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PurposeDevelopmental assessment is part of a comprehensive autism evaluation. During in-person evaluations, developmental assessment is completed via direct testing by an examiner. In telehealth evaluations, developmental assessment relies on caregiver-report instruments. This study examined correspondence between caregiver report and direct testing of developmental skills.MethodsParticipants were 93 children, aged 18-42 months, undergoing evaluation for possible autism spectrum disorder (ASD). Caregivers were interviewed with the Developmental Profile, 4th edition (DP-4) via telehealth platform and children were tested in person 2-4 weeks later using the Mullen Scales of Early Learning (MSEL).ResultsCorrelations between the DP-4 and MSEL were high (ranging from 0.50 to 0.82) across standard scores, age equivalents, and functional categories, as well as across individual subtests and overall composite scores.ConclusionThe high convergent validity found in this study suggests that the DP-4 provides a suitable proxy for direct developmental testing using the MSEL in the context of telehealth evaluations for ASD in young children, delivering a good estimate of both developmental functioning and presence of delays.Trial registrationData were obtained from registered clinical trial NCT05047224, date of registration 2021-09-07.

KCNB1, on human chromosome 20q13.3, encodes the alpha subunit of the Kv2.1 voltage gated potassium channel. Kv2.1 is ubiquitously expressed throughout the brain and is critical in controlling neuronal excitability, including in the hippocampus and pyramidal neurons. Human KCNB1 mutations are known to cause global development delay or plateauing, epilepsy, and behavioral disorders. Here, we report a sibling pair with developmental delay, absence seizures, autism spectrum disorder, hypotonia, and dysmorphic features. Whole exome sequencing revealed a heterozygous variant of uncertain significance (c. 342 C>A), p. (S114R) in KCNB1, encoding a serine to arginine substitution (S114R) in the N-terminal cytoplasmic region of Kv2.1. The siblings father demonstrated autistic features and was determined to be an obligate KCNB1 c. 342 C>A carrier based on familial genetic testing results. Functional investigation of Kv2.1-S114R using cellular electrophysiology revealed slowing of channel activation, deactivation, and inactivation, resulting in increased net current after longer membrane depolarizations. To our knowledge, this is the first study of its kind that compares the presentation of siblings each with a KCNB1 disorder. Our study demonstrates that Kv2.1-S114R has profound cellular and phenotypic consequences. Understanding the mechanisms underlying KCNB1-linked disorders aids clinicians in diagnosis and treatment and provides potential therapeutic avenues to pursue.

Monocarboxylate transporter 8 (MCT8) deficiency is a rare, X-linked disorder arising from mutations in the SLC16A2 gene and resulting from dysfunctional thyroid hormone transport. This disorder is characterized by profound neurodevelopmental delay and motor disability due to a lack of thyroid hormone in the brain, and coexisting endocrinological symptoms, due to chronic thyrotoxicosis, resulting from elevated thyroid hormone outside the central nervous system (CNS). In February 2024, we reviewed the published literature to identify relevant articles reporting on the current unmet needs of patients with MCT8 deficiency. There are several main challenges in the diagnosis and treatment of MCT8 deficiency, with decreased awareness and recognition of MCT8 deficiency among healthcare professionals (HCPs) associated with misdiagnosis and delays in diagnosis. Diagnostic delay may also be attributed to other factors, including the complex symptomology of MCT8 deficiency only becoming apparent several months after birth and pathognomonic serum triiodothyronine (T3) testing not being routinely performed. For patients with MCT8 deficiency, multidisciplinary team care is vital to optimize the support provided to patients and their caregivers. Although there are currently no approved treatments specifically for MCT8 deficiency, earlier identification and diagnosis of this disorder enables earlier access to supportive care and developing treatments focused on improving outcomes and quality of life for both patients and caregivers.

IntroductionAdverse childhood experiences (ACEs) are common and have been associated with poor developmental outcomes. We aimed to investigate the relationship between early ACE exposure, subsequent diagnosis of developmental delay, and receipt of developmental delay services by young children. In addition, we aimed to assess the impact of health-promoting behaviors such as breastfeeding and daily reading on these relationships.MethodsIn this cross-sectional analysis of nationally-representative data from the 2017-2018 National Survey of Children's Health, we examined the relationship between ACEs, prior breastfeeding, daily reading, and developmental delay diagnosis among 7837 children aged 3-5 years, using multivariate logistic regression to adjust for family, personal, and sociodemographic characteristics.ResultsWe found a dose-dependent relationship between ACEs and developmental delay diagnosis; compared to those without ACEs, developmental delay was more common among those with either one ACE (aOR = 2.03, 95% CI 1.17-3.52) or two or more ACEs (aOR = 2.34, 95% CI 1.25-4.37). Neither breastfeeding (exclusively breastfed for 6 months vs. never breastfed aOR = 0.70, 95% CI 0.33-1.46) nor daily reading (no reading versus daily reading aOR = 1.15, CI 0.57-2.33) were associated with incidence of developmental delay among study participants. There was no significant difference in receipt of services intended to meet developmental needs between children with and without ACEs.DiscussionChildren with very early ACE exposure are at increased risk for diagnosis of developmental delay. Early screening for ACEs and developmental delay may mitigate the early developmental manifestations of ACE exposure in vulnerable children.

