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.
Highlights
Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal disease characterized by night blindness, progressive visual field loss, and eventually loss of visual acuity
The retinitis pigmentosa 1 (RP1) gene consists of 4 exons and encodes a 2156-amino-acid photoreceptor-specific microtubule-associated protein containing two doublecortin (DCX) domains [6,7], via which the RP1 protein interacts with microtubules [8]
We studied a total of 607 patients with inherited retinal diseases (IRDs) from 440 families, including 475 patients from 344 families at The Jikei University Hospital, 100 patients from 67 families at Nippon Medical School Chiba Hokusoh Hospital, 23 patients from 22 families at University of Occupational and Environmental Health Hospital, and 9 patients from 7 families at Hamamatsu University Hospital, who underwent whole-exome sequencing (WES) or whole-genome sequencing (WGS) analysis
Summary
Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal disease characterized by night blindness, progressive visual field loss, and eventually loss of visual acuity. More recent studies have reported the clinical and genetic features associated with the Alu element insertion in Japanese patients with AR-RP [20,21,22]. Little is known about the longitudinal findings of patients with AR-COD/CORD, and the genotype–phenotype correlations in RP1-associated retinal dystrophies in the Japanese population. 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. 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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