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

DNA methylation is one of the body’s most important epigenetic regulatory systems. It involves the addition or removal of methyl groups at cytosine-phosphate-guanine (CpG) sites along the DNA strand, frequently in promoter regions, and these chemical tags act like volume knobs for gene expression, dialing genes up or down without altering the underlying genetic code. Methylation patterns shift dramatically during periods of physiological upheaval, and pregnancy is no exception. Previous research has documented methylation changes in maternal blood across gestation, including gains of methylation in genes involved in morphogenesis and losses in genes promoting maternal-infant bonding. Other studies have tied methylation shifts to complications such as gestational diabetes and preeclampsia. But a critical question lingered: do these pregnancy-induced changes simply wash away after delivery, or do they endure as a kind of molecular memory?

The research team, led by Su Chen and Miranda Johs of the University of Nebraska Medical Center alongside collaborators at the University of Memphis, University of Southampton, University of Michigan, Michigan State University, and the David Hide Asthma and Allergy Research Centre, was designed to answer exactly that question, and to fix two persistent gaps in the literature. First, most prior studies of parous women, those who have given birth, lacked nulliparous controls, women who have never given birth, making it impossible to isolate the effect of childbearing itself. Second, only a single small pilot study had ever examined whether methylation changes persist beyond the immediate postpartum period. The new work addressed both problems by comparing methylation profiles of parous and nulliparous women at two timepoints in young adulthood, ages 18 and 26, which correspond to pre-pregnancy and at least six months postpartum for the mothers in the sample.

The discovery cohort came from the Isle of Wight (IOW) birth cohort, a three-generation study established in the United Kingdom between 1989 and 1990 to prospectively follow the natural history of asthma and allergy. Of 750 female participants, 144 had DNA methylation measured at both ages 18 and 26, and 89 of those women had childbearing history validated through medical records. Twenty-eight had given birth at least six months before the age-26 measurement, while 61 had not. The researchers screened 389,355 CpG sites, the overlap between the Illumina HumanMethylation450 and MethylationEPIC platforms, using a training-testing screening method called ttScreening, which repeatedly splits samples into training and test sets to filter out uninformative sites. Linear regression analyses followed, adjusting for six blood cell type proportions, residual methylation at age 18, body mass index change, smoking categories, and socioeconomic status.

The result was striking: 184 CpG sites were significantly differentially methylated between parous and nulliparous women after correction for multiple testing. To guard against a cohort-specific fluke, the team pursued replication in an entirely independent population, the ELEMENT cohort from Mexico City, a multi-generation birth cohort of Hispanic women followed for nearly three decades. In the ELEMENT subsample of 54 women, 105 of the 184 CpGs showed regression coefficients pointing in the same direction as the Isle of Wight findings, and 13 of those were statistically significant. Seven of the replicated sites showed lower methylation in parous women and six showed higher methylation, a pattern consistent across both cohorts despite their differences in ethnicity, geography, and age structure. The 13 replicated CpGs mapped to 16 unique genes.

Among those genes, one stands out with particular force: TM2D3, a gene previously implicated in late-onset Alzheimer’s disease through exome-wide association analysis. In the Isle of Wight data, methylation at cg01537571, a site within a CpG island near the transcription start site of TM2D3, was significantly lower in parous women in both cohorts, and methylation at this site correlated positively with gene expression. When the team examined RNA sequencing data from blood samples at age 26, TM2D3 was the only gene among the 16 that showed significantly lower expression in parous compared with nulliparous women. This convergence is provocative given that increased parity has independently been identified as a risk factor for Alzheimer’s disease, hinting that the methylation change at TM2D3 could be one thread connecting reproductive history to neurodegenerative vulnerability.