Background: The dysmorphogenetic arachnoid cysts' pathomechanism is most favoured, and about 50% occur as middle cranial fossa cysts (MCFAC). Still being rare, management options are yet evolving. We described the clinico-radiological features, management and early outcomes of participants with MCFAC in our service. Methods: This prospective cohort study involved 29 pediatric participants recruited (from electronic health records, using ICD G93.0 D016080 for arachnoid cysts) between 01/01/2023 and 31/06/2023, following informed consent according to the ethical approval. All participants had neuro-imaging confirmed MCFAC. Baseline and follow-up data were retrieved and analyzed using summary (mean, standard deviation) and inferential (ANOVA, t-test) statistics. Results: They were averagely aged 6.2 ± 4.48 years and were mostly males (89.7%). 24.1% were asymptomatic. The commonest symptoms (n = 38) were headaches (23.7%), developmental delays (15.8%), eye complaints (15.8%) and cephalomegaly (7.9%). They were predominantly left-sided (89.7%). Galassi (G) 3 lesions were less (24.1%), with G2 and G1 lesions evenly sharing the rest. The average cyst volume was 58.4 ± 80.83cm3; there were significant differences (F = 4.682; p = 0.018) between the average volumes for G1 (14.4 ± 22.42cm3), G2 (61.7 ± 89.92cm3) and G3 (122.5 ± 94.37cm3) lesions. 44.8% of the participants had rigid-endoscopic cysto-cisternotomy (all between the ICA and oculomotor nerve into the interpeduncular cistern, using ventriculostomy forceps); including all G3, 50% of G2 and no G1 (had serial clinico-radiological observation) lesion. The average pre- (117.42cm3) and post-operative (53.48cm3) cyst volumes showed significant (t = − 2.797, p = 0.021) reductions. Conclusion: Middle cranial fossa arachnoid cysts occur predominantly amongst males, in middle childhood and left-sided. The treatment-related patient series are largely symptomatic, unlike the largely asymptomatic, screening-related series. Higher Galassi grade lesions presented with progressively, significantly larger cyst volumes and higher likelihoods of surgery. The average post-operative cyst volume at follow-up averagely showed almost 60% reduction from the pre-operative. All participants reported clinical remission. [ABSTRACT FROM AUTHOR]

Background: Encephalocele represent a group of disorders which is characterised by extracranial herniation of the leptomeninges, brain, and CSF through a structural defect in the cranium. They are usually associated with other intracranial anomalies which may impact the neurological development. Aim: This study aimed to assess the predictors of neurological development of patients undergone surgical excision of occipital encephalocele. Methods: All patients with occipital encephaloceles operated over the last decade (2012–2022). The sac size, presence of hydrocephalous, and associated anomalies were noted. The biopsy of these patients were reviewed and categorised as those which contains mature neural tissue and those without. The neurological outcomes were assessed by social, language, cognitive, and motor milestone and has been stratified into no delay, mild (1 of 4), moderate (2 or 3 of 4), and severe development delay (4 of 4). Results: Total of 35 patients were included with median age of 10 months (IQR = 5–20 months). Fifteen (42.9%) patients had sac size of ≥ 5 cm, and 23 (65.7%) patients had mature neural tissues on biopsy. The median follow-up period was 6.4 years (IQR = 4.38–10.65) years. Seventeen (49.6%) patients had moderate to severe developmental delay. The sac size of ≥ 5 cm (AOR = 33.5; 95%CI = 3.35–334.8) (p = 0.003) and presence of mature neural content in the sac (AOR = 13.32; 95%CI = 1.1–160.36) (p = 0.041) were associated with significant neurodevelopmental delay. Conclusion: The presence of a large sac of ≥ 5 cm and the presence of mature neural tissues on histopathological specimen of patients with encephalocele point towards the possibility of poor neurological development. [ABSTRACT FROM AUTHOR]

Objective: This study examines associations among fetal brain magnetic resonance imaging (MRI) injury patterns, etiologies, and outcomes in fetal intraparenchymal hemorrhage (IPH). Methods: This is a retrospective, single‐center cohort study of IPH diagnosed on fetal MRI (1996–2022). IPH and associated abnormalities were categorized by 2 pediatric neuroradiologists; electronic medical records were reviewed by 2 pediatric neurologists to classify etiology and outcomes including cerebral palsy, epilepsy, developmental delay, and death. Results: Forty‐four fetuses with IPH were identified (34 singleton and 10 twin gestations) with MRI at median 24 weeks gestation (interquartile range [IQR] = 22–28 weeks). IPH was commonly supratentorial (84%) and focal (50%) or focal with diffuse injury (43%) and was often associated with germinal matrix hemorrhage (GMH; 75%) and/or intraventricular hemorrhage (IVH; 52%). An etiology was identified in 75%, including twin‐twin transfusion syndrome (TTTS, n = 10), COL4A1/2 variants (n = 8), or other fetal/maternal conditions (n = 15). COL4A1/2 variants were associated with focal IPH and the presence of hemorrhagic porencephaly, and intrauterine transfusion was associated with infratentorial hemorrhage. Twenty‐two fetuses were liveborn, and 18 pregnancies were terminated. Among those with follow‐up ≥ 12 months (median = 7 years), 12 of 13 had cerebral palsy, 6 of 13 had developmental delay, and 5 of 13 had epilepsy. Interpretation: An etiology for fetal IPH with or without GMH‐IVH is identified in most cases in our cohort and is commonly TTTS, COL4A1/2 variants, or other maternal/fetal comorbidities. Pattern of fetal IPH on MRI is associated with etiology. Cerebral palsy and neurodevelopmental impairment were common in liveborn infants. Genetic studies should be considered in cases of fetal IPH without an otherwise apparent cause. ANN NEUROL 2024;96:1137–1147 [ABSTRACT FROM AUTHOR]

