The intricate interplay between viral infections and prenatal brain development remains a foremost concern in contemporary biomedical research, especially in light of recent outbreaks such as those caused by Zika virus (ZIKV). Emerging evidence now underscores that even among dizygotic twins, where genetic differences are more pronounced, the severity of virally induced prenatal brain injury is not uniform but highly dependent on a constellation of maternal and individual risk as well as protective factors. A critical dimension in this dynamic is the role of genomic variability, which appears to modulate the susceptibility and resilience of fetal brain tissue to viral insult.
Recent studies synthesize a growing body of data implicating specific genetic risk factors that may predispose certain fetuses to more severe neurologic sequelae when exposed to neurotropic viruses such as ZIKV during gestation. Unlike earlier conceptions which treated prenatal viral brain injury as a largely stochastic phenomenon, current research advocates for a nuanced understanding driven by host genomics. The differential gene expression profiles and specific genetic polymorphisms in both the maternal and fetal genomes are now believed to shape the neuroimmune response and influence viral replication dynamics within the developing central nervous system.
This shift in perspective bears considerable significance because it provides a plausible molecular basis for the perplexing heterogeneity observed in clinical manifestations of congenital Zika syndrome (CZS). Among dizygotic twins, who share roughly half their segregating alleles, striking differences in neurodevelopmental outcomes following identical viral exposures have been documented. This suggests that beyond the mere presence of the virus, intrinsic genomic factors critically determine the severity and nature of brain injury.
.adsslot_ucP9tSi2xl{width:728px !important;height:90px !important;}
@media(max-width:1199px){ .adsslot_ucP9tSi2xl{width:468px !important;height:60px !important;}
}
@media(max-width:767px){ .adsslot_ucP9tSi2xl{width:320px !important;height:50px !important;}
}
ADVERTISEMENT
At the mechanistic level, research is uncovering how genetic variants in genes related to innate immunity, neurodevelopmental processes, and cell-signaling pathways may influence vulnerability or protection. For instance, differential expression of pattern recognition receptors such as toll-like receptors (TLRs) can modulate the initial immune response to ZIKV particles, thereby affecting viral load and subsequent neuroinflammation. Polymorphisms in cytokine genes may further alter inflammatory milieu within the fetal brain, exacerbating or ameliorating neuronal apoptosis and malformation.
In tandem, maternal genetic factors also exert a profound influence on vertical transmission efficiency and placental barrier integrity. The placenta is the critical interface between mother and fetus, serving as both a physical and immunological barrier. Genetic variations affecting placental receptor expression or cytokine regulation may modulate the degree to which ZIKV can traverse this barrier, thereby dictating fetal exposure levels. These findings implicate maternal-fetal genomic crosstalk as a determinant of viral pathogenesis during pregnancy.
Complicating this genomic landscape is the involvement of epigenetic regulation, wherein viral infections may induce modifications in DNA methylation patterns, histone acetylation, or non-coding RNA activity—mechanisms that can have lasting effects on gene expression without altering the DNA sequence itself. Such epigenetic alterations may prime the developing brain for increased susceptibility to damage or, conversely, activate protective gene networks that mitigate injury severity.
Moreover, environmental and maternal health factors interact with genetic predispositions to create a multifactorial risk profile. Nutritional status, co-infections, and maternal immune health can influence viral pathogenesis and neural outcomes, often in conjunction with underlying genetic variables. This interdependence highlights the necessity for integrative models that incorporate genomics, maternal physiology, and external exposures to predict risk accurately.
The translational implications of understanding genetic determinants of ZIKV-induced brain injury are profound. Identification of high-risk genotypes may facilitate prenatal screening and enable targeted surveillance for adverse neurodevelopmental outcomes. Furthermore, elucidating genetic pathways involved in host response to ZIKV offers potential therapeutic targets; for example, modulating innate immune signaling or enhancing neuroprotective gene expression through pharmacologic or gene-editing approaches.
Given the rapid evolution of genomic technologies, comprehensive sequencing of maternal-fetal dyads affected by congenital Zika syndrome is now becoming feasible. Such studies promise to delineate the constellation of common and rare variants that confer susceptibility or resilience, providing insight into the molecular architecture of prenatal viral brain injury. Integration with transcriptomic and proteomic data will enrich the mechanistic understanding even further.
However, challenges remain in disentangling the complex gene–environment interactions and in translating genomic insights into clinical practice. Large-scale, longitudinal cohorts and systems biology approaches are essential to validate candidate genetic markers and to comprehend their functional consequences during critical windows of fetal neurodevelopment. Ethical considerations involving prenatal genetic screening and counseling also warrant careful deliberation.
In the context of global health, refining our grasp of genetically mediated vulnerability to prenatal viral brain injury holds promise for improving outcomes in regions prone to arboviral epidemics. It also underscores the importance of personalized medicine approaches in pediatric neurology and infectious diseases, where individualized risk profiles can guide prevention strategies and therapeutic interventions.
The synthesis of current research not only advances the scientific frontier but also raises pressing questions about the interplay between host genetics and emerging viral threats. As ZIKV and other neurotropic viruses continue to pose public health challenges, harnessing genomic knowledge offers a powerful avenue to mitigate the devastating impacts on vulnerable populations such as developing fetuses.
Continued investigation into the genetic underpinnings of ZIKV-induced fetal brain damage is critical. It is only through multidisciplinary collaboration, leveraging genomics, immunology, virology, and developmental neuroscience, that we can hope to unravel the complex biological networks driving this condition. Such endeavors hold the key to novel diagnostics, preventive measures, and therapeutic modalities that could transform perinatal care.
In summary, the evidence indicates that genetic risk factors—both maternal and fetal—are central to understanding the heterogeneous outcomes seen in prenatal Zika virus infections. This genomic perspective enriches the classical infectious disease paradigm and signals a new era of precision medicine tailored to prenatal health. By decoding the host’s genetic blueprint, researchers illuminate pathways to protect the developing brain against viral insults and foster healthier neurodevelopmental trajectories.
Subject of Research: Genetic risk factors determining the severity of prenatal brain injury caused by Zika virus infection.
Article Title: Genetic risk factors associated to Zika virus virally induced brain injury: a scoping review.
Article References:
Marques, F.J.P., Ruan, J., Razal, R.B. et al. Genetic risk factors associated to Zika virus virally induced brain injury: a scoping review. Pediatr Res (2025). https://doi.org/10.1038/s41390-025-04252-1
Image Credits: AI Generated
DOI: https://doi.org/10.1038/s41390-025-04252-1
Tags: dizygotic twins brain injuryfetal susceptibility to virusesgenetic polymorphisms and brain injurygenomic variability in prenatal healthmaternal genetic factors Zikamaternal-fetal genetic interactionsneuroimmune response to Zikaneurotropic virus effectsprenatal brain developmentviral infections and geneticsviral replication in fetal brainZika virus genetic risks
