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

Autor:	Nikopoulos K; Unit of Medical Genetics, Department of Computational Biology, University of Lausanne, 1015, Lausanne, Switzerland.; Service of Medical Genetics, Lausanne University Hospital (CHUV), 1011, Lausanne, Switzerland., Cisarova K; Unit of Medical Genetics, Department of Computational Biology, University of Lausanne, 1015, Lausanne, Switzerland., Quinodoz M; Unit of Medical Genetics, Department of Computational Biology, University of Lausanne, 1015, Lausanne, Switzerland., Koskiniemi-Kuendig H; Unit of Medical Genetics, Department of Computational Biology, University of Lausanne, 1015, Lausanne, Switzerland., Miyake N; Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan., Farinelli P; Unit of Medical Genetics, Department of Computational Biology, University of Lausanne, 1015, Lausanne, Switzerland., Rehman AU; Unit of Medical Genetics, Department of Computational Biology, University of Lausanne, 1015, Lausanne, Switzerland., Khan MI; Department of Human Genetics, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.; Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, 6525 GA, Nijmegen, The Netherlands., Prunotto A; Unit of Medical Genetics, Department of Computational Biology, University of Lausanne, 1015, Lausanne, Switzerland., Akiyama M; Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, 230-0045, Japan., Kamatani Y; Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, 230-0045, Japan., Terao C; Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, 230-0045, Japan., Miya F; Department of Medical Science Mathematics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, 113-8510, Japan., Ikeda Y; Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan., Ueno S; Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan., Fuse N; Department of Integrative Genomics, Tohoku Medical Megabank Organization, Sendai, 980-8573, Japan., Murakami A; Department of Ophthalmology, Juntendo University School of Medicine, Tokyo, 113-8421, Japan., Wada Y; Yuko Wada Eye Clinic, Sendai, 980-0011, Japan., Terasaki H; Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan., Sonoda KH; Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan., Ishibashi T; Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan., Kubo M; RIKEN Center for Integrative Medical Sciences, Yokohama, 230-0045, Japan., Cremers FPM; Department of Human Genetics, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.; Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, 6525 GA, Nijmegen, The Netherlands., Kutalik Z; Institute of Social and Preventive Medicine, Lausanne University Hospital, 1011, Lausanne, Switzerland., Matsumoto N; Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan., Nishiguchi KM; Department of Ophthalmology, Tohoku University Graduate School of Medicine, Sendai, 980-8574, Japan.; Department of Advanced Ophthalmic Medicine, Tohoku University Graduate School of Medicine, Sendai, 980-8574, Japan., Nakazawa T; Department of Ophthalmology, Tohoku University Graduate School of Medicine, Sendai, 980-8574, Japan.; Department of Advanced Ophthalmic Medicine, Tohoku University Graduate School of Medicine, Sendai, 980-8574, Japan., Rivolta C; Unit of Medical Genetics, Department of Computational Biology, University of Lausanne, 1015, Lausanne, Switzerland. carlo.rivolta@iob.ch.; Department of Genetics and Genome Biology, University of Leicester, Leicester, LE1 7RH, UK. carlo.rivolta@iob.ch.; Institute of Molecular and Clinical Ophthalmology Basel (IOB), 4031, Basel, Switzerland. carlo.rivolta@iob.ch.; University of Basel, 4001, Basel, Switzerland. carlo.rivolta@iob.ch.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2019 Jun 28; Vol. 10 (1), pp. 2884. Date of Electronic Publication: 2019 Jun 28.
DOI:	10.1038/s41467-019-10746-4
Abstrakt:	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.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu