Autism Spectrum Disorder (ASD) is a neurodevelopmental psychiatric condition that shares significant clinical and genetic overlap with intellectualdisability (ID) and other neurodevelopmental disorders. Genetic testingin ASD lags far behind that for ID, even though Professional Societiesrecommend genetic testing for all ASD individuals and insurance reimbursement is relatively good. The core competencies for child and adolescent psychiatrists include determining the etiology and diagnosisfor all childhood psychopathology, including ID and ASD. Child psychiatrists should recommend and order genetic testing by exomeor genome sequencing on all children with ASD.

Individuals with germline PTEN variants (PHTS) have increased risks of the seemingly disparate phenotypes of cancer and neurodevelopmental disorders (NDD), including autism spectrum disorder (ASD). Etiology of the phenotypic variability remains elusive. Here, we hypothesized that decreased genomic diversity, manifested by increased homozygosity, may be one etiology. Comprehensive analyses of 376 PHTS patients of European ancestry revealed significant enrichment of homozygous common variants in genes involved in inflammatory processes in the PHTS-NDD group and in genes involved in differentiation and chromatin structure regulation in the PHTS-ASD group. Pathway analysis revealed pathways germane to NDD/ASD, including neuroinflammation and synaptogenesis. Collapsing analysis of the homozygous variants identified suggestive modifier NDD/ASD genes. In contrast, we found enrichment of homozygous ultra-rare variants in genes modulating cell death in the PHTS-cancer group. Finally, homozygosity burden as a predictor of ASD versus cancer outcomes in our validated prediction model for NDD/ASD performed favorably.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects nearly 3% of children and has a strong genetic component. While hundreds of ASD risk genes have been identified through sequencing studies, the genetic heterogeneity of ASD makes identifying additional risk genes using these methods challenging. To predict candidate ASD risk genes, we developed a simple machine learning model, ASiDentify (ASiD), using human genomic, RNA- and protein-based features. ASiD identified over 1,300 candidate ASD risk genes, over 300 of which have not been previously predicted. ASiD made accurate predictions of ASD risk genes using 6 features predictive of ASD risk gene status, including mutational constraint, synapse localization and gene expression in neurons, astrocytes and non-brain tissues. Particular functional groups of proteins found to be strongly implicated in ASD include RNA-binding proteins (RBPs) and chromatin regulators. We constructed additional logistic regression models to make predictions and assess informative features specific to RBPs, including mutational constraint, or chromatin regulators, for which both expression level in excitatory neurons and mutational constraint were informative. The fact that RBPs and chromatin regulators had informative features distinct from all protein-coding genes suggests that specific biological pathways connect risk genes with different molecular functions to ASD.

Copy number variants (CNVs) are robustly associated with psychiatric disorders and changes in brain structures. However, because CNVs contain many genes, the precise gene-phenotype relationship remains unclear. Although various volumetric alterations in the brains of 22q11.2 CNV carriers have been identified in humans and mouse models, it is unknown how each gene encoded in the 22q11.2 region contributes to structural alterations, associated mental illnesses, and their dimensions. Our previous studies identified Tbx1, a T-box family transcription factor encoded in the 22q11.2 CNV, as a driver gene for social interaction and communication, spatial and working memory, and cognitive flexibility. However, it remains unclear how TBX1 impacts the volumes of various brain regions and their functionally linked behavioral dimensions. In this study, we used volumetric magnetic resonance imaging analysis to comprehensively evaluate brain region volumes and behavioral alterations relevant to affected structures in congenic Tbx1 heterozygous mice. Our data showed that the volumes of the anterior and posterior portions of the amygdaloid complex and its surrounding cortical regions were most robustly reduced in Tbx1 heterozygous mice. In an amygdala-dependent task, Tbx1 heterozygous mice were impaired in their ability to learn the incentive value of a social partner. The volumes of the primary and secondary auditory cortexes were increased, and acoustic, but not non-acoustic, sensorimotor gating was impaired in Tbx1 heterozygous mice. Our findings identify the brain's regional volume alterations and their relevant behavioral dimensions associated with Tbx1 heterozygosity.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by multiple dysfunctions in behavior, the nervous system, and the immune system. Increasing evidence suggests that mitochondrial DNA (mtDNA) plays a crucial role in the pathology of ASD. In clinical practice, altered mtDNA levels have been observed in various tissues of individuals with ASD. Mutation or oxidation of mtDNA is also closely related to the immune response associated with the pathology of autism. With mtDNA identified as a causal factor, much interest has focused on how its production affects neurodevelopment and neurophysiology. Here, we review how mtDNA leads to dysfunction of cellular mitochondria and immune response. We also illustrate the relationship between mtDNA alterations and the pathology of autism. Finally, we discuss the existing evidence on cell-free mtDNA associated with ASD and look forward to its application in clinical diagnosis and treatment.

