Genetic mechanisms of neurodevelopmental disorders

Handb Clin Neurol. 2020;173:307-326. doi: 10.1016/B978-0-444-64150-2.00024-1.


Neurodevelopmental disorders encompass a broad range of conditions, which include autism, epilepsy, and intellectual disability. These disorders are relatively common and have associated clinical and genetic heterogeneity. Technology has driven much of our understanding of these diseases and their genetic underlying mechanisms, particularly highlighted by the study of large cohorts with comparative genomic hybridization and the more recent implementation of next-generation sequencing (NGS). The mapping of copy number variants throughout the genome has highlighted the recurrent, highly penetrant, de novo variation in syndromic forms of neurodevelopmental disease. NGS of affected individuals and their parents led to a dramatic shift in our understanding as these studies showed that a significant proportion of affected individuals carry rare, de novo variants within single genes that explain their disease presentation. Deep sequencing studies further implicate mosaicism as another mechanism of disease. However, it has also become clear that while rare variants explain a significant proportion of sporadic neurodevelopmental disease, rare variation still does not fully account for the familial clustering and high heritability observed. Common variants, including those within these known disease genes, are also shown to contribute significantly to overall risk. There is also increasing awareness of the important contribution of epigenetic factors and gene-environment interactions.

Keywords: Autism; Copy number variants; De novo dominant inheritance; Epilepsy; Intellectual disability; Mosaicism; Multifactorial inheritance; Next-generation sequencing.

MeSH terms

  • Comparative Genomic Hybridization
  • DNA Copy Number Variations / genetics
  • Genome
  • Humans
  • Intellectual Disability* / genetics
  • Neurodevelopmental Disorders* / genetics