Evaluating a Novel Disability Education and Awareness Event for Health Professions Trainees.

BACKGROUND: People with intellectual and developmental disabilities (IDD) are at high risk for unmet health care needs and face barriers to equitable care, yet few health professions students receive adequate training to meet these needs. OBJECTIVES: An interactive panel discussion with Special Olympics Pennsylvania (SOPA) athletes and staff was planned and implemented so that health professions students/trainees would gain knowledge of IDD, health barriers, SOPA resources, and volunteer opportunities. METHODS: Panelists included two SOPA athletes and their mentors; questions solicited responses about personal health care experiences (Fall 2019). Attendees completed a mixed-methods post-event survey capturing event satisfaction, reflections, and interest in learning more about patients with IDD. RESULTS: Sixty individuals attended, and 43 (72%) completed post-event evaluation. Attendees reported high satisfaction (88%), desire for future trainings (100%), and interest in learning about communicating (88%), providing care (88%), and addressing IDD health barriers (91%). CONCLUSIONS: Collaborative community panels could be effective in engaging health care students in discussion about caring for patients with IDD.

Effect of the OPHN1 novel variant c.1025+1 G>A on RNA splicing: insights from a minigene assay.

This research analyzes the clinical data, whole-exome sequencing results, and in vitro minigene functional experiments of a child with developmental delay and intellectual disability. The male patient, aged 4, began experiencing epileptic seizures at 3 months post-birth and has shown developmental delay. Rehabilitation training was administered between the ages of one and two. There were no other significant family medical histories. Through comprehensive family exome genetic testing, a hemizygous variant in the 11th exon of the OPHN1 gene was identified in the affected child: c.1025 + 1G > A. Family segregation analysis confirmed the presence of this variant in the patient's mother, which had not been previously reported. According to the ACMG guidelines, this variant was classified as a likely pathogenic variant. In response to this variant, an in vitro minigene functional experiment was designed and conducted, confirming that the mutation affects the normal splicing of the gene's mRNA, resulting in a 56 bp retention on the left side of Intron 11. It was confirmed that OPHN1: c.1025 + 1G > A is the pathogenic cause of X-linked intellectual disabilities in the child, with clinical phenotypes including developmental delay and seizures.

Development of a culturally enhanced caregiver-facilitated language nutrition intervention "+Language is Medicine" to address developmental delay in Diné (Navajo) toddlers.

Introduction: Developmental Delay (DD) is highly common in American Indian and Alaska Native (AI/AN; Indigenous) toddlers and leads to high numbers of AI/AN children who eventually need special education services. AI/AN children are 2.89 times more likely to receive special education compared to other children in the U.S., yet developmental disorders are more frequently under diagnosed and untreated in AI/AN infants and toddlers. DD, which can be identified as early as toddlerhood, can lead to negative impacts on developmental trajectories, school readiness, and long-term health. Signs of DD can be identified early with proper developmental screening and remediated with high quality early intervention that includes effective parent training. There are many evidence-based language facilitation interventions often used in Early Intervention programs. However, in communities in rural parts of the Navajo Nation where there are limited services and resources, infants and toddlers with early signs of DD are often missed and do not get the culturally responsive support and evidence-based intervention they deserve. Methods: The community-based +Language is Medicine (+LiM) study team partnered with tribal home visitors, community members, and a Diné linguist/elder using a collaborative virtual workgroup approach in 2021 and 2022 to present the +LiM pilot study aims and to discuss strategies for enhancing a language intervention for toddlers experiencing DD in their tribal community. This paper will detail the stages of community engagement, intervention enhancement and preparation for field testing of the +LiM intervention to address elevated rates of DD in toddlers in the Northern Agency of the Navajo Nation. Results: Two major outcomes from this collaborative workgroup included: (1) a team-initiated redefining of language nutrition to align with Indigenous values that center cultural connectedness and native language use and (2) a five-lesson caregiver-facilitated curriculum titled +Language is Medicine which includes caregiver lessons on language nutrition, language facilitation, shared book reading, pretend play, and incorporation of native language into home routines. These two workgroup outcomes were leveraged to develop a pilot pre-/post-intervention study to test the effectiveness of the +LiM intervention with caregiver-toddler dyads living on the Navajo Nation. Discussion: Delivering tailored child interventions through tribal home visiting are cost-effective and innovative methods for reaching reservation-based families who benefit from culturally responsive parent coaching and instruction. The +LiM team has applied a precision tribal home visiting approach to enhance methods of early intervention for children with DD. Our enhancement process was grounded in Indigenous community-based participatory research that centered culture and language.

