Neurodevelopmental Disorders: From Genetics to Functional Pathways

Highlights

• NDDs are caused by the disruption of essential neurodevelopmental processes. Many genes and mutations are associated with NDDs, pointing to a heterogeneous origin of these disorders.

• Genotype–phenotype correlations are difficult to establish due to the existence of multiple genetic as well as environmental factors that influence the phenotypical outcome. The two-hit model and the existence of multiple molecular diagnoses are important factors that should be taken into account when addressing NDDs.

• Most of the known NDDs genes belong to few common frequently affected molecular pathways. Functional and molecular studies elucidating how different mutations can disturb the converging pathways can lead to the identification of potential targets, thereby opening perspectives for future treatment.

Neurodevelopmental disorders (NDDs) are a class of disorders affecting brain development and function and are characterized by wide genetic and clinical variability. In this review, we discuss the multiple factors that influence the clinical presentation of NDDs, with particular attention to gene vulnerability, mutational load, and the two-hit model. Despite the complex architecture of mutational events associated with NDDs, the various proteins involved appear to converge on common pathways, such as synaptic plasticity/function, chromatin remodelers and the mammalian target of rapamycin (mTOR) pathway. A thorough understanding of the mechanisms behind these pathways will hopefully lead to the identification of candidates that could be targeted for treatment approaches.