Chromosomal disorders are multisystemic conditions frequently presenting developmental delay and epilepsy as primary neurological symptoms. Epilepsy in these syndromes significantly impacts morbidity, quality of life, and neurodevelopment. Angelman syndrome, ring chromosome 20, Down syndrome, Dup15q syndrome, and others display suggestive electroclinical profiles that may help diagnose and treatment. Understanding the associated electroencephalographic (EEG) findings is critical for clinicians to tailor interventions and optimize outcomes. This review highlights the prevalence, onset, seizure types, EEG characteristics, and treatment approaches for epilepsy in major chromosomal disorders. Angelman syndrome features epilepsy with atypical absences and myoclonic seizures, often associated with specific EEG patterns such as rhythmic delta activity. Ring chromosome 20 syndrome presents with focal frontal seizures, including non-convulsive status epilepticus. Down syndrome has a biphasic epilepsy distribution, from infantile spasms to late-onset myoclonic epilepsy. Similarly, Dup15q syndrome is marked by drug-resistant epilepsy, with EEG showing beta rhythms and hypsarrhythmia. Knowing the electroclinical patterns associated with chromosomal disorders may improve diagnosis and epilepsy management, which enhances patient care and prognosis accuracy.

We describe the development and validation of PANDABox-EEG, a novel protocol for remote EEG assessment with no on-site technician, tailored for Angelman syndrome (AS). We argue that this protocol is reliable, valid, and widely acceptable for use in families affected by Angelman syndrome. AS is a rare neurogenetic condition characterized by developmental delays, sleep problems, seizures, and a happy demeanor. People with AS are frequently monitored via EEG to inform clinical care, and EEG-measured delta activity has been proposed as a reliable biomarker to monitor treatment effectiveness. Traditional EEG assessments pose logistical and financial burdens for families due to the need to travel to a medical center to complete assessments. Telehealth methods, however, offer a pathway forward. PANDABox-EEG was developed through multidisciplinary collaboration with psychologists, psychophysiologists, engineers, and special-education scholars, incorporating caregiver feedback and user-centered design principles. It pairs PANDABox, a telehealth platform for biobehavioral assessment in rare disorders, with a dry electrode EEG system. Twenty-eight participants (7 AS, 7 siblings, 14 caregivers) completed three 5-min EEG sessions each over the course of a week. Caregivers were asked to provide feedback on acceptability of the design, and EEG data was quantified and assessed for metrics of reliability and validity. PANDABox-EEG demonstrated high feasibility and acceptability, with 91% of caregivers reporting strong satisfaction assessment comfort. EEG data quality was promising, with high internal consistency (split-half reliability range for children with AS: r = .96-.98) and test-retest reliability for delta power among (test-retest reliability range for children with AS: ρ = .88-.96). Finally, we successfully detected the characteristic increased delta power in AS (effect size between AS and non-AS siblings: d = 1.56-2.85) and its association with age (effect size between non-AS siblings and caregivers: d = 2.19-2.72). PANDABox-EEG provides a feasible, cost-effective, and reliable method for remote EEG assessment in AS. Its high caregiver satisfaction and ability to capture relevant neurophysiological markers suggest potential for broader application. With further validation, PANDABox-EEG can enhance accessibility and inclusivity, benefiting clinical management and research in AS and other clinical populations in need of frequent EEG monitoring by eliminating the need to travel.

Parenting a child with rare paediatric neurological diseases (RPNDs) severely affects parents' quality of life and the caregiver burden. Since mothers tend to be the primary caregivers more often, this study focuses on previously unexplored experiences of mothers of four RPNDs: 22q11.2 deletion syndrome (22q11.2DS), Angelman syndrome (AS), Dravet syndrome (DS) and Williams syndrome (WS). A cross-sectional survey of 302 mothers revealed that, while caring for RPND children seriously impacts well-being and stress in all mothers, there also exist some significant differences in diagnostic experiences, quality of life and the caregiver burden across conditions. DS and AS mothers reported difficulties in the access to and reimbursement for modern genetic testing and psychological support. DS and WS mothers were concerned over the impact of the delayed diagnosis on unnecessary hospitalisations and medication in their children. 22q11.2DS mothers felt more supported than others. While DS and AS mothers reported a greater burden in caregiving and reduced quality of life, WS mothers reported significantly lower burdens and higher scores across all quality-of-life domains. Mothers' financial well-being, employment status and early diagnosis significantly influenced their experiences. These findings underscore the need for tailored support for RPND mothers, with a focus on early diagnosis and financial and psychological help.

