PDF(Pubmed)
Abstract：
Niemann-Pick type C (NPC, ORPHA: 646) is a neuro-visceral, psychiatric disease caused predominantly by pathogenic variants in the NPC1 gene or seldom in NPC2. The rarity of the disease, and its wide range of clinical phenotypes and ages of onset, turn the diagnosis into a significant challenge. Other than the detailed clinical history, the typical diagnostic work-up for NPC includes the quantification of pathognomonic metabolites. However, the molecular basis diagnosis is still of utmost importance to fully characterize the disorder. Here, the authors provide an overview of splicing variants in the NPC1 and NPC2 genes and propose a new workflow for NPC diagnosis. Splicing variants cover a significant part of the disease-causing variants in NPC. The authors used cDNA analysis to study the impact of such variants, including the collection of data to classify them as leaky or non-leaky pathogenic variants. However, the presence of naturally occurring spliced transcripts can misdiagnose or mask a pathogenic variant and make the analysis even more difficult. Analysis of the NPC1 cDNA in NPC patients in parallel with controls is vital to assess and detect alternatively spliced forms. Moreover, nonsense-mediated mRNA decay (NMD) analysis plays an essential role in evaluating the naturally occurring transcripts during cDNA analysis and distinguishing them from other pathogenic variants\' associated transcripts.
摘要：
尼曼-皮克C型(NPC，ORPHA：646）是一种神经内脏，主要由NPC1基因致病变异或NPC2少见引起的精神疾病。这种疾病的稀有性，其广泛的临床表型和发病年龄，把诊断变成一个重大挑战。除了详细的临床病史，NPC的典型诊断工作包括病理代谢产物的定量。然而,分子基础诊断仍然是最重要的充分表征疾病。这里,作者概述了NPC1和NPC2基因中的剪接变异,并提出了一种新的NPC诊断工作流程.剪接变体涵盖了NPC中致病变体的重要部分。作者使用cDNA分析来研究这些变异的影响，包括收集数据，将它们分类为泄漏或非泄漏致病变异。然而,天然存在的剪接转录本的存在可能会误诊或掩盖致病变异，使分析更加困难。与对照平行分析NPC患者中的NPC1cDNA对于评估和检测选择性剪接形式至关重要。此外，无义介导的mRNA衰变（NMD）分析在cDNA分析过程中评估天然存在的转录本并将其与其他致病变体相关的转录本区分开来中起着至关重要的作用。