Aim: To examine child‐led goal setting and evaluation tools and approaches for children with a disability or developmental delay. Method: Six databases were searched for studies that included population (children aged less than 18 years with disability or developmental delay); construct (child‐led goal setting tool or approach); and context (developmental therapy or rehabilitation). The utility of tools and approaches across the goal setting and evaluation process was investigated using abductive content analysis. Results: Fifty articles met the inclusion criteria. Three approaches and four tools for child‐led goal setting and evaluation were identified. No studies reported the clinimetric properties of tools specifically for child self‐respondents. Qualitative analysis revealed six distinct goal phases in which tools and approaches were used, which were synthesized into a new framework for child‐led goal setting and evaluation titled DECIDE: Direct children to goal setting; Elicit goal topics and priorities; Construct a goal statement; Indicate baseline goal performance; Develop an action plan to address the goal; and Evaluate goal progress after the intervention. Interpretation: Children actively participated in goal setting and evaluation across six DECIDE goal phases. Further clinimetric information is required to support use of goal setting and evaluation tools with child self‐respondents. Future research should emphasize the development of multi‐phase goal setting tools and approaches for diverse populations of children. [ABSTRACT FROM AUTHOR]

CASK (MIM#300172), encoding a calcium/calmodulin‐dependent serine protein kinase, is crucial for synaptic transmission and gene regulation during neural development. Pathogenic variants of CASK are known to cause several neurodevelopmental disorders, including X‐linked intellectual disability and microcephaly with pontine and cerebellar hypoplasia (MICPCH). This study introduces a novel, de novo synonymous CASK variant (NM_001367721.1: c.1737G>A, p.(Glu579=)), discovered in a male patient diagnosed with MICPCH, characterized by microcephaly, developmental delay, visual impairment, and myoclonic seizures. The variant disrupts a donor splice‐site at the end of exon 18. Transcriptomic analysis of blood identified 12 different CASK transcripts secondary to the synonymous variant. Nearly one third of these transcripts were predicted to result in nonsense mediated decay or protein degradation. Protein modeling revealed structural alterations in the PDZ functional domain of CASK, due to exon 18 deletion. Our findings highlight the utility of transcriptomic analysis in demonstrating the underlying disease mechanism in neurodevelopmental disorders. [ABSTRACT FROM AUTHOR]

Heterozygous microdeletions at 13q12.3 are associated with a rare genetic disorder, 13q12.3 microdeletion syndrome, characterized by intellectual disability, microcephaly, development delay, facial dysmorphisms, atopy, and obesity. Reported 13q12.3 microdeletions vary in size and typically encompass multiple genes. Previous studies have defined a minimal overlap region of 13q12.3 microdeletions and suggested that most of the phenotype associated with the 13q12.3 microdeletion syndrome could be attributed to the loss of the high mobility group box 1 (HMGB1) gene within the overlap region. Here, we report a pediatric patient who had typical phenotypic features of 13q12.3 microdeletion syndrome, including motor and moderate speech developmental delays, microcephaly, and severe atopy, along with anxiety and aggressive behaviors. Trio‐based microarray analysis identified a 62‐kb apparently de novo heterozygous deletion at 13q12.3 in the proband, fully encompassing all coding exons of the HMGB1 gene yet not affecting any other neighboring genes. This case report presents a rare HMGB1 single‐gene deletion in a patient with classic features of 13q12.3 microdeletion syndrome, allowing a better delineation of clinical phenotypes associated with the loss of HMGB1. Our findings, together with previous reports, strongly support the pathogenic role of HMGB1 haploinsufficiency in the 13q12.3 microdeletion syndrome. [ABSTRACT FROM AUTHOR]

ABSTRACT Shprintzen‐Goldberg‐syndrome (SGS) is caused by pathogenic exon 1 variants of SKI. Symptoms include dysmorphic features, skeletal and cardiovascular comorbidities, and cognitive and developmental impairments. We delineated the neurodevelopmental and behavioral features of SGS, as they are not well‐documented. We collected physician‐reported data of people with molecularly confirmed SGS through an international collaboration. We identified and deep‐phenotyped the neurodevelopmental and behavioral features in four patients. Within our cohort, all exhibited developmental delays in motor skills and/or speech, with the average age of first words at 2 years and 6 months and independent walking at 3 years and 5 months. All four had learning disabilities and difficulties regulating emotions and behavior. Intellectual disability, ranging from borderline to moderate, was present in all four participants. Moreover, we reviewed the literature and identified 52 additional people with SGS, and summarized the features across both datasets. Mean age was 23 years (9–48 years). When combining our cohort and reported cases, we found that 80% (45/56) had developmental and/or cognitive impairment, with the remainder having normal intelligence. Our study elucidates the developmental, cognitive, and behavioral features in participants with SGS and contributes to a better understanding of this rare condition. [ABSTRACT FROM AUTHOR]

Introduction: Developmental delay (DD) and intellectual disability (ID) are key manifestations of neurodevelopmental disorders (NDDs), characterized by considerable clinical and genetic variability, which complicates genetic diagnosis. Whole exome sequencing (WES) has become an effective method for uncovering genetic causes in patients with unexplained DD/ID. Methods: We retrospectively analyzed WES data from 280 patients diagnosed with unexplained DD/ID. Demographic information and genetic variants identified through WES were assessed, along with an evaluation of clinical factors that might influence the detection of genetic causes. Results: Pathogenic variants were detected in 73 cases (36.07%), including 25 cases involving pathogenic chromosomal copy number variations. Clinical factors such as age, sex, gestational age, birth weight, anoxia, jaundice, associated symptoms, family history, muscle strength, muscle tone, epilepsy, brain MRI findings, EEG results, and the severity of DD/ID did not significantly impact the WES outcomes. However, a significant correlation was observed between delivery mode and positive WES results, with a higher diagnostic yield among patients delivered via caesarean section. Conclusions: WES is a valuable approach for identifying genetic causes in patients with unexplained DD/ID, providing benefits for patient management, family genetic counseling, and long-term prognosis assessment. Clinical trial number: Not applicable. [ABSTRACT FROM AUTHOR]

