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Background: Identifying the underlying etiology of developmental delay/intellectual disability (DD/ID) is challenging but important. The genetic diagnosis of unexplained DD/ID helps in the treatment and prognosis of the disability in patients. In this study, we reported our experience of using whole exome sequencing (WES) of children with unexplained DD/ID. Methods: We conducted a retrospective analysis of WES results of children under 19 years of age with unexplained DD/ID between January 2020 and December 2021. The demographic data of all patients and variants identified through WES were evaluated. Furthermore, we evaluated the clinical characteristics that influenced the identification of genetic causes. Results: Forty-one patients with DD/ID were included, of whom 21 (51.2 %) were male. The average age at symptom onset was 1.6 ± 1.3 years, and the duration from symptom onset to diagnosis was 3.1 ± 3.7 years. Hypotonia was the most common symptom (17 patients, 41.5 %), and epilepsy was confirmed in 10 patients (24.4 %). Twenty-two pathogenic/likely pathogenic variants were identified in 20 patients, and three variants of uncertain significance were identified in three patients. Family-based trio Sanger sequencing for candidate variants of 12 families was conducted; 10 variants were de novo, one variant paternally inherited, and two variants compound heterozygous. The diagnostic yield of WES for DD/ID was 48.8 % and was significantly high in patients with an early onset of DD/ID and facial dysmorphism. In contrast, patients with autism spectrum disorder (ASD) were more likely to have negative WES results compared with others without ASD. Conclusion: The diagnostic yield of WES was 48.8 %. We conclude that patients’ characteristics, such as dysmorphic features and the age of symptom onset, can predict the likelihood that WES will identify a causal variant of a phenotype.

Summary: Background: Pathogenic missense variants in the essential synaptic vesicle protein synaptotagmin-1 (SYT1) cause a neurodevelopmental disorder characterised by motor delay and intellectual disability, hyperkinetic movement disorder, episodic agitation, and visual impairments. SYT1 is the presynaptic calcium sensor that triggers synchronous neurotransmitter release. We have previously shown that pathogenic variants around the calcium-sensing region of the critical C2B domain decrease synaptic vesicle exocytosis in neurons. Methods: Here, we have used cultured hippocampal neurons transfected with SYT1-pHluorin to examine how variants within the C2A and C2B domain of SYT1 impact evoked exocytosis. Findings: We show that recently identified variants within the facilitatory C2A domain of the protein (L159R, T196K, E209K, E219Q), as well as additional variants in the C2B domain (M303V, S309P, Y365C, G369D), share an underlying pathogenic mechanism, causing a graded and variant-dependent dominant-negative impairment in exocytosis. We establish that the extent of evoked exocytosis observed in vitro in the presence of SYT1 variants correlates with neurodevelopmental impacts of this disorder. Specifically, the severity of motor and communication impairments exhibited by individuals harbouring these variants correlates with multiple measures of exocytic efficiency. Interpretation: Together, this suggests that there is a genotype-function-phenotype relationship in SYT1-associated neurodevelopmental disorder, centring impaired evoked neurotransmitter release as a common pathogenic driver. Moreover, this points toward a direct link between control of neurotransmitter release and development of adaptive functions, providing a tractable target for therapeutic amelioration. Funding: Australian National Health and Medical Research Council, UK Medical Research Council, Great Ormond Street Hospital Children's Charity, University of Melbourne.

Background: Intellectual disability (ID) is a developmental disorder that causes considerably below-average intellectual performance and adaptive behaviour. In the context of the present study, families raising a child with ID are reported to experience multiple challenges that appear not to be well documented in Pakistan. Methods and procedures: Pakistan, which was conducted in Karachi, Pakistan, followed participatory action research, in which the researcher and participants examined their existing experiences of informal social support and then created, implemented, and evaluated actions to strengthen this informal social support. A total of five families (n = 25) participated in the study. These participating families comprise parents, siblings, and significant others, i.e., aunts, uncles, and grandparents, living with the child with ID. Families with children with ID were selected through a school for children with ID who are under 12 years old. This qualitative action research was conducted in two distinct parts, i.e., a) exploratory part and b) action part. This paper presents the findings of the first exploratory part of the study. Aim: The exploratory phase aimed to explore and examine the experiences and challenges families may experience with informal social support while caring for a child with an intellectual disability in Karachi, Pakistan. Findings: Parents often sacrifice their personal needs and aspirations for their children, leading to decreased tolerance and anxiety. Lack of communication, support, and assistance from family members is another significant issue. Stigmatisation and discrimination from school, relatives, and friends can cause depression and distress. The study emphasises the need for a unified and coordinated approach to support and care. Religious beliefs, siblings, and close friends provide comfort and well-being. When parents manage to connect with similar families, they have the opportunity to express a collective commitment to caregiving. Conclusion: To strengthen the situation, families propose enhancing intimacy and competency within homes and taking action at the governmental level. Governments must provide appropriate services, such as nurses supporting families, support groups, and religious traditions, to promote acceptance and holistic development for intellectually disabled children.

Summary: Neurodevelopmental disorder with or without autism or seizures (NEDAUS) is a neurodevelopmental disorder characterized by global developmental delay, speech delay, seizures, autistic features, and/or behavior abnormalities. It is caused by CUL3 (Cullin-3 ubiquitin ligase) haploinsufficiency. We collected clinical and molecular data from 26 individuals carrying pathogenic variants and variants of uncertain significance (VUS) in the CUL3 gene, including 20 previously unreported cases. By comparing their DNA methylation (DNAm) classifiers with those of healthy controls and other neurodevelopmental disorders characterized by established episignatures, we aimed to create a diagnostic biomarker (episignature) and gain more knowledge of the molecular pathophysiology. We discovered a sensitive and specific DNAm episignature for patients with pathogenic variants in CUL3 and utilized it to reclassify patients carrying a VUS in the CUL3 gene. Comparative epigenomic analysis revealed similarities between NEDAUS and several other rare genetic neurodevelopmental disorders with previously identified episignatures, highlighting the broader implication of our findings. In addition, we performed genotype-phenotype correlation studies to explain the variety in clinical presentation between the cases. We discovered a highly accurate DNAm episignature serving as a robust diagnostic biomarker for NEDAUS. Furthermore, we broadened the phenotypic spectrum by identifying 20 new individuals and confirming five previously reported cases of NEDAUS.

Objective: Serious games can serve as easily accessible interventions to support siblings of children with disabilities, who are at risk of developing mental health problems. The Dutch serious game ‘Broodles’ was developed for siblings aged 6–9 years. The current study aims to assess the cultural applicability, desirability, feasibility, and acceptability of ‘Broodles’ in Norway. Methods: Norwegian siblings (N = 16) aged 6–13 years and parents (N = 12) of children with intellectual disabilities assessed the game. Their feedback data from interviews and questionnaires were sorted using a model of engagement factors in serious games. Results: At pre-use, participants showed interest in the game, and after initial use the participants were overall positive about the format, content and objectives, including validation of emotions and recognition. The participants had suggestions for improved engagement and feasibility. Conclusion: The game was found to be culturally applicable, desirable and acceptable, although Norwegian translation is necessary for further evaluation. Recommendations to enhance engagement were provided, including suggestions to play the game with parents or in a group. Innovation: This initial assessment of the serious game Broodles in a non-Dutch setting shows promise for an innovative way of supporting siblings of children with disabilities.

Background: HMGXB4 (additionally known as HMG2L1) is a non-histone DNA-binding protein that contains a single HMG-box domain. HMGXB4 was originally described in Xenopus where it was seen to negatively regulate the Wnt/β-catenin signaling pathway. Materials and methods: In this study, we conducted a genetic and clinical evaluation of a single family with three affected individuals suffering from intellectual disability (ID), global developmental delay (GDD) and dysmorphic facial features.Whole genome sequencing (WGS) and Sanger sequencing were performed on the affected individuals' DNA to identify genetic variations. Additionally, a reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to assess gene expression in both the affected and unaffected individuals in the family. Result: WGS identified a homozygous frameshift variant c.1193_1196del p. (Lys398Argfs × 25) in exon 5 of the HMGXB4 gene (OMIM 604702), which completely segregated the disease phenotype in the family. Furthermore, RT-qPCR revealed a substantial decrease in the HMGXB4 gene expression in the affected individuals as compared to the unaffected individuals of the family. Conclusions: The current study is the first evidence linking a genetic variant in the HMGXB4 gene to ID, GDD, and dysmorphic facial features. Therefore, it is possible that HMGXB4 contributes significantly to developmental milestones and may be responsible for neurodevelopmental disorders in humans.

