The review, led by Katarzyna Bilińska and Magdalena Pasińska of Nicolaus Copernicus University in Poland together with Fernando de Castro of the Cajal Institute in Madrid, systematically combed through publicly available genomic databases and the scientific literature to identify CNVs reported in individuals with anosmia, hyposmia, or structural abnormalities of the olfactory system. Rather than treating all reported associations as equally reliable, the authors stratified the strength of evidence linking each CNV to olfactory dysfunction using a four-tier framework: established, probable, possible, and speculative. This approach allows well-supported loci with documented human olfactory phenotypes and mechanistic evidence to be distinguished from hypothesis-generating observations based primarily on isolated cases or biological plausibility alone.

Copy number variants are submicroscopic chromosomal abnormalities involving the loss or gain of DNA segments, typically ranging from a few kilobases to several megabases. While often undetectable by conventional cytogenetic methods, they can be readily identified using high-resolution genomic approaches such as array comparative genomic hybridization and next-generation sequencing. The molecular mechanisms by which CNVs exert their effects are diverse and often locus-dependent. In the context of olfactory dysfunction, CNVs may contribute to the phenotype through gene dosage effects, where altered copy number of dosage-sensitive genes disrupts the delicate balance of molecular pathways required for olfactory system development; gene interruption, where partial deletion or duplication truncates coding sequences; gene fusion, where CNVs juxtapose exons from two different genes; position effects, where structural changes relocate genes relative to regulatory elements; unmasking of recessive alleles, where deletion of one allele exposes pathogenic variants in the remaining allele; and regulatory disruption, where noncoding CNVs affect long-range regulatory elements or allele-allele communication.

Among the strongest associations identified in the review are deletions involving the SEMA3A gene at locus 7q21.11. In an extensive study involving a cohort of 120 patients diagnosed with Kallmann syndrome, a condition characterized by the coexistence of anosmia and hypogonadotropic hypogonadism, SEMA3A was identified as contributing to the molecular pathogenesis of the disorder. Comparative genomic hybridization identified a heterozygous 213 kb deletion at 7q21.11 in a male patient with Kallmann syndrome and complete anosmia, encompassing 11 of the 17 exons of SEMA3A. A similar finding was reported in another male patient carrying a heterozygous deletion encompassing the entire SEMA3A locus. SEMA3A is a well-established member of the secreted semaphorin family that signals primarily through neuropilin-containing receptor complexes and plays an important role in cell migration and axonal guidance during central nervous system development, including the formation of the lateral olfactory tract. Additional supporting evidence comes from mutant mouse models lacking a functional semaphorin-binding domain in neuropilin-1, which show abnormal olfactory system development and defective embryonic migration of gonadotropin-releasing hormone neurons.

Deletions involving the 8p11.22 region represent another well-supported association, with FGFR1 as the principal candidate gene for the olfactory and neuroendocrine phenotype. FGFR1 encodes a fibroblast growth factor receptor essential for embryonic development, including skeletal formation and the establishment of the olfactory and neuroendocrine systems. It plays a key role in the development of the olfactory placode and in shaping the migratory environment guiding GnRH neurons toward the hypothalamus. Disruption of FGFR1 signaling impairs olfactory bulb development and indirectly affects GnRH neuronal migration, leading to congenital anosmia or hyposmia in the context of Kallmann syndrome. However, the frequently multigenic nature of these rearrangements complicates interpretation, as larger deletions encompassing FGFR1 have been associated with a broad phenotypic spectrum including spherocytosis, growth delay, micrognathia, and bilateral crumpled ears.

The 22q11.2 deletion, typically spanning approximately 1.5 to 2.54 megabases, underlies the classical 22q11.2 deletion syndrome, also known as DiGeorge syndrome or velocardiofacial syndrome, which occurs in approximately 1 in 4,000 to 5,000 live births. Assessment using the University of Pennsylvania Smell Identification Test has shown that up to 68 percent of children with 22q11.2 deletion syndrome exhibit olfactory deficits, compared with 13 percent of their unaffected siblings. These impairments are not attributable to general intellectual disability, although they may be influenced by velopharyngeal insufficiency and altered nasal airflow. The deleted region encompasses multiple dosage-sensitive genes implicated in central nervous system development and olfactory processing, including COMT, PRODH, DGCR8, and CRKL, providing a plausible genetic basis for the high prevalence of olfactory dysfunction in this population.

