Perception of genetic testing among patients with inherited retinal disease: Benefits and challenges in a Japanese population.

Inherited retinal disease (IRD) is clinically and genetically heterogeneous. Awareness of the importance of genetic testing for IRD in the clinical setting is increasing with the recent development of new therapeutic strategies, such as gene therapy. Here, the perception of genetic testing, including its benefits and potential challenges, among patients with IRD was investigated to establish strategies for IRD genetic testing and counseling practices that can meet the requirements of the patients in Japan. An anonymous self-administered questionnaire was distributed to 275 patients with IRD who underwent genetic testing after clinical consultation and genetic counseling to investigate the motivations for genetic testing, benefits, challenges, status of communication of results to family, and attitude to timing of genetic testing. In total, 228 (82.9%) responses were analyzed. Several major motivations for genetic testing were identified, including gaining information on future treatment options and clarification of the inheritance pattern, among others. No association was found between the sharing of results with family members and the results of genetic testing. Moreover, according to patients who received positive results, the benefits of genetic testing included information on the inheritance pattern, additional information on the diagnosis, and mental preparation for the future. Even patients who received negative or inconclusive (variant of uncertain significance) results reported certain informative and psychological benefits. Altogether, these findings suggest that provisions for genetic testing and genetic counseling are necessary within a certain period after clinical diagnosis and it is necessary to facilitate appropriate family communication about genetic testing results while paying attention to the background of family relationships. Moreover, the benefits of genetic testing can be influenced by the careful interpretation and information provided on the test results during genetic counseling and consultation.

Truncating Variants Contribute to Hearing Loss and Severe Retinopathy in USH2A-Associated Retinitis Pigmentosa in Japanese Patients.

USH2A is a common causal gene of retinitis pigmentosa (RP), a progressive blinding disease due to retinal degeneration. Genetic alterations in USH2A can lead to two types of RP, non-syndromic and syndromic RP, which is called Usher syndrome, with impairments of vision and hearing. The complexity of the genotype-phenotype correlation in USH2A-associated RP (USH2A-RP) has been reported. Genetic and clinical characterization of USH2A-RP has not been performed in Japanese patients. In this study, genetic analyses were performed using targeted panel sequencing in 525 Japanese RP patients. Pathogenic variants of USH2A were identified in 36 of 525 (6.9%) patients and genetic features of USH2A-RP were characterized. Among 36 patients with USH2A-RP, 11 patients had syndromic RP with congenital hearing problems. Amino acid changes due to USH2A alterations were similarly located throughout entire regions of the USH2A protein structure in non-syndromic and syndromic RP cases. Notably, truncating variants were detected in all syndromic patients with a more severe retinal phenotype as compared to non-syndromic RP cases. Taken together, truncating variants could contribute to more serious functional and tissue damages in Japanese patients, suggesting important roles for truncating mutations in the pathogenesis of syndromic USH2A-RP.

Development of a molecular diagnostic test for Retinitis Pigmentosa in the Japanese population.

PURPOSE: Retinitis Pigmentosa (RP) is the most common form of inherited retinal dystrophy caused by different genetic variants. More than 60 causative genes have been identified to date. The establishment of cost-effective molecular diagnostic tests with high sensitivity and specificity can be beneficial for patients and clinicians. Here, we developed a clinical diagnostic test for RP in the Japanese population. STUDY DESIGN: Evaluation of diagnostic technology, Prospective, Clinical and experimental study. METHODS: A panel of 39 genes reported to cause RP in Japanese patients was established. Next generation sequence (NGS) technology was applied for the analyses of 94 probands with RP and RP-related diseases. After interpretation of detected genetic variants, molecular diagnosis based on a study of the genetic variants and a clinical phenotype was made by a multidisciplinary team including clinicians, researchers and genetic counselors. RESULTS: NGS analyses found 14,343 variants from 94 probands. Among them, 189 variants in 83 probands (88.3% of all cases) were selected as pathogenic variants and 64 probands (68.1%) have variants which can cause diseases. After the deliberation of these 64 cases, molecular diagnosis was made in 43 probands (45.7%). The final molecular diagnostic rate with the current system combining supplemental Sanger sequencing was 47.9% (45 of 94 cases). CONCLUSIONS: The RP panel provides the significant advantage of detecting genetic variants with a high molecular diagnostic rate. This type of race-specific high-throughput genotyping allows us to conduct a cost-effective and clinically useful genetic diagnostic test.