Introduction: Extensive literature has investigated the prenatal risk factors of developmental delay in children, with evidence highlighting the impact of prenatal health, mental health, and behavioural factors. While a deficit discourse has underscored Indigenous health research and policies, strengths-based approaches provide an opportunity to reframe this discourse, to illustrate and celebrate the strength and resilience of Australian Indigenous families. As such, this study aimed to identify the protective impact of healthy pregnancy and lifestyle in mothers on developmental delay in Indigenous Australian children; and whether it varies by child birthweight adjusted for gestational age. Further, we also tested whether child birthweight for adjusted gestational age mediates the association between a healthy pregnancy and lifestyle in mothers and developmental delay in their Indigenous offspring. Methods: Strength-based analysis was conducted using data from 8 longitudinal waves of LSIC study in Australia. Random-effect models were used to longitudinally measure the impact of maternal healthy pregnancy and lifestyle on developmental delays in their children between 2008 and 2018. A composite score (ranging from 0 to 3, score = 3 refers to most healthy pregnancy) was created for a healthy pregnancy and lifestyle variable using three criteria − (1) a lack of medical conditions, (2) no substance use including smoking/alcohol/illicit drugs, and (3) intake of iron/folic acid during pregnancy. All models were adjusted for potential covariates. Results: Of the 780 mother-child dyads analysed, 65.4% of mothers reported healthy pregnancy and lifestyle; while 73.5% of children born with a recommended appropriate birthweight adjusted for gestational age, and 91.4% reported no developmental delays. In children born in the recommended range of appropriate birthweight adjusted for gestational age, healthy pregnancy in mothers (most healthy, aOR: 4.76, 95% CI: 1.12–20.18; and 2nd most healthy, aOR: 4.02, 95% CI: 1.09–14.83) was protective against development delay compared to maternal unhealthy pregnancy. Living in remote areas (vs. major city, and regional) was also found to be protective against developmental delay in those who were born within the recommended range of birthweight adjusted for gestational age. Further, the current study found that child birthweight for adjusted gestational age does not have any mediating effect on the association between healthy pregnancy in mothers and developmental delay in their children. Conclusion: This strengths-based study suggests healthy pregnancy in mothers should be advocated to prevent developmental delay in their offspring in the Australian Indigenous population. The findings also found living in remote areas has a protective effect against developmental delay in Indigenous children who born within the recommended range of birthweight adjusted for gestational age. These findings have implications for challenging and reframing the deficit discourse surrounding Indigenous Australian health research and policymaking. Further studies are needed to investigate the positive relationship between Indigenous Australians' health and social and emotional well-being (SEWB) and their connection to their country and culture. [ABSTRACT FROM AUTHOR]

Background: Hereditary sensory and autonomic neuropathy type 9 (HSAN9) is a rare genetic disorder caused by genetic alterations in the TECPR2 locus and is characterized by developmental and intellectual disability, respiratory dysfunction, gastroesophageal reflux disease (GERD), and sensory and autonomic dysfunction, which are shared among the HSAN family. Methods: Whole-exome sequencing (WES) was performed on samples from both probands, and the relevant genetic variants were confirmed in their families using Sanger sequencing. Additionally, a comprehensive literature review was conducted on previously reported cases of HSAN9, and the clinical and genetic data were assessed to provide insight into the genetic and clinical characteristics of the disease. Results: We identified two new cases of HSAN9 with a shared novel variant of TECPR2 (NM_014844.5), c.1568del: p.Ser523PhefsTer12, classified as pathogenic according to ACMG guidelines. The probands showed characteristics of GERD, respiratory dysfunction, gait abnormalities, and developmental and speech delay, and both cases were deceased as a result of severe respiratory infection. The results of the literature review included 34 cases from 9 studies, revealing a wide range of genetic and clinical characteristics. Conclusions: Our study identified two new cases of HSAN9 with a novel variant in TECPR2, confirmed by WES. The clinical characteristics of the patients as well as the conduction of a comprehensive literature review are crucial in the early diagnosis and management of the disease and establishment of genotype-phenotype correlations. [ABSTRACT FROM AUTHOR]

Background: Phelan-McDermid syndrome (PMS) is a rare genetic syndrome characterized by developmental delay/intellectual disability, absent or delayed speech, physical dysmorphic features and high rates of autistic features. However, it is currently unknown whether people with PMS have similar neurocognitive atypicalities to those previously identified in idiopathic autism. Disruption in social orienting has previously been suggested as an early hallmark feature of idiopathic autism that impacts social learning and social interaction. Methods: This study used a semi-naturalistic task to explore orienting to social versus non-social stimuli and its relation to clinical features in individuals diagnosed with PMS, autism, and neurotypical children recruited in the United States and the United Kingdom. Results: At the group level, autistic and neurotypical children responded on average more often to social than non-social stimuli, while children with PMS responded similarly to both stimulus types. Both clinical groups responded significantly less often to social stimuli than neurotypical children. In addition, we found considerable variability in orienting responses within each group that were of clinical relevance. In the autism group, non-social orienting was associated with mental age, while in the PMS group social and non-social orienting were related to strength of autistic features. Conclusions: These findings do not support specific social motivation difficulties in either clinical group. Instead, they highlight the importance of exploring individual differences in orienting responses in Phelan-McDermid Syndrome in relation to autistic features. Trial registration: NA. [ABSTRACT FROM AUTHOR]

