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Bipolar disorder (BD) has a substantial genetic component, but progress in identification of BD risk genes has been slow. MBD5 (methyl-CpGbinding domain protein 5) is a dosage-sensitive gene on 2q23.1 and is a member of a family of genes involved in DNA methylation and chromatin remodeling. 1,2 Disruption of MBD5 by deletions or other variants causes MBD5-associated neurodevelopmental disorder (MAND). The phenotypic spectrum of MAND includes intellectual disability, autism spectrum disorder, and epilepsy. [1][2][3] Detailed phenotypic evaluation revealed that

The aims of the present study were: (i) to examine the association between schizophrenia (SCZ) and 47, XXY or 47, XXX in a large case-control sample; and (ii) to characterize the clinical features of patients with SCZ with these X chromosome aneuploidies.Methods: To identify 47, XXY and 47, XXX, array comparative genomic hybridization (aCGH) was performed in 3188 patients with SCZ and 3586 controls. We examined the association between 47, XXY and 47, XXX and SCZ in males and females separately using exact conditional tests to control for platform effects. Clinical data were retrospectively examined for patients with SCZ with X chromosome aneuploidies.Results: Of the analyzed samples, 3117 patients (97.8%) and 3519 controls (98.1%) passed our quality control. X chromosome aneuploidies were exclusively identified in patients: 47, XXY in seven patients (0.56%), 47, XXX in six patients (0.42%). Statistical analysis revealed a significant association between SCZ and 47, XXY (P = 0.028) and 47, XXX (P = 0.011). Phenotypic data were available from 12 patients. Treatment-resistance to antipsychotics and manic symptoms were observed in six patients each (four with 47, XXY and two with 47, XXX for both), respectively. Statistical analysis revealed that treatment-resistance to antipsychotics, mood stabilizer use, and manic symptoms were significantly more common in patients with 47, XXY than in male patients without pathogenic copy number variations. Conclusion:These findings indicate that both 47, XXY and 47, XXX are significantly associated with risk for SCZ. Patients with SCZ with 47, XXY may be characterized by treatment-resistance and manic symptoms.

Recent genetic studies have found common genomic risk variants among schizophrenia (SCZ), autism spectrum disorder (ASD), and bipolar disorder (BP), strongly suggesting the overlaps in their molecular and cellular mechanism. Our research group identified the variant in ASTN2 as one of the candidate risk factors across these psychiatric disorders by whole-genome copy number variation analysis. However, the alterations in the human neuronal cells resulting from ASTN2 variants identified in patients remain unknown. To address this, we used patient-derived and genome-edited iPS cells with ASTN2 deletion; cells were further differentiated into neuronal cells. A comprehensive gene expression analysis revealed that the expression level of ZNF558, a gene specifically expressed in human forebrain neural progenitor cells, was greatly reduced in ASTN2-deleted neuronal cells. Furthermore, the expression of the mitophagy-related gene SPATA18, which is repressed by ZNF558, and mitophagy activity were increased in ASTN2-deleted neuronal cells. These phenotypes were detected in both neuronal cells from patient-derived and genome-edited iPS cells with ASTN2 deletion. Our results suggest that ASTN2 deletion is related to the common pathogenic mechanism of SCZ, ASD, and BP by regulating mitophagy via ZNF558.