De novo variants adjacent to the canonical splicing sites or in the well-defined splicing-related regions are more likely to impair splicing but remain under-investigated in autism spectrum disorder (ASD). By analyzing large, recent ASD genome sequencing cohorts, we find a significant burden of de novo potential splicing-disrupting variants (PSDVs) in 5048 probands compared to 4090 unaffected siblings. We identified 55 genes with recurrent de novo PSDVs that were highly intolerant to variation. Forty-six of these genes have not been strongly implicated in ASD or other neurodevelopmental disorders previously, including GSK3B. Through international, multicenter collaborations, we assembled genotype and phenotype data for 15 individuals with GSK3B variants and identified common phenotypes including developmental delay, ASD, sleeping disturbance, and aggressive behavior. Using available single-cell transcriptomic data, we show that GSK3B is enriched in dorsal progenitors and intermediate forms of excitatory neurons in the developing brain. We showed that Gsk3b knockdown in mouse excitatory neurons interferes with dendrite arborization and spine maturation which could not be rescued by de novo missense variants identified from affected individuals. In summary, our findings suggest that PSDVs may play an important role in the genetic etiology of ASD and allow for the prioritization of new ASD candidate genes. Importantly, we show that genetic variation resulting in GSK3B loss-of-function can lead to a neurodevelopmental disorder with core features of ASD and developmental delay.

Genome-wide enrichment of gene-specific tandem repeat expansions has been linked to autism spectrum disorder. One such mutation is the CTG tandem repeat expansion in the 3' untranslated region of the DMPK gene, which is known to cause myotonic muscular dystrophy type 1. Although there is a clear clinical association between autism and myotonic dystrophy, the molecular basis for this connection remains unknown. Here, we report that sequestration of MBNL splicing factors by mutant DMPK RNAs with expanded CUG repeats alters the RNA splicing patterns of autism-risk genes during brain development, particularly a class of autism-relevant microexons. We demonstrate that both DMPK-CTG expansion and Mbnl null mouse models recapitulate autism-relevant mis-splicing profiles, along with social behavioral deficits and altered responses to novelty. These findings support our model that myotonic dystrophy-associated autism arises from developmental mis-splicing of autism-risk genes.

Discerning clinically relevant autism spectrum disorder (ASD) candidate variants from whole-exome sequencing (WES) data is complex, time-consuming, and labor-intensive. To this end, we developed AutScore, an integrative prioritization algorithm of ASD candidate variants from WES data and assessed its performance to detect clinically relevant variants. We studied WES data from 581 ASD probands, and their parents registered in the Azrieli National Center database for Autism and Neurodevelopment Research. We focused on rare allele frequency (< 1%) and high-quality proband-specific variants affecting genes associated with ASD or other neurodevelopmental disorders (NDDs). We developed AutScore and AutScore.r and assigned each variant based on their pathogenicity, clinical relevance, gene-disease association, and inheritance patterns. Finally, we compared the performance of both AutScore versions with the rating of clinical experts and the NDD variant prioritization algorithm, AutoCaSc. Overall, 1161 rare variants distributed in 687 genes in 441 ASD probands were evaluated by AutScore with scores ranging from - 4 to 25, with a mean ± SD of 5.89 ± 4.18. AutScore.r cut-off of ≥ 0.335 performs better than AutoCaSc and AutScore in detecting clinically relevant ASD variants, with a detection accuracy rate of 85% and an overall diagnostic yield of 10.3%. Five variants with AutScore.r of ≥ 0.335 were distributed in five novel ASD candidate genes. AutScore.r is an effective automated ranking system for ASD candidate variants that could be implemented in ASD clinical genetics pipelines.

Development among autistic youth varies widely. A subgroup of children experiences regression, defined as the loss of previously acquired developmental skills. Various genetic and environmental factors have been suggested as potential contributors. This study aimed to compare the developmental profiles of children and youth with regression to those without and identify factors associated with regression. Data from the Province of Ontario Neurodevelopmental Disorders (POND) Network was analyzed, including 930 eligible participants. Regression classification was based on the Autism Diagnostic Interview-Revised (ADI-R). Differences in demographic information, medical history, mental health, cognitive and adaptive functioning, and molecular genetic findings were examined between individuals with regressive and non-regressive autism. Among participants, 211 (22.7%) had regressive autism. Lower Full-Scale IQ (p corrected = 0.015) and adaptive function (ABAS-2) scores (p corrected = 0.015) were identified in the regressive group. No statistically significant differences in mental health outcomes (measured by the Child Behavior Checklist, CBCL) or socialization and core symptom severity (measured by the Social Communication Questionnaire, SCQ) were found. There were no notable differences in other factors hypothesized to contribute to regression, such as pregnancy duration, family history of autism, caregivers' education levels, or sleep disorders, except for a higher prevalence of epilepsy in the regressive group (p = 0.001). Rare and common genetic features of both groups are described. In conclusion, autistic youth with regression tend to have lower cognitive and adaptive scores and may experience higher epilepsy rates. Further powered studies are needed to explore the genomic architecture of autistic regression.