Developmental outcomes in abusive head trauma.

Abusive head trauma (AHT) is associated with high mortality and poorer outcomes compared to accidental head injuries. The short and long-term developmental outcomes for AHT are not well identified. Variability in outcome measures, small sample sizes, difficulty in measuring domain-specific developmental skills, co-existence of comorbidities, genetic and environmental factors and high attrition rates all contribute to the challenges on providing data in this area. The objective of this article is to review the scientific literature on the developmental outcomes of AHT, highlighting factors that affect outcomes, the available assessment tools, and short and long-term developmental outcomes, recommended follow up, societal costs, and future opportunities for research. Authors searched OVID Medline and PubMed for articles published between 2013 and 2023 using the terms "abuse", "craniocerebral trauma" and "development". Fifty-five records were included for this review. The data shows that injuries sustained from AHT result in a spectrum of outcomes ranging from normal development to death. There are more than 100 outcome assessment tools limiting the ability to compare studies. More than half of patients are left with disabilities post discharge. Gross motor and cognition/academics are the 2 most common domains studied. Advancement in surgical and neurocritical care management has influenced AHT outcomes. Close long-term follow up is recommended to maximize each child's developmental potential, irrespective of the presence of disability at discharge. We suggest that future research should focus on adopting a consistent diagnostic and assessment approach and explore the social environmental factors that can affect recovery.

Preeclampsia, Fetal Growth Restriction, and 24-Month Neurodevelopment in Very Preterm Infants.

Importance: Preeclampsia has direct influences on a developing fetus and may impact postnatal health, and fetal growth restriction (FGR) is often seen co-occurring with preeclampsia. The development of children born very preterm after preeclampsia diagnosis with and without FGR is not well characterized. Objective: To examine the associations of preeclampsia and FGR with developmental and/or behavioral outcomes in a cohort of very preterm infants. Design, Setting, and Participants: In this cohort study, infants in the prospective Neonatal Neurobehavior and Outcomes in Very Preterm Infants study were enrolled between April 2014 and June 2016 from 9 US university-affiliated neonatal intensive care units (NICUs). Eligible infants were born before 30 weeks' gestation. Infants were excluded for any major congenital anomalies and for maternal age younger than 18 years or cognitive impairment impacting the ability to provide informed consent. Data analysis was performed from November 2023 to January 2024. Exposure: Maternal preeclampsia and FGR in very preterm infants. Main Outcomes and Measures: The Bayley-III cognition, motor, and language scores less than 85 (-1 SD) indicated developmental delay. Child Behavior Checklist/Preschool 1.5-5 T-scores greater than or equal to 64 for internalizing, externalizing, or total problems indicated clinical importance. Results: Of 704 infants enrolled, 529 (mean [SD] gestational age, 27.0 [1.9] weeks; 287 male [54.3%]) were studied at 24-month follow-up. A total of 94 infants' mothers had preeclampsia (23.2%), and 46 infants (8.7%) had FGR. In adjusted models, preeclampsia was not associated with Bayley-III (cognitive, B = 3.43 [95% CI, -0.19 to 6.66]; language, B = 3.92 [95% CI, 0.44 to 7.39]; motor, B = 1.86 [95% CI, -1.74 to 5.47]) or Child Behavior Checklist/Preschool 1.5-5 (internalizing, B = -0.08 [95% CI, -2.58 to 2.73]; externalizing, B = 0.69 [95% CI, -1.76 to 3.15]; total, B = 0.21 [95% CI, -2.48 to 2.91]) outcomes. FGR was associated with significantly lower Bayley-III scores (cognitive, B = -8.61 [95% CI, -13.33 to -3.89]; language, B = -8.29 [95% CI, -12.95 to -3.63]; motor, B = -7.60 [95% CI, -12.40 to -2.66]), regardless of preeclampsia status. Conclusions and Relevance: In this cohort study of preterm infants, preeclampsia was not associated with developmental and/or behavioral outcomes, but infants with FGR may be prone to developmental delays. These findings suggest future areas of research for understanding the roles of preeclampsia and FGR separately and together in early child development for preterm infants.

