Kei Mizobuchi1, Takaaki Hayashi1,2, Noriko Oishi3, Daiki Kubota3, Shuhei Kameya3, Koichiro Higasa4, Takuma Futami5, Hiroyuki Kondo5, Katsuhiro Hosono6, Kentaro Kurata6, Yoshihiro Hotta6, Kazutoshi Yoshitake7, Takeshi Iwata7, Tomokazu Matsuura8, Tadashi Nakano1. 1. Department of Ophthalmology, The Jikei University School of Medicine, 3-19-18, Nishi-shimbashi, Minato-ku, Tokyo 105-8471, Japan. 2. Department of Ophthalmology, Katsushika Medical Center, The Jikei University School of Medicine, 6-41-2 Aoto, Katsushika-ku, Tokyo 125-8506, Japan. 3. Department of Ophthalmology, Nippon Medical School Chiba Hokusoh Hospital, 1715 Kamagari, Inzai, Chiba 270-1694, Japan. 4. Department of Genome Analysis, Institute of Biomedical Science, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka 573-1010, Japan. 5. Department of Ophthalmology, University of Occupational and Environmental Health, 1-1, Iseigaoka, Yahatanishi-ku Kitakyushu-shi, Fu-kuoka 807-8555, Japan. 6. Department of Ophthalmology, Hamamatsu University School of Medicine, 1-20-1, Handayama, Higashi-ku, Shizuoka, Hamamatsu 431-3192, Japan. 7. National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, 2-5-1 Higashigaoka, Meguro-ku, Tokyo 152-8902, Japan. 8. Department of Laboratory Medicine, The Jikei University School of Medicine, 3-19-18, Nishi-shimbashi, Minato-ku, Tokyo 105-8471, Japan.
Abstract
BACKGROUND: Little is known about genotype-phenotype correlations of RP1-associated retinal dystrophies in the Japanese population. We aimed to investigate the genetic spectrum of RP1 variants and provide a detailed description of the clinical findings in Japanese patients. METHODS: In total, 607 patients with inherited retinal diseases were examined using whole-exome/whole-genome sequencing (WES/WGS). PCR-based screening for an Alu element insertion (c.4052_4053ins328/p.Tyr1352AlafsTer9) was performed in 18 patients with autosomal-recessive (AR)-retinitis pigmentosa (RP) or AR-cone dystrophy (COD)/cone-rod dystrophy (CORD), including seven patients with heterozygous RP1 variants identified by WES/WGS analysis, and 11 early onset AR-RP patients, in whom no pathogenic variant was identified. We clinically examined 25 patients (23 families) with pathogenic RP1 variants, including five patients (five families) with autosomal-dominant (AD)-RP, 13 patients (11 families) with AR-RP, and seven patients (seven families) with AR-COD/CORD. RESULTS: We identified 18 pathogenic RP1 variants, including seven novel variants. Interestingly, the Alu element insertion was the most frequent variant (32.0%, 16/50 alleles). The clinical findings revealed that the age at onset and disease progression occurred significantly earlier and faster in AR-RP patients compared to AD-RP or AR-COD/CORD patients. CONCLUSIONS: Our results suggest a genotype-phenotype correlation between variant types/locations and phenotypes (AD-RP, AR-RP, and AR-COD/CORD), and the Alu element insertion was the most major variant in Japanese patients with RP1-associated retinal dystrophies.
BACKGROUND: Little is known about genotype-phenotype correlations of RP1-associated retinal dystrophies in the Japanese population. We aimed to investigate the genetic spectrum of RP1 variants and provide a detailed description of the clinical findings in Japanese patients. METHODS: In total, 607 patients with inherited retinal diseases were examined using whole-exome/whole-genome sequencing (WES/WGS). PCR-based screening for an Alu element insertion (c.4052_4053ins328/p.Tyr1352AlafsTer9) was performed in 18 patients with autosomal-recessive (AR)-retinitis pigmentosa (RP) or AR-cone dystrophy (COD)/cone-rod dystrophy (CORD), including seven patients with heterozygous RP1 variants identified by WES/WGS analysis, and 11 early onset AR-RP patients, in whom no pathogenic variant was identified. We clinically examined 25 patients (23 families) with pathogenic RP1 variants, including five patients (five families) with autosomal-dominant (AD)-RP, 13 patients (11 families) with AR-RP, and seven patients (seven families) with AR-COD/CORD. RESULTS: We identified 18 pathogenic RP1 variants, including seven novel variants. Interestingly, the Alu element insertion was the most frequent variant (32.0%, 16/50 alleles). The clinical findings revealed that the age at onset and disease progression occurred significantly earlier and faster in AR-RP patients compared to AD-RP or AR-COD/CORD patients. CONCLUSIONS: Our results suggest a genotype-phenotype correlation between variant types/locations and phenotypes (AD-RP, AR-RP, and AR-COD/CORD), and the Alu element insertion was the most major variant in Japanese patients with RP1-associated retinal dystrophies.
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