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.

Keywords: clinical implementation; de novo mutation; network analysis; neurodevelopmental and psychiatric disorder; whole exome sequencing.

Figure 1

The analytical pipeline for DNMs detected from exome studies in psychiatric disorders. (A) The discovery flow of DNMs from trios, including sample collection, data Quality Control (QC), alignment, variants calling, annotation. (B) The functional annotation step, e.g., applying computational tools, such as SIFT and CADD to predict the functional consequences of the detected mutation. (C) The large-scale data integration step to investigate the underlying disease genetics. (D) The functional enrichment analyses and interpretation step, which help understand the disease etiology. (E) The functional studies phase is the experimental validation step. (F) The clinical application step of the DNM pipeline, which can utilize the verified DNMs as the mutation screening profile for clinical diagnosis in psychiatric patients.

Figure 2

Summary of DNMs detected from exome studies in psychiatric disorders. (A) The overview of the numbers of WES studies in psychiatric disorders increased over the past few years (until the end of 2017). (B) The distribution of de novo LoF, missense, and synonymous mutations detected in four different disorders across large studies (Table 1). (C) Venn Diagram of the overlap of genes hit by DNMs from major studies of patients with psychiatric disorders. (D) The overlap between the genes carrying DNMs and genes hit by the de novo CNVs in four different disorders. ASD, Autism Spectrum Disorder; ID/DD, Intellectual Disability, Developmental Delay; SCZ, Schizophrenia; BD, Bipolar Disorder.