Psychiatric disorders are highly heritable and polygenic, influenced by environmental factors and often comorbid. Large-scale genome-wide association studies (GWASs) through consortium efforts have identified genetic risk loci and revealed the underlying biology of psychiatric disorders and traits. However, over 85% of psychiatric GWAS participants are of European ancestry, limiting the applicability of these findings to non-European populations. Latin America and the Caribbean, regions marked by diverse genetic admixture, distinct environments and healthcare disparities, remain critically understudied in psychiatric genomics. This threatens access to precision psychiatry, where diversity is crucial for innovation and equity. This Review evaluates the current state and advancements in psychiatric genomics within Latin America and the Caribbean, discusses the prevalence and burden of psychiatric disorders, explores contributions to psychiatric GWASs from these regions and highlights methods that account for genetic diversity. We also identify existing gaps and challenges and propose recommendations to promote equity in psychiatric genomics.

Neurodevelopmental disorders (NDDs) are a group of highly heterogeneous diseases that affect children's social, cognitive, and emotional functioning. The etiology is complicated with genetic factors playing an important role. During the past decade, large-scale whole exome sequencing (WES) and whole genome sequencing (WGS) have vastly advanced the genetic findings of NDDs. Various forms of variants have been reported to contribute to NDDs, such as de novo mutations (DNMs), copy number variations (CNVs), rare inherited variants (RIVs), and common variation. By far, over 200 high-risk NDD genes have been identified, which are involved in biological processes including synaptic function, transcriptional and epigenetic regulation. In addition, monogenic, oligogenic, polygenetic, and omnigenic models have been proposed to explain the genetic architecture of NDDs. However, the majority of NDD patients still do not have a definitive genetic diagnosis. In the future, more types of risk factors, as well as noncoding variants, are await to be identified, and including their interplay mechanisms are key to resolving the etiology and heterogeneity of NDDs.

Genetics is an important contributor to autism spectrum disorder (ASD). Clinical guidelines endorse genetic testing in the medical workup of ASD, particularly tests that use whole genome sequencing (WGS) technology. While the clinical utility of genetic testing in ASD is demonstrated, the breadth of impact of results can depend on the variant and/or gene being reported.

We reviewed research results returned to families enrolled in our ASD WGS study between 2012 and 2023. For significant results, we grouped the outcome of each genetic finding into three outcome categories: (1) genetic diagnosis, (2) counselling benefits and (3) support to family.

Out of 202 families who received genome sequencing results, 100 had at least one clinically relevant finding related to ASD. With detailed examples, we show that all significant results led to a genetic diagnosis and counselling benefits.

Our findings show the relevance of genome sequencing in ASD and provide illustrative examples of how the information can be used.

The opaque relationship between biology and behavior is an intractable problem for psychiatry, and it increasingly challenges longstanding diagnostic categorizations. While various big data sciences have been repeatedly deployed as potential solutions, they have so far complicated more than they have managed to disentangle. Attending to categorical misalignment, this article proposes one reason why this is the case: Datasets have to instantiate clinical categories in order to make biological sense of them, and they do so in different ways. Here, I use mixed methods to examine the role of the reuse of big data in recent genomic research on autism spectrum disorder (ASD). I show how divergent regimes of psychiatric categorization are innately encoded within commonly used datasets from MSSNG and 23andMe, contributing to a rippling disjuncture in the accounts of autism that this body of research has produced. Beyond the specific complications this dynamic introduces for the category of autism, this paper argues for the necessity of critical attention to the role of dataset reuse and recombination across human genomics and beyond.

The authors provide recommendations on incorporating recent advances in psychiatric genetics into clinical practice for mental health clinicians.

The International Society for Psychiatric Genetics Education Committee met monthly to come to a consensus on priority topics in psychiatric genetics. Topics were then assigned to small teams of subspecialty experts to summarize the current knowledge base and create an illustrative clinical case. Topics included, familial aggregation, common and rare genetic variants, epigenetics, gene-environment interactions, pharmacogenomics, genetic counseling, and ethical and social implications. Each section was reviewed and revised by all committee members and then finalized by the Committee Chair.

