American Journal of Medical Genetics Part B: Neuropsychiatric Genetics最新文献

{"title":"Autistic traits in youth with familial adenomatous polyposis: A Dutch–Canadian case–control study","authors":"Polina Perlman Danieli,&nbsp;Ny Hoang,&nbsp;Thanuja Selvanayagam,&nbsp;Alvin Yang,&nbsp;Elemi Breetvelt,&nbsp;Merit Tabbers,&nbsp;Christine Cohen,&nbsp;Arthur S. Aelvoet,&nbsp;Brett Trost,&nbsp;Thomas Ward,&nbsp;Kara Semotiuk,&nbsp;Carol Durno,&nbsp;Melyssa Aronson,&nbsp;Zane Cohen,&nbsp;Evelien Dekker,&nbsp;Jacob Vorstman","doi":"10.1002/ajmg.b.32999","DOIUrl":"10.1002/ajmg.b.32999","url":null,"abstract":"<p>This study investigated the neurodevelopmental impact of pathogenic adenomatous polyposis coli (<i>APC</i>) gene variants in patients with familial adenomatous polyposis (FAP), a cancer predisposition syndrome. We hypothesized that certain pathogenic APC variants result in behavioral–cognitive challenges. We compared 66 FAP patients (cases) and 34 unaffected siblings (controls) to explore associations between APC variants and behavioral and cognitive challenges. Our findings indicate that FAP patients exhibited higher Social Responsiveness Scale (SRS) scores, suggesting a greater prevalence of autistic traits when compared to unaffected siblings (mean 53.8 vs. 47.4, Wilcoxon <i>p</i> = 0.018). The distribution of SRS scores in cases suggested a bimodal pattern, potentially linked to the location of the APC variant, with scores increasing from the 5′ to 3′ end of the gene (Pearson's <i>r</i> = 0.33, <i>p</i> = 0.022). While we observed a trend toward lower educational attainment in cases, this difference was not statistically significant. This study is the first to explore the connection between APC variant location and neurodevelopmental traits in FAP, expanding our understanding of the genotype–phenotype correlation. Our results emphasize the importance of clinical assessment for autistic traits in FAP patients, shedding light on the potential role of <i>APC</i> gene variants in these behavioral and cognitive challenges.</p>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":"195 8","pages":""},"PeriodicalIF":1.6,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.b.32999","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141533357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Network-based artificial intelligence approaches for advancing personalized psychiatry","authors":"Sivanesan Rajan,&nbsp;Emanuel Schwarz","doi":"10.1002/ajmg.b.32997","DOIUrl":"10.1002/ajmg.b.32997","url":null,"abstract":"<p>Psychiatric disorders have a complex biological underpinning likely involving an interplay of genetic and environmental risk contributions. Substantial efforts are being made to use artificial intelligence approaches to integrate features within and across data types to increase our etiological understanding and advance personalized psychiatry. Network science offers a conceptual framework for exploring the often complex relationships across different levels of biological organization, from cellular mechanistic to brain-functional and phenotypic networks. Utilizing such network information effectively as part of artificial intelligence approaches is a promising route toward a more in-depth understanding of illness biology, the deciphering of patient heterogeneity, and the identification of signatures that may be sufficiently predictive to be clinically useful. Here, we present examples of how network information has been used as part of artificial intelligence within psychiatry and beyond and outline future perspectives on how personalized psychiatry approaches may profit from a closer integration of psychiatric research, artificial intelligence development, and network science.