Alexander Kolevzon

ADNP‐related Helsmoortel–Van der Aa syndrome (ADNP‐related HVDAS) is a single gene form of autism spectrum disorder (ASD) caused by pathogenic sequence variants in the activity‐dependent neuroprotective protein ( ADNP ) gene. In addition to ASD, ADNP‐related HVDAS is associated with a wide range of cognitive, behavioral, and physical health features that may lead to profound impairment in functioning and significantly impact quality of life for affected individuals, their families, and caregivers. However, because it remains rare, most clinicians are not familiar with the syndrome and lack knowledge to guide assessment and monitoring. The goals of this study are to (1) provide an updated systematic review of the clinical manifestations of ADNP‐related HVDAS, (2) establish recommendations for assessment and monitoring that can be used by caregivers when advocating for their children, and (3) be applied practically by clinicians caring for affected individuals. A literature review was conducted by searching PubMed, PsycInfo, and Embase databases using “ADNP”, “ADNP Syndrome,” and “Helsmoortel–Van der Aa Syndrome” through July 18, 2026. Articles were included if they reported on clinical manifestations of ADNP‐related HVDAS and were excluded if they did not describe at least one individual with the diagnosis. A total of 28 publications met inclusion criteria including case reports, case series, and small cohort studies; data were extracted for 209 cases and organized by clinical domain. A formal risk of bias assessment was not performed, and results were limited by the rarity of ADNP‐related HVDAS and thus small sample sizes, as well as variability in symptom reporting. Our updated review highlights the complex symptomatology of ADNP‐related HVDAS and the importance of early diagnosis, comprehensive evaluations, and individualized treatment planning.

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.

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.

Purpose: Racial differences in prevalence rates of autism spectrum disorder (ASD) have shifted in the United States (US) since the 1990s. This review addresses the nature and context of this shift and discusses potential contributing factors and areas for future research. Methods: Seventeen population-based epidemiological birth cohort studies on ASD prevalence in the US that included race as a variable are included in the review. Studies were identified via a keyword search on PubMed. To be included, studies were required to include race or ethnicity as a variable in the prevalence estimates, include at least 1000 cases with autism, and be published in English by June 3rd, 2023. Results: Results suggest that in nearly all birth cohorts prior to 2010, ASD prevalence rates were highest among White children. ASD prevalence rates among Black, Hispanic, and Asian/Pacific Islander (API) children (22.3, 22.5, and 22.2 per 1000, respectively) surpassed prevalence rates among White children (21.2 per 1000) in the 2010 birth cohort and continued to increase in the 2012 birth cohorts. Conclusions: There are persistent racial differences in ASD prevalence in the US, and these differences were inverted after 2010, when ASD prevalence among Black, Hispanic, & API children surpassed ASD prevalence among White children. Possible drivers of this racial repatterning of ASD prevalence include changes in ASD screening and diagnosis, changes to health insurance policy, changes to immigration policy, and increased education attainment by minority groups.

Background: Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder caused by SHANK3 haploinsufficiency with clinical manifestations that can be devastating and profoundly affect quality of life. Results: The Externally Led Patient-Focused Drug Development (EL-PFDD) meeting was an opportunity for families affected by PMS to share with the Food and Drug Administration (FDA) how symptoms impact their lives and how treatments could be most meaningful. The Voice of the Patient report serves as a summary of this meeting to influence upcoming drug development and clinical trials. The purpose of this report is to provide a clinical perspective on the results of the EL-PFDD meeting to amplify the voice of these caregivers to the scientific community. Conclusions: Caregivers prioritize an improved quality of life for their loved ones characterized by improved cognitive function, improved communication, increased independence, and reduced risk of regression. With these caregiver priorities in mind, this report provides the FDA and the scientific community with a clear understanding of which aspects of PMS should influence the development of future therapeutics.

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.