[Analysis of a child with developmental disorder and epilepsy due to a homozygous variant of SLC25A12 gene].

OBJECTIVE: To explore the genetic basis for a child featuring global developmental delay and epilepsy. METHODS: A child who had presented at Guangzhou Women and Children's Medical Center Liuzhou Hospital on February 19, 2023 was selected as the study subject. Clinical data of the child was collected. The child was subjected to whole exome sequencing, and candidate variant was validated by Sanger sequencing and bioinformatic analysis. RESULTS: The child, an 8-month-old girl, had manifested with global developmental delay, epilepsy, and hyperlactacidemia. Cranial MRI revealed diverse hypomyelinating leukodystrophies. Electroencephalogram showed slow background activities. Genetic testing revealed that she has harbored a homozygous variant of the SLC25A12 gene, namely c.115T>G (p.Phe39Val), for which both of her parents were heterozygous carriers. Based on the guidelines from the American College of Medical Genetics and Genomics, the variant was predicted to be of uncertain significance (PM2_Supporting+PM3_Supporting+PP3_Moderate+PP4_Moderate). I-Mutant v3.0 software predicted that the variant may affect the stability of protein product. CONCLUSION: The homozygous c.115T>G (p.Phe39Val) variant of the SLC25A12 gene probably underlay the pathogenesis of the disease in this child.

Development of a sexual consent intervention for adolescents with intellectual and developmental disabilities.

BACKGROUND: Tailored sexuality education for adolescents with intellectual and developmental disabilities is a crucial, yet unmet, need as this population is particularly at risk for sexual abuse and victimisation. However, there are no evidence-based interventions to specifically address this need. This paper presents the development of an intervention framework to address equity in sexuality education and support adolescents with intellectual and developmental disabilities to understand and provide sexual consent, a foundational aspect of sexuality education and sexual health. METHODS: The Sexual Health Equity Project team used a Community-Based Participatory Research approach to develop a four-module sexual consent intervention for adolescents with intellectual and developmental disabilities. We leveraged a diverse, interdisciplinary team in a suburban Midwestern school district, and used Backward Design to create objectives and assessments which were rooted in findings from qualitative data by special education teachers. RESULTS: The resulting sexual consent intervention, Ask Me First-Choices, is comprised of four modules covering topics including definition of sexual consent; decision-making strategies and practice; communicating consent and refusal, identifying situations of consent and non-consent; and legal issues surrounding consent. Each module is divided into five components for content delivery: (1) introduction, (2) lecture, (3) supplemental activity, (4) assessment, and (5) conclusion. We detail the intervention's unique aspects, emphasising areas where we used Universal Design for Learning principles to support teachers' instruction and students' learning. CONCLUSION: Our efforts to create a sexual consent intervention directly address sexuality education equity issues. We offer commentary on our design process and decisions, as well as recommendations for future groups who want to develop sexual health interventions in similar contexts for students with intellectual and developmental disabilities. Next steps include further testing and validation of the sexual consent intervention to build the evidence-base of sexuality education for adolescents with intellectual and developmental disabilities.

[Clinical phenotype and genetic analysis of a child with Intellectual developmental disorder and epilepsy due to variant of CLTC gene].

OBJECTIVE: To explore the clinical features and genetic basis for a child with Intellectual developmental disorder (IDD) and epilepsy. METHODS: A child who was admitted to the Children's Medical Center of the Affiliated Hospital of Guangdong Medical University in February 2021 was selected as the study subject. Clinical data of the child was collected. Peripheral blood samples of the child and her parents were collected and subjected to whole exome sequencing (WES). Candidate variant was verified by Sanger sequencing. RESULTS: The patient, a 3-month-and-27-day female infant, had developed the symptoms in the neonatal period, which included severe developmental delay, respiratory difficulties and pauses, increased muscle tone of four limbs, feeding difficulty, and seizures. Cerebral MRI revealed bilateral cerebellar hypoplasia, and video EEG showed slightly increased sharp waves emanating predominantly from the right parietal, occipital, and posterior temporal regions. WES revealed that she has harbored a missense c.3196G>A (p.Glu1066Lys) variant of the CLTC gene, which was confirmed to be de novo by Sanger sequencing. Based on the guideline from the American College of Medical Genetics and Genomics (ACMG), the variant was classified as likely pathogenic (PS2+PM2_Supporting+PP3). CONCLUSION: The c.3196G>A (p.Glu1066Lys) missense variant of the CLTC gene probably underlay the pathogenesis in this child. Above finding has facilitated her diagnosis and treatment.