Key findings highlight the importance of understanding the genetic architecture of psychiatric disorders, the potential applications of genetic information in risk assessment, diagnosis, treatment selection, and patient education, as well as the ethical and social considerations surrounding the use of genetic data. The committee emphasizes the need for a nuanced approach that integrates genetic factors with environmental and experiential factors in a holistic model of care.

As psychiatric genetics continues to evolve rapidly, mental health clinicians must stay informed about the latest findings and their clinical implications. Ongoing education, collaboration with genetics professionals, and effective communication strategies are crucial to harness the power of genetics while avoiding potential pitfalls such as genetic determinism and stigma. The committee recommends a balanced perspective that recognizes the complex interplay of genetic and non-genetic factors in shaping mental health outcomes.

Mutations in ATP-dependent chromatin remodeler CHD8 cause one of the most frequent monogenetic forms of autism and are associated with brain overgrowth. Nevertheless, the activities of CHD8 in autism-relevant cell types are still poorly understood. Here, we purify the CHD8 protein from human neural stem cells and determine its interaction partners using mass spectrometry. We identify the TRRAP complex, a coactivator of MYC and E2F transcription factors, as a prominent CHD8 interaction partner. CHD8 colocalizes genome-wide with TRRAP and binds together at MYC and E2F target gene promoters in human neural stem cells. Depletion of CHD8 or TRRAP in human neural stem cells shows downregulation of MYC and E2F target genes as the most prominent gene-regulatory events. Depletion of CHD8 diminishes cell-cycle entry into S-phase. MYC and E2F transcription factors are established oncogenes and regulate cell growth. Our results link CHD8 to TRRAP in facilitating the regulation of MYC and E2F target genes in human neural stem cells.

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social interaction and repetitive, stereotyped behaviors. There is no universally effective pharmacological treatment targeting its core symptoms.Oxytocin, an endogenous polypeptide known as the "social hormone", has shown potential in improving emotional recognition and social interactions in individuals with ASD. However, its clinical application has been limited due to its short half-life and poor blood-brain barrier penetration. To address these challenges, we utilized peptide lipidation technology to enhance the pharmacokinetic properties and brain bioavailability of oxytocin. A series of lipidated oxytocin analogs was designed and synthesized, exhibiting superior brain distribution and pharmacokinetic profiles in valproic acid-induced autistic rat models compared to unmodified oxytocin. Among theseanalogs, C16-modified oxytocin (C16-OT), administered intrathecally, achieved the most extensive brain distribution with limited presence in the blood, resulting in long-lasting improvements in autistic behaviors. These improvements, including enhanced social behaviors and reduced stereotypical actions, were sustained for up to 42 days, contrasting with the brief effects typically reported in previous studies. Furthermore, a comparison of administration routes revealed that intrathecal injection achieved higher brain concentrations and more prolonged social behavioral improvements than intranasal delivery. These findings provide robust preclinical evidence that C16-OT, through optimized lipidation and intrathecal delivery, offers sustained central nervous system activity and significant, long-term reversal of social behavioral deficits in rats with autism.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social communication impairments and restricted, repetitive behaviors. ASD exhibits a strong genetic basis, with rare and common genetic variants contributing to its etiology. Copy number variations (CNVs), deletions or duplications of chromosomal segments, have emerged as key contributors to ASD risk. Rare CNVs often demonstrate large effect sizes and can directly cause ASD, while common variants collectively exert subtle influences. Recent advances have identified numerous ASD-associated CNVs, including recurrent loci such as 1q21.1, 2p16.3, 7q11.23, 15q11.2, 15q11-q13, 16p11.2 and 22q11.2. Mouse models carrying these CNVs have provided profound insights into the underlying neurobiological mechanisms. Recent studies integrating transcriptomic, proteomic, and functional imaging approaches have revealed alterations in synaptic function, neuronal differentiation, myelination, metabolic pathways, and circuit connectivity. Notably, investigations leveraging conditional knockout models, high magnetic field MRI, and single-cell analyses highlight disruptions in excitatory-inhibitory balance, white matter integrity, and dynamic gene regulatory networks. Parallel human-based approaches, including iPSC-derived neurons, cerebral organoids, and large-scale single-nucleus sequencing, are combined with animal model data. These integrative strategies promise to refine our understanding of ASD's genetic architecture, bridging the gap between fundamental discoveries in model organisms and clinically relevant biomarkers, subtypes, and therapeutic targets in humans. This review summarizes key findings from recent CNV mouse model studies and highlights emerging technologies applied to human ASD samples. Finally, we outline prospects for translating findings from mouse studies to humans. By illuminating both unique and convergent genetic mechanisms, these advances offer a critical framework for unraveling etiological complexity in ASD.

