Wen-Hann Tan

Purpose: This study examined longitudinal trajectories of adaptive functioning in 331 individuals with Angelman syndrome (AS) using the Vineland Adaptive Behavior Scales, Third Edition (Vineland-3) and examined differences by molecular subtype. Methods: A total of 331 individuals (156 females, 47%) with genetically confirmed AS (ages 6 months to 52 years) were assessed between 2018 and 2025, including 207 with a deletion subtype, 63 with uniparental disomy or imprinting defect, and 61 with a UBE3A point mutation. Growth scale values were analyzed using linear mixed-effects models with log ₂ -transformed age. Results: Individuals with deletion subtypes demonstrated significantly lower adaptive functioning across domains compared to those with non-deletion subtypes. Adaptive skills across all Vineland-3 subdomains increased nonlinearly with age, showing faster growth early in life that slowed over time, with largely parallel trajectories across subtypes. Conclusion: Individuals with AS demonstrate slow but steady growth in adaptive functioning that continues into adulthood, with progress varying by molecular subtype. These findings provide updated natural history benchmarks and demonstrate the utility of the Vineland-3 for clinical trials.

Background: Angelman syndrome (AS) is a developmental disorder caused by one of four molecular aetiologies. Affected individuals have intellectual disability (ID), limited speech, seizures and sleep problems. Parents of individuals with AS exhibit elevated stress compared to parents of individuals with other IDs. We examined parental stress and family quality of life (FQOL) over time in families of individuals living with AS.Methods: Data were collected in a natural history study of AS. The Parenting Stress Index, Third Edition (PSI) and the Beach Center FQOL Scale assessed parental stress and FQOL. Stress and FQOL were examined across AS molecular subtypes, and predictors were analysed using a generalised linear model. Relationships between parental stress and FQOL were examined using Pearson correlations and a stepwise mixed‐linear model approach.Results: Our sample consisted of 231 families of individuals living with AS. Parental stress was clinically elevated and was highest in families of individuals with UBE3A pathogenic variants, whereas FQOL did not differ across subtypes in most domains. Increasing age predicted a decrease in parental stress but did not predict FQOL. Elevated parental stress was additionally predicted by maladaptive behaviours and child male sex, whereas lower FQOL was predicted by child male sex, parent marital status and family income. Parental stress had a small negative impact on FQOL.Conclusions: Stress is elevated in parents of individuals with AS across subtypes and has a negative impact on FQOL. Interventions to reduce stress have the potential to improve individual and family well‐being.

Objectives To develop within-patient meaningful score differences (MSDs) on the Bayley Scales of Infant Development, Fourth Edition (Bayley-4), and the Vineland Adaptive Behavior Scales, Third Edition (Vineland-3), for individuals with Angelman syndrome (AS). Methods A Delphi method, involving a panel of 19 caregivers of individuals with AS, was used to establish MSDs for Bayley-4 and Vineland-3 Growth Scale Values. MSD was defined as the smallest change that would noticeably impact the daily functioning of an individual with AS or family quality of life in a way that was important to the individual with AS or their family. For each subscale of the Bayley-4 and Vineland-3, the panel was presented with 2 to 4 vignettes describing varying levels of baseline functioning and asked to select a MSD from a range of potential values. An iterative process involving three rounds of ratings and two rounds of discussion was used to build consensus. The median caregiver rating from round 3 was retained as the final recommended MSD value for each vignette. Results Final MSD ratings for the five subscales of Bayley-4 and 10 subscales of the Vineland-3 had an agreement rate of 70% or higher. MSD thresholds for each subscale were not single cut-offs, but rather reflected a range of MSD values dependent on level of baseline functioning. Conclusions The Delphi Panel method incorporates the caregiver perspective to provide preliminary estimates of what constitutes meaningful within person change on the Bayley-4 and Vineland-3 in individuals with AS with various levels of baseline functioning. Highlights ⍰ To acquire regulatory approval in drug development, sponsors must demonstrate both statistical significance and clinical meaningfulness of a treatment effect.While several clinical trials are underway in AS, within person meaningful score difference thresholds are not yet established for the most commonly used outcome measures, namely the Bayley and Vineland. ⍰ Aligning with FDA guidance, we have developed an innovative qualitative approach using a Delphi panel to incorporate caregiver perspectives in defining meaningful change and generated preliminary patient-informed meaningful score differences (MSDs) for individuals with Angelman Syndrome. ⍰ What caregivers of individuals with AS consider to be a MSD on the measures depends primarily on the baseline severity of their child’s presentation.