Variants of NAV3, a neuronal morphogenesis protein, cause intellectual disability, developmental delay, and microcephaly.

Microtubule associated proteins (MAPs) are widely expressed in the central nervous system, and have established roles in cell proliferation, myelination, neurite formation, axon specification, outgrowth, dendrite, and synapse formation. We report eleven individuals from seven families harboring predicted pathogenic biallelic, de novo, and heterozygous variants in the NAV3 gene, which encodes the microtubule positive tip protein neuron navigator 3 (NAV3). All affected individuals have intellectual disability (ID), microcephaly, skeletal deformities, ocular anomalies, and behavioral issues. In mouse brain, Nav3 is expressed throughout the nervous system, with more prominent signatures in postmitotic, excitatory, inhibiting, and sensory neurons. When overexpressed in HEK293T and COS7 cells, pathogenic variants impaired NAV3 ability to stabilize microtubules. Further, knocking-down nav3 in zebrafish led to severe morphological defects, microcephaly, impaired neuronal growth, and behavioral impairment, which were rescued with co-injection of WT NAV3 mRNA and not by transcripts encoding the pathogenic variants. Our findings establish the role of NAV3 in neurodevelopmental disorders, and reveal its involvement in neuronal morphogenesis, and neuromuscular responses.

Menstrual education programs for girls and young women with intellectual and developmental disabilities: A systematic review.

BACKGROUND: Providing menstrual education and guidance for menstrual management for girls and young women with intellectual disabilities is recommended to ensure smooth pubertal transitions and to support menstrual self-agency. METHOD: The purpose of this systematic review is to explore menstrual education interventions for girls and young women with intellectual disabilities. RESULTS: Nine studies were included. Interventions were provided in small groups (n = 4) and individually (n = 5). Most studies used dolls (n = 7) and task analysis (n = 7) to teach pad-replacement skills. All reported significant improvements in participant skills and/or knowledge following the intervention. Only one study addressed self-agency and self-esteem as an outcome of the intervention. Menstrual education for girls and young women with intellectual disabilities is largely focused on pad-replacement skills. CONCLUSION: Further research is needed to understand the impact of menstrual health and hygiene education on variables apart from skill improvement such as self-agency and long-term health outcomes related to menstrual health.

Clinical features and ALDH5A1 gene findings in 13 Chinese cases with succinic semialdehyde dehydrogenase deficiency.

BACKGROUND AND AIMS: To investigate the clinical features, ALDH5A1 gene variations, treatment, and prognosis of patients with succinic semialdehyde dehydrogenase (SSADH) deficiency. MATERIALS AND METHODS: This retrospective study evaluated the findings in 13 Chinese patients with SSADH deficiency admitted to the Pediatric Department of Peking University First Hospital from September 2013 to September 2023. RESULTS: Thirteen patients (seven male and six female patients; two sibling sisters) had the symptoms aged from 1 month to 1 year. Their urine 4-hydroxybutyrate acid levels were elevated and were accompanied by mildly increased serum lactate levels. Brain magnetic resonance imaging (MRI) showed symmetric abnormal signals in both sides of the globus pallidus and other areas. All 13 patients had psychomotor retardation, with seven showing epileptic seizures. Among the 18 variants of the ALDH5A1 gene identified in these 13 patients, six were previously reported, while 12 were novel variants. Among the 12 novel variants, three (c.85_116del, c.206_222dup, c.762C > G) were pathogenic variants; five (c.427delA, c.515G > A, c.637C > T, c.755G > T, c.1274T > C) were likely pathogenic; and the remaining four (c.454G > C, c.479C > T, c.1480G > A, c.1501G > C) were variants of uncertain significance. The patients received drugs such as L-carnitine, vigabatrin, and taurine, along with symptomatic treatment. Their urine 4-hydroxybutyric acid levels showed variable degrees of reduction. CONCLUSIONS: A cohort of 13 cases with early-onset SSADH deficiency was analyzed. Onset of symptoms occurred from 1 month to 1 year of age. Twelve novel variants of the ALDH5A1 gene were identified.

