PDF(Pubmed)
Abstract：
Non-coding regions are areas of the genome that do not directly encode protein and were initially thought to be of little biological relevance. However, subsequent identification of pathogenic variants in these regions indicates there are exceptions to this assertion. With the increasing availability of next generation sequencing, variants in non-coding regions are often considered when no causative exonic changes have been identified. There is still a lack of understanding of normal human variation in non-coding areas. As a result, potentially pathogenic non-coding variants are initially classified as variants of uncertain significance or are even overlooked during genomic analysis. In most cases where the phenotype is non-specific, clinical suspicion is not sufficient to warrant further exploration of these changes, partly due to the magnitude of non-coding variants identified. In contrast, inborn errors of metabolism (IEMs) are one group of genetic disorders where there is often high phenotypic specificity. The clinical and biochemical features seen often result in a narrow list of diagnostic possibilities. In this context, there have been numerous cases in which suspicion of a particular IEM led to the discovery of a variant in a non-coding region. We present four patients with IEMs where the molecular aetiology was identified within non-coding regions. Confirmation of the molecular diagnosis is often aided by the clinical and biochemical specificity associated with IEMs. Whilst the clinical severity associated with a non-coding variant can be difficult to predict, obtaining a molecular diagnosis is crucial as it ends diagnostic odysseys and assists in management.
摘要：
非编码区是基因组中不直接编码蛋白质的区域，最初被认为几乎没有生物学相关性。然而,随后对这些地区的致病变异进行的鉴定表明，这种说法存在例外。随着下一代测序的日益普及,当尚未发现致病外显子变化时,通常会考虑非编码区的变异.在非编码领域仍然缺乏对正常人类变异的理解。因此,潜在致病性非编码变异最初被归类为不确定意义的变异,或者在基因组分析中甚至被忽视.在大多数情况下，表型是非特异性的，临床怀疑不足以保证进一步探索这些变化，部分原因是识别出的非编码变体的数量。相比之下,先天性代谢错误（IEM）是一类遗传性疾病，通常具有很高的表型特异性。看到的临床和生化特征通常导致诊断可能性的狭窄列表。在这种情况下，在许多情况下，怀疑特定的IEM导致在非编码区发现变体。我们介绍了4例IEM患者，其中分子病因在非编码区域被鉴定。分子诊断的确认通常通过与IEM相关的临床和生化特异性来帮助。尽管与非编码变体相关的临床严重程度可能难以预测，获得分子诊断是至关重要的，因为它结束了诊断错误并协助管理。
