Clinical, genetic, and cognitive correlates of seizure occurrences in Phelan-McDermid syndrome.

BACKGROUND: Phelan-McDermid syndrome (PMS) is a genetic neurodevelopmental disorder caused by SHANK3 haploinsufficiency and is associated with an increased risk for seizures. Previous literature indicates that around one third of individuals with PMS also have epilepsy or seizures, with a wide range of types and ages of onset. Investigating the impact of seizures on intellectual and adaptive functioning for PMS is a primary concern for caregivers and is important to understanding the natural history of this syndrome. METHODS: We report on results from 98 individuals enrolled in a prospective, longitudinal study. We detailed seizure frequency, type, and age of onset, and we analyzed seizure occurrence with best estimate IQ, adaptive functioning, clinical features, and genotype. We conducted multiple linear regression analyses to assess the relationship between the presence of seizures and the Vineland Adaptive Behavior Scale, Second Edition (VABS-II) Adaptive Behavior Composite score and the best estimate full-scale IQ. We also performed Chi-square tests to explore associations between seizure prevalence and genetic groupings. Finally, we performed Chi-square tests and t-tests to explore the relationship between seizures and demographic features, features that manifest in infancy, and medical features. RESULTS: Seizures were present in 41% of the cohort, and age of onset was widely variable. The presence of seizures was associated with significantly lower adaptive and intellectual functioning. Genotype-phenotype analyses were discrepant, with no differences in seizure prevalence across genetic classes, but with more genes included in deletions of participants with 22q13 deletions and seizures compared to those with 22q13 deletions and no seizures. No clinical associations were found between the presence of seizures and sex, history of pre- or neonatal complications, early infancy, or medical features. In this cohort, generalized seizures were associated with developmental regression, which is a top concern for PMS caregivers. CONCLUSIONS: These results begin to eludicate correlates of seizures in individuals with PMS and highlight the importance of early seizure management. Importantly, presence of seizures was associated with adaptive and cognitive functioning. A larger cohort might be able to identify additional associations with medical features. Genetic findings suggest an increased capability to realize genotype-phenotype relationships when deletion size is taken into account.

Genome-wide association study identifies 30 obsessive-compulsive disorder associated loci.

Obsessive-compulsive disorder (OCD) affects ~1% of the population and exhibits a high SNP-heritability, yet previous genome-wide association studies (GWAS) have provided limited information on the genetic etiology and underlying biological mechanisms of the disorder. We conducted a GWAS meta-analysis combining 53,660 OCD cases and 2,044,417 controls from 28 European-ancestry cohorts revealing 30 independent genome-wide significant SNPs and a SNP-based heritability of 6.7%. Separate GWAS for clinical, biobank, comorbid, and self-report sub-groups found no evidence of sample ascertainment impacting our results. Functional and positional QTL gene-based approaches identified 249 significant candidate risk genes for OCD, of which 25 were identified as putatively causal, highlighting WDR6, DALRD3, CTNND1 and genes in the MHC region. Tissue and single-cell enrichment analyses highlighted hippocampal and cortical excitatory neurons, along with D1- and D2-type dopamine receptor-containing medium spiny neurons, as playing a role in OCD risk. OCD displayed significant genetic correlations with 65 out of 112 examined phenotypes. Notably, it showed positive genetic correlations with all included psychiatric phenotypes, in particular anxiety, depression, anorexia nervosa, and Tourette syndrome, and negative correlations with a subset of the included autoimmune disorders, educational attainment, and body mass index.. This study marks a significant step toward unraveling its genetic landscape and advances understanding of OCD genetics, providing a foundation for future interventions to address this debilitating disorder.

Identification of moderate effect size genes in autism spectrum disorder through a novel gene pairing approach.

Autism Spectrum Disorder (ASD) arises from complex genetic and environmental factors, with inherited genetic variation playing a substantial role. This study introduces a novel approach to uncover moderate effect size (MES) genes in ASD, which individually do not meet the ASD liability threshold but collectively contribute when paired with specific other MES genes. Analyzing 10,795 families from the SPARK dataset, we identified 97 MES genes forming 50 significant gene pairs, demonstrating a substantial association with ASD when considered in tandem, but not individually. Our method leverages familial inheritance patterns and statistical analyses, refined by comparisons against control cohorts, to elucidate these gene pairs' contribution to ASD liability. Furthermore, expression profile analyses of these genes in brain tissues underscore their relevance to ASD pathology. This study underscores the complexity of ASD's genetic landscape, suggesting that gene combinations, beyond high impact single-gene mutations, significantly contribute to the disorder's etiology and heterogeneity. Our findings pave the way for new avenues in understanding ASD's genetic underpinnings and developing targeted therapeutic strategies.