The glymphatic system allows cerebrospinal fluid (CSF) flow along the brain's perivascular spaces (PVS), aiding in the removal of harmful substances into the venous system. Previous studies have suggested that younger males with severe autism spectrum disorder (ASD) exhibit enlarged PVS (ePVS), although the specific regions or extent of PVS enlargement remain unclear. Additionally, it is still unknown whether the localization of ePVS correlates with specific ASD symptoms. Using automated MRI-based PVS quantification, we conducted a descriptive observational study to map the number, diameter, and volume of PVS across 72 brain areas, correlating these features with the clinical severity of autism and the presence or absence of three distinct ASD symptoms: language impairment, stereotypies, and hypersensoriality. The study involved 36 children with ASD (ages 1-9 years). A thorough analysis of ePVS in the white matter underlying 72 cortical areas revealed that different ASD symptoms exhibit specific ePVS localizations. Moreover, ePVS in the white matter beneath the two rostral middle frontal regions were associated with the overall clinical severity of ASD as well as specific symptoms (verbal dysfunction, stereotypies, and hypersensoriality). When these prefrontal subregions experience excessive PVS enlargement, it may lead to hypoactivity in the dorsolateral prefrontal cortex (DLPFC), contributing to the manifestation of ASD symptoms.

Duchenne and Becker Muscular Dystrophy are dystrophinopathies with a prevalence of 1:5000-6000 males, caused by pathogenic variants in DMD. These conditions are often accompanied by neurodevelopmental disorders (NDDs) like autism (ASD; ~20%) and intellectual disability (ID; ~30%). However, their low penetrance in dystrophinopathies suggests additional contributing factors. In our study, 83 individuals with dystrophinopathies were clinically evaluated and categorized based on ASD (36 individuals), ID risk (12 individuals), or controls (35 individuals). Exome sequencing analysis revealed an enrichment of risk de novo variants (DNVs) in ASD-DMD individuals (adjusted p value = 0.0356), with the number of DNVs correlating with paternal age (p value = 0.0133). Additionally, DMD-ASD individuals showed a higher average of rare risk variants (RRVs) compared to DMD-Controls (adjusted p value = 0.0285). Gene ontology analysis revealed an enrichment of extracellular matrix-related genes, especially collagens, and Ehlers-Danlos syndrome genes in ASD-DMD and DMD-ID groups. These findings support an oligogenic model for ASD in dystrophinopathies, highlighting the importance of investigating homogenized samples to elucidate ASD's genetic architecture.

It is frequently assumed that the phenotypic heterogeneity in autism spectrum disorder reflects underlying pathobiological variation. However, direct evidence in support of this hypothesis is lacking. Here, we leverage cross-species functional neuroimaging to examine whether variability in brain functional connectivity reflects distinct biological mechanisms. We find that fMRI connectivity alterations in 20 distinct mouse models of autism (n=549 individual mice) can be clustered into two prominent hypo- and hyperconnectivity subtypes. We show that these connectivity profiles are linked to distinct signaling pathways, with hypoconnectivity being associated with synaptic dysfunction, and hyperconnectivity reflecting transcriptional and immune-related alterations. Extending these findings to humans, we identify analogous hypo- and hyperconnectivity subtypes in a large, multicenter resting state fMRI dataset of n=940 autistic and n=1036 neurotypical individuals. Remarkably, hypo- and hyperconnectivity autism subtypes are replicable across independent cohorts (accounting for 25.1% of all autism data), exhibit distinct functional network architecture, are behaviorally dissociable, and recapitulate synaptic and immune mechanisms identified in corresponding mouse subtypes. Our cross-species investigation, thus, decodes the heterogeneity of fMRI connectivity in autism into distinct pathway-specific etiologies, offering a new empirical framework for targeted subtyping of autism.

