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Copy number variants (CNVs) have been implicated in many human diseases, including psychiatric disorders. Whole genome sequencing offers advantages in CNV calling compared to previous array-based methods. Here we present a robust and transparent CNV calling pipeline, PECAN (PEdigree Copy number vAriaNt calling), for short-read, whole genome sequencing data, comprised of a novel combination of four calling methods and structural variant genotyping. This method is scalable and can incorporate pedigree information to retain lower-confidence CNVs that would otherwise be discarded. We have robustly benchmarked PECAN using gold-standard CNV calls for two well-established evaluation samples, NA12878 and HG002, showing that PECAN performs with high precision and recall on both datasets, outperforming another pedigree-based CNV calling pipeline. As part of this work, we provide a list of high-confidence gold standard CNVs for the NA12878 reference sample, curated from multiple studies. We applied PECAN to a collection of pedigrees multiply affected with schizophrenia and identified a rare deletion that perfectly co-segregates with schizophrenia in one of the pedigrees. The CNV overlaps the gene PITRM1, which has been implicated in a complex phenotype including ataxia, developmental delay, and schizophrenia-like episodes in affected adults., (© 2024. The Author(s).)

MECP2 and its product, Methyl-CpG binding protein 2 (MeCP2), are mostly known for their association to Rett Syndrome (RTT), a rare neurodevelopmental disorder. Additional evidence suggests that MECP2 may underlie other neuropsychiatric and neurological conditions, and perhaps modulate common presentations and pathophysiology across disorders. To clarify the mechanisms of these interactions, we develop a method that uses the binding properties of MeCP2 to identify its targets, and in particular, the genes recognized by MeCP2 and associated to several neurological and neuropsychiatric disorders. Analysing mechanisms and pathways modulated by these genes, we find that they are involved in three main processes: neuronal transmission, immuno-reactivity, and development. Also, while the nervous system is the most relevant in the pathophysiology of the disorders, additional systems may contribute to MeCP2 action through its target genes. We tested our results with transcriptome analysis on Mecp2-null models and cells derived from a patient with RTT, confirming that the genes identified by our procedure are directly modulated by MeCP2. Thus, MeCP2 may modulate similar mechanisms in different pathologies, suggesting that treatments for one condition may be effective for related disorders.

Rare genetic variants of large effect can help elucidate the pathophysiology of brain disorders. Here we expand the clinical and genetic analyses of a family with a (1;11)(q42;q14.3) translocation multiply affected by major psychiatric illness and test the effect of the translocation on the structure and function of prefrontal, and temporal brain regions. The translocation showed significant linkage (LOD score 6.1) with a clinical phenotype that included schizophrenia, schizoaffective disorder, bipolar disorder, and recurrent major depressive disorder. Translocation carriers showed reduced cortical thickness in the left temporal lobe, which correlated with general psychopathology and positive psychotic symptom severity. They showed reduced gyrification in prefrontal cortex, which correlated with general psychopathology severity. Translocation carriers also showed significantly increased activation in the caudate nucleus on increasing verbal working memory load, as well as statistically significant reductions in the right dorsolateral prefrontal cortex glutamate concentrations. These findings confirm that the t(1;11) translocation is associated with a significantly increased risk of major psychiatric disorder and suggest a general vulnerability to psychopathology through altered cortical structure and function, and decreased glutamate levels., Competing Interests: S.M.L. has received financial support for research from Roche and Abbvie in relation to therapeutic studies of people with schizophrenia. He has also received personal payment for input into educational initiatives from Roche, Janssen, and Sunovion. These received funds do not present a conflict of interest with the present study. B.W., J.D., N.J.B., and Z.A.H. are all current or former employees of Pfizer. J.D. and N.J.B. are current employees of AstraZeneca. The remaining authors declare no conflict of interest.