Search Results (893)

Germline mutations in the X-linked cohesin subunit gene SMC1A have been increasingly recognized as a cause of developmental and epileptic encephalopathy (DEE); however, the underlying basis of its marked phenotypic heterogeneity remains elusive. In our narrative review, starting from all literature-reported clinical cases of SMC1A-related DEE, we propose an integrative framework summarizing all the clinical and genetic features, stratified by mutation type, mosaic fraction, and X-chromosome inactivation (XCI) patterns to provide valuable support for genetic diagnosis and variants, found to date. Also, we discuss how somatic mosaicism and epigenetic variability underlie the clinical diversity of SMC1A-associated epilepsy and systematically describe the entire phenotypic spectrum, from early-onset, therapy-resistant seizures to milder intellectual disability profiles. We further examine how SMC1A mutations perturb cohesin’s canonical roles in chromatin loop formation and sister-chromatid cohesion, leading to widespread transcriptional dysregulation of neurodevelopmental gene networks. Evidence that XCI skewing can ameliorate or exacerbate neuronal cohesin deficits and, thus modulate seizure threshold, is presented. Full article

Background: Germline pathogenic variants in NSD1 cause Sotos syndrome, a developmental disorder characterised by overgrowth, intellectual disability, macrocephaly, developmental anomalies, and, in some cases, tumour development. Familial cases of Sotos syndrome are rare and genotype–phenotype correlations are not well described. NSD1, a lysine-specific histone methyltransferase, is an important epigenetic regulator and pathogenic variants in NSD1 are associated with a distinctive blood DNA methylation pattern (episignature). We described a family with an NSD1 exon 3 deletion and an atypical clinical phenotype. Methods: DNA episignature profiling was undertaken with a next generation sequencing-based approach. Results: Within the family, the three affected individuals showed clinical variability with the proband being most severely affected, although none showed unequivocal macrocephaly or the characteristic facial features of Sotos syndrome. DNA methylation profiling was performed in the three affected family members, eight individuals with Sotos syndrome, and compared to control samples. The eight individuals with Sotos syndrome displayed genome-wide hypomethylation as previously described. DNA hypomethylation was also apparent in the three family members with the NSD1 exon 3 deletion with the proband being most similar to the episignature observed in confirmed Sotos syndrome patients. The two more mildly affected relatives had less pronounced DNA hypomethylation. Conclusions: A familial germline exon 3 NSD1 deletion was associated with mild Sotos syndrome phenotype with variable expressivity and a DNA methylation episignature that was less marked in milder cases than in individuals with classical Sotos syndrome. These findings support the use of methylation episignature analysis to explore intrafamilial variability in chromatin disorders. Full article

Background: Dominantly acting variants in TUBB2B have primarily been associated with cortical dysplasia complex with other brain malformations 7 (CDCBM7), a disorder in which cortical brain abnormalities are typically linked to developmental delay/intellectual disability (DD/ID) and seizures. While the majority of TUBB2B pathogenic variants have been linked to isolated CDCBM7, only one family with CDCBM7 and congenital fibrosis of the extraocular muscles (CFEOM) has been reported so far. We describe a second individual with a severe phenotype of CFEOM combined with CDCBM7 carrying a pathogenic TUBB2B missense variant previously reported in two individuals with isolated CDCBM7. Methods: A trio-based WGS analysis was performed. The structural impact of the identified substitution was assessed by using the UCSF Chimera (v.1.17.3) software and PyMOL docking plugin DockingPie tool. Results: WGS analysis identified a de novo missense TUBB2B variant (p.Ile202Thr, NM_178012.5), previously associated with isolated CDCBM7. Structural analysis and docking simulations revealed that Ile202 contributes to establishing a proper hydrophobic environment required to stabilize GTP/GDP in the β-tubulin pocket. p.Ile202Thr was predicted to disrupt these interactions. Conclusions: Our findings broaden the mutational spectrum of TUBB2B-related CFEOM, targeting a different functional domain of the protein, and further document the occurrence of phenotypic heterogeneity. We also highlight the limitations of exome sequencing in accurately mapping TUBB2B coding exons due to its high sequence homology with TUBB2A and suggest targeted or genome analyses when clinical suspicion is strong. Full article