Transient peripheral blood transcriptomic response to ketamine treatment in children with ADNP syndrome.

Activity-dependent neuroprotective protein (ADNP) syndrome is a rare neurodevelopmental disorder resulting in intellectual disability, developmental delay and autism spectrum disorder (ASD) and is due to mutations in the ADNP gene. Ketamine treatment has emerged as a promising therapeutic option for ADNP syndrome, showing safety and apparent behavioral improvements in a first open label study. However, the molecular perturbations induced by ketamine remain poorly understood. Here, we investigated the longitudinal effect of ketamine on the blood transcriptome of 10 individuals with ADNP syndrome. Transcriptomic profiling was performed before and at multiple time points after a single low-dose intravenous ketamine infusion (0.5mg/kg). We show that ketamine triggers immediate and profound gene expression alterations, with specific enrichment of monocyte-related expression patterns. These acute alterations encompass diverse signaling pathways and co-expression networks, implicating up-regulation of immune and inflammatory-related processes and down-regulation of RNA processing mechanisms and metabolism. Notably, these changes exhibit a transient nature, returning to baseline levels 24 hours to 1 week after treatment. These findings enhance our understanding of ketamine's molecular effects and lay the groundwork for further research elucidating its specific cellular and molecular targets. Moreover, they contribute to the development of therapeutic strategies for ADNP syndrome and potentially, ASD more broadly.

An evolutionary perspective on complex neuropsychiatric disease.

The forces of evolution-mutation, selection, migration, and genetic drift-shape the genetic architecture of human traits, including the genetic architecture of complex neuropsychiatric illnesses. Studying these illnesses in populations that are diverse in genetic ancestry, historical demography, and cultural history can reveal how evolutionary forces have guided adaptation over time and place. A fundamental truth of shared human biology is that an allele responsible for a disease in anyone, anywhere, reveals a gene critical to the normal biology underlying that condition in everyone, everywhere. Understanding the genetic causes of neuropsychiatric disease in the widest possible range of human populations thus yields the greatest possible range of insight into genes critical to human brain development. In this perspective, we explore some of the relationships between genes, adaptation, and history that can be illuminated by an evolutionary perspective on studies of complex neuropsychiatric disease in diverse populations.

Latin American Trans-ancestry INitiative for OCD genomics (LATINO): Study protocol.

Obsessive-compulsive disorder (OCD) is a debilitating psychiatric disorder. Worldwide, its prevalence is ~2% and its etiology is mostly unknown. Identifying biological factors contributing to OCD will elucidate underlying mechanisms and might contribute to improved treatment outcomes. Genomic studies of OCD are beginning to reveal long-sought risk loci, but >95% of the cases currently in analysis are of homogenous European ancestry. If not addressed, this Eurocentric bias will result in OCD genomic findings being more accurate for individuals of European ancestry than other ancestries, thereby contributing to health disparities in potential future applications of genomics. In this study protocol paper, we describe the Latin American Trans-ancestry INitiative for OCD genomics (LATINO, https://www.latinostudy.org). LATINO is a new network of investigators from across Latin America, the United States, and Canada who have begun to collect DNA and clinical data from 5000 richly phenotyped OCD cases of Latin American ancestry in a culturally sensitive and ethical manner. In this project, we will utilize trans-ancestry genomic analyses to accelerate the identification of OCD risk loci, fine-map putative causal variants, and improve the performance of polygenic risk scores in diverse populations. We will also capitalize on rich clinical data to examine the genetics of treatment response, biologically plausible OCD subtypes, and symptom dimensions. Additionally, LATINO will help elucidate the diversity of the clinical presentations of OCD across cultures through various trainings developed and offered in collaboration with Latin American investigators. We believe this study will advance the important goal of global mental health discovery and equity.

Acetate supplementation rescues social deficits and alters transcriptional regulation in prefrontal cortex of Shank3 deficient mice.

