Abstract
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.
Highlights
Our findings suggest that oligogenic heredity of human diseases may not be limited to a low number of cases with ultra-rare conditions, as shown up to now[34,35,53,54], but could extend to more frequent phenotypes and represent a bridge between monogenic and complex inheritance
The study was initiated following the approval by the Institutional Review Boards of our respective Institutions (University of Lausanne, Yokohama City University Graduate School of Medicine, Radboud University Medical Center, Kyushu University, Nagoya University Graduate School of Medicine, Tohoku Medical Megabank Organization, Juntendo University School of Medicine, Tohoku University Graduate School of Medicine, and Tokyo Medical and Dental University)
All subjects provided written informed consent, and the study was conducted in adherence with the Declaration of Helsinki
Summary
In the framework of a screening effort of 331 unrelated Japanese patients, we identified a novel, unusual mutation by wholegenome sequencing, consisting in the insertion of a mobile Alu element in exon 4 of the RP1 gene (m1, or NM_006269.1: c.4052_4053ins328/p.Tyr1352Alafs*9) in a female individual from a recessive HRD family. C > T/p.Arg1933* (m3, four unrelated individuals) that was previously identified in the general population and is present in dbSNP as entry #rs118031911 (Supplementary Table 1) Both variants, detected by direct Sanger sequencing, co-segregated with the disease in relevant families, according to an autosomal recessive pattern of inheritance (Fig. 1b–d). Note: The top 10 hits from this test are shown OR odds ratio, CI confidence interval *p-values retaining statistical significance
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