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). 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. 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. 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. ⍰ 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.

Gait disturbance is a common motor symptom in Angelman syndrome (AS), but its characteristics have been poorly studied quantitatively. This study aimed to analyze gait characteristics in school-age children with AS using three-dimensional gait analysis (3DGA). Patients with clinically and genetically confirmed AS and healthy children aged 6-15 years were included. For gait assessments, 3DGA was performed using an eight-camera motion analysis system and eight force plates. Gait metrics, including gait speed, step length, step width, gait variability, gait deviation index, and kinematic and kinetic data of lower extremity joints were compared between the groups. Eight children with AS and 24 healthy controls were evaluated. Seven children with AS had flat feet. While step length and gait speed were similar between groups, children with AS showed greater variability in these parameters and larger step widths. Their average gait deviation index was 74.5, indicating significant gait disturbance, and characteristic features included anterior pelvic tilt, insufficient hip extension, excessive knee flexion during early stance, and reduced ankle joint power. School-age children with AS exhibit unstable, prancing gait characterized by knee flexion in the early stance phase, quantifiable using 3DGA. These findings provide foundation for evaluating therapeutic interventions.

Hypothesis-free DNA methylation profiling in a 66-year-old male with unexplained neurodevelopmental disorder enabled the exclusion of ZNF142-related disease (left panel) and led to a retrospective diagnosis of Angelman syndrome, highlighting the diagnostic potential of single-patient epigenetic screening (right panel).

As a rare neuro-genetic disease, Angelman syndrome (AS) affects about 15 to 500 thousand people worldwide. The AS is an imprinting genomic disease characterized by the loss of function of the maternal UBE3A gene, located in the 15q11-q13. This gene encodes a ~100 kDa protein, the Ubiquitin-protein ligase E3A (UBE3A), that participates in the ubiquitination process, one of the post-translational protein modifications. In the brain, under normal conditions, the paternal allele of the UBE3A gene is silenced, with only the maternal allele being active. However, in individuals with AS, the maternal loss of function of this gene leads to the complete absence of UBE3A expression, resulting in multiple pathological features. Clinically, children diagnosed with AS exhibit a characteristic behavioral phenotype, including a happy demeanor, frequent and unmotivated laughter, movement, speech impairment, severe intellectual disability, and sleep problems. Since its discovery in 1965, significant progress has been made in understanding the genetic and pathophysiological aspects of AS. However, despite these advances, the molecular mechanisms underlying the disease remain incompletely understood, and no effective treatment currently exists. Current therapies focus solely on symptom management, and no approach has yet succeeded in reactivating the silenced paternal UBE3A allele. Therefore, this review highlights the epigenetic aspects involved in the AS in order to provide a better understanding and clarification of the mechanisms, hopefully paving the way for future research to improve the treatment of affected individuals.