BACKGROUND: The pathophysiology of autism spectrum disorder (ASD) involves genetic and environmental factors. Mounting evidence demonstrates a role for the gut microbiome in ASD, with signaling via short-chain fatty acids (SCFA) as one mechanism. Here, we utilize mice carrying deletion to exons 4-22 of Shank3 (Shank3KO) to model gene by microbiome interactions in ASD. We identify SCFA acetate as a mediator of gut-brain interactions and show acetate supplementation reverses social deficits concomitant with alterations to medial prefrontal cortex (mPFC) transcriptional regulation independent of microbiome status. METHODS: Shank3KO and wild-type (Wt) littermates were divided into control, Antibiotic (Abx), Acetate and Abx + Acetate groups upon weaning. After six weeks, animals underwent behavioral testing. Molecular analysis including 16S and metagenomic sequencing, metabolomic and transcriptional profiling were conducted. Additionally, targeted serum metabolomic data from Phelan McDermid Syndrome (PMS) patients (who are heterozygous for the Shank3 gene) were leveraged to assess levels of SCFA's relative to ASD clinical measures. RESULTS: Shank3KO mice were found to display social deficits, dysregulated gut microbiome and decreased cecal levels of acetate - effects exacerbated by Abx treatment. RNA-sequencing of mPFC showed unique gene expression signature induced by microbiome depletion in the Shank3KO mice. Oral treatment with acetate reverses social deficits and results in marked changes in gene expression enriched for synaptic signaling, pathways among others, even in Abx treated mice. Clinical data showed sex specific correlations between levels of acetate and hyperactivity scores. CONCLUSION: These results suggest a key role for the gut microbiome and the neuroactive metabolite acetate in regulating ASD-like behaviors.

Updated consensus guidelines on the management of Phelan-McDermid syndrome.

Phelan-McDermid syndrome (PMS) is a genetic condition caused by SHANK3 haploinsufficiency and characterized by a wide range of neurodevelopmental and systemic manifestations. The first practice parameters for assessment and monitoring in individuals with PMS were published in 2014; recently, knowledge about PMS has grown significantly based on data from longitudinal phenotyping studies and large-scale genotype-phenotype investigations. The objective of these updated clinical management guidelines was to: (1) reflect the latest in knowledge in PMS and (2) provide guidance for clinicians, researchers, and the general community. A taskforce was established with clinical experts in PMS and representatives from the parent community. Experts joined subgroups based on their areas of specialty, including genetics, neurology, neurodevelopment, gastroenterology, primary care, physiatry, nephrology, endocrinology, cardiology, gynecology, and dentistry. Taskforce members convened regularly between 2021 and 2022 and produced specialty-specific guidelines based on iterative feedback and discussion. Taskforce leaders then established consensus within their respective specialty group and harmonized the guidelines. The knowledge gained over the past decade allows for improved guidelines to assess and monitor individuals with PMS. Since there is limited evidence specific to PMS, intervention mostly follows general guidelines for treating individuals with developmental disorders. Significant evidence has been amassed to guide the management of comorbid neuropsychiatric conditions in PMS, albeit mainly from caregiver report and the experience of clinical experts. These updated consensus guidelines on the management of PMS represent an advance for the field and will improve care in the community. Several areas for future research are also highlighted and will contribute to subsequent updates with more refined and specific recommendations as new knowledge accumulates.

Missense variants in RPH3A cause defects in excitatory synaptic function and are associated with a clinically variable neurodevelopmental disorder.

PURPOSE: RPH3A encodes a protein involved in the stabilization of GluN2A subunit of N-methyl-D-aspartate (NMDA)-type glutamate receptors at the cell surface, forming a complex essential for synaptic plasticity and cognition. We investigated the effect of variants in RPH3A in patients with neurodevelopmental disorders. METHODS: By using trio-based exome sequencing, GeneMatcher, and screening of 100,000 Genomes Project data, we identified 6 heterozygous variants in RPH3A. In silico and in vitro models, including rat hippocampal neuronal cultures, have been used to characterize the effect of the variants. RESULTS: Four cases had a neurodevelopmental disorder with untreatable epileptic seizures [p.(Gln73His)dn; p.(Arg209Lys); p.(Thr450Ser)dn; p.(Gln508His)], and 2 cases [p.(Arg235Ser); p.(Asn618Ser)dn] showed high-functioning autism spectrum disorder. Using neuronal cultures, we demonstrated that p.(Thr450Ser) and p.(Asn618Ser) reduce the synaptic localization of GluN2A; p.(Thr450Ser) also increased the surface levels of GluN2A. Electrophysiological recordings showed increased GluN2A-dependent NMDA ionotropic glutamate receptor currents for both variants and alteration of postsynaptic calcium levels. Finally, expression of the Rph3AThr450Ser variant in neurons affected dendritic spine morphology. CONCLUSION: Overall, we provide evidence that missense gain-of-function variants in RPH3A increase GluN2A-containing NMDA ionotropic glutamate receptors at extrasynaptic sites, altering synaptic function and leading to a clinically variable neurodevelopmental presentation ranging from untreatable epilepsy to autism spectrum disorder.