</p>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":"195 8","pages":""},"PeriodicalIF":1.6,"publicationDate":"2024-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.b.32997","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141552629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interview with Stephen Glatt. Editor-in-Chief, American Journal of Medical Genetics: Neuropsychiatric Genetics","authors":"Paul Trevorrow,&nbsp;Stephen J. Glatt","doi":"10.1002/ajmg.b.32998","DOIUrl":"10.1002/ajmg.b.32998","url":null,"abstract":"","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":"195 8","pages":""},"PeriodicalIF":1.6,"publicationDate":"2024-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141548275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The impact of family-genetic risk scores on social functioning in individuals affected with six major psychiatric and substance use disorders in a Swedish National Sample","authors":"Kenneth S. Kendler,&nbsp;Henrik Ohlsson,&nbsp;Jan Sundquist,&nbsp;Kristina Sundquist","doi":"10.1002/ajmg.b.32996","DOIUrl":"10.1002/ajmg.b.32996","url":null,"abstract":"<p>To examine whether the level of genetic risk in psychiatric disorders impacts the social functioning of affected individuals, we examine the relationship between genetic risk factors for major depression (MD), anxiety disorders (AD), bipolar disorder (BD), non-affective psychosis (NAP), alcohol use disorder (AUD), and drug use disorder (DUD) in disordered individuals and five adverse social outcomes: unemployment, residence in areas of social deprivation, social welfare, early retirement, and divorce. We examine all cases with registration for these disorders from 1995 to 2015 in individuals born in Sweden. Genetic risk was assessed by the family genetic risk score (FGRS) and statistical estimates by Cox proportional hazard models. High genetic risk was significantly and modestly associated with poorer social outcomes in 23 of 30 analyses. Overall, genetic risk for MD, AD, AUD, and DUD impacted social functioning more strongly in affected individuals than did genetic risk for BD and NAP. Social welfare had the strongest associations with genetic risk, and residence in areas of high deprivation had the weakest. In individuals suffering from psychiatric and substance use disorders, high levels of genetic risk impact not only clinical features but also diverse measures of social functioning.</p>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":"195 8","pages":""},"PeriodicalIF":1.6,"publicationDate":"2024-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.b.32996","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141417230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic underpinnings of the autistic mind: Histone modifications and prefrontal excitation/inhibition imbalance","authors":"Yasaman Arman Fard,&nbsp;Elham Najjar Sadeghi,&nbsp;Zohreh Pajoohesh,&nbsp;Zahra Gharehdaghi,&nbsp;Dorsa Mousavi Khatibi,&nbsp;Shaghayegh Khosravifar,&nbsp;Yasamin Pishkari,&nbsp;Shadi Nozari,&nbsp;Ahmed Hijazi,&nbsp;SeyedAbbas Pakmehr,&nbsp;Sepideh Karkon Shayan","doi":"10.1002/ajmg.b.32986","DOIUrl":"10.1002/ajmg.b.32986","url":null,"abstract":"<p>Autism spectrum disorder (ASD) is complex neurobehavioral condition influenced by several cellular and molecular mechanisms that are often concerned with synaptogenesis and synaptic activity. Based on the excitation/inhibition (E/I) imbalance theory, ASD could be the result of disruption in excitatory and inhibitory synaptic transmission across the brain. The prefrontal cortex (PFC) is the chief regulator of executive function and can be affected by altered neuronal excitation and inhibition in the course of ASD. The molecular mechanisms involved in E/I imbalance are subject to epigenetic regulation. In ASD, altered enrichment and spreading of histone H3 and H4 modifications such as the activation-linked H3K4me2/3, H3K9ac, and H3K27ac, and repression-linked H3K9me2, H3K27me3, and H4K20me2 in the PFC result in dysregulation of molecules mediating synaptic excitation (ARC, EGR1, mGluR2, mGluR3, GluN2A, and GluN2B) and synaptic inhibition (BSN, EphA7, SLC6A1). Histone modifications are a dynamic component of the epigenetic regulatory elements with a pronounced effect on patterns of gene expression with regards to any biological process. The excitation/inhibition imbalance associated with ASD is based on the excitatory and inhibitory synaptic activity in different regions of the brain, including the PFC, the ultimate outcome of which is highly influenced by transcriptional activity of relevant genes.