Background: Previous studies in mouse,Xenopusand zebrafish embryos show strongtfap2eexpression in progenitor cells of neuronal and neural crest tissues suggesting its involvement in neural crest specification. However, the role of human transcription factor activator protein 2 (TFAP2E)in human embryonic central nervous system (CNS), orofacial and maxillofacial development is unknown.Methods: Through a collaborative work, exome survey was performed in families with congenital CNS, orofacial and maxillofacial anomalies. Exome variant prioritisation promptedTFAP2Egene for functional analysis in zebrafish embryos. Embryonic morphology and development were assessed after antisense morpholino (MO) knockdown (KD), CRISPR/Cas9 knockout and overexpression oftfap2ein fluorescent zebrafish reporter lines using in vivo microscopy. Computational structural protein modelling of the identified human variants was performed.Results: In total, exome survey identified novel or ultra-rare heterozygous missense variants inTFAP2Ein seven individuals from five independent families with predominantly CNS, orofacial and maxillofacial anomalies. One variant was found de novo and another variant segregated in an affected multiplex family. Protein modelling of the identified variants indicated potential distortion of TFAP2E in the transactivation or dimerisation domain. MO KD and CRISPR/Cas9 knockout oftfap2ein zebrafish revealed hydrocephalus and a significant reduction of brain volume, consistent with a microencephaly phenotype. Furthermore, mRNA overexpression ofTFAP2Eindicates dosage-sensitive phenotype expression. In addition, zebrafish showed orofacial and maxillofacial anomalies followingtfap2eKD, recapitulating the human phenotype.Conclusion: Our human genetic data and analysis of Tfap2e manipulation in zebrafish indicate a potential role ofTFAP2Ein human CNS, orofacial and maxillofacial anomalies.

Angelman syndrome (AS) is a severe genetic neurodevelopmental disorder with an estimated prevalence of 1:20,000. Life expectancy appears to be normal, however, data regarding lifespan in AS are scarce. Until 2018, there was no unique diagnosis code for AS, thus true incidence, prevalence, mortality and morbidity rates are unknown. A social media effort was launched by caregivers of people with AS to gather community‐sourced data to understand AS mortality risks. Information on 220 deaths was verified with obituaries and public postings. Respiratory illness was the primary cause of death among people with AS overall, followed by accidents and seizures. Surprisingly, sudden unexpected death in sleep (SUDS) was the fourth most common cause, which has not been reported previously. Approximately 91% of people with AS have epilepsy, thus some SUDS cases may represent sudden unexpected deaths in epilepsy (SUDEP). Causes of death vary by age, and differ from the general population. Though there are obvious limitations to data collected through social media, grass roots science is a starting point to amass preliminary data and inform future epidemiological research on AS.

In the current study, we examined adaptive skills and trajectories over time in 257 individuals with Angelman syndrome (AS) using the Vineland Adaptive Behavior Scales, 2nd Edition. Multilevel linear models were used to examine differences between molecular subtypes over time, from one year to 13 years of age, in the adaptive domains of communication, daily living skills, socialization and motor skills. Individuals with non-deletion subtypes typically demonstrated a higher level of adaptive skills compared to those with deletion subtypes. Statistically significant growth was observed in all adaptive domains through at least early adolescence. Individuals with AS should continue to receive developmental services and educational supports through adolescence and into adulthood given the slow rates of growth being observed across adaptive domains.

Purpose The primary goal of this analysis is to describe the health-related quality of life (HRQoL), medical history, and medication use among adolescents and adults individuals with Angelman syndrome (AS). Methods The analysis uses baseline data collected during the STARS study, a double-blind placebo controlled trial of gaboxadol (OV101) in adolescents and adults with AS. The HRQoL was estimated using EuroQoL 5-Dimension 5-Level (EQ-5D) health questionnaire proxy 1 version, which was completed by the caregivers. EQ-5D consists of two parts, a 5-dimension descriptive and a visual analogue scale (VAS) component. The utility score derived from EQ-5D ranges from 0 to 1 (perfect health) and VAS ranges from 0 to 100 (perfect health). Results 87 individuals with AS were included in the present analysis. The mean utility score was 0.44 ± 0.20 and VAS score was 84 ± 1.5. The EQ-5D data indicated that the self-care, mobility and daily activities were most impacted. All adolescents (100%) and most adults (93%) had at least moderate problems with self-care activities, such as washing or dressing themselves. More than half (55%) of the adolescents and adults had at least moderate issues with mobility and usual activities. Approximately, 30% of adolescents and adults had moderate to extreme problems with anxiety/depression. High baseline concomitant use of medications was observed across both age groups with an average of 5 medications being used per person. Conclusion This study highlights the impact of AS on HRQoL and medication utilization among adolescents and adults individuals with AS.