Angelman Syndrome (AS) is a neurodevelopmental disorder caused by the loss of function of ubiquitin-protein ligase E3A (UBE3A), resulting in marked changes in synaptic plasticity. In AS mice, a dysregulation of Ca/calmodulin-dependent protein kinase II alpha (CaMKIIα) was previously described. This has been convincingly validated through genetic rescue of prominent phenotypes in mouse cross-breeding experiments. Selective ligands that specifically stabilize the CaMKIIα central association (hub) domain and affect different conformational states in vitro are now available. Two of these ligands, 3-hydroxycyclopent-1-enecarboxylic acid (HOCPCA) and (E)-2-(5-hydroxy-2-phenyl-5,7,8,9-tetrahydro-6H-benzo[7]annulen-6-ylidene)acetic acid (Ph-HTBA), confer neuroprotection after ischemic stroke in mice where CaMKIIα is known to be dysregulated. Here, we sought to investigate whether pharmacological modulation with these prototypical CaMKIIα hub ligands presents a viable approach to alleviate AS symptoms. We performed an in vivo functional evaluation of AS mice treated for a total of 14 days with either HOCPCA or Ph-HTBA (7 days pre-treatment and 7 days of behavioural assessment). Both compounds were well-tolerated but unable to revert robust phenotypes of motor performance, anxiety, repetitive behaviour or seizures in AS mice. Biochemical experiments subsequently assessed CaMKIIα autophosphorylation in AS mouse brain tissue. Taken together our results indicate that pharmacological modulation of CaMKIIα via the selective hub ligands used here is not a viable treatment strategy in AS.

Loss of production of ubiquitin protein ligase E3A (UBE3A) in neurons leads to Angelman Syndrome (AS). There are limited methods to reliably measure UBE3A in cerebrospinal fluid (CSF), which negatively impacts therapeutic development. To overcome this gap, we developed and analytically validated a novel method for CSF UBE3A quantitation, which includes an immunoprecipitation protein capture step followed by tryptic digestion and high-resolution mass spectrometry detection of a unique UBE3A peptide. Our data suggest that we can reliably detect UBE3A at concentrations as low as 2.5 pg/mL. The assay was used to show that UBE3A could be detected in CSF samples of both healthy adults and patients with AS. As expected, CSF UBE3A levels in healthy adults (24.76 ± 6.75 pg/mL, N = 14) were significantly higher (p < 0.01) than the CSF UBE3A levels measured in two AS cohorts (5.30 ± 0.42 pg/mL, N = 19 and 5.59 ± 0.40 pg/mL, N = 10), with no significant difference in UBE3A levels observed between the two AS cohorts. There was also no significant difference in CSF UBE3A levels when comparing AS patients carrying either a mutation or chromosomal deletion in either cohort. Overall, these data demonstrate the utility of this novel CSF UBE3A assay for UBE3A quantitation in studies of AS.

Wearable technology has potential benefits for clinical measurement with children who have neurodevelopmental disorders (NDDs). However, this cohort may experience sensory processing disorder, behavioral dysregulation, and cognitive challenges. For effective and considerate implementation, the experiences and views of parents of children with NDDs on this topic need in-depth investigation. This qualitative semi-structured interview study used purposeful sampling of families with experience with wearable technology in a research setting. The cohort included 12 parents of 14 children with a diagnosis of Fragile X (n = 6), Prader-Willi (n = 4), or Angelman (n = 4) syndromes. The data were processed using NVivo software (QSR International Ltd. 1999-2013). Data analysis was conducted using reflexive thematic analysis. Theme 1: Parents are willing to use wearable technology in the home or community if it is feasible. Aspects of feasibility were the ease of embedding technology into existing routines, device robustness, and device invasiveness. Theme 2: Parents are guided by previous healthcare and research experiences. Wearables were considered low burden in the context of everything else their child experiences through health care. Theme 3: Early engagement with families in the design and research process of new technologies is important. Parents had strong views on how to introduce a wearable to their child. In this article, parents stressed that the child's behavioral phenotype needs to be considered early in the design and rollout phases. A shared decision-making approach between researchers and parents will improve the uptake and success of NDD-focused research adopting wearable technology approaches for clinical measurement.

