A frequent variant in the Japanese population determines quasi-Mendelian inheritance of rare retinal ciliopathy.
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28 juin 2019
- doi: 10.1038/s41467-019-10746-4
- issn: 2041-1723
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info:eu-repo/semantics/altIdentifier/urn/urn:nbn:ch:serval-BIB_5CE00AD41EAE7
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K. Nikopoulos et al., « A frequent variant in the Japanese population determines quasi-Mendelian inheritance of rare retinal ciliopathy. », Serveur académique Lausannois, ID : 10.1038/s41467-019-10746-4
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Résumé
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.