Another gene of interest is SEMA3A, which encodes semaphorin 3A, a guidance cue signaling molecule that directs developing neurons during embryogenesis and continues to regulate neuroplasticity in adulthood. SEMA3A showed decreased methylation in parous women and appeared in the study’s gene-disease network linked to neoplasms, mental disorders, and reproductive conditions. The gene plays paradoxical roles in cancer: it promotes tumor progression in hepatocellular carcinoma by enhancing proliferation, migration, and invasion, yet acts as a tumor suppressor in head, neck, and breast cancers, where it boosts antitumoral M1 macrophage proliferation and recruits CD8-positive T cells and natural killer cells to repress tumor growth. The authors speculate that lower methylation near the SEMA3A transcription start site in parous women could conceivably relate to their reduced breast cancer risk, though they caution that whether blood methylation mirrors changes in breast tissue remains unknown.

Beyond these two headline genes, the disease association analysis using the DisGeNET database painted a broader picture. Ten of the 16 genes, including SEMA3A, AKAP13, SLC15A2, DOK2, ADAMTS17, ADARB2, NUP37, PLD5, TPK1, and SLC15A3, were most notably linked with neoplasms, mental disorders, and nervous system diseases such as Parkinson’s disease, schizophrenia, and autism, along with substance use disorders. The breadth surprised even the researchers, who had anticipated connections to reproductive cancers but had not expected substance abuse disorders to surface. Gene expression data confirmed that methylation at cg19086905 (ADAMTS17) and cg13375690 (PDE7A) was negatively associated with expression of those genes, providing functional support for at least some of the methylation signals. Notably, several of the identified genes are expressed in the brain, including TM2D3, SLC15A2, PLD5, ADARB2, and PARPBP, while MAP1LC3C, NUP37, and ADAMTS17 are expressed in breast tissue, tissue-specific patterns that may matter enormously for translating blood-based findings into disease mechanisms.

The study’s design carries genuine strengths. Comparing parous women at pre- and post-pregnancy timepoints against matched nulliparous controls in both discovery and replication cohorts is rare, and the six-month minimum postpartum window avoided the transient methylation fluctuations that may have confounded earlier work sampling just two to four days after delivery. Replication across a 98 percent White UK cohort and an all-Hispanic Mexican cohort supports both internal validity and generalizability. Yet the authors are candid about limitations: the parous groups were small, with 28 women in the Isle of Wight and roughly 20 in the ELEMENT analysis; nulliparous status relied on medical records; the duration required for postpartum methylation to stabilize is unknown; and blood serves only as a proxy for changes in other tissues, with roughly half of the identified genes not routinely expressed in whole blood. Factors that change during pregnancy, such as smoking or income, could not be assessed in nulliparous women at comparable times.

Even with those caveats, the implications are considerable. If the methylation changes observed in blood leukocyte DNA reflect parallel epigenetic remodeling in tissues such as the breast or brain, they could furnish a plausible mechanism for how childbearing reshapes a woman’s disease risk across her lifetime, offering a molecular bridge between reproductive history and outcomes ranging from cancer to Alzheimer’s disease. The researchers emphasize that further studies are needed, particularly cohorts with follow-up into later life, to determine whether these parous-related methylation signatures actually predict health outcomes rather than merely accompanying them. For now, the study adds a compelling piece to a growing body of evidence, from brain imaging traces of childbirth to parity-linked dementia risk, that motherhood writes itself into the body in ways science is only beginning to read, one methyl group at a time.

Subject of Research: Persistent effects of childbearing on blood DNA methylation in women

Article Title: Assessing the effect of childbearing on blood DNA methylation through comparison of parous and nulliparous females

Article References: Chen, S., Johs, M., Karmaus, W., Holloway, J. W., Kheirkhah Rahimabad, P., Goodrich, J. M., Peterson, K. E., Dolinoy, D. C., Arshad, S. H., & Ewart, S. (2024). Assessing the effect of childbearing on blood DNA methylation through comparison of parous and nulliparous females. Epigenetics Communications, 4(1), Article 2. https://doi.org/10.1186/s43682-024-00025-9

Image Credits: AI Generated

DOI: 10.1186/s43682-024-00025-9

Keywords: DNA methylation, pregnancy, childbearing, epigenetics, parous, nulliparous, CpG sites, TM2D3, SEMA3A, Alzheimer's disease, breast cancer, Isle of Wight cohort