</p>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":"195 8","pages":""},"PeriodicalIF":1.6,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141259013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genomics of severe and treatment-resistant obsessive–compulsive disorder treated with deep brain stimulation: A preliminary investigation","authors":"Long Long Chen,&nbsp;Matilda Naesström,&nbsp;Matthew Halvorsen,&nbsp;Anders Fytagoridis,&nbsp;Stephanie B. Crowley,&nbsp;David Mataix-Cols,&nbsp;Christian Rück,&nbsp;James J. Crowley,&nbsp;Diana Pascal","doi":"10.1002/ajmg.b.32983","DOIUrl":"10.1002/ajmg.b.32983","url":null,"abstract":"<p>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 cases who qualify for DBS, and here we report results from whole exome sequencing and microarray genotyping of our first five cases. All participants had previously received DBS in the bed nucleus of stria terminalis (BNST), with two patients responding to the surgery and one showing a partial response. Our analyses focused on gene-disruptive rare variants (GDRVs; rare, predicted-deleterious single-nucleotide variants or copy number variants overlapping protein-coding genes). Three of the five cases carried a GDRV, including a missense variant in the ion transporter domain of <i>KCNB1</i>, a deletion at 15q11.2, and a duplication at 15q26.1. The <i>KCNB1</i> variant (hg19 chr20-47991077-C-T, NM_004975.3:c.1020G&gt;A, p.Met340Ile) causes substitution of methionine for isoleucine in the trans-membrane region of neuronal potassium voltage-gated ion channel KV2.1. This <i>KCNB1</i> substitution (Met340Ile) is located in a highly constrained region of the protein where other rare missense variants have previously been associated with neurodevelopmental disorders. The patient carrying the Met340Ile variant responded to DBS, which suggests that genetic factors could potentially be predictors of treatment response in DBS for OCD. In sum, we have established a protocol for recruiting and genomically characterizing trOCD cases. Preliminary results suggest that this will be an informative strategy for finding risk genes in OCD.</p>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":"195 8","pages":""},"PeriodicalIF":1.6,"publicationDate":"2024-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.b.32983","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140800725","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Leveraging DNA methylation to predict treatment response in major depressive disorder: A critical review","authors":"Jan Dahrendorff,&nbsp;Glenn Currier,&nbsp;Monica Uddin","doi":"10.1002/ajmg.b.32985","DOIUrl":"10.1002/ajmg.b.32985","url":null,"abstract":"<p>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 seek to identify DNAm signatures associated with treatment response in individuals with MDD. Searches were conducted in the databases PubMed, Scopus, and Web of Science with the concepts and keywords MDD, DNAm, antidepressants, psychotherapy, cognitive behavior therapy, electroconvulsive therapy, transcranial magnetic stimulation, and brain stimulation therapies. We identified 32 studies implicating DNAm patterns associated with MDD treatment outcomes. The majority of studies (<i>N</i> = 25) are focused on selected target genes exploring treatment outcomes in pharmacological treatments (<i>N</i> = 22) with a few studies assessing treatment response to electroconvulsive therapy (<i>N</i> = 3). Additionally, there are few genome-scale efforts (<i>N</i> = 7) to characterize DNAm patterns associated with treatment outcomes. There is a relative dearth of studies investigating DNAm patterns in relation to psychotherapy, electroconvulsive therapy, or transcranial magnetic stimulation; importantly, most existing studies have limited sample sizes. Given the heterogeneity in both methods and results of studies to date, there is a need for additional studies before existing findings can inform clinical decisions.</p>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":"195 7","pages":""},"PeriodicalIF":1.6,"publicationDate":"2024-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140800581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Revolutionizing dementia detection: Leveraging vision and Swin transformers for early diagnosis","authors":"Rini P L,&nbsp;Gayathri K S","doi":"10.1002/ajmg.b.32979","DOIUrl":"10.1002/ajmg.b.32979","url":null,"abstract":"<p>Dementia, an increasingly prevalent neurological disorder with a projected threefold rise globally by 2050, necessitates early detection for effective management. The risk notably increases after age 65. Dementia leads to a progressive decline in cognitive functions, affecting memory, reasoning, and problem-solving abilities. This decline can