Long-read genome sequencing improves detection and functional interpretation of structural and repeat variants in autism

Cell Genomics · 2026-03-09 · 2 citations

Long-read whole-genome sequencing (LR-WGS) technologies enhance the discovery of structural variants (SVs) and tandem repeats (TRs). We performed LR-WGS on 267 individuals from 63 autism spectrum disorder (ASD) families and generated an integrated call set combining long- and short-read data. LR-WGS increased detection of gene-disrupting SVs and TRs by 33% and 38%, respectively, and enabled identification of novel exonic de novo germline and somatic SVs. We observed complex SV patterns, including a class of nested duplication-deletion events. By joint analysis of phased genetic variation and DNA methylation, we identified deletions of imprinted genes and demonstrated the effect of intermediate TR expansions (35-54 CGG) on the methylation of FMR1 promoter. Rare SVs, TRs, and damaging SNVs together accounted for 7.4% (95% confidence interval [CI], 2.7%-17%) of the heritability of ASD. These findings demonstrate how LR-WGS can resolve complex genetic variation and its functional consequences and regulatory effects in a single assay.

295. Reidentification of Anti-PAGE5 Autoantibodies in Early-Onset Psychosis

Biological Psychiatry · 2026-04-25

Comparative Evaluation of Wearable Sensor Form Factors for Physiological Monitoring in Youth with Autism Spectrum Disorder

medRxiv · 2026-05-07

Abstract Sudden behavioral outbursts in youth with autism spectrum disorder (ASD) are difficult to predict and create substantial caregiving burdens. Wearable physiological monitoring might enable prediction, but sustained use may be limited by tolerability. We evaluated adherence and data completeness in 40 youth with ASD over a two-week period across four device types (wristband, headband, adhesive chest patch, and finger ring) alongside caregiver-reported useability and comfort. Data completeness varied markedly by device, with the patch achieving the highest completeness (∼80%), followed by the wristband (∼60%), headband (∼50%), and ring (∼20%). In multivariate analyses, adherence was driven by the device form factor rather than participant-level clinical characteristics. Devices rated as more comfortable did not yield higher completeness, revealing a divergence between reported preference and actual use. These findings suggest that device choice is a key consideration for studies in ASD youths, highlighting the need for research into model stability across sensor types in neurodivergent populations.

Long-Read Genome Sequencing in Clinical Psychiatry: <i>RFX3</i> Haploinsufficiency in a Hospitalized Adolescent With Autism, Intellectual Disability, and Behavioral Decompensation

American Journal of Psychiatry · 2025-04-09 · 3 citations

Neurobehavioral Signatures in Overgrowth Intellectual Disability Syndromes: Dissecting Genotype-Phenotype Relationships in the PI3K-AKT-MTOR Pathway

medRxiv · 2025-08-24 · 1 citations

Overgrowth intellectual disability syndromes (OGIDs) caused by mutations in the PI3K-AKT-MTOR pathway present significant neurobehavioral challenges. While PTEN Hamartoma Tumor Syndrome (PHTS) has been behaviorally characterized, Smith-Kingsmore Syndrome (SKS) has not, limiting our understanding of shared and unique features across OGIDs. We conducted comprehensive neurobehavioral assessments in 17 individuals with SKS and compared them to previously characterized cohorts with PHTS (n=74), macrocephaly-associated autism (n=33), and healthy controls (n=32). Assessments included standardized measures of motor coordination, adaptive functioning, social interaction, and executive functioning. We performed genotype-phenotype correlation analyses and developed diagnostic classification models using recursive partitioning. Individuals with SKS showed significant impairments across multiple domains compared to controls. Compared to the PTEN-ASD group, SKS individuals demonstrated particularly severe deficits in motor coordination and adaptive functioning, while executive functioning and behavioral regulation were similarly impaired. Novel clinical features were identified, including immune dysregulation and chronic constipation in SKS, and notably high rates of neonatal teeth (44.7%) in PHTS. Diagnostic classification models incorporating both behavioral and medical features achieved above-chance accuracy in distinguishing between conditions, with neonatal teeth emerging as a key distinguishing feature for PHTS. Domain-specific analyses showed variants in the PTEN phosphatase domain were associated with more severe social and executive function deficits compared to C2 domain variants. Correlation analyses between variant pathogenicity scores and clinical measures revealed limited consistent associations, though Combined Annotation Dependent Depletion (CADD) scores showed stable correlations with sensory processing measures across cohorts. Our findings establish distinct neurobehavioral profiles between SKS and PHTS, suggesting different impacts of MTOR versus PTEN mutations on neural circuit development. The identification of novel phenotypic features expands the clinical spectrum of these disorders and provides new diagnostic markers. The limited predictive value of variant pathogenicity scores for neurobehavioral outcomes emphasizes the need for comprehensive individual assessments. These results provide a foundation for developing targeted interventions while highlighting the complexity of genotype-phenotype relationships in PI3K-AKT-MTOR pathway disorders.