Drug-resistant epilepsy (DRE) affects 20-30% of patients with epilepsy who fail to achieve seizure control with antiseizure medications, posing a significant therapeutic challenge. In this narrative review, we examine the clinical efficacy and safety of the classic ketogenic diet (cKD) and its variants, including the modified Atkins diet (MAD), medium-chain triglyceride diet (MCTD), and low glycemic index treatment (LGIT), in patients with genetically confirmed drug-resistant epilepsy. These diets induce a metabolic shift from glucose to ketones, enhance mitochondrial function, modulate neurotransmitter balance, and exert anti-inflammatory effects. However, genetic factors strongly influence the efficacy and safety of the cKD, with absolute indications including glucose transporter type 1 deficiency syndrome (GLUT1DS) and pyruvate dehydrogenase complex deficiency (PDCD). Preferred adjunctive applications of the KD include genetic epilepsies, such as -related Dravet syndrome, -related tuberous sclerosis complex, and -related Angelman syndrome. However, because of the risk of metabolic decompensation, the cKD is contraindicated in patients with pathogenic variants of pyruvate carboxylase and . Recent advancements in precision medicine suggest that genetic and microbiome profiling may refine patient selection and optimize KD-based dietary interventions. Genome-wide association studies and multiomics approaches have identified key metabolic pathways influencing the response to the cKD, and these pave the way for individualized treatment strategies. Future research should integrate genomic, metabolomic, and microbiome data to develop biomarker-driven dietary protocols with improved efficacy and safety. As dietary therapies continue to evolve, a personalized medical approach is essential to maximize their clinical utility for genetic epilepsy and refractory epilepsy syndromes.

3p Deletion syndrome is a rare genetic disorder characterized by intellectual disability, growth delay, hypotonia, and distinctive facial features, with considerable phenotypic variability. Previous reports have highlighted the significance of deletions within the 3p25.3 region contributing to the development of Angelman-like features, such as stereotypic movements, a happy demeanor, epilepsy, and characteristic electroencephalogram (EEG) patterns. This study analyzed 22 patients of 3p deletion syndrome, focusing on epilepsy and EEG findings. A newly defined short smallest region of overlap (sSRO) within 3p25.3, encompassing approximately 52 kb and partially including SLC6A1 and SLC6A11, was associated with Angelman-like features, particularly epilepsy and EEG patterns. Patients with sSRO deletions exhibited a high incidence of seizures (60 %), characterized by myoclonic or absence seizures, with EEG showing generalized high-amplitude slow waves. In contrast, larger deletions beyond the sSRO were linked to dysmorphological features of 3p-syndrome, generalized tonic-clonic seizure, and non-specific EEG findings. These findings suggest that SLC6A1 dysfunction contributes to epilepsy and EEG abnormalities, possibly via impaired GABA transport, whereas patients with larger or non-overlapping deletions exhibited more typical 3p-syndrome features, suggesting that multiple neurological genes in the broader deletion region may independently contribute to more severe neurological phenotypes. In conclusion, it is important to consider GABA-related disorders, including a specific chromosomal abnormality known as 3p-syndrome with a microdeletion in the SRO region, when observing characteristic epilepsy and EEG findings resembling Angelman syndrome.

Synaptic Rho guanosine triphosphatase (GTPase) guanine nucleotide exchange factors (RhoGEFs) play vital roles in regulating the activity-dependent neuronal plasticity that is critical for learning. Ephexin5, a RhoGEF implicated in the etiology of Alzheimer's disease and Angelman syndrome, was originally reported in neurons as a RhoA-specific GEF that negatively regulates spine synapse density. Here, we show that Ephexin5 activates both RhoA and Cdc42 in the brain. Furthermore, using live imaging of GTPase biosensors, we demonstrate that Ephexin5 regulates activity-dependent Cdc42, but not RhoA, signaling at single synapses. The selectivity of Ephexin5 for Cdc42 activation is regulated by tyrosine phosphorylation, which is regulated by neuronal activity. Last, in contrast to Ephexin5's role in negatively regulating synapse density, we show that, downstream of neuronal activity, Ephexin5 positively regulates synaptic growth and stabilization. Our results support a model in which plasticity-inducing neuronal activity regulates Ephexin5 tyrosine phosphorylation, driving Ephexin5-mediated activation of Cdc42 and the spine structural growth and stabilization vital for learning.

