Genomic copy number variation in disorders of cognitive development

Abstract

Objective: To highlight recent discoveries in the area of genomic copy number variation in neuropsychiatric disorders including intellectual disability, autism, and schizophrenia. To emphasize new principles emerging from this area, involving the genetic architecture of disease, pathophysiology, and diagnosis.

Method: Review of studies published in PubMed including classic studies of genomic disorders and microarray and copy number studies in normal controls, intellectual disability, autism, and schizophrenia.

Results: The advent of novel microarray technology has led to a revolution in the discovery of classic and novel copy number variants (CNVs) in various disorders affecting cognitive development. Across autism and schizophrenia, global CNV burden and de novo CNV burden are associated with disease. Also, specific recurrent CNVs may be associated with several DSM conditions. Each condition is also associated with heterogeneous and individually rare CNVs.

Conclusions: CNVs play an important role in the genetic architecture of the childhood neuropsychiatric disorders discussed. This discovery appears to suggest an important role for the strict regulation of gene dosage in the neurodevelopmental roots of these conditions. Microarrays have emerged as high-yield tests in the diagnosis and molecular subtyping of the childhood-onset disorders involving cognitive development. In summary, CNV studies in disorders of cognitive development have revealed interesting and important new insights and have opened an avenue of investigation that holds great promise for neuropsychiatric disease.

Figure 1

Copy number variants. Note: Typical loci are copy number 2 because one maternal copy and one paternal copy are inherited. Certain loci may undergo duplications or deletions and may vary in size, involving none to dozens of genes, represented by boxes. These copy number variable regions of genome are frequently flanked by low copy repeats or segmental duplications, represented by arrows.

Figure 2

Copy number (CN) variants may be de novo or inherited, associated with disease (highly penetrant or incompletely penetrant), benign, or of unknown significance. Note: The pedigree on the left represents a highly penetrant de novo variant (not present in parents' somatic cells, but here occurring spontaneously in the paternal germline). Pedigree on the right represents an inherited copy number variant that may be associated with disease with incomplete penetrance. BAP = broader autism phenotype.

Figure 3

Nonallelic homologous recombination represents one mechanism that gives rise to copy number variants and is schematized by recombination within neighboring but nonallelic segmental duplications, represented by arrows.

Figure 4

Schematic of case-control studies for rare copy number variants where cases are represented by people on left and controls by people on the right. Note: Genders are noted by boxes (male) and circles (female). Darkening represents carriers of copy number variants of interest. A larger number of copy number variant cases over controls suggests association with susceptibility to disease.