Rare deleterious variants in SHANK3 are established causes of autism spectrum disorder (ASD), but the extent to which they define a phenotypically and genetically coherent ASD subgroup remains unclear. Using the SPARK cohort, we identified 132 SHANK3 variant carriers; 108 had phenotype data and were compared with 47,555 non-carrier ASD cases. SHANK3 damaging variant carriers showed lower cognitive ability, poorer motor coordination, and delayed developmental milestones. Protein-truncating variant and deletion carriers showed similarly severe phenotypic profiles, whereas duplication carriers did not differ from non-carriers. A combined threshold of intelligence quotient (IQ) < 70 and impaired motor coordination (DCDQ total score) < 35 defined a discriminative cognitive-motor phenotype among cases meeting this cognitive-motor phenotype. Beyond SHANK3 , SLC6A1 was the only additional gene reaching false discovery rate significance, while pathway analyses implicated synaptic and chromatin-related processes. Phenotype-meeting cases did not show elevated ASD polygenic risk, supporting a rare-variant-enriched cognitive-motor subgroup within ASD.

Transient beta events (TBE) during electroencephalography (EEG) reflect thalamocortical activity, bridging genotype to phenotype and impacting sensory responsivity. Compared to typically developing controls, we found elevated TBE rate in some children with idiopathic Autism Spectrum Disorder (ASD) and a majority of children with Phelan-McDermid Syndrome, Rett Syndrome, and SYNGAP1-related disorder. TBE rate thus offers promise as a stratification biomarker with divergent and convergent properties across ASD and neurogenetic conditions, respectively.

OBJECTIVES:To examine changes in the male to female ratio in diagnoses of autism spectrum disorder (ASD) over a 35 year period, providing temporal trends in diagnosis (incidence rate), the male to female ratio, and the age-cohort specific cumulative male to female ratio (cMFR). DESIGN:Population based, prospectively collected birth cohort study. PARTICIPANTS:2 756 779 liveborn children recorded in the Swedish medical birth register between 1985 and 2020. SETTING:Sweden. MAIN OUTCOME MEASURE:Age-period cohort analysis investigating associations between ASD and age at diagnosis, calendar period, birth cohort, and sex, quantified by incidence rate ratios and associated two sided 95% confidence intervals. RESULTS:Among 2 756 779 individuals born in Sweden between 1985 and 2020, ASD was diagnosed in 78 522 (2.8%) by the end of follow-up (2022). The incidence rate for ASD increased with each five year age interval throughout childhood, peaking at 645.5 (per 100 000 person years) for the male cohort at age 10-14 years and 602.6 for the female cohort at age 15-19 years in 2020-2022, and then decreased. Age specific incidence of ASD increased for each calendar period and birth cohort between 1985 and 2020. The male to female ratio decreased with increasing age at diagnosis and, for those older than 10 years, by calendar period. For the final year of follow-up in 2022, the cumulative male to female ratio for incidence of ASD was 1.2 by age 20 years. Further projection of these trends suggested that the cumulative male to female ratio would reach parity at age 20 years by 2024. CONCLUSION:Findings indicate that the male to female ratio for ASD has decreased over time and with increasing age at diagnosis. This male to female ratio may therefore be substantially lower than previously thought, to the extent that, in Sweden, it may no longer be distinguishable by adulthood. This finding highlights a need to investigate why girls and women receive diagnoses of ASD later than boys and men.

