Pietro
AU - Rehman, Atta Ur
AU - Khan, Muhammad Imran
AU - Prunotto, Andrea
AU - Akiyama, Masato
AU - Kamatani, Yoichiro
AU - Terao, Chikashi
AU - Miya, Fuyuki
AU - Ikeda, Yasuhiro
AU - Ueno, Shinji
AU - Fuse, Nobuo
AU - Murakami, Akira
AU - Wada, Yuko
AU - Terasaki, Hiroko
AU - Sonoda, Koh Hei
AU - Ishibashi, Tatsuro
AU - Kubo, Michiaki
AU - Cremers, Frans P.M.
AU - Kutalik, Zoltán
AU - Matsumoto, Naomichi
AU - Nishiguchi, Koji M.
AU - Nakazawa, Toru
AU - Rivolta, Carlo
N1 - Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85068400390
UR - https://www.scopus.com/pages/publications/85068400390#tab=citedBy
U2 - 10.1038/s41467-019-10746-4
DO - 10.1038/s41467-019-10746-4
M3 - Article
C2 - 31253780
AN - SCOPUS:85068400390
SN - 2041-1723
VL - 10
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 2884
ER -