Prospective phenotyping of CHAMP1 disorder indicates that coding mutations may not act through haploinsufficiency.

CHAMP1 disorder is a genetic neurodevelopmental condition caused by mutations in the CHAMP1 gene that result in premature termination codons. The disorder is associated with intellectual disability, medical comorbidities, and dysmorphic features. Deletions of the CHAMP1 gene, as part of 13q34 deletion syndrome, have been briefly described with the suggestion of a milder clinical phenotype. To date, no studies have directly assessed differences between individuals with mutations in CHAMP1 to those with deletions of the gene. We completed prospective clinical evaluations of 16 individuals with mutations and eight with deletions in CHAMP1. Analyses revealed significantly lower adaptive functioning across all domains assessed (i.e., communication, daily living skills, socialization, and motor skills) in the mutation group. Developmental milestones and medical features further showed difference between groups. The phenotypes associated with mutations, as compared to deletions, indicate likely difference in pathogenesis between groups, where deletions are acting through CHAMP1 haploinsufficiency and mutations are acting through dominant negative or gain of function mechanisms, leading to a more severe clinical phenotype. Understanding this pathogenesis is important to the future of novel therapies for CHAMP1 disorder and illustrates that mechanistic understanding of mutations must be carefully considered prior to treatment development.

Postsynaptic Protein Shank3a Deficiency Synergizes with Alzheimer's Disease Neuropathology to Impair Cognitive Performance in the 3xTg-AD Murine Model.

Synaptic loss is intrinsically linked to Alzheimer's disease (AD) neuropathology and symptoms, but its direct impact on clinical symptoms remains elusive. The postsynaptic protein Shank3 (SH3 and multiple ankyrin repeat domains) is of particular interest, as the loss of a single allele of the SHANK3 gene is sufficient to cause profound cognitive symptoms in children. We thus sought to determine whether a SHANK3 deficiency could contribute to the emergence or worsening of AD symptoms and neuropathology. We first found a 30%-50% postmortem loss of SHANK3a associated with cognitive decline in the parietal cortex of individuals with AD. To further probe the role of SHANK3 in AD, we crossed male and female 3xTg-AD mice modelling Aß and tau pathologies with Shank3a-deficient mice (Shank3Δex4-9). We observed synergistic deleterious effects of Shank3a deficiency and AD neuropathology on object recognition memory at 9, 12, and 18 months of age and on anxious behavior at 9 and 12 months of age in hemizygous Shank3Δex4-9-3xTg-AD mice. In addition to the expected 50% loss of Shank3a, levels of other synaptic proteins, such as PSD-95, drebrin, and homer1, remained unchanged in the parietotemporal cortex of hemizygous Shank3Δex4-9 animals. However, Shank3a deficiency increased the levels of soluble Aß42 and human tau at 18 months of age compared with 3xTg-AD mice with normal Shank3 expression. The results of this study in human brain samples and in transgenic mice are consistent with the hypothesis that Shank3 deficiency makes a key contribution to cognitive impairment in AD.SIGNIFICANCE STATEMENT Although the loss of several synaptic proteins has been described in Alzheimer's disease (AD), it remains unclear whether their reduction contributes to clinical symptoms. The results of this study in human samples show lower levels of SHANK3a in AD brain, correlating with cognitive decline. Data gathered in a novel transgenic mouse suggest that Shank3a deficiency synergizes with AD neuropathology to induce cognitive impairment, consistent with a causal role in AD. Therefore, treatment aiming at preserving Shank3 in the aging brain may be beneficial to prevent AD.

Direct additive genetics and maternal effect contribute to the risk of Tourette disorder.