Care providers in intellectual disability care use various health information systems (HIS) to document the care they provide. This generates a substantial amount of structured and unstructured data with significant potential for reuse, which is currently underexploited. To enhance data reuse, it is important to understand the architecture of health information systems in intellectual disability care, including their commonalities and variabilities (differences), as well as to identify related privacy and security issues. Our study adopts a multiple-case study approach, examining the architectures of four health information systems in the Netherlands. We conducted interviews with seven stakeholders from four HISs and reviewed multiple documents concerning system infrastructure. We identified commonalities and differences between these systems and outlined the primary challenges regarding privacy and security for data reuse. For each HIS, four architectural views were developed: a context diagram, decomposition view, layered view, and deployment view. The study discusses crucial security and privacy aspects for data reuse in intellectual disability care and highlights several challenges that must be addressed to unlock the full potential of this data. This research provides initial guidelines for overcoming these challenges.

Background: Adaptive behavior is an important characteristic of people with intellectual disabilities, and it has been associated with a person's performance in social and work contexts. Indeed, adaptive behavior denotes what a person does independently, without help, support, reminders, or prompts. In Peru, available measures of adaptive behavior are commercial; thus, there is a need for an open-access tool to assess the adaptive behavior of people with intellectual disabilities. For this reason, the aim of the study was to design and develop a new Adaptive Behavior Test Battery for people from 13 to 60 years old with intellectual disabilities who have an interest in being part of the economically active population. Methods: A cross-sectional design was defined, starting with a qualitative approach to designing and constructing the item pool for the test battery. Then, quantitative indexes Aiken's V for content validity and Krippendorff's alpha for inter-observer reliability were estimated, resulting in a first version of the three subscales that comprised the test battery. The initial versions were tested on a sample of 566 persons with intellectual disabilities from two regions of Peru: Lima (Coast) and San Martín (Jungle). The internal structure was analyzed under a factor analysis approach, along with internal consistency measures of reliability. Further analyses of invariance regarding gender, region, and age were carried out. Results: Three observer subscales were proposed: Daily living activities (11 items), Instrumental skills (4 items), and Communication (9 items). All subscales showed excellent psychometric properties denoted by the Aiken's V coefficient, Krippendorff's alpha, factor analysis, internal consistency analysis, and invariance analyses. Conclusion: The developed a new Adaptive Behavior Test Battery is a useful tool for the measurement of adaptive behavior and the monitoring of social and labor inclusion programs for people with intellectual disabilities.

Intellectual disability (ID) is a progressive disorder that affects around 1–3% of the world's population. The heterogeneity of intellectual disability makes it difficult to diagnose as a complete disease. Genetic factors and major mutations play a noticeable role in the development and progression of ID. There is a high need to explore novel variants that may lead to new insights into the progressive aspects of ID. In the current course of study, 31 samples of ID from different studies available on GEO (GSE77742, GSE74263, GSE90682, GSE98476, GSE108887, GSE145710, and PRJEB21964) datasets were taken for the study. These datasets were analyzed for differential gene expression and single nucleotide polymorphism (SNPs). The SNPs of high impact were compared with the differentially expressed genes. Comparison leads to the identification of the priority gene ie NPR3 gene. The identified priority gene further was evaluated for the effect of the mutation using a Mutation Taster. Structure comparison analysis of the wild and mutated proteins of the NPR3 gene was further carried out by UCSF Chimera. Structural analysis reveals the anomalies in protein expression affecting the regulations of the NPR3 gene. These findings identified a novel nonsense mutation (E222*) in the downregulated NPR3 gene that leads to anomalies in the regulation of its protein expression. This missense mutation reveals a major role in causing ID. Our study concludes that the decrease in the expression of the NPR3 gene causes delayed sensory, motor, and physiological functions of the human brain leading to neurodevelopmental delay that causes ID.

Background: Family-Centered Care (FCC) is an approach to healthcare planning, delivery and evaluation, based on beneficial partnerships between health professionals, patients and families. FCC may be particularly relevant for families with children with intellectual disability (ID), given their needs of continuum care. Objective: To identify which components of the FCC are practiced and which health outcomes are considered effective in families with children with ID. Method: A systematic review guided by the PRISMA STATEMENT 2020 approach and the STROBE reporting guidelines was performed on specific databases through the EBSCOhost Web platform: MEDLINE with Full Text, CINAHL PLUS with Full Text, Academic Search Complete and Psychology and Behavioral Sciences Collection. Peer-reviewed articles published in English or Portuguese languages from 2018 to September 2023 were retrieved. Methodological quality was established using the Quality Assessment Tool for Observational, Cohort and Cross-Sectional Studies – NHLBI, NIH. Results: Ten studies met the eligibility criteria and were synthetized. The results revealed nine components, reflecting the way FCC was developed: shared decision-making; family education; respect for culture; family engagement; recognition of the family's needs, characteristics and interests; specialized care support; social and emotional support; family functionality; and family seen as a unit. The health outcomes demonstrate effective gains in improving children's health through family satisfaction with health services. Also achieved psychological and social benefits, with improved family well-being and quality of life, favoring family empowerment. Conclusions: The evidence suggests that FCC components involves an effective partnership between the family and health professionals as the main key in developing care plans, as well as the experience that the family unit brings to the delivery of care. FCC approach include all family members as decision-makers, providing emotional, physical and instrumental levels of support. Health outcomes emerged in three strands; for children with ID, families and health services.

Mutations of the human TRAFFICKING PROTEIN PARTICLE COMPLEX SUBUNIT 9 (TRAPPC9) cause a neurodevelopmental disorder characterised by microcephaly and intellectual disability. Trappc9 constitutes a subunit specific to the intracellular membrane-associated TrappII complex. The TrappII complex interacts with Rab11 and Rab18, the latter being specifically associated with lipid droplets (LDs). Here we used non-invasive imaging to characterise Trappc9 knock-out (KO) mice as a model of the human hereditary disorder. KOs developed postnatal microcephaly with many grey and white matter regions being affected. In vivo magnetic resonance imaging (MRI) identified a disproportionately stronger volume reduction in the hippocampus, which was associated with a significant loss of Sox2-positive neural stem and progenitor cells. Diffusion tensor imaging indicated a reduced organisation or integrity of white matter areas. Trappc9 KOs displayed behavioural abnormalities in several tests related to exploration, learning and memory. Trappc9-deficient primary hippocampal neurons accumulated a larger LD volume per cell following Oleic Acid stimulation, and the coating of LDs by Perilipin-2 was much reduced. Additionally, Trappc9 KOs developed obesity, which was significantly more severe in females than in males. Our findings indicate that, beyond previously reported Rab11-related vesicle transport defects, dysfunctions in LD homeostasis might contribute to the neurobiological symptoms of Trappc9 deficiency.

Background: Autosomal recessive intellectual developmental disorder-3 is caused by homozygous or compound heterozygous mutations in the CC2D1A gene. The disorder is characterized by intellectual disability (ID) and autism spectrum disorder (ASD). To date, 39 patients from 17 families with CC2D1A -related disorders have been reported worldwide, in whom only six pathogenic or likely pathogenic loss-of-function variants and three variants of uncertain significance (VUS) in the CC2D1A gene have been identified in these patients. Methods: We described a patient with ID from a non-consanguineous Chinese family and whole-exome sequencing (WES) was used to identify the causative gene. Results: The patient presented with severe ID and ASD, speech impairment, motor delay, hypotonia, slight facial anomalies, and finger deformities. Threatened abortion and abnormal fetal movements occurred during pregnancy with the proband but not his older healthy sister. WES analysis identified a homozygous nonsense variant, c.736C > T (p.Gln246Ter), in the CC2D1A gene. In addition, six novel likely pathogenic CC2D1A variants were identified by a retrospective review of the in-house database. Conclusions: This study expands the genetic and clinical spectra of CC2D1A-associated disorders, and may aid in increasing awareness of this rare condition. Our findings have provided new insights into the clinical heterogeneity of the disease and further phenotype-genotype correlation, which could help to offer scope for more accurate genetic testing and counseling to affected families.