Background: Understanding the status of early childhood development (ECD) and its associated factors could serve as the basis for future policy efforts and interventions. Therefore, this study aimed to determine the status of ECD and its associated factors among children aged 36–59 months in Afghanistan. Methods: We used data from the Afghanistan Multiple Indicator Cluster Survey 2022–2023 (MICS) to assess ECD status. The outcome variable was a binary measure, indicating whether a child was developmentally on track or not. To explore the associations between ECD status and various explanatory variables, we applied binary logistic regression models, presenting both univariate and multivariate analyses. Results: Among the 13,866 children aged 36 to 59 months included in the analysis, 29.95% (95% CI: 29.19-30.72%) were found to be developmentally on track. The likelihood of being developmentally on track was higher in children whose mothers had secondary [adjusted odds ratio (AOR) 1.36 (95%CI 1.04–1.77)] and higher education [1.73 (1.08–2.76)], in children whose fathers had primary [1.32 (1.05–1.67)], secondary [1.40 (1.10–1.79) and higher education [1.60 (1.21–2.11)], and in children belonging to the higher household wealth status [1.46 (1.18–1.82)]. On the other hand, the likelihood of being developmentally on track was lower in children aged 48–59 months [0.35 (0.30–0.40)], in children living in rural areas [0.77 (0.62–0.96)], in children with stunting [0.77 (0.61–0.96)], and in underweight children [0.61 (0.52–0.72)]. Conclusion: Our findings indicate that 29.95% of children aged 36–59 months in Afghanistan are developmentally on track. Positive associations were found between ECD and higher parental education and household wealth status. However, living in rural areas, underweight and stunted growth were negatively associated with ECD. To improve early childhood development programs in Afghanistan, targeted interventions are needed to address the factors identified in this study. [ABSTRACT FROM AUTHOR]

This study aimed to reveal the effects of the COVID-19 pandemic on neuromotor development in infants (aged 6–24 months). A total of 75 infants were included in this cross-sectional observational study. Neuromotor development was assessed using the Alberta Infant Motor Scale (AIMS) and the Denver Developmental Screening Test II (DDST II). The AIMS results showed that 14.7% were classified as abnormal, 10.6% as suspicious, and 74.7% as normal. The DDST II results showed that 14.7% of the participants were classified as suspicious, 13.3% as abnormal, and 72% as normal. This study found that 25% of infants aged 6–24 months who experienced the COVID-19 pandemic exhibited questionable or abnormal neurological development. This reveals the negative impact of the pandemic on neuromotor development. Delays were observed more frequently in fine and gross motor areas.Trial registration: ClinicalTrials.gov identifier: NCT05778357. [ABSTRACT FROM AUTHOR]

WD repeat domain 83 opposite strand (WDR83OS) encodes the 106-aa (amino acid) protein Asterix, which heterodimerizes with CCDC47 to form the PAT (protein associated with ER translocon) complex. This complex functions as a chaperone for large proteins containing transmembrane domains to ensure proper folding. Until recently, little was known about the role of WDR83OS or CCDC47 in human disease traits. However, biallelic variants in CCDC47 were identified in four unrelated families with trichohepatoneurodevelopmental syndrome, characterized by a neurodevelopmental disorder (NDD) with liver dysfunction. Three affected siblings in an additional family share a homozygous truncating WDR83OS variant and a phenotype of NDD, dysmorphic features, and liver dysfunction. Using family-based rare variant analyses of exome sequencing (ES) data and case matching through GeneMatcher, we describe the clinical phenotypes of 11 additional individuals in eight unrelated families (nine unrelated families, 14 individuals in total) with biallelic putative truncating variants in WDR83OS. Consistent clinical features include NDD (14/14), facial dysmorphism (13/14), intractable itching (9/14), and elevated bile acids (5/6). Whereas bile acids were significantly elevated in 5/6 of individuals tested, bilirubin was normal and liver enzymes were normal to mildly elevated in all 14 individuals. In three of six individuals for whom longitudinal data were available, we observed a progressive reduction in relative head circumference. A zebrafish model lacking Wdr83os function further supports its role in the nervous system, craniofacial development, and lipid absorption. Taken together, our data support a disease-gene association between biallelic loss-of-function of WDR83OS and a neurological disease trait with hypercholanemia. [Display omitted] Through a combined approach of international gene matching, deep phenotyping, and model organism functional studies, we provide evidence to establish ASTERIX (WDR83OS) loss of function as underlying a recessive human neurological disease trait with liver disease (hypercholanemia). This condition overlaps with trichohepatoneurodevelopmental syndrome caused by variants in CCDC47, a binding partner of ASTERIX. [ABSTRACT FROM AUTHOR]

Aims Methods Results Conclusions Neonatal diabetes is a monogenic condition which can be the presenting feature of complex syndromes. The aim of this study was to identify novel genetic causes of neonatal diabetes with neurological features including developmental delay and epilepsy.We performed genome sequencing in 27 individuals with neonatal diabetes plus epilepsy and/or developmental delay of unknown genetic cause. Replication studies were performed in 123 individuals with diabetes diagnosed aged ≤1 year without a known genetic cause using targeted next‐generation sequencing.Three individuals, all diagnosed with diabetes in the first week of life, shared a rare homozygous missense variant, p.(Arg327Gln), in TARS2. Replication studies identified the same homozygous variant in a fourth individual diagnosed with diabetes at 1 year. One proband had epilepsy, one had development delay and two had both.Biallelic TARS2 variants cause a mitochondrial encephalopathy (COXPD‐21) characterised by severe hypotonia, epilepsy and developmental delay. Diabetes is not a known feature of COXPD‐21. Current evidence suggests that the p.(Arg327Gln) variant disrupts TARS2's regulation of the mTORC1 pathway which is essential for β‐cells.Our findings establish the homozygous p.(Arg327Gln) TARS2 variant as a novel cause of syndromic neonatal diabetes and uncover a role for TARS2 in pancreatic β‐cells. [ABSTRACT FROM AUTHOR]