Deletions in the Xp22.3 region encompassing the ANOS1 gene, formerly known as KAL1, represent perhaps the most well-established molecular basis for congenital anosmia. ANOS1 encodes anosmin-1, a protein essential for the proper development and interconnection of olfactory structures and migration of GnRH neurons during embryonic development. Anosmin-1 exerts its function through protein-protein interactions within the extracellular matrix, notably modulating FGF signaling via interaction with FGFR1. Classic studies documented intragenic deletions of ANOS1 in families with X-linked Kallmann syndrome, with affected males typically showing anosmia or severe hyposmia, delayed puberty, and hypogonadism, while carrier mothers were unaffected. More recent studies have expanded the spectrum of ANOS1 defects, demonstrating that both point mutations and CNVs, including exon-level and whole-gene deletions, contribute substantially to Kallmann syndrome and normosmic isolated hypogonadotropic hypogonadism, with ANOS1 defects accounting for approximately 14 percent of cases in one cohort.

Among the probable associations, large terminal deletions of the distal long arm of chromosome 6 at 6q27 have been linked to olfactory bulb aplasia and anosmia. In two unrelated individuals, high-resolution MRI revealed hydrocephalus, midline brain anomalies, and bilateral aplasia of the olfactory bulbs. While the adult patient had clinically confirmed anosmia, anosmia was strongly suspected based on neuroimaging findings in the 3-year-old child. Olfactory bulb aplasia and anosmia had not been widely recognized features of 6q27 microdeletion before this report, and the authors proposed these as part of the expanded phenotype. Over two dozen patients with terminal 6q27 deletions of similar size have been described in the literature and the DECIPHER database, and while there is a consistent association with brain malformations and intellectual disability, the prevalence of anosmia remains uncertain and may be underreported.

The review also highlights several possible and speculative associations that warrant further investigation. Haploinsufficiency of ARID1B at 6q25, a member of the SWI/SNF chromatin-remodeling complex, has been associated with Coffin-Siris syndrome, and some patients exhibit absent olfactory bulbs and anosmia. Structural variants involving the CHD7 gene at 8q12.2, which encodes a chromatin remodeler playing critical roles in neural crest development and olfactory system development, have been reported in patients with CHARGE syndrome, in which anosmia or hyposmia is frequently observed. Experimental evidence indicates that CHD7 regulates neural progenitor proliferation in the olfactory placode and influences the expression of key developmental genes including FGFR1, BMP4, and OTX2. A de novo 2.38 megabase deletion at 9q31.2 encompassing six protein-coding genes has been reported in a patient with congenital hypogonadotropic hypogonadism and anosmia, while a de novo heterozygous microduplication of approximately 178 kilobases at 9q34.3 including the NSMF gene has been identified in a male patient with Kallmann syndrome.

The authors emphasize that the interpretation of CNVs in olfactory disorders raises several challenges. Distinguishing pathogenic from benign CNVs is difficult due to incomplete penetrance, variable expression, and the frequent occurrence of CNVs in the general population. Phenotypic variability among individuals carrying the same CNV complicates genotype-phenotype correlations, suggesting the presence of genetic modifiers, epigenetic influences, or environmental interactions. Many candidate genes within olfactory-related CNVs remain poorly characterized in humans, and much of the knowledge derives from animal models, which may not fully reflect human biology. Another major limitation is the heterogeneity of olfactory phenotyping, as standardized psychophysical testing was available only for a subset of reported cases, whereas other observations relied on clinical history, self-report, or structural abnormalities detected by neuroimaging. The absence of reported olfactory dysfunction cannot be interpreted as evidence of normal olfactory function when smell was not specifically assessed. More systematic use of validated olfactory tests, together with dedicated assessment of olfactory bulb and tract morphology, would substantially improve genotype-phenotype correlations and may ultimately inform diagnostics and guide the development of targeted therapies for individuals affected by congenital or syndromic loss of smell.

Subject of Research: Genetics

Article Title: Olfactory dysfunction and submicroscopic abnormalities: unveiling hidden pathologies

Article References: Bilińska, K., Pasińska, M., & de Castro, F. (2026). Olfactory dysfunction and submicroscopic abnormalities: unveiling hidden pathologies. Frontiers in Molecular Neuroscience, 19, Article 1861373. https://doi.org/10.3389/fnmol.2026.1861373

Image Credits: AI Generated

DOI: 10.3389/fnmol.2026.1861373

Keywords: copy number variants, CNVs, anosmia, olfactory dysfunction, Kallmann syndrome, microdeletion, microduplication, SEMA3A, FGFR1, ANOS1, 22q11.2 deletion syndrome, genetics