Background: Smith-Lemli-Opitz syndrome (SLOS) is an inherited disorder of cholesterol biosynthesis associated with congenital malformations, growth delay, intellectual disability and behavior problems. SLOS is caused by bi-allelic mutations in DHCR7, which lead to reduced activity of 7-dehydrocholesterol reductase that catalyzes the last step in cholesterol biosynthesis. Symptoms of SLOS are thought to be due to cholesterol deficiency and accumulation of its precursor 7-dehydrocholesterol (7-DHC) and 8-dehydrocholesterol (8-DHC), and toxic oxysterols. Therapy for SLOS often includes dietary cholesterol supplementation, but lipids are poorly absorbed from the diet, possibly due to impaired bile acid synthesis. We hypothesized that bile acid supplementation with cholic acid would improve dietary cholesterol absorption and raise plasma cholesterol levels. Methods: Twelve SLOS subjects (10 M, 2F, ages 2–27 years) who had plasma cholesterol ≤125 mg/dL were treated with cholic acid (10 mg/kg/day) divided twice daily for 2 months. Plasma cholesterol, 7-DHC and 8-DHC were measured by GC–MS. Oxysterols were measured by ultra-high-performance LC-MS/MS. Data were analyzed using paired t-tests. Results: At baseline, plasma cholesterol was 75 ± 24 mg/dL (mean ± SD; range 43–125, n = 12). After 2 months on cholic acid, mean plasma cholesterol increased to 97 ± 29 mg/dL (p = 0.011). Eleven of 12 subjects showed an increase in plasma cholesterol that varied from 3.8% to 85.7% (mean 38.7 ± 23.3%). 7-Hydroxycholesterol decreased by 20.6% on average (p = 0.013) but no significant changes were seen in 7-DHC or 8-DHC. Mean body weight tended to increase (3.6% p = 0.069). Subjects tolerated cholic acid well and experienced no drug-related adverse events. Conclusions: In this pilot study, cholic acid supplementation was well tolerated and safe and resulted in an increase in plasma cholesterol in most SLOS subjects. Further controlled longitudinal studies are needed to look for the sustainability of the biochemical effect and possible clinical benefits.

Purpose: To evaluate gestational age (GA) and small-for-gestational age (SGA) as continuums and gender on the incidences of autism spectrum disorder (ASD) and co-occurring intellectual disability (ID). Methods: This is a population-based cohort study using the 2004–2008 Taiwan Maternal and Child Health Database. The diagnosis of ASD was determined by International Classification of Diseases, 9th Revision (ICD-9). Generalized estimating equations models were fit to evaluate associations between perinatal variables and ASD. Results: This study included 916,315 individuals. A total of 9474 (1.0%) children were diagnosed with ASD, among whom 1594 (16.8%) had co-occurring ID. Lower GA carried higher odds of ASD with ID (GA < 28 weeks, aOR: 4.26, 95% CI: 2.13, 8.50; GA 28–30 weeks, aOR: 2.80, 95% CI: 1.57, 4.97; GA 31–33 weeks, aOR: 1.63, 95% CI: 1.05, 2.55; GA 34–36 weeks, aOR: 1.39, 95% CI: 1.16, 1.67) and ASD without ID (GA < 28 weeks, aOR:2.05, 95% CI: 1.25, 3.36; GA 28–30 weeks, aOR: 2.02, 95% CI: 1.46, 2.79; GA 31–33 weeks, aOR: 1.42, 95% CI: 1.13, 1.77; GA 34–36 weeks, aOR: 1.18, 95% CI: 1.08, 1.29). Male preterm infants had ASD risks negatively correlated to GA, while ASD risks were significantly increased only among female infants born late preterm. The degree of SGA showed a stepwise increased risk for ASD with and without ID in both male and female infants. Conclusion: Lower GA and the degree of SGA are both associated with ASD susceptibility, either with or without co-occurring ID, and remarkably increased the risk of ID.

Background: A higher rate of atypical handedness prevalence (non-right-handedness or left-, mixed-hand dominance) has been recurrently reported in individuals diagnosed with autism spectrum disorder (ASD) compared to individuals with other types of developmental disabilities. However, the exact magnitude of this difference as well as the presence of possible contributing factors remained unknown. The main aim of this study was to understand caregivers’ impression of the handedness of their child with developmental disabilities and its relationship with assessments of the child using a hand preference scale. Methods and procedures: The sample of the present study was 1116 individuals with developmental disabilities from two countries, 541 (51.5%) individuals from Iran and 575 (48.5%) individuals from the Kurdistan Region of Iraq (KRI). The handedness of the sample was evaluated based on the parental report and utilizing a standardized scale (The Hand-Preference Demonstration Test “HPDT”). Outcomes and results: There was a statistically significant difference between caregivers' reports on their dependents' handedness and the application of a valid hand preference scale and they do not necessarily overlap. There was a statistically significant relationship between handedness and type of developmental disabilities based on caregivers' reports and individuals with ASD were more non-right-handed compared to individuals with ID based on the caregivers’ report. Hence similar difference was not seen between the ASD and ID groups when HDTP was applied as a diagnostic scale. While left-handedness in the ASD and ID group was similar (23–24%), mixed-handedness in the ASD group was 38% compared to 33% in the ID group. Conclusions and implications: The Hand-Preference Demonstration Test (HPDT) was a valid way to determine the hand preference of individuals with ASD and ID. It is concluded that parental reports on their offspring with ASD's hand preference need to be approved through the application of a scale and caregivers and professionals need to be more aware of early motor symptoms such as handedness. Further research should focus on the role of handedness in the development of fine motor skills and eye-hand coordination in children with differing developmental disabilities and variations among those differing impairments.

Phosphodiesterase 2 A (PDE2A) is an enzyme involved in the homeostasis of cAMP and cGMP and is the most highly expressed PDE in human brain regions critical for socio-cognitive behavior. In cerebral cortex and hippocampus, PDE2A expression level is upregulated in Fmr1-KO mice, a model of the Fragile X Syndrome (FXS), the most common form of inherited intellectual disability (ID) and autism spectrum disorder (ASD). Indeed, PDE2A translation is negatively modulated by FMRP, whose functional absence causes FXS. While the pharmacological inhibition of PDE2A has been associated to its pro-cognitive role in normal animals and in models of ID and ASD, homozygous PDE2A mutations have been identified in patients affected by ID, ASD and epilepsy. To clarify this apparent paradox about the role of PDE2A in brain development, we characterized here Pde2a+/− mice (homozygote animals being not viable) at the behavioral, cellular, molecular and electrophysiological levels. Pde2a+/− females display a milder form of the disorder with reduced cognitive performance in adulthood, conversely males show severe socio-cognitive deficits throughout their life. In males, these phenotypes are associated with microglia activation, elevated glutathione levels and increased externalization of Glutamate receptor (GluR1) in CA1, producing reduced mGluR-dependent Long-term Depression. Overall, our results reveal molecular targets of the PDE2A-dependent pathway underlying socio-cognitive performance. These results clarify the mechanism of action of pro-cognitive drugs based on PDE2A inactivation, which have been shown to be promising therapeutic approaches for Alzheimer's disease, schizophrenia, FXS as well as other forms of ASD.

Alpha-thalassemia X-linked intellectual disability syndrome (ATRX) is a rare genetic disorder caused by mutations in the ATRX gene. It is characterized by distinct dysmorphic features, alpha thalassemia, varying degrees of intellectual disability, and the presence of epilepsy in approximately 30 % of affected individuals. We present the case of a 36-year-old patient with severe intellectual disability and epilepsy due to a hemizygous pathogenic variant, c.736c > T, p. (Arg246Cys), in the ATRX gene. During inpatient treatment, numerous respiratory pauses were detected. Repeated video EEG recordings revealed seizure patterns with a left frontocentral origin and an occasional spread to the bifrontal region and episodes of apnea without an EEG correlate. This case report adds to the current literature, as it shows a co-occurrence of ictal and non-ictal apnea in ATRX syndrome, expanding our understanding of respiratory disturbances in this rare genetic disorder.