Organisational culture in 'better' group homes for adults with intellectual and developmental disabilities in England: A qualitative study.

BACKGROUND: Previous research identifies organisational culture as one of a number of factors associated with the quality of life outcomes of group home residents' with intellectual and developmental disabilities. This study aims to elaborate on the dimensions of group home culture in settings in England. METHOD: Participant observations and semi-structured interviews with staff were carried out in two group homes. Field-notes, interview notes and transcripts were analysed using inductive thematic analysis by a researcher naïve to the project and the previous literature. Initial coding was re-examined after sensitisation to theorised models in previous literature to identify the most parsimonious fit. The two settings were rated and compared using a five-point Likert scale for each of the dimensions. RESULTS: The findings describe group home culture across seven dimensions. There were mixed ratings across the different dimensions reflecting inconsistencies in culture that were reflected in staff practice. The challenge in assigning a global rating of culture in group homes, which includes interactions across multiple staff and multiple residents over time, was highlighted. CONCLUSION: The development of an observational measure of culture is highlighted as potentially helpful in understanding and responding to culture in services for individuals with intellectual and developmental disabilities.

Prevalence and socio-economic determinants of growth and developmental delays among Iranian children aged under five years: A cross sectional study.

BACKGROUND: The main cause of growth and development delays remains unknown, but it can occur as an interaction between genetic, environmental, and socio-economic factors. OBJECTIVE: The aim of the study was to investigate the prevalence and social determinants of growth and developmental delays among children aged under five years in Qazvin, Iran. METHODS: A cross-sectional study was conducted between January 2019 to December 2020 with participation of 1800 mothers with children aged 4-60 months who were referred to comprehensive health centers in Qazvin city, Iran. Structural and intermediate social determinants of health were assessed including: parents and children socio-demographic characteristics, families' living and economic status, parents' behavioral factors, household food security, mother's general health, and perceived social support. Children's growth was assessed based on their anthropometric assessment and their development was assessed using their age-specific Ages and Stages Questionnaire. Data were analyzed using univariable and multivariable logistic regression models using SPSS software version 24 and Stata version 14. RESULTS: The prevalence of developmental problems in each domain were 4.28% for personal and social delay, 5.72% for gross motor delay, 6.5% for communication delay, 6.72% for fine motor delay, and 8% for problem-solving delay. The prevalence of weight growth delays was 13.56% and height growth delays was 4.66%. Communication, gross motor, and problem-solving delays were higher among children whose fathers' smoked cigarettes. Fine motor delays were lower among mothers with education status of high school diploma and university degree vs. the under diploma group. Personal and social delay was significantly higher among families with fair economic status and lower among children when their fathers were employed (vs. unemployed). Weight and height growth delays were higher among mothers who had experienced pregnancy complications and household food insecure families, respectively. CONCLUSION: There are different predictors of growth and developmental delay problems among Iranian children aged under five years including fathers' smoking, families' economic status, and household food insecurity as well as history of mothers' pregnancy complications. The present study's findings can be used to screen for at-risk of growth and developmental delays among children and could help in designing and implementation of timely interventions.

An Unclassified Deletion Involving the Proximal Short Arm of Chromosome 10: A New Syndrome?

To date, only 13 studies have described patients with large overlapping deletions of 10p11.2-p12. These individuals shared a common phenotype characterized by intellectual disability, developmental delay, distinct facial dysmorphic features, abnormal behaviour, visual impairment, cardiac malformation, and cryptorchidism in males. Molecular cytogenetic analysis revealed that the deletion in this chromosomal region shares a common smallest region of overlap (SRO) of 80 kb, which contains only the WAC gene (WW-domain-containing adaptor with coiled coil). In this clinical case report, we report a 5-year-old girl, born from non-consanguineous parents, with a 10p11.22p11.21 microdeletion. She presents clinical features that overlap with other patients described in the literature, such as dysmorphic traits, speech delay, and behavioural abnormalities (hyperactivity), even though the WAC gene is not involved in the microdeletion. Our results are the first to highlight that the deletion described here represents a contiguous gene syndrome that is enough to explain the distinct phenotype but partially overlaps with the previous cases reported in the literature, even though the same genes are not involved. In particular, in this study, we speculate about the role of the WAC gene that seems to be associated with normal motor development. In fact, we found that our patient is the only one described in the literature with a large deletion in the 10p11.22p11.21 region without the involvement of the WAC gene deletion, and, interestingly, the patient did not have motor delay.