Background/Objectives: CLIFAHDD syndrome (OMIM # 616266) is a rare neurodevelopmental disorder caused by mutations in the NALCN gene. It is characterized by hypotonia, developmental delay, and congenital contractures of the limbs and face. We report a 33-year-old Italian woman with a mild form of CLIFAHDD who exhibited early-onset language difficulties and mild intellectual disability and later developed gait and balance impairments in adulthood. Methods and Results: Whole Exome Sequencing (WES) identified a novel missense variant c.1514A>T; p.(Lys505Met) in the NALCN gene. The allele frequency of this variant is not detected (MAF = 0.0), the variant is classified as likely pathogenic according to ACMG criteria, and predicted to be probably damaging by PolyPhen-2. It affects a critical residue within the second pore-forming domain of the NALCN channel, potentially altering lipid interactions and channel regulation. Sanger sequencing and segregation analysis confirmed the variant to be heterozygous and de novo. Conclusions: The patient’s milder symptoms and later onset, compared to severe pediatric cases, suggest that the clinical spectrum of CLIFAHDD syndrome may be broader than previously recognized. These findings underscore the potential influence of mutation location on disease presentation and severity. Full article

Background/Objectives: Living with a disabled family member has extensive implications for the whole family involved in their care, and there is dependency on healthcare support for maintaining quality of life. This qualitative study, conducted in Northern Ireland, investigated the support needs of different family members living with a severely impaired individual across the lifespan. A key objective was to identify support needs for intervention. Methods: In-depth semi-structured interviews were conducted to obtain data from eight mothers, fathers, sisters and brothers of a profoundly disabled child or sibling. Data was analyzed using Interpretive Phenomenological Analysis, allowing for the application of double hermeneutic in which the researchers derived meaning from the lived experiences of participants. Results: The analysis yielded five themes in total. Three themes were related to gaps in healthcare systems: Support Needs in Childhood, Support in Transition into Adult Services, and Worry for the Future; and two themes were linked with support needs: Associative Disability in Family Members; and Stigma. All family members had caregiving roles, and these had similarities and differences according to the relationship with the care-receiver. Participants recognized their families were survivors, however maintained a family tragedy rather than positive change outlook. Conclusions: Recommendations derived from the findings to alleviate the stressors of the situation for family members include increasing community support and age-related respite facilities. Additionally, improving and enhancing education of disabilities in schools, and immersing and further integrating individuals with disability into society, will alleviate the alienation, isolation and loneliness experienced by family members. Full article

Background: Autosomal dominant intellectual developmental disorder 51 (MIM #617788) is caused by pathogenic variants in KMT5B, a histone methyltransferase essential for transcriptional repression and central nervous system development. The disorder manifests as a complex neurodevelopmental syndrome with variable neurological and systemic features. Methods: Two adolescents with nonsense KMT5B variants underwent detailed clinical, neuropsychological, and neuroimaging evaluations, including MRI and ¹⁸FDG PET/CT, analyzed with Statistical Parametric Mapping against matched controls. RNA sequencing was performed, and the literature was reviewed to assess genotype–phenotype correlations. Results: Both patients showed global developmental delay, progressing to autism spectrum disorder (ASD) and developmental coordination disorder (DCD), without intellectual disability (ID). The MRI was normal, but neuropsychological testing revealed executive function impairment, expressive language deficits, and behavioral disturbances. PET/CT consistently demonstrated cerebellar and temporal lobe hypometabolism, correlating with symptom severity. RNA sequencing identified shared dysregulated pathways, notably DDIT4 upregulation, linked to synaptic dysfunction and neuronal atrophy in animal models. Conclusions: The findings highlight cerebellar involvement in DCD and ASD, medial temporal lobe contribution to ASD and executive dysfunction, and DDIT4 as a possible molecular signature of KMT5B loss-of-function. An integrative multimodal approach refined genotype–phenotype correlations and revealed novel brain regions and pathways implicated in KMT5B-related disorders. Full article

This study applies psychological network analysis to explore the structure and dynamics of parental stress, offering a novel perspective beyond traditional latent variable approaches. Rather than treating parental stress as a unidimensional construct, network analysis conceptualizes it as a system of interrelated emotional, behavioral, and contextual symptoms. Using cross-sectional data from Latinx parents of children with intellectual and developmental disabilities (IDD), we compared and identified key central and bridge stress symptoms of Latinx parents of children with autism versus other disabilities that hold influential positions within the stress network. These findings suggest that certain stressors may act as hubs, reinforcing other stress components and potentially serving as high-impact targets for intervention. Network analysis also highlights how symptom relationships vary by types of disabilities, offering insight into tailored support strategies. Overall, this approach provides a dynamic and clinically actionable framework for understanding parental stress, with implications for assessment, early intervention, and personalized mental health care for parents. Full article