Background:The 40Hz auditory steady-state response (ASSR) is a measure of gamma-band neural synchrony sensitive to excitation-inhibition (E/I) balance. Disruptions to E/I balance have been implicated in autism spectrum disorder (ASD), making ASSR an efficient tool for investigating neural synchrony development in this population. Whether age-related differences in 40Hz ASSR are detectable across development in ASD remains understudied. Phelan-McDermid syndrome (PMS), a rare genetic disorder with a phenotype overlapping with autism, caused by SHANK3 disruption, provides a genetically defined model for further investigating E/I-related neural synchrony disruptions. Methods:We examined 40Hz inter-trial phase coherence (ITPC) as an index of neural synchrony across a wide age range (2-37 years) in 127 participants from four groups: TD (n=43), ASD without intellectual disability (w/o ID; n=37), ASD with intellectual disability (w/ID; n=24), and PMS (n=23). Given the distinct age and cognitive profiles of ASD subgroups in this sample, analyses were conducted in separate models: TD vs. ASD w/o ID across all ages, and TD vs. ASD w/ID vs. PMS restricted to participants under 18. Results:For the first time in a cross-sectional sample spanning a large age range, we show that 40Hz ITPC increases significantly with age in TD individuals, while this developmental trajectory is absent in ASD without intellectual disability. Among children and adolescents under 18, 40Hz ITPC did not differ across TD, ASD w/ID, and PMS, and IQ did not predict ITPC in clinical groups. A post-hoc analysis revealed higher ITPC in TD males than females, with no sex differences in ASD or PMS. Conclusions:We demonstrate that gamma-band ITPC trajectories diverge between TD and ASD, specifically in adulthood, with no such difference detectable in childhood. No significant group differences were found among TD, ASD w/ID, and PMS individuals under 18. These findings highlight the importance of age as a critical variable when measuring ASSR, and underscore the need for lifespan studies, particularly in genetically defined conditions such as PMS, to determine whether similar divergence emerges in adulthood.

Estimating the prevalence of genetic disorders is complicated by many factors including sampling bias and differing methods of estimation. However, establishing the true prevalence of these disorders is critical for understanding disease burden, pharmacoeconomic modeling, and resource allocation for testing and care. Phelan-McDermid syndrome (PMS) is a genetic neurodevelopmental disorder with an unknown true prevalence and previous estimates vary from 2.5-10 per million births. The study team reached out to a multitude of sources, including clinical genetic testing laboratories, research centers, and clinical centers. Sites provided the number of PMS diagnoses made out of the total number participants with autism tested at their site. Further extrapolations were made to adjust for the proportion of individuals with PMS who do not have autism, autism diagnosis age limitations, and type of genetic variant. Lastly, Centers for Disease Control estimates of autism rates were used to extrapolate to the general population. Ten sources participated and data from 179,837 autism cases were evaluated. The frequency of PMS diagnoses ranged from 1% to ~2.5%. However, the studies had different levels of sensitivity depending on the assay(s) used, and therefore raw results should not be directly compared. After applying extrapolations, including adjustments for assay sensitivity and other factors, the final weighted average was 13.7 per 100,000 (95% CI 10.02-18.60 per 100,000), indicating 1 in ~7300 individuals in the general population have PMS. We leveraged a diverse set of genetic data from multiple sources to generate a population-level estimate of the prevalence of PMS. Our findings indicate that PMS affects approximately 13.7 per 100,000 individuals, substantially higher than previous estimates.

BackgroundAutism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition influenced by both genetic and environmental factors. Prenatal and perinatal exposures have been implicated in ASD etiology, but their influence may vary across clinical subgroups, including subgroups defined by co-occurring intellectual disability (ID).MethodsWe conducted a population-based case-control study in southern Sweden including all children diagnosed with ASD before the age of 9, and whose mothers were born in Sweden. Diagnoses were confirmed through detailed medical record review, and information on ASD severity, ID status, and familial ASD were collected for subgroup analyses. A total of 996 ASD cases and 9,960 age- and sex-matched controls were identified from a regional perinatal database. Multivariable logistic regression estimated adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for maternal, obstetric, and neonatal factors.ResultsHigher maternal body mass index (BMI) in early pregnancy was associated with increased likelihood of ASD (adjusted odds ratio [aOR] 1.41-1.76 for overweight and obesity compared with normal weight), with broadly similar associations observed across ASD subgroups defined by severity, intellectual disability, and familial ASD. Maternal smoking in early pregnancy (aOR 1.49, 95% CI 1.22-1.82) and both elective (aOR 1.22, 95% CI 1.01-1.48) and emergency cesarean delivery (aOR 1.40, 95% CI 1.15-1.81) were also associated with higher odds of ASD, with generally stronger associations in children without intellectual disability and in those with less severe ASD. Subgroup-specific associations were observed for maternal epilepsy and gestational diabetes, while prematurity showed weaker associations than anticipated and was mainly observed in severe ASD and non-familial cases. Low Apgar scores at 5 minutes showed no consistent association with ASD.ConclusionsMultiple maternal and perinatal factors were associated with ASD in this large Swedish cohort. Stratified analyses by ASD severity, ID status, and familial ASD revealed both shared and subgroup-specific association patterns, underscoring the value of considering ASD heterogeneity in studies of neurodevelopmental variation.