Clinical determinants of psychiatric care in genetic neurodevelopmental disorders: a cross-sectional analysis

Journal of Neurodevelopmental Disorders · 2025-10-07

This study aims to identify clinical and developmental factors associated with psychotropic medication exposure and subspecialty psychiatric service utilization among patients with genetic neurodevelopmental disorders (GNDDs). We conducted a retrospective analysis of 316 patients from the Care and Research in Neurogenetics (CARING) Clinic at the University of California, Los Angeles (UCLA). We assessed the association between neurodevelopmental and psychiatric diagnoses, behavioral histories, family history, and service utilization with two outcomes: (1) the number of psychotropic medication classes trialed before clinic intake and (2) whether the patient was evaluated by a CARING psychiatrist. Poisson and logistic regression models were used to evaluate associations while adjusting for demographic and clinical covariates. Individuals with more severe behavioral disturbances had higher psychiatric service needs, while intellectual disability was associated with greater psychotropic medication exposure but not increased psychiatric consultation, possibly due to prior community-based care. The presence of a pathogenic/likely pathogenic genetic variant was not associated with either outcome, suggesting that genetic diagnosis alone does not predict psychiatric needs. Instead, behavioral comorbidities, not genetic status, were the primary drivers of psychotropic use and psychiatric referrals. A history of developmental delay was negatively associated with psychiatric consultation, and mediation analyses indicated that early intervention services partly explained this relationship. Additionally, patients receiving behavioral therapies had higher psychotropic exposure, reflecting greater clinical complexity and frequent use of multimodal treatment strategies. Our findings suggest that psychiatric needs in GNDDs are more closely tied to behavioral comorbidities than to genetic diagnosis status, reinforcing the importance of symptom-driven psychiatric evaluation. The observed relationship between early developmental interventions and psychiatric service utilization warrants further longitudinal investigation. These results highlight opportunities to optimize psychiatric care pathways through early screening, integrated behavioral and pharmacologic interventions, and targeted resource allocation for individuals with neurodevelopmental disorders.

Long-Read Genome Sequencing Improves Detection and Functional Interpretation of Structural and Repeat Variants in Autism

medRxiv · 2025-07-23 · 3 citations

Long–read whole genome sequencing (LR–WGS) technologies enhance the discovery of structural variants (SVs) and tandem repeats (TRs). We performed LR–WGS on 267 individuals from 63 ASD families and generated an integrated call set combining long– and short–read data. LR–WGS increased detection of gene–disrupting SVs and TRs by 33% and 38%, respectively, and enabled identification of novel exonic de novo germline and somatic SVs. We observed complex SV patterns, including a class of nested duplication–deletion events. By joint analysis of phased genetic variation and DNA methylation, we identified deletions of imprinted genes, and demonstrated the effect of intermediate TR expansions (35–54 CGG) on the methylation of FMR1 promoter. Rare SVs, TRs, and damaging SNVs together accounted for 7.4% (95% CI: 2.7–17%) of the heritability of ASD. These findings demonstrate how LR–WGS can resolve complex genetic variation and its functional consequences and regulatory effects in a single assay.

24.3 Genome Sequencing in Early-Onset Psychosis: Impact on Clinical Utility and Parental Empowerment

Journal of the American Academy of Child & Adolescent Psychiatry · 2025-10-01

Common and rare variant genetic contributions in African Americans with autism

medRxiv · 2025-11-19 · 2 citations

Abstract The absence of non-European cohorts in genetic studies of neurodevelopmental and neuropsychiatric disorders severely limits the understanding of their full genetic architecture and undermines implementation of precision medicine. Here, we directly addressed this issue by recruiting African Americans (AfrAms) with autism spectrum disorder (ASD) and analyzing their rare and common genetic variation. We performed both global and local ancestry analyses to characterize the complex patterns of admixture at the individual level and compare genetic factors between European (EUR) and African (AFR) genetically inferred ancestries (GIAs) across multiple cohorts in a total of 38,483 autistic individuals. We showed consistent common variant genetic effect sizes for ASD in EUR and AFR GIAs through genome-wide association studies. We demonstrated the limited transferability of EUR-derived polygenic scores (PGSs) based on polygenic transmission disequilibrium and ancestry partial PGS analysis. We found significant autism association for high-impact rare copy number variants in both GIAs. We identified a set of candidate ASD loci based on rare deletions observed in AFR GIA carriers, including SMC2 , DMTN , SORCS1 , and ROGDI , and detected a signal for de novo missense variants of predicted low impact in AFR GIA individuals. Finally, we uncovered significant depletion of AFR GIA autistic carriers of rare variants in known associated genes found in EUR cohort studies. These findings are the first to detail common and rare variant genetic contributions to ASD in AfrAms and demonstrate that their involvement in neurodevelopmental and neuropsychiatric disorders’ genomic research is essential to advance discovery.

Clinical Genetic Testing in Schizophrenia: A Systematic Review and Meta-Analysis

Biological Psychiatry · 2025-09-30

BACKGROUND: Genetic testing may provide important diagnostic information for individuals with schizophrenia, but the frequency with which clinically significant variants are identified across different testing approaches has not been systematically evaluated. METHODS: statistic. RESULTS: = 95.9%). Geographic representation was limited, with no studies from Latin America, South Asia, or Africa. CONCLUSIONS: Genetic testing identifies clinically informative variants in approximately 6% of individuals with schizophrenia. However, substantial heterogeneity across studies and limited geographic representation underscore the need for more standardized testing approaches and broader population sampling in future genetic research on schizophrenia.