Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka, Japan.
Department of Human Genetics, The University of Tokyo, Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan.
J Med Genet. 2022 Nov;59(11):1133-1138. doi: 10.1136/jmedgenet-2022-108428. Epub 2022 Jun 15.
Despite the successful identification of causative genes and genetic variants of retinitis pigmentosa (RP), many patients have not been molecularly diagnosed. Our recent study using targeted short-read sequencing showed that the proportion of carriers of pathogenic variants in , the cause of autosomal recessive RP, was unexpectedly high in Japanese patients with unsolved RP. This result suggested that causative genetic variants, which are difficult to detect by short-read sequencing, exist in such patients. Using long-read sequencing technology (Oxford Nanopore), we analysed the whole genomes of 15 patients with RP with one heterozygous pathogenic variant in detected in our previous study along with structural variants (SVs) in and another 88 RP-associated genes. Two large exon-overlapping deletions involving six exons were identified in in two patients with unsolved RP. An analysis of an independent patient set (n=1189) suggested that these two deletions are not founder mutations. Our results suggest that searching for SVs by long-read sequencing in genetically unsolved cases benefits the molecular diagnosis of RP.
尽管已经成功鉴定出致盲性视网膜色素变性（RP）的致病基因和遗传变异，但许多患者仍未得到分子诊断。我们最近的一项研究使用靶向短读长测序发现，在日本未解决 RP 患者中，导致常染色体隐性 RP 的 的致病变异携带者比例出人意料地高。这一结果表明，此类患者存在难以通过短读长测序检测的致病遗传变异。我们使用长读长测序技术（Oxford Nanopore）分析了 15 名 RP 患者的全基因组，这些患者在我们之前的研究中均携带一个杂合致病性变异，同时还分析了 和另外 88 个与 RP 相关的基因中的结构变异（SVs）。在两名未解决 RP 患者中发现了两个涉及六个外显子的大型外显子重叠缺失。对一个独立患者组（n=1189）的分析表明，这两种缺失不是创始突变。我们的研究结果表明，在遗传上未解决的病例中通过长读长测序寻找 SVs 有助于 RP 的分子诊断。
