A genetic model for neurodevelopmental disease

The genetic basis of neurodevelopmental and neuropsychiatric diseases has been advanced by the discovery of large and recurrent copy number variants significantly enriched in cases when compared to controls. The pattern of this variation strongly implies that rare variants contribute significantly to neurological disease; that different genes will be responsible for similar diseases in different families; and that the same 'primary' genetic lesions can result in a different disease outcome depending potentially on the genetic background. Next-generation sequencing technologies are beginning to broaden the spectrum of disease-causing variation and provide specificity by pinpointing both genes and pathways for future diagnostics and therapeutics.

► Current mutation discovery efforts for neurodevelopmental disorders are focused on large CNVs and small protein-coding SNVs and indels. Between these extremes lies an under-ascertained range of genetic variants between 1 and 50 kbp, representing a promising range for future expansion of gene discovery. ► Extensive phenotypic variability has been documented for large CNVs with seemingly similar breakpoints. There is evidence in support of an oligogenic model, where multiple rare variants of large effect may aggregate within individuals and underlie this variability. ► Despite extreme locus heterogeneity and seemingly disparate phenotypes, genetic studies are beginning to converge on a core set of biological pathways across a diverse array of neurodevelopmental conditions. This suggests that a large component of the genetic etiology may be shared. These pathways are important targets for diagnosis and therapeutic development.