Comprehensive genomic analysis of patients with disorders of cerebral cortical development

Eur J Hum Genet. 2018 Aug;26(8):1121-1131. doi: 10.1038/s41431-018-0137-z. Epub 2018 Apr 30.


Malformations of cortical development (MCDs) manifest with structural brain anomalies that lead to neurologic sequelae, including epilepsy, cerebral palsy, developmental delay, and intellectual disability. To investigate the underlying genetic architecture of patients with disorders of cerebral cortical development, a cohort of 54 patients demonstrating neuroradiologic signs of MCDs was investigated. Individual genomes were interrogated for single-nucleotide variants (SNV) and copy number variants (CNV) with whole-exome sequencing and chromosomal microarray studies. Variation affecting known MCDs-associated genes was found in 16/54 cases, including 11 patients with SNV, 2 patients with CNV, and 3 patients with both CNV and SNV, at distinct loci. Diagnostic pathogenic SNV and potentially damaging variants of unknown significance (VUS) were identified in two groups of seven individuals each. We demonstrated that de novo variants are important among patients with MCDs as they were identified in 10/16 individuals with a molecular diagnosis. Three patients showed changes in known MCDs genes and a clinical phenotype beyond the usual characteristics observed, i.e., phenotypic expansion, for a particular known disease gene clinical entity. We also discovered 2 likely candidate genes, CDH4, and ASTN1, with human and animal studies supporting their roles in brain development, and 5 potential candidate genes. Our findings emphasize genetic heterogeneity of MCDs disorders and postulate potential novel candidate genes involved in cerebral cortical development.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cadherins / genetics
  • DNA Copy Number Variations*
  • Exome*
  • Female
  • Genetic Heterogeneity
  • Humans
  • Male
  • Malformations of Cortical Development / genetics*
  • Malformations of Cortical Development / pathology
  • Nerve Tissue Proteins / genetics
  • Polymorphism, Single Nucleotide*
  • Receptors, Cell Surface / genetics


  • ASTN1 protein, human
  • Cadherins
  • Nerve Tissue Proteins
  • R-cadherin
  • Receptors, Cell Surface