Environmental and treatment-related factors associated with developmental outcomes in genetic epilepsies.

Early clinical prediction of neurodevelopmental outcome in KCNQ2-related disorders

These prediction models demonstrate the feasibility of early prognostication in KCNQ2-RD and support future prospective external validation and enable more accurate individualised counselling by integrating clinical and genetic information readily available at time of genetic diagnosis.

Familial Co-Aggregation of Neurodevelopmental Conditions and Childhood-Onset Type 1 Diabetes.

AIM Childhood-onset Type 1 diabetes (T1D) is associated with neurodevelopmental conditions (NDCs). We examined whether this association extends to relatives and assessed phenotypic, genetic, and environmental correlations between T1D and NDCs. METHODS Using Swedish registers, we identified 4 066 634 individuals born 1973-2015 and linked them to siblings and cousins; 23 212 (0.57%) had T1D before 18 years. Logistic regression estimated odds of receiving a diagnosis of any and each of the examined NDCs among individuals with T1D and their relatives. Bivariate quantitative genetic models estimated phenotypic, additive genetic, shared environmental, and non-shared environmental correlations. Analyses were conducted in April 2025. RESULTS NDCs were more prevalent among individuals with T1D than in those without (10.3% vs. 6.4%). T1D was associated with higher odds of receiving a diagnosis of any NDCs (OR 1.43; 95% CI 1.37-1.49). Full siblings also had higher odds (OR 1.12; 95% CI 1.06-1.18), whereas no significant associations were observed among other relatives. Cross-trait phenotypic correlations were small (0.06-0.08). CONCLUSION Individuals with childhood-onset T1D and their full siblings had higher odds of recorded NDC diagnoses. Shared familial factors appeared to contribute only modestly, while differential ascertainment and family-level consequences of T1D may also play a role. These findings support access to neurodevelopmental expertise in paediatric diabetes services.

Caregiver-reported quality of life among individuals with neurodevelopmental genetic conditions.

AIM To investigate correlates of quality of life (QoL) in individuals with neurodevelopmental genetic conditions (NGCs), such as PTEN hamartoma tumor syndrome (PHTS), SYNGAP1-related conditions, and Malan syndrome, and their families. METHOD Caregivers of 201 individuals with NGCs (50.2% male; 43.3% with PHTS) filled out a battery of online questionnaires. Two five-step hierarchical regressions were used to identify key correlates of both caregiver-reported family QoL (FQoL) and health-related QoL (HRQoL). RESULTS In the final step of the regression model predicting FQoL, greater social communication and interaction, higher speech level, fewer challenging behaviors, and greater executive functioning skills were related to higher FQoL. With regard to HRQoL, male sex, decreased mood dysregulation, and fewer sleep problems (more specifically, less restless sleep and difficulty waking) were related to greater HRQoL. INTERPRETATION These findings highlight the complex interplay of factors affecting distinct aspects of QoL, underscoring the need for interventions that go beyond focusing on features of autism by incorporating a focus on broader clinical, developmental, and cognitive profiles.

Evaluating the performance of polygenic indices of neuropsychiatric conditions and brain endophenotypes in four UK population samples

Paternal Valproate Exposure and Offspring Neurodevelopmental Outcomes.

BACKGROUND AND OBJECTIVES Evidence remains inconclusive on whether paternal valproate exposure during spermatogenesis is associated with adverse offspring outcomes, with findings lacking beyond Nordic countries. This study aimed to assess the risks of neurodevelopmental disorders (NDDs) and congenital malformations in offspring attributable to paternal exposure to valproate and other antiseizure medications (ASMs) during sperm development. METHODS This nationwide birth cohort study used data from the Taiwan National Health Insurance Research Database, including individuals born 2001-2016 who were followed up through 2021. Paternal exposure to valproate or other ASMs was defined during the time of spermatogenesis (3 months before conception). Exposure discordant sibling sets were identified for sibling-comparison analysis to control for shared genetic and lifestyle factors. NDDs-including autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), intellectual disability (ID), and tic disorder-and congenital malformations were defined by outpatient and inpatient medical record(s). Relative risks were estimated through Cox proportional hazards models for NDDs (hazard ratios [HRs]) and logistic regression for congenital malformations (odds ratios [ORs]). RESULTS In the population cohort of 2,583,503 individuals, 1,701 were exposed to paternal use of valproate and 548 exposure-discordant sibling sets were available for sibling-comparison analysis. In population-based analyses, paternal valproate exposure was not associated with the risk of NDDs (HRs = 0.86 [95% CI 0.61-1.22] for ASD, 1.02 [0.88-1.18] for ADHD, 0.80 [0.53-1.20] for tic disorders, and 0.81 [0.55-1.19] for ID) or congenital malformations (OR = 1.07 [0.83-1.37]) in offspring. These null effects persisted when restricting analyses to children of fathers with epilepsy to control for confounding by indication, and when the sibling-comparison analysis was conducted. For other ASMs, a few associations appeared at nominal significance, but none remained in sibling-comparison analyses. DISCUSSION In this large population-based study in Asia, we found no increased risk of NDDs in offspring following paternal exposure to valproate or other ASMs. These findings may contribute to ongoing debates about the management of valproate in men of reproductive age, although additional evidence is needed before drawing conclusions about changes to current practice.

An Initial Genetic Correlation Analysis of Externalizing Behavior and Neuroimaging Phenotypes in the ABCD Cohort

Adolescent externalizing behavior is a major risk factor for later substance use and other psychiatric outcomes. Understanding its genetic architecture and its relationship with brain imaging phenotypes requires scalable genome-wide methods applied to youth cohorts. Using data from the Adolescent Brain Cognitive Development (ABCD) Study, we implemented a pipeline for genome-wide association studies (GWAS) of longitudinally measured externalizing traits and multimodal neuroimaging-derived phenotypes (IDPs). We performed quality-controlled genotype processing and constructed harmonized phenotype and covariate datasets. GWAS analyses were conducted using REGENIE in a two-step framework, with Step 1 ridge regression models trained on LD-pruned variants and Step 2 association testing performed genome-wide. Externalizing traits measured at baseline and summarized as longitudinal means and slopes, together with approximately 200 IDPs measured at baseline and summarized as longitudinal means and slopes, were analyzed. We further constructed a custom linkage disequilibrium (LD) reference panel using unrelated individuals and computed LD scores using LDSC. Genetic correlations between externalizing traits and imaging phenotypes were estimated using LD Score Regression. This exploratory study systematically evaluated genome-wide genetic correlations between regional cortical morphology and externalizing phenotypes in adolescence. Although several associations reached nominal significance, none remained significant after correction for multiple comparisons. These findings should not be interpreted as demonstrating an absence of shared genetic architecture. Rather, the precision of the estimates was constrained by the available imaging GWAS sample size, uncertainty in SNP-heritability estimates, and the large number of regional comparisons. Larger imaging-genetics samples and independent replication will be required to determine whether modest or regionally specific genetic correlations exist.