This study examined the psychometric properties of the Family Empowerment Scale (FES) among Latinx parents of children with intellectual and developmental disabilities (IDDs), a population historically underrepresented in empowerment research. Given the cultural and contextual factors that may shape empowerment experiences, Exploratory Structural Equation Modeling (ESEM) was utilized to assess the scale’s structural validity. ESEM supports a four-factor model that aligns with, but also refines, the original structure of the FES. The lack of loading for several items indicates the need for revisions that better reflect the lived experiences of Latinx parents. ESEM provided a more nuanced view of the scale’s dimensional structure, reinforcing the value of culturally informed psychometric evaluation. These results underscore the importance of validating empowerment measures within diverse populations to inform equitable family-centered practices. Full article

Background/Objectives: Leisure participation is vital for children’s development and family inclusion, yet families of children with developmental delays and disabilities face significant barriers. Guided by a health literacy framework, this study examined how personal and organizational health literacy shape access to inclusive leisure opportunities. Methods: Semi-structured interviews were conducted with 14 caregivers of young children (aged 2 to 6 years) with developmental delays and disabilities. A qualitative content analysis was applied to identify family and environmental factors shaping leisure participation. Results: Families with stronger personal health literacy engaged in diverse leisure activities, prioritizing children’s development through park visits and structured home routines. In contrast, weak organizational health literacy—reflected in limited inclusive facilities and support systems—restricted opportunities, increased caregiver stress, and forced adaptations such as traveling farther or rescheduling activities. These barriers underscored families’ vulnerability to exclusion while also highlighting their resilience in navigating daily life. Conclusions: This study demonstrates that health literacy functions at both personal and organizational levels to shape leisure participation. Beyond identifying barriers, it shows that leisure is intertwined with developmental needs and school readiness. By applying a health literacy lens, the study contributes to understanding family dynamics in inclusive leisure and underscores the need for responsive community services and inclusive policies. Full article

Background: Adolescents with autism spectrum disorder (ASD) display distinct neurodevelopmental trajectories marked by atypical neural activation and white matter maturation compared to neurotypical peers. Introduction: While improvements in face recognition and cognitive skills occur during childhood and adolescence, individuals with ASD often experience a plateau in these areas as they transition to adulthood, impacting daily living, executive function, social cognition, and emotional awareness. Results: Neuroimaging studies reveal altered white matter growth and connectivity in brain regions associated with social processing, which may underlie these functional challenges. Intellectual disability further compounds developmental difficulties by limiting foundational abilities and slowing progress. Discussion: The multifaceted and persistent service needs spanning legal, educational, vocational, health, and psychosocial domains highlight the necessity for coordinated, individualized, and family-centered approaches, particularly during the transition to adulthood. Advances in research integrating genetic, neurobiological, and behavioral data hold potential for refining diagnostic subgroups and personalizing interventions. Conclusion: Continued advocacy and innovation in service delivery are essential to address gaps in adult support systems and enhance long-term outcomes for individuals with ASD. Full article

Background: Adults with developmental disabilities often experience accelerated aging, but the magnitude of this phenomenon is not well quantified. This study aimed to measure the disparity in functional ability and chronic illness prevalence between adults with developmental and other disabilities. Methods: A “functional age” was calculated for adults with developmental disabilities. This metric, designed as a statistical index of disparity, was derived from normative regression models of ADL and IADL based on a reference group of adults with other disabilities. Results: A profound gap was found between chronological and functional age. On average, a 44-year-old individual with a developmental disability exhibited a level of functional limitation equivalent to a person over 100 years older in the reference population for both ADL and IADL (p < 0.001). Conclusions: Accelerated aging in this population manifests as a severe, early onset functional disadvantage rather than an elevated burden of general chronic disease. Policies should shift toward function-based, not age-based, models of care to address these lifelong support needs. Full article

X chromosome inactivation (XCI) is a fundamental epigenetic process that balances X-linked gene expression between females and males by silencing one X chromosome in female cells. Variability or skewing of XCI can influence the clinical presentation of X-linked disorders. Bain type X-linked intellectual disability syndrome (MRXSB), caused by mutations in the X-linked HNRNPH2 gene, is characterized by intellectual disability, developmental delay, and neurological abnormalities. In female patients, XCI heterogeneity complicates disease modeling and therapeutic development. Induced pluripotent stem cells (iPSCs) offer a unique platform to study patient-specific disease mechanisms, but the dynamics of XCI during iPSC reprogramming, maintenance, and differentiation are not fully understood. In this study, we generated 12 iPSC clones from fibroblasts of a female MRXSB patient heterozygous for the HNRNPH2 c.340C > T mutation. Four clones expressed the mutant HNRNPH2 allele and eight expressed the wild-type allele, indicating X chromosome reactivation (XCR) followed by random XCI during reprogramming. Importantly, these XCI patterns remained stable during long-term iPSC propagation and subsequent differentiation into the three germ layers and neural stem cells. Our findings provide new insights into XCI and XCR dynamics in the context of X-linked neurodevelopmental disorders and emphasize the importance of careful clone selection for accurate disease modeling using iPSC-based approaches. Full article