BACKGROUND: Risk for Tourette disorder, and chronic motor or vocal tic disorders (referenced here inclusively as CTD), arise from a combination of genetic and environmental factors. While multiple studies have demonstrated the importance of direct additive genetic variation for CTD risk, little is known about the role of cross-generational transmission of genetic risk, such as maternal effect, which is not transmitted via the inherited parental genomes. Here, we partition sources of variation on CTD risk into direct additive genetic effect (narrow-sense heritability) and maternal effect. METHODS: The study population consists of 2 522 677 individuals from the Swedish Medical Birth Register, who were born in Sweden between 1 January 1973 and 31 December 2000, and followed for a diagnosis of CTD through 31 December, 2013. We used generalised linear mixed models to partition the liability of CTD into: direct additive genetic effect, genetic maternal effect and environmental maternal effect. RESULTS: We identified 6227 (0.2%) individuals in the birth cohort with a CTD diagnosis. A study of half-siblings showed that maternal half-siblings had twice higher risk of developing a CTD compared with paternal ones. We estimated 60.7% direct additive genetic effect (95% credible interval, 58.5% to 62.4%), 4.8% genetic maternal effect (95% credible interval, 4.4% to 5.1%) and 0.5% environmental maternal effect (95% credible interval, 0.2% to 7%). CONCLUSIONS: Our results demonstrate genetic maternal effect contributes to the risk of CTD. Failure to account for maternal effect results in an incomplete understanding of the genetic risk architecture of CTD, as the risk for CTD is impacted by maternal effect which is above and beyond the risk from transmitted genetic effect.

Maternal rheumatoid arthritis and risk of autism in the offspring.

BACKGROUND: Maternal Rheumatoid Arthritis (RA) is suggested to increase the risk of Autism Spectrum Disorder (ASD) in the offspring, mainly through inflammation/autoimmunity, but the association is unclear. A prospective population-based cohort study was implemented to examine the association between maternal RA and offspring ASD. METHODS: We included all children born alive in Sweden from 1995 to 2015, followed up through 2017. Diagnoses of ASD and RA were clinically ascertained from National Patient Register. We quantified the association by hazard ratios (HR) and two-sided 95% confidence intervals (CI), from Cox regression after detailed adjustment for potential confounders. We examined RA serostatus, etiological subgroups and the timing of exposure. To closer examine the underlying mechanism for the association, we included a negative control group for RA, arthralgia, with similar symptomology as RA but free from inflammation/autoimmunity. RESULTS: Of 3629 children born to mothers with RA, 70 (1.94%) were diagnosed with ASD, compared to 28 892 (1.92%) of 1 503 908 children born to mothers without RA. Maternal RA before delivery was associated with an increased risk of offspring ASD (HR = 1.43, 95% CI 1.11-1.84), especially for seronegative RA (HR = 1.61, 95% CI 1.12-2.30). No similar association was observed for paternal RA, maternal sisters with RA, or RA diagnosed after delivery. Maternal arthralgia displayed as high risks for offspring ASD as did maternal RA (HR = 1.41, 95% CI 1.24-1.60). CONCLUSIONS: In Sweden, maternal RA before delivery was associated with an increased risk of offspring ASD. The comparable association between maternal arthralgia and ASD risk suggests other pathways of risk than autoimmunity/inflammation, acting jointly or independently of RA.

Skewed X-chromosome inactivation in unsolved neurodevelopmental disease cases can guide re-evaluation For X-linked genes.

Despite major advances in genome technology and analysis, >50% of patients with a neurodevelopmental disorder (NDD) remain undiagnosed after extensive evaluation. A point in case is our clinically heterogeneous cohort of NDD patients that remained undiagnosed after FRAXA testing, chromosomal microarray analysis and trio exome sequencing (ES). In this study, we explored the frequency of non-random X chromosome inactivation (XCI) in the mothers of male patients and affected females, the rationale being that skewed XCI might be masking previously discarded genetic variants found on the X chromosome. A multiplex fluorescent PCR-based assay was used to analyse the pattern of XCI after digestion with HhaI methylation-sensitive restriction enzyme. In families with skewed XCI, we re-evaluated trio-based ES and identified pathogenic variants and a deletion on the X chromosome. Linkage analysis and RT-PCR were used to further study the inactive X chromosome allele, and Xdrop long-DNA technology was used to define chromosome deletion boundaries. We found skewed XCI (>90%) in 16/186 (8.6%) mothers of NDD males and in 12/90 (13.3%) NDD females, far beyond the expected rate of XCI in the normal population (3.6%, OR = 4.10; OR = 2.51). By re-analyzing ES and clinical data, we solved 7/28 cases (25%) with skewed XCI, identifying variants in KDM5C, PDZD4, PHF6, TAF1, OTUD5 and ZMYM3, and a deletion in ATRX. We conclude that XCI profiling is a simple assay that targets a subgroup of patients that can benefit from re-evaluation of X-linked variants, thus improving the diagnostic yield in NDD patients and identifying new X-linked disorders.

