Abstract
Intellectual disability (ID) is a highly heterogeneous neurodevelopmental condition characterized by deficits in intellectual and adaptive functioning. Comprehensive cognitive and adaptive behavior assessments are essential for investigating its underlying causes. While environmental factors contribute, particularly in mild cases, genetic etiologies predominate in moderate to severe forms, accounting for over 50% of these cases. This review explores the complex genomic architecture of ID, including chromosomal abnormalities, monogenic disorders, de novo mutations, polygenic inheritance, and epigenetic dysregulation. We highlight emblematic genetic syndromes such as trisomy 21 (Down syndrome) and Fragile X syndrome, illustrating how diverse genetic mechanisms from gene dosage effects to dynamic mutations—translate into specific neurocognitive and behavioral phenotypes. Further, we examine developmental channelopathies and chromatinopathies, emphasizing the critical role of neuronal excitability and epigenetic regulation in brain development.
The advent of next-generation sequencing (NGS) has revolutionized diagnostic capabilities, facilitating the identification of causal variants and significantly reducing the diagnostic odyssey for families. These advances have also paved the way for precision medicine, with emerging therapeutic approaches including gene therapy, RNA-based strategies, targeted pharmacology, and drug repurposing showing promise in clinical trials. However, the complexity of the brain, developmental timing, and challenges in clinical trial design especially for rare disorders remain significant hurdles. This review underscores the transformative impact of genomic technologies not only on the understanding and diagnosis of ID but also on the development of personalized treatments aimed at improving outcomes for individuals with ID.
Keywords
Intellectual disability, Neurodevelopmental disorders, Genetic etiologies, Chromosomal aberrations, Monogenic disorders, Polygenic inheritance, Epigenetic regulation, Precision medicine, Next generation sequencing