This qualitative study investigates the impact of multigrade classroom arrangements on learners with disabilities in the Harry Gwala District of KwaZulu-Natal, South Africa. Drawing on Bronfenbrenner’s Ecological Systems Theory, the research explores how systemic factors, from classroom-level practices to broader policy environments, shape inclusive education in rural multigrade settings. Data were collected through semi-structured interviews and focus group discussions with twenty teachers and ten principals. Thematic analysis revealed five key themes: instructional challenges, emotional and professional strain on teachers, systemic resource limitations, leadership constraints, and long-term developmental implications for learners with disabilities. Participants reported that multigrade settings hinder differentiated instruction, leading to frustration and disengagement among learners with disabilities. Teachers expressed emotional exhaustion and a lack of training tailored to inclusive multigrade contexts. Principals highlighted chronic resource shortages and unclear policy directives, which limited their ability to support inclusive practices. Despite these challenges, some school principals demonstrated strong commitment and agency, suggesting that leadership can be a catalyst for change even in under-resourced environments. The study contributes to the literature by disentangling the lived experiences of teachers from policy interpretations and by foregrounding the voices of those navigating inclusive education in complex rural settings. It recommends structural reforms, including context-sensitive teacher training, improved resource allocation, and leadership development. These findings align with international commitments such as Article 24 of the UNCRPD and offer practical insights for policymakers, teachers, and researchers committed to advancing equity in education. Full article

Background: Children with neurodevelopmental disorders (NDDs) commonly experience executive function (EF) impairments that impact daily life and academics. While bilingualism has generally been associated with cognitive advantages in typically developing (TD) children, its relationship with EF in children with NDDs remains unclear and represents a critical knowledge gap for families and clinicians considering bilingual exposure in these populations. Methods: For this scoping review, we searched PubMed, ProQuest, CogNet, PsycINFO, Scopus, ERIC, Embase, CINAHL, Linguistics Abstracts Online, and Google Scholar for studies published between database inception and December 2024, without language restrictions. We included quantitative, qualitative, and mixed-methods studies that (i) involved participants aged 4–12 years with diagnosed NDDs; (ii) examined children with bilingual language exposure; (iii) employed validated instruments for measuring cognitive or executive function; (iv) presented original empirical findings; and (v) were published in English. We excluded studies lacking comparisons between groups and longitudinal studies. Data on study characteristics, participants, EF assessments, and main findings were extracted. This study is registered with OSF Registries. Findings: Fifteen cross-sectional studies met the inclusion criteria, all of which focused exclusively on children with autism spectrum disorder (ASD), with no studies examining other NDDs. The studies involved 982 children with ASD (463 monolingual; 404 bilingual) and 644 TD children. Most studies (n = 11) revealed that, compared with monolingual children with ASD, bilingual children with ASD demonstrated advantages in working memory, cognitive flexibility, and inhibitory control on performance-based tasks. However, findings were inconsistent for spatial inhibition tasks, and parent-reported measures sometimes failed to detect bilingual-related differences. Interpretation: Bilingualism is associated with specific EF benefits for children with ASD, adding to evidence that questions longstanding concerns about the negative impacts of bilingual exposure in NDD populations. The evidence suggests that bilingual exposure could potentially serve as a complementary approach to traditional interventions for addressing EF impairments in children with ASD, although this evidence is limited to cross-sectional designs and requires further studies. However, the exclusive focus on ASD limits generalisability across the broader spectrum of NDDs. Further research is needed across diverse NDD populations employing comprehensive, multi-method EF assessments that combine performance-based tasks with parent-reported measures to better inform parenting, clinical, and educational practices. Full article

Prematurity, defined as a birth before 37 weeks of gestation, affects approximately 15 million infants worldwide yearly. Beyond the Neonatal Intensive Care Unit and the possibility of long-term developmental challenges affecting children’s quality of life, prematurity influences family dynamics, including parental mental health, financial stability, employment, and daily life. On a broader scale, research highlights the significant socioeconomic consequences of preterm birth that influence public healthcare policies, healthcare systems, and long-term costs. Addressing these challenges requires a multidisciplinary approach, beginning in the NICUs, with parental inclusion as a key component. The shift toward parental inclusion in the NICU may represent a fundamental transition from a medical to a social model of prematurity. The concept of a social model of prematurity parallels the social model of disability, from disability studies, focusing on premature babies, strengthening their abilities and nurturing early caregiver—infant relationships. It highlights how societal structures, such as accessibility and support systems, shape developmental outcomes and inclusion of premature infants, rather than framing prematurity solely in terms of survival and treatment. Full article