Schizophrenia risk conferred by rare protein-truncating variants is conserved across diverse human populations.

Schizophrenia (SCZ) is a chronic mental illness and among the most debilitating conditions encountered in medical practice. A recent landmark SCZ study of the protein-coding regions of the genome identified a causal role for ten genes and a concentration of rare variant signals in evolutionarily constrained genes1. This recent study-and most other large-scale human genetics studies-was mainly composed of individuals of European (EUR) ancestry, and the generalizability of the findings in non-EUR populations remains unclear. To address this gap, we designed a custom sequencing panel of 161 genes selected based on the current knowledge of SCZ genetics and sequenced a new cohort of 11,580 SCZ cases and 10,555 controls of diverse ancestries. Replicating earlier work, we found that cases carried a significantly higher burden of rare protein-truncating variants (PTVs) among evolutionarily constrained genes (odds ratio = 1.48; P = 5.4 × 10-6). In meta-analyses with existing datasets totaling up to 35,828 cases and 107,877 controls, this excess burden was largely consistent across five ancestral populations. Two genes (SRRM2 and AKAP11) were newly implicated as SCZ risk genes, and one gene (PCLO) was identified as shared by individuals with SCZ and those with autism. Overall, our results lend robust support to the rare allelic spectrum of the genetic architecture of SCZ being conserved across diverse human populations.

Genome-wide Association Study Points to Novel Locus for Gilles de la Tourette Syndrome.

BACKGROUND: Tourette syndrome (TS) is a childhood-onset neurodevelopmental disorder of complex genetic architecture and is characterized by multiple motor tics and at least one vocal tic persisting for more than 1 year. METHODS: We performed a genome-wide meta-analysis integrating a novel TS cohort with previously published data, resulting in a sample size of 6133 individuals with TS and 13,565 ancestry-matched control participants. RESULTS: We identified a genome-wide significant locus on chromosome 5q15. Integration of expression quantitative trait locus, Hi-C (high-throughput chromosome conformation capture), and genome-wide association study data implicated the NR2F1 gene and associated long noncoding RNAs within the 5q15 locus. Heritability partitioning identified statistically significant enrichment in brain tissue histone marks, while polygenic risk scoring of brain volume data identified statistically significant associations with right and left thalamus volumes and right putamen volume. CONCLUSIONS: Our work presents novel insights into the neurobiology of TS, thereby opening up new directions for future studies.

Comorbidities in autism spectrum disorder and their etiologies.

Individuals with autism spectrum disorder (ASD), in addition to the core features of the disease, experience a higher burden of co-occurring medical conditions. This study sought to describe the frequency and distribution of comorbidit conditions in individuals with ASD, and systematically evaluate the possibility that pre- and postnatal exposures (e.g., preterm birth, hypoxia at birth, traumatic brain injury, and fetal alcohol syndrome) associated with ASD may also be linked with distinct comorbidities. We used the SPARK study database, launched by the Simons Foundation Autism Research Initiative (SFARI). Comorbidities considered in the study included neurological, cognitive, psychiatric, and physical conditions. The study sample consisted of 42,569 individuals with ASD and their 11,389 non-ASD siblings (full and half siblings). Majority (74%) of individuals with ASD had at least one comorbidity, and had a greater average number of comorbidities than their non-ASD siblings. Preterm birth and hypoxia at birth were the most common peri-natal exposures in the sample. In logistic regression models adjusted for covariates, these exposures were associated with several distinct comorbidities in ASD cases, including attention and behavior problems, psychiatric and neurological disorders, and growth conditions. A similar pattern of association was also observed in non-ASD siblings. Our findings underscore that individuals with ASD experience a greater burden of comorbidities, which could be partly attributable to the higher rates of perinatal exposures compared to their non-ASD siblings. Study findings, if replicated in other samples, can inform the etiology of comorbidity in ASD.

