The diverse genetic landscape of neurodevelopmental disorders

Abstract

Advances in genetic tools and sequencing technology in the past few years have vastly expanded our understanding of the genetics of neurodevelopmental disorders. Recent high-throughput sequencing analyses of structural brain malformations, cognitive and neuropsychiatric disorders, and localized cortical dysplasias have uncovered a diverse genetic landscape beyond classic Mendelian patterns of inheritance. The underlying genetic causes of neurodevelopmental disorders implicate numerous cell biological pathways critical for normal brain development.

Keywords: autism; brain malformations; neurodevelopment; somatic mutations.

Figure 1

Schematic of neocortical development. The development of the cortex begins at the ventricular zone (VZ) for excitatory projection neurons and at the ganglionic eminences for inhibitory interneurons. Both progenitor populations undergo multiple rounds of proliferation before differentiating into neurons and migrating into the cortical plate, where they integrate into functional circuitry. (For additional details, see sidebar Overview of Neuronal Development.) Abbreviations: SP, subplate; SVZ, subventricular zone. Adapted from Greig et al. (48) with permission.

Figure 2

Schematic showing how neurodevelopmental disorder mutations affect genes that function at different stages of neurodevelopment. Defects in the proliferation of progenitors in the ventricular zone or the cortex can lead to microcephaly or hemimegalencephaly, respectively. Defects affecting the migration of neurons from the ventricular zone to the cortex give rise to lissencephaly. Connectivity defects are thought to underlie autism, intellectual disability, and neuropsychiatric disorders.

Figure 3

Circle plot illustrating the allelic and phenotypic diversity of a subset of neurodevelopmental disease genes. Mutations in the same gene cause diverse neurodevelopmental phenotypes. Advances in high-throughput sequencing techniques have expedited the identification of hypomorphic and somatic mutations, increasing the spectrum of phenotypes associated with any single gene. Phenotypes are grouped into structural brain defects and abnormalities without any structural brain defects. Abbreviations: ASD, autism spectrum disorder; CLOVE, congenital lipomatous overgrowth, vascular malformations, and epidermal nevi; ID, intellectual disability.