Purpose: ARID1B is one of the most frequently mutated genes in intellectual disability cohorts. Thus, far few adult-aged patients with ARID1B-related disorder have been described, which limits our understanding of the disease’s natural history and our ability to counsel patients and their families. Methods: Data on patients aged 18+ years with ARID1B-related disorder were collected through an online questionnaire completed by clinicians and parents. Results: Eighty-seven adult patients with ARID1B were included. Cognitive functioning ranged from borderline to severe intellectual disability. Patients identified through the genetic workup of their child were either mosaic or had a variant in exon 1. New clinical features identified in this population are loss of skill (16/64, 25%) and recurrent patella luxation (12/45, 32%). Self-sustainability data showed that 88% (45/51) could eat independently, and 16% (7/45) could travel alone by public transport. Facial photo analysis showed that patients’ photographs taken at different ages clustered consistently, separate from matched controls. Conclusion: The ARID1B spectrum is broad, and as patients age, there is a significant shift in the medical aspects requiring attention. To address the changing medical needs with increasing age, we have formulated recommendations to promote timely intervention in an attempt to mitigate disease progression.

Purpose: Structured HCT models addressing planning, transfer, and integration into adult care for adolescents and young adults with childhood-acquired chronic conditions are becoming more prevalent. However, consensus on outcome measures to assess health care transition (HCT) interventions particularly for intellectual and developmental disabilities (IDD) population is lacking. This scoping review identified potential HCT outcome measures for young adults (aged 18–26) with IDD using the Quadruple Aim Framework. Methods: On August 6, 2021 and April 27, 2023, Medline Ovid, Embase, Web of Science, PsycINFO, and Cochrane databases were searched using the terms “young adult,” “intellectual disability,” “developmental disability, “cognitive dysfunction,” “autism,” “cerebral palsy,” “spina bifida,” and “transition to adult care.” Searches were limited to publications in English and published from 2000 to present. Observational and experimental (qualitative or quantitative) studies were included if participants were young adults (median/mean ages 18–26) with IDD (Autism, cerebral palsy, Down syndrome, spina bifida, or other IDD-related conditions) and study outcomes addressed one of the Quadruple Aim domains (population health, patient/family experience, cost/utilization, and healthcare provider/caregiver experience). Studies were excluded if participants had attention deficit/hyperactivity disorder or learning disability only, if outcomes were primarily educational or vocational, or if publications were reviews, abstracts, or not in English. Results: One hundred and three articles were included data extraction. Articles were categorized under the Quadruple Aim domains: Population Health (43), Patient/Caregiver Healthcare Experience included (23), Cost/Utilization (24), and Healthcare Provider/Caregiver Experience (15). Most articles were observational and utilized a variety of assessments or internally developed questions as measures. Conclusions: While studies describing HCT outcomes for the IDD population are limited and measures are inconsistent, studies pertaining to Quadruple Aim outcomes identified in this review can further direct efforts towards consensus and standardization of HCT outcome measures to address the needs of individuals with IDD, their families, and caregivers/providers.

Discourses regarding intellectual disability (ID) have traditionally excluded people with this label from sexual and reproductive health education (SRHE). While politically, much has changed, deficit-oriented narratives about labeled people remain and threaten their access to sexual and reproductive health services. Although SRHE providers in Germany are described as crucial for labeled people's sexual literacy, critical and in-depth analyses of SRHE providers' accounts are lacking thus far. To address this gap, people that offer SRHE to labeled individuals in Bavaria, Germany, were interviewed virtually. Data were collected until the categories were saturated, leading to 14 interviews. One core category was constructed using a constructivist grounded theory: ‘promoting integration through SRHE.’ Overall, participants described SRHE as an important part of labeled people's education that aims to facilitate sexual autonomy. Nevertheless, the analysis illustrates how participants recreated traditional narratives about ID and sexuality, despite their attempt to advocate for their target group. This highlights the pervasiveness of deficit-oriented discourses and stresses the need for questioning cognitive ableism to address the root causes of stigmatization that limit the sexual health of labeled people.

Background: The global population is experiencing accelerated biopsychosocial aging. Cognitive impairment is frequently associated with functional impairment in basic and instrumental daily living activities. To maintain optimal cognitive and functional functioning, health professionals recommend that older adults participate in cognitive training. Aims: This study examines the cognitive and functional evolution of older adults with and without Intellectual Disability and the factors associated with favourable evolution following the intervention of a multicomponent programme based on the human occupational model and the person-centred care model. Methods and procedures: 247 people participated. Descriptive and univariate analyses were performed to examine baseline data. The Wilcoxon paired samples test was used to compare cognitive and functional evolution one year after the intervention. Linear regression was used to detect factors predicting favourable evolution. Outcomes and results: Both populations improved cognitively. There was no change in basic activities of daily living. There was an improvement in instrumental activities of daily living in the group with Intellectual Disability. None of the variables collected was a predictor of greater improvement. Conclusions and implications: This study demonstrated that older people with Intellectual Disability who have supports to cope with this life stage can improve their cognitive and functional abilities.

This study explores bullying targeting students with intellectual disability, specifically the extent to which they are subjected to bullying during their intermediate school years. Utilizing students’ personal experiences, it identifies the patterns of bullying behavior to which they are exposed by their neurotypical peers, and its repercussions. The study employs a qualitative approach with eight female student participants with intellectual disability enrolled in intermediate stage special classes attached to inclusive schools. The research finds that all of the participants experienced bullying during their time in intermediate school. The most prominent forms of which were physical and verbal bullying. The study reports that the bullying the students were subjected to by their neurotypical peers caused embarrassment, tears, anger, nervousness, feelings of oppression, withdrawal, and a preference for associating others with a disability, rather than their neurotypical peers. The study's participants suggested ways to minimize bullying, including the promotion of neurotypical students’ respect and appreciation for their peers with a disability, and recommended that administrators, teachers, counsellors, and parents play an active role in guiding neurotypical students to respect and value students with intellectual disability.

Background: Snoezelen focuses on multisensory stimulation in an adapted environment and was originally developed for people with severe and profound intellectual (and multiple) disabilities. Snoezelen has been used for many years with various target groups and for different purposes. Variation in its application has resulted in a lack of understanding of snoezelen's application characteristics and of how they may relate to effects. Objective: The aim of this review was to provide an overview of the application and effects of snoezelen in people with intellectual disability or dementia in order to analyse the relationship between application characteristics and effects. Design: A systematic review. Methods: Five databases were searched for snoezelen studies that took place in a specially adapted environment. The methodological quality of the included studies was assessed using the Mixed Methods Appraisal Tool. The application characteristics (that is, the stimuli used, environment, and support given) and the effects were extracted. Reported effects were categorized into different human functioning dimensions using the model of intellectual disabilities of the American Association on Intellectual and Developmental Disabilities. Results: In total, 62 studies involving people with intellectual disability (n = 30) or dementia (n = 32) were included. An overview of snoezelen used in other target groups (n = 24) is provided as supplementary material. Details on the application of snoezelen were often lacking. A total of 10 application characteristics (for example, frequency, role of the support person) were extracted. All studies reported the presence of a support person (n = 62; 100%). Effects were found in all five human functioning dimensions. The most-reported effects (61.3% overall) related to mental health, such as a reduction in challenging behaviour and improved mood. In a minority of studies (n = 10, 16.1%), effects on the support person were also reported. Due to limited details about the application of snoezelen and the large variation in measured effects, analysing the relationship between these was impossible. Conclusions: The majority of studies lacked details on application characteristics during snoezelen. Reported effects varied, although most related to mental health. Future research should analyse in detail the relationship between application and effects.

Background: To date, there is little evidence on the characteristics of defendants with intellectual disability when presenting to the criminal court system. This study was developed to recognise and examine the characteristics related to gender, ethnicity, mental health and index offences of defendants with intellectual disability and compare these to defendants without intellectual disability within Court Liaison & Diversion Services in London, England. Methods: This is a retrospective data analysis of routine administrative data collected by the Liaison and Diversion services across five Magistrates courts in London, England. Data were analysed on defendants identified through screening to have an intellectual disability and compared to defendants without an intellectual disability. Results: 9088 defendants were identified, of these 4%, (349) were screened as having an intellectual disability. The study found an overrepresentation of defendants of black ethnicity along with high rates of comorbid mental illness and personality disorder amongst both non-intellectual disability and intellectual disability defendants. Defendants with intellectual disability self-reported self-harm and suicidal behaviour at higher rates. For neurodevelopmental disorders (NDD), those with intellectual disability were over 4 times more likely to have comorbid ADHD and over 14 times more likely to have ASD. Index offences were mostly similar although defendants with intellectual disability had elevated rates of being charged with sexual offences and breach of the peace. Conclusion: The findings confirm the presence of a small but significant number of defendants with intellectual disability presenting to the Court Liaison & Diversion services who have significant needs in terms of comorbidity and risk for suicide and self-harm behaviour. Further research is needed to understand the experiences of defendants with intellectual disability presenting to the Court including how best to deliver service models to improve recognition and respond to their high rates of health needs.

