Shogo Numa, Akio Oishi, Koichiro Higasa, Maho Oishi, Manabu Miyata, Tomoko Hasegawa, Hanako Ohashi Ikeda, Yuki Otsuka, Fumihiko Matsuda, Akitaka Tsujikawa
Next-generation sequencing (NGS) has greatly advanced the studies of causative genes and variants of inherited diseases. While it is sometimes challenging to determine the pathogenicity of identified variants in NGS, the American College of Medical Genetics and Genomics established the guidelines to help the interpretation. However, as to the genetic screenings for patients with retinitis pigmentosa (RP) in Japan, none of the previous studies utilized the guidelines. Considering that EYS is the major causative gene of RP in Japan, we conducted stepwise genetic screening of 220 Japanese patients with RP utilizing the guidelines. Step 1–4 comprised the following, in order: Sanger sequencing for two major EYS founder mutations; targeted sequencing of all coding regions of EYS; whole genome sequencing; Sanger sequencing for Alu element insertion in RP1, a recently determined founder mutation for RP. Among the detected variants, 2, 19, 173, and 1 variant(s) were considered pathogenic and 8, 41, 44, and 5 patients were genetically solved in step 1, 2, 3, and 4, respectively. Totally, 44.5% (98/220) of the patients were genetically solved, and 50 (51.0%) were EYS-associated and 5 (5.1%) were Alu element-associated. Among the unsolved 122 patients, 22 had at least one possible pathogenic variant.
The global estimate of retinitis pigmentosa (RP), the most prevalent form of the inherited retinal dystrophies (IRD) across all nations and ethnicities, is 1:4000, and it is a leading cause of severe visual disabilities and blindness in developed countries. It is clinically and genetically heterogeneous. About 100 causative genes have been identified and novel causative genes and mutations are now being reported annually.
Recent studies have revealed the spectrum of causative genes and steadily laid the groundwork for genetic approaches to treatments for IRD. Many clinical trials of gene therapies are also ongoing. The approval of Voretigene neparvovec as the first gene therapy for Leber congenital amaurosis (LCA), signaled the dawn of gene therapy for IRD. Given this background, identifying causative genes and their mutations for each IRD among various ethnicities will become more important.
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