Genetics and mechanisms leading to human cortical malformations

Semin Cell Dev Biol. 2018 Apr;76:33-75. doi: 10.1016/j.semcdb.2017.09.031. Epub 2017 Oct 11.


Cerebral cortical development involves a complex series of highly regulated steps to generate the laminated structure of the adult neocortex. Neuronal migration is a key part of this process. We provide here a detailed review of cortical malformations thought to be linked to abnormal neuronal migration. We have focused on providing updated views related to perturbed mechanisms based on the wealth of genetic information currently available, as well as the study of mutant genes in animal models. We discuss mainly type 1 lissencephaly, periventricular heterotopia, type II lissencephaly and polymicrogyria. We also discuss functional classifications such as the tubulinopathies, and emphasize how modern genetics is revealing genes mutated in atypical cases, as well as unexpected genes for classical cases. A role in neuronal migration is revealed for many mutant genes, although progenitor abnormalities also predominate, depending on the disorder. We finish by describing the advantages of human in vitro cell culture models, to examine human-specific cells and transcripts, and further mention non-genetic mechanisms leading to cortical malformations.

Keywords: Atypical rare mutations; Cortical malformations; Exome sequencing; Heterotopia; Human in vitro cultures; Lissencephaly; Microcephaly; Neuronal migration; Polymicrogyria; Tubulinopathies; ZIKV.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Humans
  • Malformations of Cortical Development, Group I / genetics*