serval:BIB_5CE00AD41EAE
A frequent variant in the Japanese population determines quasi-Mendelian inheritance of rare retinal ciliopathy.
10.1038/s41467-019-10746-4
000473132200048
31253780
Nikopoulos
K.
author
Cisarova
K.
author
Quinodoz
M.
author
Koskiniemi-Kuendig
H.
author
Miyake
N.
author
Farinelli
P.
author
Rehman
A.U.
author
Khan
M.I.
author
Prunotto
A.
author
Akiyama
M.
author
Kamatani
Y.
author
Terao
C.
author
Miya
F.
author
Ikeda
Y.
author
Ueno
S.
author
Fuse
N.
author
Murakami
A.
author
Wada
Y.
author
Terasaki
H.
author
Sonoda
K.H.
author
Ishibashi
T.
author
Kubo
M.
author
Cremers
FPM
author
Kutalik
Z.
author
Matsumoto
N.
author
Nishiguchi
K.M.
author
Nakazawa
T.
author
Rivolta
C.
author
article
2019-06-28
Nature communications
2041-1723
2041-1723
journal
10
1
2884
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.
eng
60_published
true
peer-reviewed
Publication types: Journal Article
Publication Status: epublish
University of Lausanne
mailto:serval_help@unil.ch
http://www.unil.ch/serval
http://serval.unil.ch/disclaimer
https://serval.unil.ch/notice/serval:BIB_5CE00AD41EAE