Down syndrome (DS) or trisomy 21 is the most common genetic cause of intellectual disability (ID), but a pathogenic mechanism has not been identified yet. Studying a complex and not monogenic condition such as DS, a clear correlation between cause and effect might be difficult to find through classical analysis methods, thus different approaches need to be used. The increased availability of big data has made the use of artificial intelligence (AI) and in particular machine learning (ML) in the medical field possible.The purpose of this work is the application of ML techniques to provide an analysis of clinical records obtained from subjects with DS and study their association with ID.We have applied two tree-based ML models (random forest and gradient boosting machine) to the research question: how to identify key features likely associated with ID in DS. We analyzed 109 features (or variables) in 106 DS subjects. The outcome of the analysis was the age equivalent (AE) score as indicator of intellectual functioning, impaired in ID. We applied several methods to configure the models: feature selection through Boruta framework to minimize random correlation; data augmentation to overcome the issue of a small dataset; age effect mitigation to take into account the chronological age of the subjects.The results show that ML algorithms can be applied with good accuracy to identify variables likely involved in cognitive impairment in DS. In particular, we show how random forest and gradient boosting machine produce results with low error (MSE

Summary: Background: Intellectual disability (ID) is a disorder with unknown aetiology in many cases. Maternal alcohol use is a known risk factor for ID, but less is known about the importance of maternal and paternal substance use disorder (SUD) and risk of ID in offspring. Methods: Data from multiple nationwide registers were used to create a cohort of children born from January 01, 1978 to December 31, 2002. All participants were born in Sweden, had available parental identification information and did not emigrate or die before age 12 (n = 1,940,820). Logistic regression modelling was performed with exposure defined as having a parent who received any SUD diagnosis, including alcohol use disorder (AUD) and drug use disorder (DUD). The outcome was registration of diagnosis of any form of ID. First, we analysed the risk of ID if parental SUD was registered prior to childbirth with stepwise adjustment of multiple covariates. Second, the effect of timing of SUD diagnosis in relation to childbirth was analysed. Findings: Of 37,410 offspring with parental SUD registered prior to birth, 3.0% (n = 1110) had any form of ID compared to 1.2% (n = 23,168) of those 1,903,410 individuals without parental SUD prior birth. Parental SUD prior birth was associated with an increased risk of any form of ID (Odds Ratio [OR]: 2.3 [2.2–2.5]), with ORs similar for maternal (OR: 2.3 [2.1–2.5]) and paternal SUD (OR: 2.3 [2.1–2.5]). These ORs were reduced but remained statistically significant after adjusting for parental education, migration, psychiatric comorbidity, and co-parent SUD (OR parental SUD: 1.6 [1.5–1.8]; OR maternal SUD: 1.4 [1.2–1.5]; OR paternal SUD: 1.6 [1.5–1.7]). Parental SUD was associated with increased risk of ID in offspring irrespective of timing of diagnosis, but if mothers or fathers were diagnosed with AUD during pregnancy (OR maternal AUD: 5.0 [3.1–8.2]; OR paternal AUD: 2.8 [2.2–3.6]), the risk was significantly greater than if the AUD diagnosis was first registered after childbirth (OR maternal AUD: 1.9 [1.8–2.0]; OR paternal AUD: 1.6 [1.6–1.7]). Interpretation: Both paternal and maternal SUD were associated with an increased risk of ID in offspring, with greatest risk observed when AUD was diagnosed during pregnancy. Possible mechanisms may involve shared genetic and environmental factors, including toxic effects from alcohol intake. These findings have clinical implications in suggesting that parental SUD in either parent represents a possibly modifiable risk factor to consider when developing prevention, diagnostics and treatment programs for children with ID. Funding: Stockholm County Council, the Research Council of the Swedish Alcohol Retailing Monopoly, Fredrik and Ingrid Thurings stiftelse, Academy of Finland, the Swedish Research Council and the Swedish Research Council for Health, Working Life and Welfare, Nordforsk by the Nordic Council of Ministers and the Polish Medical Research Agency.

This paper proposes an effective approach for predicting quality of life (QoL) for dependent individuals in guardianship entities. In addition, it aims to improve the QoL of people with intellectual disabilities. The proposed QoL prediction approach employs machine learning (ML) techniques to model the relationship between eight aspects of QoL and the corresponding QoL index. It determines whether or not a person needs assistance based on the index value. The proposed approach determines the priority of care (PoC) value for each aspect of a person. Based on PoC, the deficit aspect is determined, followed by the type of assistance a person requires, based on the decision priorities. It also generates a support report with suggested actions to highlight the level in that aspect. In addition, we train multiple ML models to predict the standard score (SS), which represents the support value related to the eight aspects of QoL. Finally, we use SS values to train an ML model to predict the support intensity scale (SIS). On a dataset compiled from guardianship entities, the proposed approach is validated. The QoL index, SS, and SIS prediction models achieve average R2 values of 0.9897, 0.9998, and 0.9977 with a standard deviation of 0.0051, 0.0002, and 0.0007, respectively.

The short, non-coding RNAs known as miRNA modulate the expression of human protein-coding genes. About 90 % of genes in humans are controlled by the expression of miRNA. The dysfunction of these miRNA target genes leads to many human diseases, including neurodevelopmental disorders as well. Intellectual disability (ID) is a neurodevelopmental disorder that is characterized by adaptive behavior and intellectual functioning which includes logical reasoning, ability in learning, practical intelligence, and verbal skills. Identification of miRNA involved in ID and their associated target genes can help in the identification of diagnostic biomarkers related to ID at a very early age. The present study is an attempt to identify miRNA and their associated target genes that play an important role in the development of intellectual disability patients through the meta-analysis of available transcriptome data. A total of 6 transcriptomic studies were retrieved from NCBI and were subjected to quality check and trimming before alignment. The normalization and identification of differentially expressed miRNA were carried out using the EdgeR package of R studio. Further, the gene targets of downregulated miRNA were identified using miRDB. The system biology approaches were also applied to the study to identify the hub target genes and the diseases associated with main miRNAs.

Intellectual disability (ID) is a neurodevelopmental disorder associated with impaired cognitive and adaptive behaviors and represents a major medical issue. Although ID-patients develop behavioral problems and are diagnosed during childhood, most behavioral studies in rodent models have been conducted in adulthood, missing precocious phenotypes expressed during this critical time-window characterized by intense brain plasticity. Here, we selectively assessed postnatal ontogenesis of behavioral and cognitive processes, as well as postnatal brain development in the male Rsk2-knockout mouse model of the Coffin-Lowry syndrome, an X-linked disorder characterized by ID and neurological abnormalities. While Rsk2-knockout mice were born healthy, a longitudinal MRI study revealed a transient secondary microcephaly and a persistent reduction of hippocampal and cerebellar volumes. Specific behavioral parameters from postnatal day 4 (P4) unveiled delayed acquisition of sensory-motor functions and alterations of spontaneous and cognitive behaviors during adolescence, which together, represent hallmarks of neurodevelopmental disorders. Together, our results suggest for the first time that RSK2, an effector of the MAPK signaling pathways, plays a crucial role in brain and cognitive postnatal development. This study also provides new relevant measures to characterize postnatal cognitive development of mouse models of ID and to design early therapeutic approaches.