A germline alteration in the PTEN gene causes a spectrum of disorders conceptualized as PTEN hamartoma tumor syndrome (PHTS), which show high risk of tumor development and a highly variable and complex phenotype. The diagnosis of PHTS is established in a proband by identification of a heterozygous germline PTEN pathogenic variant on molecular genetic testing. In this study, to understand more PTEN-associated clinical phenotype and PHTS in a Japanese population, we extracted 128 germline PTEN rare variants from 113,535 adult Japanese registered in Biobank Japan (BBJ), and categorized 29 pathogenic/likely pathogenic variants in 30 individuals (0.0264%) with ClinVar classifications and ACMG/AMP guideline for PTEN. We examined case-control association in 75,238 patients with various types of cancer and 38,297 non-cancer controls, and identified that PTEN pathogenic variants (PVs) were significantly associated with endometrial cancer (OR = 35.7, P = 9.73E-04) and marginally associated with female breast cancer (OR = 19.5, P = 3.92E-03), especially at young onset and with multiple cancers. We observed that among the 127 disease phenotypes the PTEN PV carriers had uterine fibroid, goiter, ovarian cyst, and epilepsy, which is consistent with PTEN-related phenotypes. We also found that weight/height were significantly higher in adult female carriers with PTEN PV (P = 3.1E-04 and P = 0.0014, respectively), which is consistent with overgrowth syndrome of PHTS. Our results indicate the phenotypical features associated with PTEN PVs in a Japanese population, especially female, and can contribute to the screening for PTEN variants and its associated several phenotypes.

Contactin-5 (CNTN5), a neural adhesion molecule involved in synaptogenesis and synaptic maturation in the auditory pathway, has been associated with the pathophysiology of autism spectrum disorder (ASD), particularly hyperacusis. To investigate the role of rare CNTN5 variants in ASD susceptibility, we performed resequencing and association analysis in a Japanese population.

We resequenced the CNTN5 coding regions in 302 patients with ASD and prioritized rare putatively damaging variants. The prioritized variants were then genotyped in 313 patients with ASD and 1065 controls. Subsequently, we conducted an association study of selected variants with ASD in 614 patients with ASD and 61 057 controls. Clinical data were reviewed for patients carrying prioritized variants.

Through resequencing, we prioritized three rare putatively damaging missense variants (W69G, I227L, and L1000S) in patients with ASD. Although we found a nominally significant association between the I227L variant and ASD, it did not remain significant after post hoc correction. Hyperacusis was found in three out of nine patients carrying prioritized variants.

This study does not provide evidence for the contribution of rare CNTN5 variants to the genetic etiology of ASD in the Japanese population.

Decades of genetic association testing in human cohorts have provided important insights into the genetic architecture and biological underpinnings of complex traits and diseases. However, for certain traits, genome-wide association studies (GWAS) for common SNPs are approaching signal saturation, which underscores the need to explore other types of genetic variation to understand the genetic basis of traits and diseases. Copy number variation (CNV) is an important source of heritability that is well known to functionally affect human traits. Recent technological and computational advances enable the large-scale, genome-wide evaluation of CNVs, with implications for downstream applications such as polygenic risk scoring and drug target identification. Here, we review the current state of CNV-GWAS, discuss current limitations in resource infrastructure that need to be overcome to enable the wider uptake of CNV-GWAS results, highlight emerging opportunities and suggest guidelines and standards for future GWAS for genetic variation beyond SNPs at scale.

Autism spectrum disorder (ASD) is a genetically and phenotypically heterogeneous neurodevelopmental disorder with a strong genetic basis. Conducting the first comprehensive whole-genome sequencing (WGS) analysis of Japanese ASD trios, this study aimed to elucidate the clinical significance of pathogenic variants and enhance the understanding of ASD pathogenesis.

WGS was performed on 57 Japanese patients with ASD and their parents, investigating variants ranging from single-nucleotide variants to structural variants (SVs), short tandem repeats (STRs), mitochondrial variants, and polygenic risk score (PRS).

Potentially pathogenic variants that could explain observed phenotypes were identified in 18 patients (31.6%) overall and in 10 of 23 patients (43.5%) with comorbid intellectual developmental disorder (IDD). De novo variants in PTEN, CHD7, and HNRNPH2 were identified in patients referred for genetic counseling who exhibited previously reported phenotypes, including one patient with ASD who had profound IDD and macrocephaly with PTEN L320S. Analysis of the AlphaFold3 protein structure indicated potential inhibition of intramolecular interactions within PTEN. SV analysis identified deletions in ARHGAP11B and TMLHE. A pathogenic de novo mitochondrial variant was identified in a patient with ASD who had a history of encephalitis and cognitive decline. GO enrichment analysis of genes with nonsense variants and missense variants (Missense badness, PolyPhen-2, and Constraint >1) showed associations with regulation of growth and ATP-dependent chromatin remodeler activity. No reportable results were obtained in the analysis of STR and PRS.

Characterizing the comprehensive genetic architecture and phenotypes of ASD is a fundamental step towards unraveling its complex biology.