Background: Genetic disorders could also contribute to intellectual disability. Using whole exome sequencing (WES), several variants have been identified as autosomal-dominant inheritance intellectual disability. Thus, the application of WES has demonstrated its critical role in distinguishing intellectual disability in children patients, which provides essential diagnosis and promotes therapeutic strategy. Case presentation: The proband, an 18-month-old female patient, presented with a complex clinical profile characterized by profound developmental delay, epilepsy, and neurological developmental impairment. WES identified a heterozygous c.913A>G variant in exon 2 of NACC1 , resulting in disease caused by a change in the amino acid sequence, affecting the protein features and resulting in splice site changes, as revealed by MutationTaster analysis. The protein structure of NAC1 was built and named AF-Q96RE7-F1, and the mutant site was beyond the BTB/POZ, NLS, and BEN domains. Subsequently, PyMOL software was used to illustrate the molecular structure between the wild type and the mutant type of NAC1. The residues around the 304 site of amino acid changed in NAC1 p.T304A with an altered hydrogen bond, indicating an unstable structure. The patient was diagnosed with intellectual disability and profound developmental delay with epilepsy harboring a novel de novo NACC1 variant. Upon hospital admission, a comprehensive treatment regimen was initiated, including antiseizure medications, nutritional supplements, and rehabilitation training. As a result, the patient's movement performance improved. However, recurrent epilepsy attacks still occurred. Conclusion: This is the first case revealing a novel NACC1 c.903A>G variant that induced a neurological impairment in an infant. This report expanded the understanding of the non-domain-associated variant of NACC1 and developmental disorder. [ABSTRACT FROM AUTHOR]

Cockayne syndrome (CS) is a progressive multisystem disorder characterized by growth failure, microcephaly, developmental delay, and photosensitivity. The characteristic symptoms appear during early childhood in most patients with CS. Herein, we report a mild case of CS with a novel start-loss variant in ERCC8 that did not show the characteristic symptoms of CS during early childhood and exhibited sudden growth failure after the age of 10 years. [ABSTRACT FROM AUTHOR]

WWOX developmental and epileptic encephalopathy is characterised by drug-resistant epilepsy with onset within the first year of life and severe psychomotor developmental delay. This report presents for the first time a clinical case of an adult patient with a homozygous likely pathogenic variant (p.Thr12Met) in the WWOX gene, with more than 40 years of follow-up. The patient had refractory epilepsy with various types of seizures during his life: mainly epileptic spasms, autonomic, myoclonic, tonic seizures, and absences. The patient had a prominent developmental delay with a lack of expressive speech, but by the age of 3, he had acquired the skills to sit, crawl, and walk with support. In adolescence, there was an acute regression of acquired skills to a total absence of independent motor activity. The patient had dysmorphic features, such as upslanting palpebral fissures, arched eyebrows, and hypertelorism. For many years, the patient was given a diagnosis of cerebral palsy; 38 years after the onset of the disease, he was given a molecular genetic diagnosis of WWOX -associated developmental and epileptic encephalopathy. Our observation illustrates the natural history of WWOX -DEE and the high clinical significance of early genetic diagnostics for identifying the cause of developmental delay and resistant epilepsy. [ABSTRACT FROM AUTHOR]

Background: Genetic testing for neurodevelopmental disorders is now considered the standard of care for unexplained epilepsy as well as autism spectrum disorders, intellectual disability, and developmental delays with as many as 50% of individuals identified as having an underlying genetic etiology. Capicua (CIC) is a transcriptional repressor and is widely expressed among human brain tissue. Patients in the literature with pathogenic variants in CIC present with a broad spectrum of phenotypic abnormalities. Common features include epilepsy, developmental delay, intellectual disability, autism spectrum disorder, and MRI abnormalities amongst other neurodevelopmental symptoms. Variant type, age of onset, sex, and severity of manifestation also differ amongst probands. However, the full genotypic and phenotypic spectrum of CIC-related neurodevelopmental disorder has not been elucidated. Methods: Here we review patients reported in the literature with CIC variants and present two additional patients representing a novel genotype and phenotype. Results: Whole exome sequencing (WES) in this proband identified a novel paternally inherited likely pathogenic variant in CIC c.1526del p.(Pro509Hisfs*14). Both proband and father present with isolated epilepsy without other significant neurodevelopmental disorders. A review of the previous literature identified 20 individuals harboring CIC variants; the majority of these individuals present with a combination of neurodevelopmental features. Sixteen distinct variants were identified amongst these 20 patients. Conclusions: This family represents an expansion of the genotypic and phenotypic spectrum of CIC-related neurodevelopmental disorder. This information may lead to clinically actionable management changes for future patients identified with CIC variants considering standard anti-epileptic medication-weaning protocols. [ABSTRACT FROM AUTHOR]

Objective: Phenotypic heterogeneity presents challenges in providing clinical care to patients with pathogenic SCN8A variants, which underly a wide disease spectrum ranging from neurodevelopmental delays without seizures to a continuum of mild to severe developmental and epileptic encephalopathies (DEEs). An important unanswered question is whether there are clinically important subgroups within this wide spectrum. Using both supervised and unsupervised machine learning (ML) approaches, we previously found statistical support for two and three subgroups associated with loss‐ and gain‐ of‐ function vari‐ants, respectively. Here, we test the hypothesis that the unsupervised subgroups (U1–U3) are distinguished by differential contributions of developmental and epileptic components. Methods: We predicted that patients in the U1 and U2 subgroups would differ in timing of developmental delay and seizure onset, with earlier and concurrent onset of both features for the U3 subgroup. Standard statistical procedures were used to test these predictions, as well as to investigate clinically relevant associations among all five subgroups. Results: Two‐population proportion and Kruskal–Wallis tests supported the hypothesis of a reversed order of developmental delay and seizure onset for patients in U1 and U2, and nearly synchronous developmental delay/seizure onset for the U3 (termed DEE) subgroup. Association testing identified subgroup variation in treatment response, frequency of initial seizure type, and comorbidities, as well as different median ages of developmental delay onset for all five subgroups. Significance: Unsupervised ML approaches discern differential developmental and epileptic components among patients with SCN8A‐related epilepsy. Patients in U1 (termed developmental encephalopathy) typically gain seizure control yet rarely experience improvements in development, whereas those in U2 (termed epileptic encephalopathy) have fewer if any developmental impairments despite difficulty in achieving seizure control. This understanding improves prognosis and clinical management and provides a framework to discover mechanisms underlying variability in clinical outcome of patients with SCN8A‐related disorders. [ABSTRACT FROM AUTHOR]