Resumen: El diagnóstico precoz de los trastornos del desarrollo permite detectar causas tratables, realizar intervenciones oportunas y dar respuestas a inquietudes de la familia evitando procedimientos innecesarios. Se requiere un enfoque clínico que permita distinguir entre retraso en la emergencia de habilidades, desarrollo atípico o pérdida de habilidades ya adquiridas, como también si se trata de un retraso en un área específica del desarrollo o compromete el desarrollo en forma global. Es necesario considerar el retraso global del desarrollo o discapacidad intelectual como un fenotipo amplio y heterogéneo, manifestación de diversos trastornos o etiologías subyacentes, por lo que se han diseñado algoritmos estructurados por asociaciones académicas, que incluyen estrategias para la sospecha etiológica y recomendaciones de estudios de neuroimagen, metabólicos o genéticos, reconociendo a la historia y el examen físico como fundamentales en el proceso de diagnóstico, permitiendo además la pesquisa de trastornos asociados de visión o audición y el manejo oportuno de comorbilidad psiquiátrica de mayor prevalencia en este grupo de niños. Considerando que el estudio diagnóstico puede requerir bastante tiempo, se deben iniciar intervenciones en los problemas detectados y en apoyo a los padres y al desarrollo del niño mientras se esperan resultados.Participar en estrategias de prevención de discapacidad intelectual, tanto como en las de promoción de desarrollo óptimo en la infancia, es una responsabilidad para todos los profesionales dedicados a desarrollo infantil. Abstract: Early diagnosis of developmental disorders makes it possible to detect treatable causes, carry out timely interventions and respond to family concerns, avoiding unnecessary procedures. A clinical approach is required to distinguish between delay in the emergence of skills, atypical development or loss of skills already acquired, as well as whether it is a delay in a specific area of development or compromises development globally. It is necessary to consider global developmental delay or intellectual disability as a broad and heterogeneous phenotype, a manifestation of various disorders or underlying etiologies, which is why algorithms structured by academic associations have been designed, which include strategies for etiological suspicion and recommendations for studies of neuroimaging, metabolic or genetic, recognizing the history and physical examination as fundamental in the diagnostic process, also allowing the investigation of associated vision or hearing disorders and the timely management of psychiatric comorbidity of greater prevalence in this group of children. Considering that the diagnostic study can take a long time, interventions should be started on the problems detected and in support of the parents and the child's development while the results are awaited.Participating in strategies for the prevention of intellectual disability, as well as in those for the promotion of optimal development in childhood, is a responsibility for all professionals dedicated to child development

Introduction: Informal caregivers of children and adolescents with intellectual disabilities and attention deficit/hyperactivity disorder (ADHD) face numerous challenges. However, no study has yet compared the HRQoL of the caregivers of children and adolescents with these two conditions. We aimed to compare the HRQoL and perceived stress of caregivers of children and adolescents with intellectual disabilities and ADHD. Methods: The HRQoL and perceived stress of informal caregivers of children and adolescents with intellectual disabilities and ADHD (40 in each group) were compared using the perceived stress scale and the Quality of Life Enjoyment and Satisfaction Questionnaire – Short Form, respectively. Results: HRQoL was significantly worse in most dimensions in caregivers of children and adolescents with severe ADHD than in caregivers of children and adolescents with severe intellectual disabilities. However, perceived stress was similar. Conclusion: Differences in the impact of intellectual disability and ADHD on family members' HRQoL should be considered while developing educational programs for patients and their families.

Creatine transporter deficiency is an X-linked genetic disorder caused by a variant in the SLC6A8 gene located on the X chromosome (Xq28). This condition varies in severity with features often including intellectual disabilities, speech delay, autistic features, attention deficit hyperactivity and gastrointestinal issues. While creatine transporter deficiency primarily affects males, females may also demonstrate severe phenotypes. However, screening of creatine transporter deficiency in females can be especially difficult as urine creatine/creatinine screenings often have values falling within normative ranges. Also, females may not demonstrate the characteristic reduction of creatine concentrations in the brain visualized with in vivo proton magnetic resonance spectroscopy. Identification typically results from exome sequencing. In this report, we present the clinical, imaging, and spectroscopy features of a heterozygous female with a severe presentation of creatine transporter deficiency.

Short stature and intellectual disability are two of the major components of many dysmorphic syndromes. Jansen–de Vries syndrome (JDVS) is a rare syndromic disorder that was discovered recently using next-generation sequencing. It is characterized by hypotonia, developmental delay, a dysmorphic face, short stature, and high pain threshold and is caused by the variants of the protein phosphatase magnesium-dependent 1D (PPM1D) gene. Here, we report the first two cases of PPM1D mutations in Taiwan; both had de novo variants in exon 6. Both presented with short stature, developmental delay, and dysmorphic faces. In addition to the characteristics listed above, syndactyly was noted in one. Genetic studies should be considered when approaching a patient with growth retardation, intellectual disability, and other major or minor dysmorphisms.

We report the case of the third patient with Tsukahara-Azuno-Kaiji syndrome. It is characterized by brachydactyly A1, dwarfism, microcephaly, scoliosis, intellectual disability, ptosis, and hearing loss. The first patient was reported in 1989, and the second in 2010. The present patient had many features in common with the previous 2 patients, with a few minor differences. Although this combination of symptoms is very characteristic, the clinicians should know about this syndrome to diagnose it. The syndrome in this patient appeared sporadically, and chromosome G-banding revealed a normal female karyotype of 46XX. However, further genetic research could not be performed. Steady accumulation of information will enable us to discover the true clinical and genetic nature of the disease and to make the diagnosis more easily.

Objectives: Adults with intellectual or developmental disabilities (IDD) face substantial barriers to accessing high-quality, patient-centered care. This paper describes the development and evolution of the Freeman Center, an integrated, interdisciplinary center developed using feedback from adults with IDD and their family members. Methods: We evaluated the reach of the Freeman Center services and described the patient population. Results: As of November, 2022, 1068 patients were seen at the Freeman Center. These patients represent about 5 % of all people with IDD in Hamilton County Ohio, where the Freeman Center is located. On average in 2022, the Freeman Center provided approximately 380 primary care visits, 47 psychiatry visits, and 85 combined primary care and psychiatry service visits per month. Conclusions: Patient demographic characteristics are largely consistent with the general population of Hamilton County, indicating patients are representative of the county the clinic primarily serves. Further work is needed to evaluate patient outcomes at the Freeman Center.

Purpose: GenIDA is an international patient registry for individuals diagnosed with intellectual disability, autism spectrum disorder, and/or epilepsy, which is based on an online questionnaire that is completed by parent caregivers. In this study, the GenIDA data on Koolen-de Vries syndrome (KdVS) was analyzed illustrating the value of GenIDA and patient/caregiver participation in rare genetic neurodevelopmental disorders (NDDs). Methods: Recruitment was done on the GenIDA website from November 2016 to February 2022. Clinical information on individuals with KdVS was extracted for in-depth analysis and for comparison with the GenIDA data of individuals diagnosed with other NDDs. Results: A total of 1417 patients/caregivers across 35 genetic conditions answered to the GenIDA questionnaire, including caregivers of 237 individuals with KdVS. GenIDA findings on KdVS were consistent with the existing literature, and there were no significant differences between individuals with a 17q21.31 microdeletion and those with a pathogenic variant in the KANSL1 gene. GenIDA provided detailed clinical information including features that are over-represented in KdVS compared with other NDDs (eg, laryngomalacia). Modeling of the natural history showed a positive development of speech and language over time and relatively good reading ability in KdVS. Valproate and oxcarbazepine were reported as effective antiepileptic drugs, and responses to open-ended questions indicated that childhood recurrent pneumonia and asthma are clinically relevant comorbidities that were not described in KdVS before. Conclusion: GenIDA is a powerful registry to collect and harness valuable data on rare NDDs. The study shows that caregiver-driven data collection is effective in terms of global recruitment and centralization of clinical data.

DYNC1H1 variants are associated with peripheral neuronal dysfunction and brain morphology abnormalities resulting in neurodevelopmental delay. However, few studies have focused on the association between DYNC1H1 variants and epilepsy. Herein, we report a case of drug-resistant focal epilepsy associated with a pathogenic variant of DYNC1H1. We further summarized the clinical, genetic, and neuroimaging characteristics of patients with DYNC1H1 variant–associated epilepsy from the relevant literature. This report expands the phenotypic spectrum of DYNC1H1-related disorder to include early-onset epilepsy, which is frequently associated with neurodevelopmental delay and intellectual disability, malformations of cortical development, and neuromuscular, ophthalmic, and orthopedic involvement.