Innovations in Phenotyping and Diagnostics Create Opportunities for Improved Treatment and Genetic Counseling for Rare Diseases.

Genetic counseling and treatment options for rare developmental disabilities (DDs) have been revolutionized by the opportunities made possible by using massively parallel sequencing for diagnostic purposes [...].

Reverse Phenotyping after Whole-Exome Sequencing in Children with Developmental Delay/Intellectual Disability-An Exception or a Necessity?

This study delves into the diagnostic yield of whole-exome sequencing (WES) in pediatric patients presenting with developmental delay/intellectual disability (DD/ID), while also exploring the utility of Reverse Phenotyping (RP) in refining diagnoses. A cohort of 100 pediatric patients underwent WES, yielding a diagnosis in 66% of cases. Notably, RP played a significant role in cases with negative prior genetic testing, underscoring its significance in complex diagnostic scenarios. The study revealed a spectrum of genetic conditions contributing to DD/ID, illustrating the heterogeneity of etiological factors. Despite challenges, WES demonstrated effectiveness, particularly in cases with metabolic abnormalities. Reverse phenotyping was indicated in half of the patients with positive WES findings. Neural network models exhibited moderate-to-exceptional predictive abilities for aiding in patient selection for WES and RP. These findings emphasize the importance of employing comprehensive genetic approaches and RP in unraveling the genetic underpinnings of DD/ID, thereby facilitating personalized management and genetic counseling for affected individuals and families. This research contributes insights into the genetic landscape of DD/ID, enhancing our understanding and guiding clinical practice in this particular field of clinical genetics.

Optical Genome Mapping Reveals Disruption of the RASGRF2 Gene in a Patient with Developmental Delay Carrying a De Novo Balanced Reciprocal Translocation.

While balanced reciprocal translocations are relatively common, they often remain clinically silent unless they lead to the disruption of functional genes. In this study, we present the case of a boy exhibiting developmental delay and mild intellectual disability. Initial karyotyping revealed a translocation t(5;6)(q13;q23) between chromosomes 5 and 6 with limited resolution. Optical genome mapping (OGM) enabled a more precise depiction of the breakpoint regions involved in the reciprocal translocation. While the breakpoint region on chromosome 6 did not encompass any known gene, OGM revealed the disruption of the RASGRF2 (Ras protein-specific guanine nucleotide releasing factor 2) gene on chromosome 5, implicating RASGRF2 as a potential candidate gene contributing to the observed developmental delay in the patient. Variations in RASGRF2 have so far not been reported in developmental delay, but research on the RASGRF2 gene underscores its significance in various aspects of neurodevelopment, including synaptic plasticity, signaling pathways, and behavioral responses. This study highlights the utility of OGM in identifying breakpoint regions, providing possible insights into the understanding of neurodevelopmental disorders. It also helps affected individuals in gaining more knowledge about potential causes of their conditions.

Creating Family-Centred Support for Preschoolers with Developmental Disabilities in Low-Income Countries: A Rapid Review to Guide Practitioners.

Preschoolers with disabilities and their caregivers have been neglected in health and social service provision in most low-income countries and arguably also in low-resourced areas of more affluent nations. Yet as this rapid review of the published literature identifies, there are low-cost, evidence-based strategies to address their needs that can be implemented in communities by local people. Five key features of the necessary supports are examined. First, the leadership functions required to create and implement the support services. Second, the family-centred, home-based support provided to caregivers and the personnel undertaking this form of support. Third, providing opportunities for peer support to flourish and encouraging the formation of advocacy groups across families. Fourth, mobilizing the support of significant groups within the community: notably, traditional healers and leaders, health services and poverty alleviation initiatives. Fifth, devising ways in which preschool educational opportunities can be offered to children as a prelude to their inclusion in primary schools. The review serves a further purpose. It provides an example of how public health researchers and academics could achieve more rapid implementation of evidence-based knowledge into existing and new support services through dissemination to community practitioners.