Neurological disorders, ranging from common conditions like Alzheimer's disease that is a progressive neurodegenerative disorder and remains the most common cause of dementia worldwide to rare disorders such as Angelman syndrome, impose a significant global health burden. Altered facial expressions are a common symptom across these disorders, potentially serving as a diagnostic indicator. Deep learning algorithms, especially convolutional neural networks (CNNs), have shown promise in detecting these facial expression changes, aiding in diagnosing and monitoring neurological conditions. This systematic review and meta-analysis aimed to evaluate the performance of deep learning algorithms in detecting facial expression changes for diagnosing neurological disorders. Following PRISMA2020 guidelines, we systematically searched PubMed, Scopus, and Web of Science for studies published up to August 2024. Data from 28 studies were extracted, and the quality was assessed using the JBI checklist. A meta-analysis was performed to calculate pooled accuracy estimates. Subgroup analyses were conducted based on neurological disorders, and heterogeneity was evaluated using the I statistic. The meta-analysis included 24 studies from 2019 to 2024, with neurological conditions such as dementia, Bell's palsy, ALS, and Parkinson's disease assessed. The overall pooled accuracy was 89.25% (95% CI 88.75-89.73%). High accuracy was found for dementia (99%) and Bell's palsy (93.7%), while conditions such as ALS and stroke had lower accuracy (73.2%). Deep learning models, particularly CNNs, show strong potential in detecting facial expression changes for neurological disorders. However, further work is needed to standardize data sets and improve model robustness for motor-related conditions.

UBE3A is an E3 ubiquitin ligase associated with several neurodevelopmental disorders. The development of several preclinical therapeutic approaches involving UBE3A, such as gene therapy, enzyme replacement therapy, and epigenetic reactivation, require the detection of its ubiquitin ligase activity. Prior commercial assays leveraged Western Blotting to detect shifts in substrate size due to ubiquitination, but these suffered from long assay times and have also been discontinued. Here we develop a new assay that quantifies UBE3A activity. It measures the fluorescence intensity of ubiquitinated p53 substrates with a microplate reader, eliminating the need for Western Blot antibodies and instruments, and enables detection in just 1 h. The assay is fast, cost-effective, low noise, and uses components with long shelf lives. Importantly, it is also highly sensitive, detecting UBE3A levels as low as 1 nM, similar to that observed in human and mouse cerebrospinal fluid. It also differentiates the activity of wild-type UBE3A and catalytic mutants. We also design a p53 substrate with a triple-epitope tag HIS-HA-CMYC on the N terminus, which allows for versatile detection of UBE3A activity from diverse natural and engineered sources. This new assay provides a timely solution for growing needs in preclinical validation, quality control, endpoint measurements for clinical trials, and downstream manufacturing testing and validation.

Angelman syndrome (AS) is a severe neurodevelopmental disorder with no effective therapies. Most of the behavioral deficits observed in AS patients arise from the absence of ubiquitin protein ligase E3A (UBE3A) in the brain during development, driven by the loss of maternally expressed UBE3A and silencing of the paternal copy of this gene through imprinting. Safe and effective therapies aiming at restoring the expression of the paternal UBE3A gene early in human life are currently lacking. In this study, we investigated whether octanoic acid (OA), a medium-chain fatty acid, could unsilence the paternal Ube3a allele in neurons and ameliorate the behavioral defects in a murine model of AS. To this end, Ube3a and Ube3a mice, as well as their wild-type littermates, were fed either a control or OA-supplemented diet from postnatal day 0 through adulthood, and the improvements in AS-related cellular and behavioral deficits were characterized. We demonstrate that dietary intake of OA activates the expression of the silenced, paternal Ube3a in neurons and improves select AS behavioral phenotypes in mice. We further show that downregulation of topoisomerase II beta and restoration of dendritic spine development may underlie the unsilencing of Ube3a and the behavioral improvements in OA-supplemented animals, respectively. Together, our findings suggest that dietary supplementation with OA could serve as an early, safe, and clinically feasible therapeutic strategy for reactivation of the paternal UBE3A allele in patients with AS.

