De novo mutations in neurological and psychiatric disorders: effects, diagnosis and prevention

Abstract

Neurological and psychiatric disorders account for a considerable proportion of the global disease burden. Although there is a high heritability and a significant genetic component in these disorders, the genetic cause of most cases has yet to be identified. Advances in DNA sequencing allowing the analysis of the whole human genome in a single experiment have led to an acceleration of the discovery of the genetic factors associated with human disease. Recent studies using these platforms have highlighted the important role of de novo mutations in neurological and psychiatric disorders. These findings have opened new avenues into the understanding of genetic disease mechanisms. These discoveries, combined with the increasing ease with which we can sequence the human genome, have important implications for diagnosis, prevention and treatment. Here, we present an overview of the recent discovery of de novo mutations using key examples of neurological and psychiatric disorders. We also discuss the impact of technological developments on diagnosis and prevention.

Figure 1

Schematic representation of de novo mutations and three genetic mechanisms. Example (a) represents the case of one gene (here, the gene encoding methyl CpG binding protein 2, MECP2), and the occurrence of multiple de novo mutations in unrelated subjects with Rett syndrome (vertical bars in graph on the right). The green, orange and purple shaded areas illustrate the methyl-CpG binding domain, the transcriptional repression domain and the nuclear localization signals, respectively. Example (b) demonstrates a current hypothesis for schizophrenia, where the majority of the de novo mutations identified in schizophrenia cases occur in different genes. These genes are likely to be part of specific networks or pathways. The last example (c) shows the 'double hit' de novo model observed in neurofibromatosis type II. Fifty percent of neurofibromatosis type II cases are caused by an acquired de novo mutation present in all cells (red star), and in some cells a second somatic de novo mutation occurs, which inactivates the normal copy of the neurofibromatosis gene (green star). Cells harboring the two hits (red and green) will lead to a tumor represented by the cluster of green cells.