Background: The BCL11A gene is involved in disorders including intellectual disability syndrome (IDS), encodes a zinc finger protein highly expressed in haematopoietic and brain and acts as a transcriptional repressor of foetal haemoglobin (HbF). De novo variants in BCL11A have been associated with IDS, which is characterized by developmental delays, autism spectrum disorder (ASD) and speech and language delays. The reports of BCL11A gene variants are still limited worldwide, and additional cases are needed to expand the variant and phenotype spectrums. Methods: The patient is a 5‐year‐old girl who was hospitalized due to developmental delays. After analysing her clinical and pathological characterizations, whole‐exome sequencing (WES) was performed for pathogenic genetic variants of developmental delay and behavioural differences. Candidate variant in BCL11A gene was identified and further validated by Sanger sequencing. Results: A heterozygous variant, c.1442delA (p.Glu481Glyfs*25), was identified in exon 4 of the BCL11A gene through WES. This variant results in a truncated expression of the encoded protein. This de novo variant was confirmed by Sanger sequencing. The language delay and behavioural differences were prominent in our patient. Conclusion: Our finding demonstrates that BCL11A variant may cause developmental delay and behavioural differences, expanding the genetic spectrum of the BCL11A gene. [ABSTRACT FROM AUTHOR]

Cerebellofaciodental syndrome characterized with dysmorphic features, intellectual disability, and brain anomalies. Now its clinical spectrum expanded more manifestations including bilateral sensorineural hearing impairment and inner ear malformation. Here, we report a 14‐month‐old boy with global developmental delay and hearing disorder. Whole exome sequencing (WES) revealed the compound heterozygous variants [NM_001519.4: c.652 T > G (p.W218G); c.915 + 1G > T] in the BRF1 gene which inherited from his parents, respectively. The MRI results showed hypoplastic cerebellar vermis, enlarged cisterna magna, and prominent fourth ventricle, the rehabilitation therapy failed to improve the symptoms for our patient. Our finding expands the genetic spectrum of BRF1 variants, which indicates patients with the developmental delay caused by BRF1 variants require other treatments instead of rehabilitation. [ABSTRACT FROM AUTHOR]

Longitudinal studies provide developmental science with invaluable information about how variables and the associations between variables change across time, but typically give limited attention to the length of time over which that change occurs. The present study re-analyzed data from previously published meta-analyses of longitudinal data across a broad range of developmental science to ascertain how lag may have impacted coefficients of stability (k meta-analyses = 6, k studies = 157) and prediction (k meta-analyses = 15, k studies = 270). We additionally analyzed how average participant age interacts with lag to test how the impact of lag might change across the lifespan. Findings indicate that conventional lags (e.g., 6 months, 12 months) were used at extremely high rates: More than 75% of lags were selected based on convention. Linear and nonlinear models indicated that lag moderated stability and predictive associations, although the significance, magnitude, and direction of this impact changed depending on the phenomenon under investigation. Average participant age interacted with lag in certain cases, providing a possibility for more time-specific developmental theory. However, these results should not be considered conclusive due to the high number of conventional lags in our sample, which likely restricted both variability in lags and the length of those lags. Future longitudinal studies should measure phenomena at varying lags, and future meta-analysts should consider both lag and average participant age when synthesizing longitudinal research. Both practices would enable developmental science to determine the interval over which a phenomenon occurs and facilitate advancements in developmental theory. [ABSTRACT FROM AUTHOR]

Introduction: Lack of knowledge of Early Intervention (EI) is a barrier to developmental delay (DD) management. We aimed to examine the feasibility of measuring pediatricians' knowledge of EI, determine the distribution of EI knowledge, and determine factors associated with increased EI knowledge. Methods: We conducted an exploratory cross-sectional study with a convenience sample from a local American Academy of Pediatrics chapter to administer a survey with 10 multiple-choice questions regarding the EI referral process, evaluation process, eligibility criteria and fee structure. Our outcome variable was a composite score of these 10 multiple-choice questions, Total Knowledge Score (TKS). Our predictor variables included physician characteristics (i.e., years of experience, percentage of patients seen with private insurance, receipt of EI training in the last 5 years) and practice characteristics (i.e., medical home status). Results: Our sample consisted of a total of 194 pediatric residents/attendings. Multivariable regression demonstrated seeing ≥ 50% patients who were privately insured, increased experience, and receiving training in the last 5 years were associated with higher TKS. Discussion: We were able to quantitatively evaluate physician's knowledge of EI and demonstrated that seeing a majority of privately insured patients, having more experience, and having received formal EI training in the last 5 years were associated with higher EI knowledge. This disproportionate distribution of EI knowledge has the potential to contribute to disparities in the management of DD. This may indicate that medical institutions, where physicians see a small percent of privately insured patients, need to hire more experienced physicians, and provide routine EI training. Significance: Physician knowledge of the Early Intervention process has been described as a potential barrier to the management of children with developmental delay. Studies have demonstrated that physician knowledge of this process has the potential to impact physician referral rates and parents' willingness to carry out a physician referral to completion. Our study is the first to quantitatively evaluate physicians' knowledge of the Early Intervention process and determine the physician factors that are associated with knowledge. Additionally, we examined whether the disproportionate distribution of physician knowledge has the potential to contribute to disparities described in the literature for developmental delay management. [ABSTRACT FROM AUTHOR]