impact the individual's ability to perform daily tasks and make decisions, underscoring the crucial importance of timely identification. With the advent of technologies like computer vision and deep learning, the prospect of early detection becomes even more promising. Employing sophisticated algorithms on imaging data, such as positron emission tomography scans, facilitates the recognition of subtle structural brain changes, enabling diagnosis at an earlier stage for potentially more effective interventions. In an experimental study, the Swin transformer algorithm demonstrated superior overall accuracy compared to the vision transformer and convolutional neural network, emphasizing its efficiency. Detecting dementia early is essential for proactive management, personalized care, and implementing preventive measures, ultimately enhancing outcomes for individuals and lessening the overall burden on healthcare systems.</p>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":"195 7","pages":""},"PeriodicalIF":1.6,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140560330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"KCNJ3 is a novel candidate gene for autosomal dominant pure hereditary spastic paraplegia identified using whole genome sequencing","authors":"Woong-Woo Lee,&nbsp;Cha Gon Lee,&nbsp;Chang-Seok Ki","doi":"10.1002/ajmg.b.32984","DOIUrl":"10.1002/ajmg.b.32984","url":null,"abstract":"<p>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 sequencing (WGS) analysis of four affected and three unaffected individuals in the family to identify the genetic cause of HSP. This family had autosomal dominant pure (uncomplicated) late childhood-onset HSP. The patients' symptoms accelerated between the ages of 20 and 30. Brain magnetic resonance images typically showed white matter changes, a thin corpus callosum, and cerebellar atrophy. We identified a heterozygous missense variant, <i>KCNJ3</i> c.1297T&gt;G (p.Leu433Val), through WGS and family genetic analysis, confirmed by Sanger sequencing. We suggest that the identification of <i>KCNJ3</i> c.1297T&gt;G (p.Leu433Val) constitutes the discovery of a potential novel gene responsible for HSP in this family. This is the first study to report the possible role of a <i>KCNJ3</i> variant in HSP pathogenesis. Our findings further expand the phenotypic and genotypic spectrum of HSP.</p>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":"195 7","pages":""},"PeriodicalIF":1.6,"publicationDate":"2024-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.b.32984","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140560197","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Behavioral and transcriptomic analyses of mecp2 function in zebrafish","authors":"Nicholas J. Santistevan,&nbsp;Colby T. Ford,&nbsp;Cole S. Gilsdorf,&nbsp;Yevgenya Grinblat","doi":"10.1002/ajmg.b.32981","DOIUrl":"10.1002/ajmg.b.32981","url":null,"abstract":"<p>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 <i>Mecp2</i> 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 <i>mecp2</i> mutants exhibit mild behavioral deficits but have not been analyzed in depth. Here, we combine transcriptomic and behavioral assays to assess baseline and stimulus-evoked motor responses and sensory filtering in zebrafish <i>mecp2</i> mutants from 5 to 7 days post-fertilization (dpf). We show that zebrafish <i>mecp2</i> function is required for normal thigmotaxis but is dispensable for gross movement, acoustic startle response, and sensory filtering (habituation and sensorimotor gating), and reveal a previously unknown role for <i>mecp2</i> in behavioral responses to visual stimuli. RNA-seq analysis identified a large gene set that requires <i>mecp2</i> function for correct transcription at 4 dpf, and pathway analysis revealed several pathways that require MeCP2 function in both zebrafish and mammals. These findings show that MeCP2's function as a transcriptional regulator is conserved across vertebrates and supports using zebrafish to complement mouse modeling in elucidating these conserved mechanisms.</p>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":"195 7","pages":""},"PeriodicalIF":1.6,"publicationDate":"2024-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.b.32981","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140317626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}