Levy Amanda M, Ganapathi Mythily, Chung Wendy K, Tümer Zeynep
Department of Clinical Genetics, Kennedy Center, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Department of Pathology & Cell Biology, Columbia University Irving Medical Center, New York City, New York, USA.
Clin Genet. 2024 Jan;105(1):77-80. doi: 10.1111/cge.14411. Epub 2023 Aug 1.
The rare autosomal dominant brain disorder DLG4-related synaptopathy is caused by de novo variants in DLG4 (encoding PSD-95), the majority of which are predicted to be protein-truncating. In addition to splice site variants, a number of synonymous and missense DLG4 variants are predicted to exert their effect through altered RNA splicing, although the pathogenicity of these variants is uncertain without functional RNA studies. Here, we describe a young boy with a deep intronic DLG4 variant (c.2105+235C>T) identified using whole genome sequencing. By using reverse-transcription PCR on RNA derived from peripheral blood, we demonstrate that DLG4 mRNA expression is detectable in blood and the deep intronic variant gives rise to two alternative DLG4 transcripts, one of which includes a pseudoexon. Both alternative transcripts are out-of-frame and predicted to result in protein-truncation, thereby establishing the genetic diagnosis for the proband. This adds to the evidence concerning the pathogenic potential of deep intronic variants and underlines the importance of functional studies, even in cases where reported tissue-specific gene expression might suggest otherwise.
罕见的常染色体显性遗传性脑部疾病DLG4相关突触病由DLG4（编码PSD-95）的新生变异引起，其中大多数预计会导致蛋白质截短。除剪接位点变异外，一些同义及错义DLG4变异预计通过改变RNA剪接发挥作用，不过在没有功能性RNA研究的情况下，这些变异的致病性尚不确定。在此，我们描述了一名通过全基因组测序鉴定出存在深度内含子DLG4变异（c.2105+235C>T）的小男孩。通过对来自外周血的RNA进行逆转录PCR，我们证明血液中可检测到DLG4 mRNA表达，且该深度内含子变异产生了两种可变的DLG4转录本，其中一种包含一个假外显子。两种可变转录本均移码且预计会导致蛋白质截短，从而为该先证者确立了基因诊断。这增加了关于深度内含子变异致病潜力的证据，并强调了功能研究的重要性，即便在已报道的组织特异性基因表达可能暗示相反情况的病例中亦是如此。
