Division of Ophthalmology, Hadassah Medical Center, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel.
Department of Human Genetics, Radboud University Medical Center, 6525 Nijmegen, The Netherlands.
Genes (Basel). 2024 Oct 24;15(11):1363. doi: 10.3390/genes15111363.
Inherited retinal diseases (IRDs) are clinically complex and genetically heterogeneous visual impairment disorders with varying penetrance and severity. Disease-causing variants in at least 289 nuclear and mitochondrial genes have been implicated in their pathogenesis.
Whole exome sequencing results were analyzed using established pipelines and the results were further confirmed by Sanger sequencing and minigene splicing assay.
Exome sequencing in a 51-year-old Ashkenazi Jewish patient with non-syndromic retinitis pigmentosa (RP) identified compound heterozygous variants in the gene: a known pathogenic missense [p.(N48K)] and a novel deep intronic variant c.254-643G>T. A minigene splicing assay that was performed aiming to study the effect of the c.254-643G>T variant on pre-mRNA splicing revealed the inclusion of a pseudo-exon that was also reported to be included in the transcript due to an adjacent variant, c.254-649T>G. However, unlike the reported c.254-649T>G variant, c.254-643G>T showed aberrant splicing in a leaky manner, implying that the identified variant is not totally penetrant.
We report on a novel deep intronic variant in causing non-syndromic RP. The non-syndromic phenotype observed in this index case may be attributed to the leaky nature of this variant, which is causing some normal transcripts to be produced.
遗传性视网膜疾病（IRDs）是具有不同外显率和严重程度的临床复杂且遗传异质性的视觉障碍疾病。至少 289 个核和线粒体基因中的致病变异与它们的发病机制有关。
使用既定的管道分析外显子组测序结果，并用 Sanger 测序和小基因拼接测定进一步证实结果。
对一名 51 岁的非综合征性视网膜色素变性（RP）的阿什肯纳兹犹太裔患者进行外显子组测序，发现 基因的复合杂合变异：一种已知的致病性错义 [p.(N48K)] 和一种新的深内含子变异 c.254-643G>T。为研究 c.254-643G>T 变异对 前 mRNA 剪接的影响而进行的小基因拼接测定显示，包含一个假外显子，该假外显子也因相邻的变异 c.254-649T>G 而被包含在转录本中。然而，与报道的 c.254-649T>G 变异不同，c.254-643G>T 以渗漏的方式发生异常剪接，这意味着鉴定的变异不完全外显。
我们报告了一个新的 基因中的深内含子变异导致非综合征性 RP。该索引病例中观察到的非综合征表型可能归因于该变异的渗漏性质，这导致一些正常的转录物被产生。
