嗅觉功能障碍与亚微观异常：揭示隐藏的病理机制

文献信息

中文摘要

背景： 高分辨率基因组技术的最新进展揭示，若干综合征与亚微观染色体缺失相关，较少见地与重复相关，从而极大地促进了人类基因组的功能注释。在这些结构变异中，复发性微缺失或微重复常破坏剂量敏感基因，导致受累个体出现共同表型。虽然先天性心脏缺陷、神经发育迟缓和智力障碍（ID）等特征已被广泛研究，但导致嗅觉功能障碍的表型仍大多未被充分探索。方法：在此，我们综述了孤立性或综合征性嗅觉损害患者中拷贝数变异（CNVs）的已报道病例，并使用预定义证据等级对CNVs与嗅觉功能障碍之间的关联强度进行分层。结果：现有证据范围从具有已记录人类嗅觉表型和机制证据的充分支持位点，到主要基于孤立病例或生物学合理性的假设生成性观察。结论：通过区分这些证据等级，我们既强调了参与嗅觉发育的已确立剂量敏感通路，也指出了当前文献的主要局限性，包括嗅觉表型不完整以及难以解释大型多基因CNVs。该框架可能有助于在先天性和综合征性嗅觉障碍中进行更严格的基因型-表型解读。

英文摘要

Recent advances in high-resolution genomic technologies have revealed that several syndromes are associated with submicroscopic chromosomal deletions and, less frequently, duplications, thereby substantially contributing to the functional annotation of the human genome. Among these structural variants, recurrent microdeletions or microduplications often disrupt dosage-sensitive genes, leading to shared phenotypic outcomes in affected individuals. While features such as congenital heart defects, neurodevelopmental delays, and intellectual disability (ID) have been extensively studied, phenotypes resulting in olfactory dysfunction remain largely underexplored. Here, we review reported cases of copy number variants (CNVs) in patients with isolated or syndromic olfactory impairment and stratify the strength of associations between CNVs and olfactory dysfunction using predefined evidence levels. The available evidence ranges from well-supported loci with documented human olfactory phenotypes and mechanistic evidence to hypothesis-generating observations based primarily on isolated cases or biological plausibility. By distinguishing these levels of evidence, we highlight both established dosage-sensitive pathways involved in olfactory development and major limitations of the current literature, including incomplete olfactory phenotyping and the difficulty of interpreting large multigenic CNVs. This framework may facilitate more rigorous genotype-phenotype interpretation in congenital and syndromic olfactory disorders.