Summary: WDR5 is a broadly studied, highly conserved key protein involved in a wide array of biological functions. Among these functions, WDR5 is a part of several protein complexes that affect gene regulation via post-translational modification of histones. We collected data from 11 unrelated individuals with six different rare de novo germline missense variants in WDR5; one identical variant was found in five individuals and another variant in two individuals. All individuals had neurodevelopmental disorders including speech/language delays (n = 11), intellectual disability (n = 9), epilepsy (n = 7), and autism spectrum disorder (n = 4). Additional phenotypic features included abnormal growth parameters (n = 7), heart anomalies (n = 2), and hearing loss (n = 2). Three-dimensional protein structures indicate that all the residues affected by these variants are located at the surface of one side of the WDR5 protein. It is predicted that five out of the six amino acid substitutions disrupt interactions of WDR5 with RbBP5 and/or KMT2A/C, as part of the COMPASS (complex proteins associated with Set1) family complexes. Our experimental approaches in Drosophila melanogaster and human cell lines show normal protein expression, localization, and protein-protein interactions for all tested variants. These results, together with the clustering of variants in a specific region of WDR5 and the absence of truncating variants so far, suggest that dominant-negative or gain-of-function mechanisms might be at play. All in all, we define a neurodevelopmental disorder associated with missense variants in WDR5 and a broad range of features. This finding highlights the important role of genes encoding COMPASS family proteins in neurodevelopmental disorders.

Learning disability is a term that can mean different things to different people. It is also a term that has undergone much revision and critique, being linked to stigma and prejudice. Consequently, talking about learning disability can be a delicate matter. This paper analyses the discursive work done by focus group participants (professionals and lay people in supportive roles) to manage their talk about learning disability. We show how participants drew on six interpretive repertoires, organised as three binary pairs, to negotiate an ideological dilemma associated with stigma and the body. We argue that the participants drew on these repertoires to maintain a particular subject position, the ‘good person’ subject position, and performed what we call ‘passing off’ behaviour to manage their talk. We conclude that some aspects of learning disability remain ‘unspeakable’, and that this has consequences for the policies and practices which determine the support available to people with learning disabilities.

Background: While intellectual disability is associated with higher mortality rates due to circulatory diseases, it is unclear whether intellectual disability is associated with higher risk of myocardial infarction (MI) and stroke than the general population., Objectives: We aimed to analyze the risk of cardiovascular diseases (CVD), specifically myocardial infarction (MI) and ischemic stroke, and death due to circulatory diseases in individuals with disability., Methods: This retrospective cohort study used data from the National Disability Registration System linked to the Korean National Health Insurance Service database. Individuals who underwent national health examinations in 2009 were followed until 2020. Cox-proportional hazard analyses were performed to estimate the risk of CVD, MI, ischemic stroke, and circulatory disease deaths with adjustment for covariates., Results: A total of 3642 individuals with intellectual disability (mean [SD] age 39.1 [12.6], 28.8 % female) and 3,889,794 individuals without intellectual disability (mean [SD] age 47.1 [13.9], 45.6 % female) were included. Compared to those without intellectual disability, those with intellectual disability had higher risk of CVD (adjusted hazard ratio [aHR] 1.71, 95 % confidence interval [CI] 1.45-2.02), ischemic stroke (aHR 2.21, 95 % CI 1.81-2.69), and death due to circulatory diseases (aHR 4.20, 95 % CI 3.24-5.45), and a non-significant risk for MI (aHR 1.24, 95 % CI 0.95-1.63) after full adjustment for covariates., Conclusions: Individuals with intellectual disability were at increased risk of CVD, in particular ischemic stroke, and death due to circulatory diseases. Healthcare professionals should be aware of increased CVD risk in individuals with intellectual disability., Competing Interests: Declaration of competing interest The authors have no potential conflicts of interest to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Spastic paraplegia, intellectual disability, nystagmus, and obesity syndrome (SINO) is a rare autosomal dominant condition caused by heterozygous variants in KIDINS220. A total of 12 individuals are reported, comprising 8 with SINO and 4 with an autosomal recessive condition attributed to biallelic KIDINS220 variants., Methods: In our international cohort, we have included 14 individuals, carrying 13 novel pathogenic KIDINS220 variants in heterozygous form. We assessed the clinical and molecular data of our cohort and previously reported individuals and, based on functional experiments, reached a better understanding of the pathogenesis behind the KIDINS220-related disease., Results: Using fetal tissue and in vitro assays, we demonstrate that the variants generate KIDINS220 truncated forms that mislocalize in punctate intracellular structures, with decreased levels of the full-length protein, suggesting a trans-dominant negative effect. A total of 92% had their diagnosis within 3 years, with symptoms of developmental delay, spasticity, hypotonia, lack of eye contact, and nystagmus. We identified a KIDINS220 variant associated with fetal hydrocephalus and show that 58% of examined individuals present brain ventricular dilatation. We extend the phenotypic spectrum of SINO syndrome to behavioral manifestations not previously highlighted., Conclusion: Our study provides further insights into the clinical spectrum, etiology, and predicted functional impact of KIDINS220 variants., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2024 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Objectives: Patient-reported experience measures (PREMs) collect essential data for service and system-wide quality improvement and performance monitoring toward value-based care. However, the experiences of people with intellectual disability, who have high healthcare utilization couple with poorer outcomes, are often omitted from system-wide PREMs and service-wide PREMs data. The use of PREMs instruments for data collection among people with intellectual disability has not been explored. This review aimed to identify and synthesize measurement tools and approaches that have been used to gather patient-reported experience data from people with intellectual disability., Methods: Rapid evidence assessment was used, in which comprehensive search strategies were applied to electronic databases and gray literature. Narrative synthesis was used with the included articles to address the review aim., Results: A total of 48 documents were included; 26 peer-reviewed journal articles and 22 articles from gray literature. Patient-reported experiences have been gathered from people with intellectual disabilities in relation to specific services or encounters, predominantly using qualitative methods. To date, there is an absence of targeted service- or system-wide surveys. Existing clinic- and condition-specific instruments provide insight for broader application., Conclusions: Patient experience assessment among people with intellectual disability requires consideration of (1) how individuals are identified and approached, (2) the content, design and structure of measurement instruments, and (3) the process by which data are collected, and (4) how it may be applied to create change. Despite the collection of patient experience data from people with intellectual disability, there is little research available about how this information is later used to support health service improvement. Applying PREMs for quality improvement is critical to realize the improvements to healthcare provision required for people with intellectual disability toward equitable care quality., Competing Interests: Author Disclosures Author disclosure forms can be accessed below in the Supplemental Material section., (Copyright © 2024. Published by Elsevier Inc.)

Although the precise underlying cause(s) of autism spectrum disorder remain unclear, more than 1000 rare genetic variations are associated with the condition. For a large number of people living with profound autism, this genetic heterogeneity has impeded the identification of common biological targets for therapy development for core and comorbid traits that include significant impairments in social communication, and repetitive and restricted behaviors. A substantial number of genes associated with autism encode proteins involved in signal transduction and synaptic transmission that are critical for brain development and function. CAMK4 is an emerging risk gene for autism spectrum disorder that encodes the Ca 2+ -calmodulin-dependent protein kinase-4 (CaMK4) enzyme. CaMK4 is a key component of a Ca 2+ -activated signaling pathway that regulates neurodevelopment and synaptic plasticity. In this review, we discuss three genetic variants of CAMK4 found in individuals with hyperkinetic movement disorder and comorbid neurological symptoms including autism spectrum disorder that are likely pathogenic with monogenic effect. We also comment on four other genetic variations in CAMK4 that display associations with autism spectrum disorder, as well as twelve examples of autism-associated variations in other genes that impact CaMK4 signaling pathways. Finally, we highlight three environmental risk factors that impact CaMK4 signaling based on studies in preclinical models of autism and/or clinical cohorts. Overall, we review molecular, genetic, physiological, and environmental evidence that suggest defects in the CaMK4 signaling pathway may play an important role in a common autism pathogenesis network across numerous patient groups, and propose CaMK4 as a potential therapeutic target., (Copyright © 2024. Published by Elsevier Inc.)

