ABSTRACT
Hereditary retinal degenerations (HRDs) are Mendelian diseases caused by ultra-rare mutations and leading to progressive blindness. Following the genomic screening of 331 unrelated Japanese patients, we identified a disruptive Alu insertion and a nonsense variant (p.Arg1933*) in the ciliary gene RP1. Surprisingly, none of these changes were rare alleles in Japan. p.Arg1933* was almost polymorphic (frequency = 0.6%, amongst 12,000 individuals), did not cause disease in homozygosis or heterozygosis, and yet was considerably enriched in patients vs. controls (frequency = 2.1%, i.e. a 3.5-fold enrichment; p-value = 1.29×10-6). Familial co-segregation and exome-wide association analyses showed that p.Arg1933*could act as a Mendelian mutation, in trans with the Alu insertion, but also caused disease in association with at least one allele elsewhere in the genome, according to 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.