PsyMuKB: An Integrative De Novo Variant Knowledge Base for Developmental Disorders

Abstract

De novo variants (DNVs) are one of the most significant contributors to severe early-onset genetic disorders such as autism spectrum disorder, intellectual disability, and other developmental and neuropsychiatric (DNP) disorders. Presently, a plethora of DNVs have been identified using next-generation sequencing, and many efforts have been made to understand their impact at the gene level. However, there has been little exploration of the effects at the isoform level. The brain contains a high level of alternative splicing and regulation, and exhibits a more divergent splicing program than other tissues. Therefore, it is crucial to explore variants at the transcriptional regulation level to better interpret the mechanisms underlying DNP disorders. To facilitate a better usage and improve the isoform-level interpretation of variants, we developed NeuroPsychiatric Mutation Knowledge Base (PsyMuKB). It contains a comprehensive, carefully curated list of DNVs with transcriptional and translational annotations to enable identification of isoform-specific mutations. PsyMuKB allows a flexible search of genes or variants and provides both table-based descriptions and associated visualizations, such as expression, transcript genomic structures, protein interactions, and the mutation sites mapped on the protein structures. It also provides an easy-to-use web interface, allowing users to rapidly visualize the locations and characteristics of mutations and the expression patterns of the impacted genes and isoforms. PsyMuKB thus constitutes a valuable resource for identifying tissue-specific DNVs for further functional studies of related disorders. PsyMuKB is freely accessible at http://psymukb.net.

Integrative Analysis Identified Key Schizophrenia Risk Factors from an Abnormal Behavior Mouse Gene Set

“…We focused on genes harboring mutations and differentially expressed genes in SCZ patients’ brains to define the subsets of different kinds of functional genes in SCZ. We first collected genes with genetic variants (MUTs), including CNVs and the DNMs of SCZ from PsyMuKB [ 16 ], as well as 2363 and 2981 genes that were identified to be differentially expressed between an adult with schizophrenia and a healthy control in DLPFC and HIPPO, respectively, with p.adj <0.05 and fold changes >1.2. Next, we extracted the AB gene set from PsyMuKB [ 16 ].…”

“…We first collected genes with genetic variants (MUTs), including CNVs and the DNMs of SCZ from PsyMuKB [ 16 ], as well as 2363 and 2981 genes that were identified to be differentially expressed between an adult with schizophrenia and a healthy control in DLPFC and HIPPO, respectively, with p.adj <0.05 and fold changes >1.2. Next, we extracted the AB gene set from PsyMuKB [ 16 ]. We observed a significant overlap between the AB gene set and the DNM gene (p.adj = 4.04 × 10 −38 calculated using a hypergeometric test and adjusted with a Bonferroni test) but no significant overlap between the AB gene set and the CNV gene (p.adj = 0.138 calculated by a hypergeometric test and adjusted by a Bonferroni test) ( Figure 2 A).…”

“…Then, we chose genes that were expressed in the brain (defined as the average RPKM > 0.1 in BrainSeq Phase 2 [ 17 ]) for further analysis. The AB gene set ( Table S1 ), CNV ( Table S2 ), and DNM ( Table S3 ) data for SCZ were collected from the PsyMuKB [ 16 ] in-house database (URL: , accessed on 17 December 2020). AB genes with an average RPKM < 0.1 in BrainSeq were also removed.…”

“…Since the 22q11.2 deletion syndrome was first linked with SCZ [ 10 ], the research on SCZ and associated mutations has rapidly progressed. So far, the evidence for the roles of CNVs and DNMs in SCZ is overwhelming [ 11 , 12 , 13 , 14 , 15 ], as summarized in mutation databases such as PsyMuKB [ 16 ]. In addition, numerous SCZ transcriptome studies have identified various differentially expressed genes (DEGs) between patients and healthy controls [ 17 , 18 ], especially in brain regions such as the hippocampus (HIPPO) [ 17 ] and dorsolateral prefrontal cortex (DLPFC) [ 18 , 19 ].…”

Alternatively Splicing Interactomes Identify Novel Isoform-Specific Partners for NSD2

“…The disease results from distal deletions on the short arm of chromosome 4 (chromosome 4p16.3) ( Descartes et al, 2017 ), which occurs in 1 in 50,000 births ( Deardorff and Zackai, 2007 ). NSD2 carries rare mutations in patients with neuropsychiatric disorders, including autism spectrum disorder (ASD), DDs, IDs, and schizophrenia (SCZ; Boczek et al, 2018 ; Park et al, 2018 ; Barrie et al, 2019 ; Lin et al, 2019 ). Early studies have reported various deleterious NSD2 variants in neuropsychiatric patients, suggesting that the haploinsufficiency of NSD2 might be partially responsible for DDs ( Katoh, 2016 ; Kim et al, 2017 ; Derar et al, 2019 ).…”