Polygenic risk score-based phenome-wide association study identifies novel associations for Tourette syndrome.

Tourette Syndrome (TS) is a complex neurodevelopmental disorder characterized by vocal and motor tics lasting more than a year. It is highly polygenic in nature with both rare and common previously associated variants. Epidemiological studies have shown TS to be correlated with other phenotypes, but large-scale phenome wide analyses in biobank level data have not been performed to date. In this study, we used the summary statistics from the latest meta-analysis of TS to calculate the polygenic risk score (PRS) of individuals in the UK Biobank data and applied a Phenome Wide Association Study (PheWAS) approach to determine the association of disease risk with a wide range of phenotypes. A total of 57 traits were found to be significantly associated with TS polygenic risk, including multiple psychosocial factors and mental health conditions such as anxiety disorder and depression. Additional associations were observed with complex non-psychiatric disorders such as Type 2 diabetes, heart palpitations, and respiratory conditions. Cross-disorder comparisons of phenotypic associations with genetic risk for other childhood-onset disorders (e.g.: attention deficit hyperactivity disorder [ADHD], autism spectrum disorder [ASD], and obsessive-compulsive disorder [OCD]) indicated an overlap in associations between TS and these disorders. ADHD and ASD had a similar direction of effect with TS while OCD had an opposite direction of effect for all traits except mental health factors. Sex-specific PheWAS analysis identified differences in the associations with TS genetic risk between males and females. Type 2 diabetes and heart palpitations were significantly associated with TS risk in males but not in females, whereas diseases of the respiratory system were associated with TS risk in females but not in males. This analysis provides further evidence of shared genetic and phenotypic architecture of different complex disorders.

Somatic comorbidities of mental disorders in pregnancy.

BACKGROUND: Mental and physical health conditions are frequently comorbid. Despite the widespread physiological and behavioral changes during pregnancy, the pattern of comorbidities among women in pregnancy is not well studied. This study aimed to systematically examine the associations between mental and somatic disorders before and during pregnancy. METHOD: The study used data from mothers of a nationally representative birth cohort of children born in Israel (1997-2008). We compared the risk of all major somatic disorders (International Classification of Diseases, Ninth Revision) in pregnant women with and without a mental disorder. All analyses were adjusted for maternal age, child's birth year, family socioeconomic status, and the total number of maternal encounters with health services around pregnancy period. RESULTS: The analytical sample included 77,030 mother-child dyads, with 30,083 unique mothers. The mean age at child's birth was 29.8 years. Prevalence of diagnosis of mental disorder around pregnancy in our sample was 4.4%. Comorbidity between mental and somatic disorders was two times higher than the comorbidity between pairs of different somatic disorders. Of the 17 somatic disorder categories, seven were positively associated with mental health disorders. The highly prevalent comorbidities associated with mental disorders in pregnancy included e.g. musculoskeletal (OR = 1.30; 95% CI = 1.20-1.42) and digestive system diseases (OR = 1.23; 95% CI = 1.13-1.34). CONCLUSIONS: We observed that associations between maternal diagnoses and mental health stand out from the general pattern of comorbidity between nonmental health diseases. The study results confirm the need for screening for mental disorders during pregnancy and for potential comorbid conditions associated with mental disorders.

DDX3X Syndrome: Summary of Findings and Recommendations for Evaluation and Care.

DDX3X syndrome is a surprisingly common newly discovered genetic neurodevelopmental disorder associated with intellectual disability, autism spectrum disorder, language delays, attention-deficit/hyperactivity disorder, and medical comorbidities. Two hundred individuals with DDX3X syndrome have been described in the literature to date, with varied levels of detail. Individuals with DDX3X syndrome often have complex presentations including symptoms in the neurological, psychiatric/psychological, ophthalmologic, and gastrointestinal domains. Owing to this complex presentation, an overview of symptom prevalence, medical recommendations, and suggested medical surveillance is vital for the care and health of individuals with DDX3X syndrome. In this article, we summarize the present clinical knowledge of DDX3X syndrome and provide recommendations for clinical assessments and care based on a comprehensive review of the existing literature and of new, not yet published DDX3X syndrome cohorts. As more is learned about DDX3X syndrome, we anticipate that these recommendations will evolve.