Autistic individuals with disproportionate megalencephaly (ASD-DM), characterized by enlarged brains relative to body height, have higher rates of intellectual disability and face more severe cognitive challenges than autistic children with average brain sizes. The cellular and molecular mechanisms underlying this neurophenotype remain poorly understood. To investigate these mechanisms, we generated human induced pluripotent stem cells from non-autistic typically developing children and autistic children with and without disproportionate megalencephaly. We assessed these children longitudinally from ages two to twelve years using magnetic resonance imaging and comprehensive cognitive and medical evaluations. We show that neural progenitor cells (NPCs) derived from ASD-DM children exhibit increased rates of cell survival and suppressed cell death, accompanied by heightened oxidative stress and ferrous iron accumulation. Despite these stressors, ASD-DM NPCs actively suppress apoptosis and ferroptosis by regulating proteins such as caspase-3 (CASP3), poly(ADP-ribose) polymerase 1 (PARP1), and glutathione peroxidase 4 (GPX4). Cellular ferroptotic signatures are further supported by elevated expression of selenocysteine genes, including GPX4 , in the blood of ASD-DM children and their mothers, suggesting potential hereditary or environmental influences. Furthermore, we show that peripheral expression of GPX4 and other selenocysteine genes correlate with cognitive outcomes (IQ). These findings underscore the role of ferroptosis in autism, pointing to potential diagnostic biomarkers and targets for intervention.

The ANK2 gene, encoding ankyrin-B, is a high-confidence risk factor for neurodevelopmental disorders (NDDs). Evidence from exome sequencing studies have repeatedly implicated rare variants in ANK2 in autism spectrum disorder. Recently, the functions of ankyrin-B isoforms on neuronal phenotypes have been investigated using a number of techniques including electrophysiology, proteomic screens and behavioral analysis using animal models with loss of distinct Ank2 isoforms or with targeted loss of Ank2 in different cell types and time points during brain development. ANK2 variants and their pathophysiology could provide valuable insights into the molecular mechanisms underlying NDDs. In this review, we focus on recently reported studies to help understand the pathological mechanisms of ANK2 loss and how it may facilitate the development of treatments for NDDs in the future.

Mitochondrial DNA (mtDNA) rearrangements are recognised factors in mitochondrial disorders and ageing, but their involvement in neurodevelopmental disorders, particularly intellectual disability (ID) and autism spectrum disorder (ASD), remains poorly understood. Previous studies have reported mitochondrial dysfunction in individuals with both ID and ASD. The aim of this study was to investigate the prevalence of large-scale mtDNA rearrangements in ID and ID with comorbid ASD (ID-ASD).

We used mtDNA-targeted next-generation sequencing and the MitoSAlt high-throughput computational pipeline in peripheral blood samples from 76 patients with ID (mean age 52.5 years, 37% female), 59 patients with ID-ASD (mean age 41.3 years, 46% female) and 32 healthy controls (mean age 42.4 years, 47% female) from Catalonia.

The study revealed a high frequency of mtDNA rearrangements in patients with ID, with 10/76 (13.2%) affected individuals. However, the prevalence was significantly lower in patients with ID-ASD 1/59 (1.7%) and in HC 1/32 (3.1%). Among the mtDNA rearrangements, six were identified as deletions (median size 6937 bp and median heteroplasmy level 2.3%) and six as duplications (median size 10 455 bp and median heteroplasmy level 1.9%). One of the duplications, MT-ATP6 m.8765-8793dup (29 bp), was present in four individuals with ID with a median heteroplasmy level of 3.9%.

Our results show that mtDNA rearrangements are frequent in patients with ID, but not in those with ID-ASD, when compared to HC. Additionally, MitoSAlt has demonstrated high sensitivity and accuracy in detecting mtDNA rearrangements, even at very low heteroplasmy levels in blood samples. While the high frequency of mtDNA rearrangements in ID is noteworthy, the role of these rearrangements is currently unclear and needs to be confirmed with further data, particularly in post-mitotic tissues and through age-matched control studies.

This review delves into the genetic landscape of Autism Spectrum Disorder (ASD) in the genomic era, with a special focus on insights from East Asian populations. We analyze a spectrum of genetic research, including whole-exome and whole-genome sequencing, to elucidate both the challenges and advancements in comprehending the genetic foundations of ASD. Critical findings from this review highlight the identification of de novo variants, particularly noting the significant role of rare variants that differ from the common variants identified in earlier research. The review emphasizes the importance of large, diverse, and meticulously maintained ASD cohorts, which are essential for advancing genetic studies and developing potential therapeutic interventions. Through collaborative international efforts, we argue for a global perspective necessary to grasp the intricate genetic factors underlying ASD.

