A contemporary view on the molecular basis of neurodevelopmental disorders

Genetic variation is a major contributor to the pathogenesis of neurodevelopmental disorders (NDDs). These disorders are defined by a disturbed development of the central nervous system resulting in deficits in personal, social and cognitive functioning that manifest during the early years of life. The NDD group encompasses intellectual disability (ID), autism spectrum disorder (ASD), attention-deficit hyperactivity disorder (ADHD), communication disorders, specific learning disorders and motor disorders. Next to these ‘classical’ neurodevelopmental disorders, the (genetically related) neurological and psychiatric disorders epilepsy, schizophrenia and bipolar disorder are often included within the NDD group. We here provide an historical overview how major technological advances in the last two decades have drastically increased the resolution of genetic aberration detection. Previously, large chromosomal anomalies could be detected with microscopic techniques and submicroscopic variation could only be detected with the targeted fluorescence in situ hybridization technique. Development of microarrays enabled the simultaneous detection of smaller copy number variants throughout the whole genome. Finally, the advances in next generation sequencing techniques now enable the detection of variation on the single base pair resolution. The lists of genetic aberrations causing the different NDDs show significant overlap, meaning that there are multiple genetic anomalies that can cause both ID or ASD for example. Interestingly, substantial overlap with genetic aberrations involved in the emergence of epilepsy and schizophrenia has also been detected. These observations strengthen the hypothesis that neurodevelopmental disorders are part of a continuous phenotypic spectrum rather than separate disease entities, with common genetic factors underlying them. Furthermore, the genes associated with the different NDDs converge to overlapping genetic networks, as demonstrated by the significant enrichment of NDD genes in common cellular processes such as chromatin remodelling and in protein-protein interaction (PPI) networks involved in synaptic function and neuronal development.

ISBN:978-0-12-814037-6

Jaar van publicatie:2020

Trefwoorden:H2 Book chapter

Toegankelijkheid:Closed