Abstract Background ADNP syndrome is a rare genetic disorder associated with global developmental delay/intellectual disability, autism, aberrant behavior, and medical comorbidities. Sensory symptoms represent a core clinical feature, even in those without autism spectrum disorder (ASD). Differences in visual evoked potentials (VEPs), an objective measure of excitatory and inhibitory postsynaptic activity, have been reported in other genetic neurodevelopmental disorders and have yet to be examined in ADNP syndrome. Methods Transient VEPs (tVEP) were collected from 12 children with ADNP syndrome, 46 autistic children without a known genetic cause, and 19 typically developing children. Time- and frequency-domain variables were compared between groups. Results Significant differences were found between the ADNP and TD groups in amplitude (P60-N75, N75-P100), latency (P60, N75), and magnitude-squared coherence (MSC). Significant differences were also found between the ADNP and ASD group in latency (P60, N75) and MSC (Band 2, 14–28 Hz). Conclusions VEP abnormalities in children with ADNP syndrome compared to an ASD group and controls were identified. Weaker amplitudes in the ADNP group are consistent with prior research in other genetic neurodevelopmental syndromes. Longer latencies and diminished 14–28 Hz band activity, however, are distinct findings and represent an important area of continued study to explore the presence of syndrome-specific VEP profiles. Establishing VEP biomarkers for ADNP syndrome is a critical direction for future clinical trials in the syndrome.

The past decade has seen remarkable progress in identifying genes that, when impacted by deleterious coding variation, confer high likelihood for autism spectrum disorder (ASD), intellectual disability and other associated developmental disorders. However, most underlying gene discovery efforts have focused on individuals of European ancestry, limiting insights into genetic liability across diverse populations. To help address this, the Genomics of Autism in Latin American Ancestries (GALA) Consortium was formed, presenting here the largest sequencing study of autism in Latin American individuals (n > 15,000, including 4,717 participants with an ASD diagnosis). We identified 35 genome-wide significant (false discovery rate < 0.05) autism-associated genes, with substantial overlap with findings from European cohorts, and highly constrained genes showing consistent signal across populations. The results provide support for emerging (for example, MARK2, YWHAG, PACS1, RERE, SPEN, GSE1, GLS, TNPO3 and ANKRD17) and established autism genes and for the utility of genetic testing approaches for deleterious variants in individuals from diverse backgrounds; the results also demonstrate the ongoing need for more inclusive genetic research and testing. We conclude that the biology of autism is consistent across populations, with no detectable influence of ancestry.

