Abstract Major depressive disorder (MDD) is a debilitating and prevalent mental disorder with a high disease burden. Despite a wide array of different treatment options, many patients do not respond to initial treatment attempts. Selection of the most appropriate treatment remains a significant clinical challenge in psychiatry, highlighting the need for the development of biomarkers with predictive utility. Recently, the epigenetic modification DNA methylation (DNAm) has emerged to be of great interest as a potential predictor of MDD treatment outcomes. Here, we review efforts to date that see ..read more

Abstract Individuals with severe and treatment-resistant obsessive-compulsive disorder (trOCD) represent a small but severely disabled group of patients. Since trOCD cases eligible for deep brain stimulation (DBS) probably comprise the most severe end of the OCD spectrum, we hypothesize that they may be more likely to have a strong genetic contribution to their disorder. Therefore, while the worldwide population of DBS-treated cases may be small (~300), screening these individuals with modern genomic methods may accelerate gene discovery in OCD. As such, we have begun to collect DNA from trOCD ..read more

Abstract Hereditary spastic paraplegia (HSP) is a group of familial diseases characterized by progressive corticospinal tract degeneration. Clinically, patients present with lower-limb spasticity and weakness. To date, more than 80 genetic HSP types have been identified. Despite advances in molecular genetics, novel HSP gene discoveries are ongoing, with a low genetic diagnostic yield. In this study, we aimed to determine pathogenic variants in a family with HSP, which was not diagnosed through conventional genetic testing. We clinically characterized a large family and conducted whole genome ..read more

Abstract Little is known about how non-suicidal and suicidal self-injury are differentially genetically related to psychopathology and related measures. This research was conducted using the UK Biobank Resource, in participants of European ancestry (N = 2320 non-suicidal self-injury [NSSI] only; N = 2648 suicide attempt; 69.18% female). We compared polygenic scores (PGS) for psychopathology and other relevant measures within self-injuring individuals. Logistic regressions and likelihood ratio tests (LRT) were used to identify PGS that were differentially associated with these outcomes. In a mu ..read more

Abstract Rett syndrome (RTT), a human neurodevelopmental disorder characterized by severe cognitive and motor impairments, is caused by dysfunction of the conserved transcriptional regulator Methyl-CpG-binding protein 2 (MECP2). Genetic analyses in mouse Mecp2 mutants, which exhibit key features of human RTT, have been essential for deciphering the mechanisms of MeCP2 function; nonetheless, our understanding of these complex mechanisms is incomplete. Zebrafish mecp2 mutants exhibit mild behavioral deficits but have not been analyzed in depth. Here, we combine transcriptomic and behavioral assa ..read more

Abstract Chronotype is a proxy sleep measure that has been associated with neuropsychiatric disorders. By investigating how chronotype influences risk for neuropsychiatric disorders and vice versa, we may identify modifiable risk factors for each phenotype. Here we used Mendelian randomization (MR), to explore causal effects by (1) studying the causal relationships between neuropsychiatric disorders and chronotype and (2) characterizing the genetic components of these phenotypes. Firstly, we investigated if a causal role exists between five neuropsychiatric disorders and chronotype using the l ..read more

Abstract Studies have consistently shown that psychiatric genetic counseling (pGC) helps people with psychiatric conditions by increasing empowerment and self-efficacy, and addressing emotions like guilt. Yet, it is not routinely provided. Genetic counselors and trainees express low confidence in their ability to provide meaningful pGC, especially in the absence of adequate training. Therefore, to address this gap a “Psychiatric Genetic Counseling for Genetic Counselors” (PG4GC) workshop was developed and delivered to 13 groups of participants (primarily qualified genetic counselors and traine ..read more

Abstract Since 2008, FOXG1 haploinsufficiency has been linked to a severe neurodevelopmental phenotype resembling Rett syndrome but with earlier onset. Most patients are unable to sit, walk, or speak. For years, FOXG1 sequencing was only prescribed in such severe cases, limiting insight into the full clinical spectrum associated with this gene. Next-generation sequencing (NGS) now enables unbiased diagnostics. Through the European Reference Network for Rare Malformation Syndromes, Intellectual and Other Neurodevelopmental Disorders, we gathered data from patients with heterozygous FOXG1 varian ..read more

American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, Volume 195, Issue 3, April 2024 ..read more

Abstract Pathogenic variants in DDX3X are associated with neurodevelopmental disorders. Communication impairments are commonly reported, yet specific speech and language diagnoses have not been delineated, preventing prognostic counseling and targeted therapies. Here, we characterized speech and language in 38 female individuals, aged 1.69–24.34 years, with pathogenic and likely pathogenic DDX3X variants (missense, n = 13; nonsense, n = 12; frameshift, n = 7; splice site, n = 3; synonymous, n = 2; deletion, n = 1). Standardized speech, language, motor, social, and adaptive behavior assessments ..read more