Olfactory dysfunction and submicroscopic abnormalities: unveiling hidden pathologies

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.