Abstract Background Phelan McDermid syndrome (PMS), caused by SHANK3 haploinsufficiency, is a genetic form of autism spectrum disorder (ASD) that provides a genetically defined model for studying ASD-related circuit dysfunction. SHANK3 mutations disrupt synaptic organization and cortical synchrony, leading to attenuated gamma-band auditory steady-state responses (ASSRs). We investigated whether PMS-related electrophysiological signatures could be identified using machine learning and whether similar patterns are present in a subset of individuals with idiopathic ASD (iASD). Methods EEG recorded during a 40-Hz ASSR paradigm was collected from 123 participants (42 TD aged 2-30, 56 iASD aged 3-31, 25 PMS aged 2-26). We extracted time-series, ERSP, FOOOF-derived spectral, and intertrial phase coherence (ITPC) features. XGBoost models with leave-one-out cross-validation classified PMS versus TD; the best age/sex-adjusted ITPC model was then applied to iASD participants to derive a Synchrony Atypicality Index (SAI). Unsupervised clustering of high-dimensional ITPC features was also performed. Results ITPC-based models showed the strongest discrimination between TD and PMS participants (AUROC = 0.83). When applied to iASD participants, 35.7% exhibited elevated SAI, indicating a PMS-like gamma-band phase-locking profile. Classification of iASD versus PMS performed poorly in the full sample but improved markedly after excluding high-SAI iASD individuals, consistent with substantial heterogeneity within iASD. Unsupervised clustering of ITPC features identified PMS-enriched clusters that also captured high-SAI iASD participants. Results were consistent after controlling for age in sensitivity analyses. Conclusions Reduced 40-Hz ITPC is a mechanistically interpretable electrophysiological signature of PMS and identifies a biologically meaningful PMS-like subgroup within iASD, supporting biomarker-guided stratification.

Background:Preterm children are at an increased risk of autism spectrum disorder (ASD), although the determinants of ASD among them remain unclear. In this systematic review and meta-analysis, we summarize the population-based literature on ASD risk factors in preterm-born individuals. Methods:We searched Ovid MEDLINE, Embase, and Web of Science through September 2023 for population-based studies on ASD risk factors in preterm cohorts (<37 weeks' gestation). From 3921 articles, 19 met inclusion criteria. Registered in PROSPERO and following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, data were extracted and analyzed using fixed and random effects meta-analysis models. Primary outcomes included ASD risk factors, pooled when consistently examined in at least 2 studies. Results:The qualitative synthesis included 16 cohort studies, 2 case-control studies, and 1 cross-sectional study, while 3 cohort studies were included in the meta-analysis. Sample sizes ranged from 410 to 515,789. Male sex was the only risk factor eligible for meta-analysis and was associated with increased risk of ASD (relative risk 3.04; 95% CI, 2.02-4.57). Low birth weight suggested a potential positive association with ASD, while neonatal jaundice showed no clear link. Pooled estimates were unavailable for these exposures due to heterogeneity in exposure definitions and effect measures. All other risk factors were examined in two or fewer studies. Conclusions:Significant knowledge gaps remain regarding the risk of ASD in individuals born preterm. The only consistent risk factor identified is male sex, with potential links to low birth weight. To better understand the differences in ASD etiology between preterm and term-born individuals, further research is crucial.

The Developmental Synaptopathies Consortium is a multisite natural history network studying rare, neurogenetic syndromes associated with synaptic dysfunction and developmental delays. One aim of the Consortium is clinical trial readiness, including identifying clinical concepts and validating their measurement. We evaluated the scope and limitations of conventional cognitive and behavioral measurement strategies in 2-21-year-olds with Phelan-McDermid syndrome (PMS; N = 98), Tuberous Sclerosis Complex (TSC; N = 98), and PTEN Hamartoma Tumor syndrome (PHTS; N = 69). On average, intellectual disability (ID) severity was severe-to-profound in PMS, mild-to-moderate for TSC, and borderline (or absent) in PHTS. Severity of ID invalidated the use of many assessments, including standardized autism diagnostic measures. These results will inform trial planning for these and other similarly medically complex neurodevelopmental conditions.

