Aminoacyl-tRNA synthetases (ARSs) are ubiquitous, ancient enzymes that charge amino acids to cognate tRNA molecules, the essential first step of protein translation. Here, we describe 32 individuals from 21 families, presenting with microcephaly, neurodevelopmental delay, seizures, peripheral neuropathy, and ataxia, with de novo heterozygous and bi-allelic mutations in asparaginyl-tRNA synthetase (NARS1). We demonstrate a reduction in NARS1 mRNA expression as well as in NARS1 enzyme levels and activity in both individual fibroblasts and induced neural progenitor cells (iNPCs). Molecular modeling of the recessive c.1633C>T (p.Arg545Cys) variant shows weaker spatial positioning and tRNA selectivity. We conclude that de novo and bi-allelic mutations in NARS1 are a significant cause of neurodevelopmental disease, where the mechanism for de novo variants could be toxic gain-of-function and for recessive variants, partial loss-of-function.
Schizophrenia (SCZ) is a chronic mental illness and among the most debilitating conditions encountered in medical practice. A recent landmark SCZ study of the protein-coding regions of the genome identified a causal role for ten genes and a concentration of rare variant signals in evolutionarily constrained genes1. This recent study—and most other large-scale human genetics studies—was mainly composed of individuals of European (EUR) ancestry, and the generalizability of the findings in non-EUR populations remains unclear. To address this gap, we designed a custom sequencing panel of 161 genes selected based on the current knowledge of SCZ genetics and sequenced a new cohort of 11,580 SCZ cases and 10,555 controls of diverse ancestries. Replicating earlier work, we found that cases carried a significantly higher burden of rare protein-truncating variants (PTVs) among evolutionarily constrained genes (odds ratio = 1.48; P = 5.4 × 10−6). In meta-analyses with existing datasets totaling up to 35,828 cases and 107,877 controls, this excess burden was largely consistent across five ancestral populations. Two genes (SRRM2 and AKAP11) were newly implicated as SCZ risk genes, and one gene (PCLO) was identified as shared by individuals with SCZ and those with autism. Overall, our results lend robust support to the rare allelic spectrum of the genetic architecture of SCZ being conserved across diverse human populations.
BackgroundCognitive behavioral therapy (CBT) is found to be effective for common mental disorders and has been delivered in self-help and guided self-help formats. Crisis and transitional case management (TCM) services play a vital role in managing clients in acute mental health crises. It is, therefore, an appropriate setting to try CBT in guided self-help format.MethodsThis was a preliminary evaluation of a formulation-driven cognitive behavioral guided self-help. Thirty-six (36) consenting participants with a diagnosis of nonpsychotic illness, attending crisis and the TCM services in Kingston, Canada, were recruited in this study. They were randomly assigned to the guided self-help plus treatment as usual (TAU) (treatment group) or to TAU alone (control group). The intervention was delivered over 8–12 weeks. Assessments were completed at baseline and 3 months after baseline. The primary outcome was a reduction in general psychopathology, and this was done using Clinical Outcomes in Routine Evaluation – Outcome Measure. The secondary outcomes included a reduction in depression, measured using the Hospital Anxiety and Depression Scale, and reduction in disability, measured using the World Health Organization Disability Assessment Schedule 2.0.FindingsParticipants in the treatment group showed statistically significant improvement in overall psychopathology (P<0.005), anxiety and depression (P<0.005), and disability (P<0.005) at the end of the trial compared with TAU group.ConclusionA formulation-driven cognitive behavioral guided self-help was feasible for the crisis and TCM clients and can be effective in improving mental health, when compared with TAU. This is the first report of a trial of guided self-help for clients attending crisis and TCM services.
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