Genetic causes of neurodevelopmental disorders (NDDs) such as epilepsy and autism spectrum disorder are rapidly being uncovered. The genetic risk factors that are responsible for various NDDs fall into many categories, and while some genes such as those involved in synaptic transmission are expected, there are several other classes of genes whose involvement in these disorders is not intuitive. One such group of genes is involved in protein synthesis and degradation, and the balance between these opposing pathways is termed proteostasis. Here, we review these pathways, the genetics of the related neurological disorders, and some potential disease mechanisms. Improved understanding of this collection of genetic disorders will be informative for the pathogenesis of these disorders and imply novel therapeutic strategies.

Among autistic individuals, a subphenotype of disproportionate megalencephaly (ASD-DM) seen at three years of age is associated with co-occurring intellectual disability and poorer prognoses later in life. However, many of the genes contributing to ASD-DM have yet to be delineated. In this study, we identified additional ASD-DM candidate genes with the aim to better define the genetic etiology of this subphenotype of autism. We expanded the previously studied sample size of ASD-DM individuals ten fold by including probands from the Autism Phenome Project and Simons Simplex Collection, totaling 766 autistic individuals meeting the criteria for megalencephaly or macrocephaly and revealing 154 candidate ASD-DM genes harboring de novo protein-impacting variants. Our findings include 14 high confidence autism genes and seven genes previously associated with DM. Five impacted genes have previously been associated with both autism and DM, including CHD8 and PTEN. By performing functional network analysis, we expanded to additional candidate genes, including one previously implicated in ASD-DM (PIK3CA) as well as 184 additional genes connected with ASD or DM alone. Using zebrafish, we modeled a de novo tandem duplication impacting YTHDF2, encoding an N6-methyladenosine (m6A)-mRNA reader, in an ASD-DM proband. Testing zebrafish CRISPR knockdown led to reduced head/brain size, while overexpressing YTHDF2 resulted in increased head/brain size matching that of the proband. Single-cell transcriptomes of YTHDF2 gain-of-function larvae point to reduced expression of Fragile-X-syndrome-associated FMRP-target genes globally and in the developing brain, providing insight into the mechanism underlying autistic phenotypes. We additionally discovered a variant impacting a different gene encoding an m6A reader, YTHDC1, in our ASD-DM cohort. Though we highlight only two cases to date, our study provides support for the m6A-RNA modification pathway as potentially contributing to this severe form of autism.

Small-molecule BRAF inhibitors (e.g., vemurafenib and dabrafenib) and MEK (MAPK/ERK) kinases inhibitors (e.g., trametinib) have distinctly improved the survival of patients suffering from BRAF-mutant cancers such as melanomas. However, the emergence of resistance to BRAF and MEK inhibitor-based melanoma therapy, as well as the reduced sensitivity of other BRAF-mutant cancers such as CRC, poses a considerable clinical problem. For instance, the reactivation of MAPK/ERK signaling hampering cell death induction mechanisms was responsible for BRAF inhibitor resistance, which can be correlated with distinct post-translational and epigenetic processes. Histone deacetylases (HDACs) are prominent epigenetic drug targets and some HDAC inhibitors have already been clinically approved for the therapy of various blood cancers. In addition, several HDACs were identified, which also play a crucial role in the drug resistance of BRAF-mutant cancers. Consequently, inhibition of HDACs was described as a promising approach to overcome resistance. This review summarizes the influence of HDACs (Zn2+-dependent HDACs and NAD+-dependent sirtuins) on BRAF-mutant cancers and BRAF inhibitor resistance based on upregulated survival mechanisms and the prevention of tumor cell death. Moreover, it outlines reasonable HDAC-based strategies to circumvent BRAF-associated resistance mechanisms based on downregulated cell death mechanisms.

The diversity of genes implicated in autism spectrum disorder (ASD) creates challenges for identifying core pathophysiological mechanisms. Aggregation of seven different classes of genetic variants implicated in ASD, in a database we call Consensus-ASD, reveals shared features across distinct types of ASD variants. Functional interrogation of 19 ASD genes and 9 neighboring long non-coding RNAs (lncRNAs) using CRISPR-Cas13 strikingly revealed differential gene expression profiles that were significantly enriched for other ASD genes. Furthermore, construction of a gene regulatory network (GRN) enabled the identification of central regulators that exhibit convergently altered activity upon ASD gene disruption. Thus, this study reveals how perturbing distinct ASD-associated genes can lead to shared, broad dysregulation of GRNs with critical relevance to ASD. This provides a crucial framework for understanding how diverse genes, including lncRNAs, can play convergent roles in key neurodevelopmental processes and ultimately contribute to ASD.