Genetic and epigenetic determinants of fetal alcohol spectrum disorders: Toward a precision medicine approach
Francesco Sessa, Marco Carotenuto, Davide Ferorelli, Massimiliano Esposito, Cristoforo Pomara, Monica Salerno
Abstract
Fetal Alcohol Spectrum Disorders (FASD) encompass a continuum of neurodevelopmental and physical impairments resulting from prenatal alcohol exposure (PAE). Despite widespread recognition of ethanol's teratogenic effects, the clinical variability observed in FASD suggests a multifactorial etiology involving genetic, biochemical, epigenetic, and environmental influences. This review provides an integrative analysis of how genetic polymorphisms in key alcohol-metabolizing enzymes (ADH1B, ADH1C, ALDH2, CYP2E1, and CAT) modulate maternal and fetal susceptibility to ethanol and its toxic metabolite, acetaldehyde. These polymorphisms influence enzymatic activity, oxidative stress responses, and detoxification efficiency, thereby shaping fetal exposure and risk. The review further explores maternal-fetal genotype interactions, gene-environment dynamics, and the timing of exposure as critical modulators of FASD outcomes. Epigenetic mechanisms, including DNA methylation, histone modifications, and microRNA regulation, are examined as mediators of long-term gene expression changes and neurodevelopmental disruption. Novel insights are provided into the roles of the 5-HTTLPR and orexin systems in neuropsychiatric vulnerability. By synthesizing molecular, genetic, and clinical perspectives, this review advocates for a precision medicine approach to FASD prevention and management. It discusses the potential of genetic screening, predictive modeling, and theranoMiRNAs for risk stratification and early intervention. Importantly, it also addresses the translational challenges, including cost, feasibility, and the risk of false positives/negatives, that must be overcome to move from theory to clinical practice. These insights support the development of personalized, ethically grounded strategies to reduce fetal harm and improve outcomes in genetically and environmentally susceptible populations.