Current clinical testing approaches for individuals with suspected imprinting disorders are complex, often requiring multiple tests performed in a stepwise manner to make a precise molecular diagnosis. We investigated whether whole-genome long-read sequencing could be used as a single data source to simultaneously evaluate copy number variants, single-nucleotide variants, structural variants, and differences in methylation in a cohort of individuals known to have either Prader-Willi or Angelman syndrome. Twenty-five individuals sequenced to an average depth of coverage of 36× on an Oxford Nanopore Technologies PromethION were evaluated. A custom one-page report was generated that could be used to assess copy number, single-nucleotide variants, and methylation patterns at select CpG sites within the 15q11.2-q13.1 region and prioritize candidate pathogenic variants in UBE3A. After training with three positive controls, three analysts blinded to the known clinical diagnosis arrived at the correct molecular diagnosis for 22 of 22 cases (20 true positive, 2 negative controls). Our findings demonstrate the utility of long-read sequencing as a single, comprehensive data source for complex clinical testing, offering potential benefits, such as reduced testing costs, increased diagnostic yield, and shorter turnaround times, in the clinical laboratory.

Neurodevelopment is an intricate process with highly regulated, overlapping stages including neuronal differentiation and axon guidance. Aberrations during these and other stages are tied to the etiology of neurodevelopmental disorders like Autism Spectrum Disorder, Angelman Syndrome, and X-linked Intellectual Disability. Ubiquitination is a dynamic and highly reversible post-translational modification conferred by E3 ubiquitin ligases. Recent discoveries have advanced the understanding of how substrate ubiquitination can guide protein localization, drive protein degradation, and alter protein post translational modifications. In this review, we highlight members of the RING and HECT E3 ligase families to discuss their novel roles in the molecular mechanisms regulating neurodevelopment. These findings are both instrumental for informing the future directions of neurodevelopmental research, and in expanding knowledge of intracellular mechanisms of protein trafficking. In addition, a deeper understanding of the molecular mechanisms of E3 ligase function in development promises to offer new insights into the pathogenesis of neurodevelopmental disorders.

Angelman syndrome (AS) is a rare neurogenetic disorder. Previous studies indicate a high prevalence of autism spectrum disorder (ASD) with considerable variability. Little is known regarding the longitudinal trajectory of autistic traits. We aim to investigate autistic traits, the effect of age on these traits, and associated features in AS children. This (partly) longitudinal clinical record study at the ENCORE Expertise Center involved 107 AS children aged 2-18 with one (N = 107), two (N = 49), or three (N = 14) measurements. Autistic traits and sensory processing issues were assessed using various instruments, and DSM classifications were used descriptively. Covariates were genotype, gender, and epilepsy. Results indicate a high prevalence of autistic traits and sensory processing issues. Children with the deletion genotype exhibited more autistic traits. Autism Diagnostic Observation Schedule (ADOS) classifications indicated higher rates of ASD compared to clinician DSM classifications. Autistic traits generally remained stable over time, except that ADOS scores significantly decreased for children with the UBE3A mutation genotype, and in the social affect domain for the entire group. In conclusion, incorporating the assessment of autistic traits and sensory processing into clinical practice for AS is important to inform adaptations of the environment to meet the child's needs. Additionally, clinicians and researchers should be mindful of the potential for overestimating ASD traits in AS when relying on the ADOS. ASD diagnosis in AS should integrate multiple diagnostic instruments, diverse hetero-anamnestic sources, and multidisciplinary expert opinions.

Angelman syndrome (AS) is a developmental disorder caused by one of four molecular etiologies. 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. Data were collected in a natural history study of AS. The Parenting Stress Index, Third Edition (PSI) and the Beach Center FQOL scale assessed parent stress and FQOL. Stress and FQOL were examined across AS molecular subtypes, and predictors were analyzed using a generalised linear model. Relationships between parental stress and FQOL were examined using Pearson correlations and a stepwise mixed-linear model approach. Our sample consisted of 231 families of individuals living with AS. Parental stress was clinically elevated and was highest in families of individuals with mutations, while FQOL did not differ across subtype 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, while lower FQOL was predicted by child male sex, parent marital status, and family income. Parental stress had a small negative impact on FQOL. Stress is elevated in parents of individuals with AS across subtypes and has a small negative impact on family quality of life. Interventions to reduce stress have potential to improve individual and family well-being.