The clinical spectrum of Phelan-McDermid syndrome (PMS) is varied, with wide-ranging degrees of intellectual disability, developmental delays, behavioral abnormalities, and medical features. Different types of genetic variation lead to PMS, and differing genotypes (e.g., size of deletion or type of variant) account for some of this variability, with strong associations between genotype and phenotype observed with degree of intellectual disability and presence of specific medical features such as renal abnormalities. To date, no studies have assessed how genotype is associated with the natural history of developmental or behavioral features in PMS over time. Here, we report on longitudinal data in developmental and behavioral domains from 154 individuals with PMS, comparing those with Class 1 (minimal) deletions, Class 2 deletions, and sequence variants, assessing both within-subject (individual change over time) and between-subject (across age) differences. Consistent with previous results, average scores per group differed in most adaptive and developmental domains, with individuals with Class 1 deletions performing best, followed by individuals with Class 2 deletions and sequence variants, who often performed similarly. However, in most domains of adaptive behavior, intellectual functioning, and behavioral features, genetic groups did not differ in their rate of change over time or in differences in scores across ages. Exceptions, notably in expressive language, existed. These results suggest that, although genotype may be related to overall degree of impairment, individuals with PMS, regardless of genotype, tend to have a similar rate of change over time and age in developmental and behavioral domains. A significant caveat is that sequencing is a relatively recent diagnostic approach, which will bias the results.

Phelan-McDermid syndrome (PMS) is a genetic condition caused by deletions of chromosome 22q13.3 or pathogenic variants in the SHANK3 gene. Neurologic features typically include intellectual disability, autism spectrum disorder, hypotonia, and absent speech, though there is considerable variability even among individuals with the same molecular cause. This prospective study aimed to explore the utility of genome sequencing to identify additional molecular diagnoses that may contribute to variability in a cohort of patients with PMS. Twenty probands diagnosed with PMS (60% with a 22q13 deletion, 40% with a SHANK3 variant) underwent trio or duo genome sequencing and chromosomal microarray. This analysis identified a second molecular finding associated with a neurological condition in 3/20 participants. Molecular diagnoses related to neurological phenotypes included: (1) spinal muscular atrophy, lower extremity-predominant, 2A, autosomal dominant (SMALED2A), (2) spastic paraplegia 7, and (3) 16p11.2 deletion syndrome. Five additional new molecular diagnoses were associated with a clinically actionable secondary or incidental finding. This exploratory study provides early evidence for the potential utility of expanded sequencing among individuals with PMS, even for those without phenotypic features outside of the expected range.

Elevated maternal pre-pregnancy body mass index (BMI) has been suggested to increase risk of offspring autism spectrum disorder (ASD) but evidence is mixed across heterogeneous studies and robust estimates spanning the full BMI range are lacking. This study examined the association between maternal BMI and offspring ASD in a harmonized, two-nation study and across the full BMI range. We included all singleton children born in Denmark 2004–2018 and Sweden 1998–2019 to parents of Nordic origin (n = 2,072,445), with follow-up from age 2 until 31 December 2021, or 2022, respectively. Maternal BMI recorded at the first antenatal visit was obtained from the Swedish and Danish Medical Birth Registers and was analyzed as a continuous variable and in World Health Organization-defined categories of underweight (BMI < 18.5), normal weight (18.5–24.9), overweight (25–29.9), obese class I (30–34.9), and obese class II–III (≥ 35). The relative risk of ASD was estimated as hazard ratios (HR) from Cox regression models, adjusted for birth year and parental age, educational level, income, and psychiatric history at time of childbirth, using data from national health and population registers. Both country-specific and pooled analyses were conducted. Subgroup and sensitivity analyses, including a sibling comparison, were performed to address the specificity and robustness of findings. A total of 58,416 (2.8

Phelan-McDermid syndrome (PMS) is a genetic condition associated with profound neurodevelopmental disabilities. This study described patterns of onset and loss of developmental milestones and associated skills using questionnaire data from the PMS International Registry (N = 374) and clinician-led assessment data from the Developmental Synaptopathies Consortium natural history study (N = 207). Across studies, an overwhelming proportion of people with PMS were reported to have delays in acquiring basic skills, and regression or loss of skills was commonly reported across multiple developmental domains, including some after the age of 10. The current descriptive study synthesizes two complementary data sources showing loss occurring in the context of significant delays and frequent lack of milestone attainment in people with PMS. Further work to elucidate mechanisms is needed.