De novo mutations from whole exome sequencing in neurodevelopmental and psychiatric disorders: From discovery to application

Abstract

Neurodevelopmental and psychiatric disorders are a highly disabling and heterogeneous group of developmental and mental disorders, resulting from complex interactions of genetic and environmental risk factors. The nature of multifactorial traits and the presence of comorbidity and polygenicity in these disorders present challenges in both disease risk identification and clinical diagnoses. The genetic component has been firmly established, but the identification of all the causative variants remains elusive. The development of next-generation sequencing, especially whole exome sequencing (WES), has greatly enriched our knowledge of the precise genetic alterations of human diseases, including brain-related disorders. In particular, the extensive usage of WES in research studies has uncovered the important contribution of de novo mutations (DNMs) to these disorders. Trio and quad familial WES are a particularly useful approach to discover DNMs. Here, we review the major WES studies in neurodevelopmental and psychiatric disorders and summarize how genes hit by discovered DNMs are shared among different disorders. Next, we discuss different integrative approaches utilized to interrogate DNMs and to identify biological pathways that may disrupt brain development and shed light on our understanding of the genetic architecture underlying these disorders. Lastly, we discuss the current state of the transition from WES research to its routine clinical application. This review will assist researchers and clinicians in the interpretation of variants obtained from WES studies, and highlights the need to develop consensus analytical protocols and validated lists of genes appropriate for clinical laboratory analysis, in order to reach the growing demands.