Background: In recognition of their status as a health disparities population, there is growing emphasis on conducting research inclusive of adults with intellectual disability to generate new knowledge and opportunities to improve health and equity. Yet they are often excluded from research, and human research participant protection experts and researchers lack agreement on effective consent protocols for their inclusion., Objective: We sought to identify approaches to consent in US-based social-behavioral research with adults with intellectual disability., Methods: We conducted a systematic review on approaches to self-consent with adults with intellectual disability published between 2009 and 2023, identified via searching eight databases and reference list hand searches. We identified 13 manuscripts and conducted a thematic analysis., Results: Our analysis identified themes related to guiding principles, strategies to enhance informed and voluntary consent, approaches to consent capacity, involving individuals subject to guardianship, and strategies for expressing decisions and enhancing ongoing decisions., Conclusions: Manuscripts largely reflected an emphasis on identifying approaches to consent that reflect disability rights principles to promote the right to be included and make one's own decisions based on assessment of relevant information, risks and benefits, and to employ reasonable modifications to achieve inclusion. To avoid the risks of exclusion and advance the responsible inclusion of adults with intellectual disability, we make recommendations to align consent approaches anchored in contemporary thinking about human research participant protections, including through integration with disability rights., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Malonyl-CoA decarboxylase (MLYCD) deficiency, also known as malonic aciduria (MAD), is a rare autosomal recessive inherited metabolic defect. In this study, we aimed to investigate the clinical and molecular features of five patients with MAD in order to increase clinicians' awareness of the disease., Methods: Sanger sequencing was used to detect and genetically analyze the MLYCD variations in the preexisting patients and their parents., Results: Five patients with MAD (5 months to 9.6 years old; two males and three females) rarely exhibited metabolic decompensation episodes or seizures. All patients exhibited varying degrees of developmental delay and hypotonia. Our study expands the spectrum of variants of the MLYCD gene. MLYCD gene variations were detected in all five patients, and five new variants were identified: c.60delG (p.Arg21Glyfs*52), c.928C > T (p.Arg310*), c.1293G > T (p.Trp431Cys), c.721T > C (p.Ser241Pro), and Exons 4-5 deletion. Additionally, there is no correlation between various genotypes and phenotypes., Conclusion: A high-medium-chain triglyceride and low-long-chain triglyceride diet supplemented with L-carnitine was effective in most patients and may improve cardiomyopathy and muscle weakness. Newborn screening may aid in the early diagnosis, treatment, and prognosis of this rare disorder., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Introduction: Increasing evidence reveals critical roles for CHD2 in children with developmental and epileptic encephalopathy., Objectives: The aim was to present clinical analysis results of five cases with CHD2 mutations and 157 reported cases with non-copy number variations (non-CNV) of CHD2., Methods: This study recruited pediatric epilepsy patients with CHD2 mutations and clinical data from November 2016 to October 2023 in the Linyi People's Hospital, China. Whole-exome and gene panel sequencing were employed to find mutations. The HGMD and PubMed databases were examined for documented cases that had CHD2 mutations., Results: This study reports five cases with CHD2 mutations: c.3543T > A, c.1850A > G, c.2536C > T, c.4233&#95;4236del, c.3782G > C. Three novel mutations (c.3543T > A, c.1850A > G, c.2536C > T) have never been reported. c.4233&#95;4236del has been reported in three cases, indicating that this locus may be a mutation hotspot. c.3782G > C has been reported in one case. All five patients had seizures before the age of four. Three patients had varying degrees of developmental delay, and four patients had varying degrees of intellectual disability. All of them had controlled seizures after Valproic acid (VPA) monotherapy or VPA in combination with other medications. Furthermore, we reviewed 157 reported cases having non-CNV mutations of CHD2. Most mutations of these cases were de novo. Epilepsy, developmental delay, and intellectual disability were the typical clinical phenotypes. We also found a significant clustering of the mutations near the C-terminus of the CHD2 protein (P < 0.001)., Conclusion: This study reports new CHD2 genotypes and analyzes reported CHD2 mutation cases. Given its significance in epileptic encephalopathies, research on the CHD2 gene may provide new insights into epileptogenesis., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier Ltd.)

Background: ARID1A/ARID1B haploinsufficiency leads to Coffin-Siris syndrome, duplications of ARID1A lead to a distinct clinical syndrome, whilst ARID1B duplications have not yet been linked to a phenotype., Methods: We collected patients with duplications encompassing ARID1A and ARID1B duplications., Results: 16 ARID1A and 13 ARID1B duplication cases were included with duplication sizes ranging from 0.1-1.2 Mb(1-44 genes) for ARID1A and 0.9-10.3 Mb(2-101 genes) for ARID1B. Both groups shared features, with ARID1A patients having more severe intellectual disability, growth delay and congenital anomalies. DNA methylation analysis showed that ARID1A patients had a specific methylation pattern in blood, which differed from controls and from patients with ARID1A or ARID1B loss-of-function variants. ARID1B patients appeared to have a distinct methylation pattern, similar to ARID1A duplication patients, but further research is needed to validate these results. Five cases with duplications including ARID1A or ARID1B initially annotated as duplications of uncertain significance were evaluated using PhenoScore and DNA methylation re-analysis, resulting in the reclassification of two ARID1A and two ARID1B duplications as pathogenic., Conclusion: Our findings reveal that ARID1B duplications manifest a clinical phenotype and ARID1A duplications have a distinct episignature that overlaps with that of ARID1B duplications, providing further evidence for a distinct and emerging BAFopathy caused by whole gene duplication rather than haploinsufficiency., (Copyright © 2024. Published by Elsevier Inc.)

Background: Identifying the underlying etiology of developmental delay/intellectual disability (DD/ID) is challenging but important. The genetic diagnosis of unexplained DD/ID helps in the treatment and prognosis of the disability in patients. In this study, we reported our experience of using whole exome sequencing (WES) of children with unexplained DD/ID., Methods: We conducted a retrospective analysis of WES results of children under 19 years of age with unexplained DD/ID between January 2020 and December 2021. The demographic data of all patients and variants identified through WES were evaluated. Furthermore, we evaluated the clinical characteristics that influenced the identification of genetic causes., Results: Forty-one patients with DD/ID were included, of whom 21 (51.2 %) were male. The average age at symptom onset was 1.6 ± 1.3 years, and the duration from symptom onset to diagnosis was 3.1 ± 3.7 years. Hypotonia was the most common symptom (17 patients, 41.5 %), and epilepsy was confirmed in 10 patients (24.4 %). Twenty-two pathogenic/likely pathogenic variants were identified in 20 patients, and three variants of uncertain significance were identified in three patients. Family-based trio Sanger sequencing for candidate variants of 12 families was conducted; 10 variants were de novo, one variant paternally inherited, and two variants compound heterozygous. The diagnostic yield of WES for DD/ID was 48.8 % and was significantly high in patients with an early onset of DD/ID and facial dysmorphism. In contrast, patients with autism spectrum disorder (ASD) were more likely to have negative WES results compared with others without ASD., Conclusion: The diagnostic yield of WES was 48.8 %. We conclude that patients' characteristics, such as dysmorphic features and the age of symptom onset, can predict the likelihood that WES will identify a causal variant of a phenotype., Competing Interests: Declaration of competing interest The authors have no potential conflicts of interest to declare with respect to the authorship and/or publication of this article., (Copyright © 2024 Taiwan Pediatric Association. Published by Elsevier B.V. All rights reserved.)

Chromosome 15q11.2-13.1 duplication (Dup15q) syndrome is one of the most common autism spectrum disorders (ASDs) associated with copy number variants (CNVs). For the analysis of CNV-relevant pathological cellular phenotypes, a CNV-corrected isogenic cell line is useful for excluding the influence of genetic background. Here, we devised a strategy to remove the isodicentric chromosome 15 by inserting a puro-ΔTK selection cassette into the extra chromosome using the CRISPR-Cas9 system, followed by a subsequent two-step drug selection. A series of assays, including qPCR-based copy number analysis and karyotype analysis, confirmed the elimination of the extra chromosome. Furthermore, cerebral organoids were generated from the parental Dup15q iPSCs and their isogenic iPSCs. scRNA-seq analysis revealed the alteration of expression levels in ion-channel-related genes and synapse-related genes in glutamatergic and GABAergic neurons in Dup15q organoids, respectively. The established isogenic cell line is a valuable resource for unraveling cellular and molecular alterations associated with Dup15q syndrome., Competing Interests: Declaration of Competing Interest This work was supported by Takeda Pharmaceutical Company Limited. H.Y. is an employee of Takeda Pharmaceutical Company Limited. No other potential conflicts of interest relevant to this article were reported., (Copyright © 2024. Published by Elsevier GmbH.)