期刊
NATURE COMMUNICATIONS
卷 10, 期 -, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-019-10746-4
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资金
- Swiss National Science Foundation [176097]
- Rotterdamse Stichting Blindenbelangen
- Stichting voor Ooglijders
- Japan Agency for Medical Research and Development [17ek0109213h0001]
- Japan Society for the Promotion of Science [16K11315]
- Research on Measures for Intractable Diseases
- BioBank Japan Project, by the Japanese Ministry of Education, Culture, Sport, Science and Technology
- PhD Fellowship in Life Sciences (Faculty of Biology and Medicine, University of Lausanne)
- Nelly Reef fund
- Japanese Agency for Medical Research and Development
- Strategic Research Program for Brain Science
- Comprehensive Research on Disability Health and Welfare
- Initiative on Rare and Undiagnosed Diseases
- BioBank Japan Project, by the Japanese Agency for Medical Research and Development
- Grants-in-Aid for Scientific Research [16K11315] Funding Source: KAKEN
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 x 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.
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