# From Genetic Determinism to Epigenetic Regulation: Paradigm Shifts in the Understanding of Neurodevelopmental Disorders

**Authors:** Ernesto Burgio, Annamaria Porru, Chiara Pettini, Ilaria Vaglini, Angelo Gemignani, Marco Pettini, Federica Fratini, Daniela Lucangeli

PMC · DOI: 10.3390/cimb48020163 · 2026-02-02

## TL;DR

This paper explores how epigenetics is changing our understanding of neurodevelopmental disorders by linking genes, environment, and health outcomes.

## Contribution

The paper synthesizes current evidence on shared mechanisms in neurodevelopmental disorders and highlights the role of epigenetics and environment.

## Key findings

- Epigenetic mechanisms mediate the interaction between genetic and environmental factors in neurodevelopmental disorders.
- Neurodevelopmental disorders show increasing prevalence and comorbidities, requiring integrated etiological models.
- The epigenome acts as a molecular interface between the genome and environmental influences across generations.

## Abstract

Over the past two decades, advances in the understanding of epigenetic mechanisms—driven by the rapid expansion of omics technologies—have catalyzed a major paradigm shift in biology: from the genetic determinism and linear causality of the Central Dogma toward the dynamic, networked complexity of systems biology and multilevel regulation. This reconceptualization extends to inheritance itself, highlighting the crucial role of the epigenome as a molecular interface between the genome and the exposome—the cumulative set of internal and external environmental influences experienced across the lifespan. Within this evolving framework, neurodevelopmental disorders exemplify the deep entanglement between genetic predisposition, environmental exposure, and epigenetic modulation. Their increasing global prevalence and frequent comorbidities underscore the need for an integrated etiological understanding that transcends reductionist models. This review tries to synthesize current evidence on the shared molecular and systemic mechanisms underlying neurodevelopmental spectrum disorders and examines how environmental and epigenetic factors jointly shape neurodevelopmental trajectories across generations. Finally, it discusses the broader implications of this paradigm shift for early diagnosis, prevention, and public health policies aimed at fostering healthy brain development in future generations.

## Full-text entities

- **Genes:** ENO2 (enolase 2) [NCBI Gene 2026] {aka HEL-S-279, NSE}, NR3C1 (nuclear receptor subfamily 3 group C member 1) [NCBI Gene 2908] {aka GCCR, GCR, GCRST, GR, GRL}, DPYSL2 (dihydropyrimidinase like 2) [NCBI Gene 1808] {aka CRMP-2, CRMP2, DHPRP2, DRP-2, DRP2, N2A3}, MIR132 (microRNA 132) [NCBI Gene 406921] {aka MIRN132, miRNA132, mir-132}, TNF (tumor necrosis factor) [NCBI Gene 7124] {aka DIF, IMD127, TNF-alpha, TNFA, TNFSF2, TNLG1F}, CDH9 (cadherin 9) [NCBI Gene 1007], IL1B (interleukin 1 beta) [NCBI Gene 3553] {aka IL-1, IL1-BETA, IL1F2, IL1beta}, ZNF266 (zinc finger protein 266) [NCBI Gene 10781] {aka HZF1}, GDA (guanine deaminase) [NCBI Gene 9615] {aka CYPIN, GAH, GUANASE, NEDASIN}, MIR134 (microRNA 134) [NCBI Gene 406924] {aka MIRN134, mir-134}, STIP1 (stress induced phosphoprotein 1) [NCBI Gene 10963] {aka HEL-S-94n, HOP, IEF-SSP-3521, P60, STI1, STI1L}, CRMP1 (collapsin response mediator protein 1) [NCBI Gene 1400] {aka CRMP-1, DPYSL1, DRP-1, DRP1, ULIP-3}
- **Diseases:** Gestational Diabetes Mellitus (MESH:D016640), Maternal autoimmune diseases (MESH:D001327), febrile (MESH:D000071072), obesity (MESH:D009765), HPA axis (MESH:D007029), mood disorders (MESH:D019964), carcinogenesis (MESH:D063646), immune-mediated disorders (MESH:C567355), Developmental Coordination Disorder (MESH:D019957), Learning Disorders (MESH:D007859), fever (MESH:D005334), PTSD (MESH:D013313), MDD (MESH:D003865), abnormal neurological syndrome (MESH:D009461), MAR (MESH:C535323), sight/hearing impairment/loss (MESH:D034381), pPROM (MESH:C563032), metabolic disorders (MESH:D008659), genetic disorder (MESH:D030342), SLE (MESH:D008180), neuropsychological disorders (MESH:D009358), neurodevelopmental and metabolic abnormalities (MESH:D024821), neoplastic diseases (MESH:D004194), neurodegenerative diseases (MESH:D019636), injury to (MESH:D014947), Chronic inflammation (MESH:D007249), neurodevelopmental conditions (MESH:D020763), alcoholism (MESH:D000437), GI syndromes (MESH:D013577), influenza (MESH:D007251), sleep disorders (MESH:D012893), ASDs (MESH:D000067877), Down syndrome (MESH:D004314), cancers (MESH:D009369), chromosomal abnormalities (MESH:D002869), mental and motor impairments (MESH:D001523), alcohol-drug-device addictions (MESH:D019966), Alzheimer's disease (MESH:D000544), Neurotoxic (MESH:D020258), Tic Disorders (MESH:D013981), anxiety (MESH:D001007), SZ (MESH:D012559), neuroinflammation (MESH:D000090862), ASD (MESH:D001321), depression (MESH:D003866), obsessive-compulsive disorders (MESH:D009771), type 2 diabetes (MESH:D003924), impaired social cognition (OMIM:300082), bacterial infections (MESH:D001424), premature (MESH:C536271), personality disorders (MESH:D010554), Eating Disorders (MESH:D001068), allergies (MESH:D004342), Bipolar Disorder (MESH:D001714), restricted interests (MESH:D002313), neuropsychiatric, and oncological conditions (MESH:D000072716), Autism and Developmental Disabilities (MESH:D002658), MIA (MESH:D000079262), neurodevelopmental problems (MESH:D019973), chronic (MESH:D002908)
- **Chemicals:** 5-mC (MESH:D044503), lindane (MESH:D001556), BPA (MESH:C006780), GABA (MESH:D005680), PAHs (MESH:D011084), neonicotinoids (MESH:D000073943), endosulfan (MESH:D004726), cortisol (MESH:D006854), pyrethroids (MESH:D011722), N(6)-methyladenine (MESH:C005955), lipids (MESH:D008055), alcohol (MESH:D000438), arsenic (MESH:D001151), dieldrin (MESH:D004026), Lead (MESH:D007854), heavy metal (MESH:D019216), manganese (MESH:D008345), 6 mA (-), PCBs (MESH:D011078), 5-hmC (MESH:C011865), mercury (MESH:D008628), -aminobutyric acid (MESH:D000613), DDT (MESH:D003634), toluene (MESH:D014050), chlorpyrifos (MESH:D004390)
- **Species:** Pan troglodytes (chimpanzee, species) [taxon 9598], Mus musculus (house mouse, species) [taxon 10090], Platyhelminthes (flatworm, phylum) [taxon 6157], Rattus norvegicus (brown rat, species) [taxon 10116], Homo sapiens (human, species) [taxon 9606]

## Figures

6 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12940089/full.md

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Source: https://tomesphere.com/paper/PMC12940089