Developmental milestones and daily living skills in individuals with Angelman syndrome.

BACKGROUND: Angelman syndrome (AS) is a neurodevelopmental disorder associated with severe global developmental delay. However, the ages at which different developmental skills are achieved in these individuals remain unclear. We seek to determine the probability and the age of acquisition of specific developmental milestones and daily living skills in individuals with AS across the different molecular subtypes, viz. class I deletion, class II deletion, uniparental disomy, imprinting defect, and UBE3A variants. METHODS: Caregivers participating in a longitudinal multicenter Angelman Syndrome Natural History Study completed a questionnaire regarding the age at which their children achieved specific developmental milestones and daily living skills. The Cox Proportional Hazard model was applied to analyze differences in the probability of achievement of skills at various ages among five molecular subtypes of AS. RESULTS: Almost all individuals, regardless of molecular subtype, were able to walk with support by five years of age. By age 15, those with a deletion had at least a 50% probability of acquiring 17 out of 30 skills compared to 25 out of 30 skills among those without a deletion. Overall, fine and gross motor skills such as holding and reaching for small objects, sitting, and walking with support were achieved within a fairly narrow range of ages, while toileting, feeding, and hygiene skills tend to have greater variability in the ages at which these skills were achieved. Those without a deletion had a higher probability (25-92%) of achieving daily living skills such as independently toileting and dressing compared to those with a deletion (0-13%). Across all molecular subtypes, there was a low probability of achieving independence in bathing and brushing teeth. CONCLUSION: Individuals with AS without a deletion are more likely to achieve developmental milestones and daily living skills at an earlier age than those with a deletion. Many individuals with AS are unable to achieve daily living skills necessary for independent self-care.

Genetic Testing for Global Developmental Delay in Early Childhood.

Importance: Global developmental delay (GDD) is characterized by a complex etiology, diverse phenotypes, and high individual heterogeneity, presenting challenges for early clinical etiologic diagnosis. Cognitive impairment is the core symptom, and despite the pivotal role of genetic factors in GDD development, the understanding of them remains limited. Objectives: To assess the utility of genetic detection in patients with GDD and to examine the potential molecular pathogenesis of GDD to identify targets for early intervention. Design, Setting, and Participants: This multicenter, prospective cohort study enrolled patients aged 12 to 60 months with GDD from 6 centers in China from July 4, 2020, to August 31, 2023. Participants underwent trio whole exome sequencing (trio-WES) coupled with copy number variation sequencing (CNV-seq). Bioinformatics analysis was used to unravel pathogenesis and identify therapeutic targets. Main Outcomes and Measures: The main outcomes of this study involved enhancing the rate of positive genetic diagnosis for GDD, broadening the scope of genetic testing indications, and investigating the underlying pathogenesis. The classification of children into levels of cognitive impairment was based on the developmental quotient assessed using the Gesell scale. Results: The study encompassed 434 patients with GDD (262 [60%] male; mean [SD] age, 25.75 [13.24] months) with diverse degrees of cognitive impairment: mild (98 [23%]), moderate (141 [32%]), severe (122 [28%]), and profound (73 [17%]). The combined use of trio-WES and CNV-seq resulted in a 61% positive detection rate. Craniofacial abnormalities (odds ratio [OR], 2.27; 95% CI, 1.45-3.56), moderate or severe cognitive impairment (OR, 1.69; 95% CI, 1.05-2.70), and age between 12 and 24 months (OR, 1.57; 95% CI, 1.05-2.35) were associated with a higher risk of carrying genetic variants. Additionally, bioinformatics analysis suggested that genetic variants may induce alterations in brain development and function, which may give rise to cognitive impairment. Moreover, an association was found between the dopaminergic pathway and cognitive impairment. Conclusions and Relevance: In this cohort study of patients with GDD, combining trio-WES with CNV-seq was a demonstrable, instrumental strategy for advancing the diagnosis of GDD. The close association among genetic variations, brain development, and clinical phenotypes contributed valuable insights into the pathogenesis of GDD. Notably, the dopaminergic pathway emerged as a promising focal point for potential targets in future precision medical interventions for GDD.