Subjects

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.

Tohoku University School of Medicine, Kyushu University School of Medicine, and Nagoya University School of Medicine, all based in Japan, were the centers where all Japanese patients with HRD were recruited. HRD was diagnosed clinically after excluding possible secondary causes of retinal degeneration such as toxicity and uveitis. Final diagnosis required the presence of reduced electroretinogram (ERG) responses, visual field loss, and funduscopic abnormalities consistent with retinal degeneration (retinal vascular narrowing and abnormalities of the retinal pigment epithelium etc.) symmetrically in both eyes.

Genotypes from individuals without HRD were collected from both published and unpublished databases [the BioBank Japan Project (N = 12,379), the ToMMo Japanese Reference Panel Project (3.5KJPN release, N = 3554)³¹, the Tohoku University School of Medicine (N = 95), the Yokohama City University Graduate School of Medicine (N = 429)] or were obtained experimentally by direct genotyping of genomic DNA, with standard molecular biology techniques.

Summary phenotypes of carriers of m1, m2, or m3 mutations are listed in Supplementary Table ¹.