Vici syndrome (VICIS) is a congenital disorder characterized by agenesis of the corpus callosum, cataracts, hypopigmentation, cardiomyopathy, combined immunodeficiency, microcephaly, and failure to thrive. This study aimed to elucidate the number of patients with VICIS, its clinical characteristics and relevant genetic information in Japan. After developing diagnostic criteria for VICIS, we conducted a nationwide questionnaire-based survey of VICIS in Japan. In the initial survey, we investigated the number of VICIS patients who fulfilled definite or probable criteria. The second survey was used to obtain detailed clinical and genetic information of VICIS from institutions that responded to the initial survey. Clinical information was available for 15 patients (12 definite, three probable). As of October 2023, nine patients (60%) were alive and six (40%) had died. All patients presented with developmental delay, agenesis of the corpus callosum, elevated serum aspartate/alanine aminotransferase, hypopigmentation and hypotonia. Developmental delay was profound. Most patients developed recurrent infection, high-arched palate, epilepsy, failure to thrive, and microcephaly. Cardiomyopathy and cataracts, both initially described as principal features in VICIS, were notably uncommon in our study. Based on the information collected, all 14 patients for whom information was available received home medical care: 11 (79%) received tube feeding, three (21%) required noninvasive ventilation, four (29%) required tracheostomy, and four (29%) required home subcutaneous immunoglobulin administration. This study revealed for the first time the nationwide status of patients with VICIS in Japan. The mortality rate of patients with VICIS is as high as 40%, and almost all VICIS patients require various forms of home medical care, necessitating comprehensive management. Additionally, we identified one adult patient, underscoring the need for comprehensive medical management extending into adulthood for patients with VICIS. [ABSTRACT FROM AUTHOR]

Background & Objective: Autosomal recessive cerebellar ataxias (ARCA) are rare heterogenous neurodegenerative disorders characterized by degeneration of the cerebellum and spinal cord with an early onset before the age of 20 years. PMPCA (MIM: 613036), is a key enzyme in mitochondrial protein processing which is critical for cell survival and growth. Our objective was to investigate Peptidase, Mitochondrial Processing Subunit Alpha (PMPCA) mutations linked with Spinocerebellar ataxia, autosomal recessive 2 (SCAR2). Method: In the current study, Whole Exome Sequencing (WES) was done followed by Sanger sequencing for the validation of the WES results. Results: WES results identified a novel homozygous variant, NM_015160.2: c.802C>T p.(Arg268Trp) in PMPCA gene. Mutation in this gene leads to progressive cerebellar ataxia with fine motor skills difficulties, intentional tremors, slow slurred speech and learning difficulties in a 12-year-old Saudi patient. WES results were further validated by Sanger sequencing technique. Conclusions: Identified phenotype in our case was similar as previously described for SCAR2 related conditions. To our knowledge, this is the first reported mutation in PMPCA gene leading to SCAR2 in Saudi Arabia. These findings will enrich the scarce literature, further provide a new insight on the role of PMPCA gene-related disorders leading to SCAR2 and expand the disease concept. In addition, this will help to establish a database for the disease and its causative factors will further help in controlling diseases resulting from consanguinity in Saudi population. [ABSTRACT FROM AUTHOR]

Aminoacyl‐tRNA synthetases (aaRSs) are essential enzymes to support protein synthesis in all organisms. Recent studies, empowered by advancements in genome sequencing, have uncovered an increasing number of disease‐causing mutations in aaRSs. Monoallelic aaRS mutations typically lead to dominant peripheral neuropathies such as Charcot–Marie–Tooth (CMT) disease, whereas biallelic aaRS mutations often impair the central nervous system (CNS) and cause neurodevelopmental disorders. Here, we review recent progress in the disease onsets, molecular basis, and potential therapies for diseases caused by aaRS mutations, with a focus on biallelic mutations in cytoplasmic aaRSs. [ABSTRACT FROM AUTHOR]

Cases of isolated spinal cord ischemia resulting in symptoms in neonates are rare, and there are even fewer reported cases in atraumatic births. We present a case of a presumed isolated cervical cord ischemic injury, discuss differentials to consider when evaluating a neonatal spinal cord injury, and highlight the difficulties of diagnosing a spinal cord infarction. [ABSTRACT FROM AUTHOR]

Genetic testing of patients with neurodevelopmental disabilities (NDDs) is critical for diagnosis, medical management, and access to precision therapies. Because genetic testing approaches evolve rapidly, professional society practice guidelines serve an essential role in guiding clinical care; however, several challenges exist regarding the creation and equitable implementation of these guidelines. In this scoping review, we assessed the current state of United States professional societies' guidelines pertaining to genetic testing for unexplained global developmental delay, intellectual disability, autism spectrum disorder, and cerebral palsy. We describe several identified shortcomings and argue the need for a unified, frequently updated, and easily‐accessible cross‐specialty society guideline. ANN NEUROL 2024;96:900–913 [ABSTRACT FROM AUTHOR]

In the autism field, there is increasing interest in translating evidence-based interventions (EBIs) into systems that serve young autistic children and their families. Public Early Intervention systems have been a focal point of research-based implementation efforts given that these systems are federally mandated to provide services to children birth to three years of age with developmental delays under Part C of the Individuals with Disabilities Education Act. Although a growing number of research studies are now training Early Intervention providers to deliver autism EBIs, this work has been conducted on a relatively small scale and has only just begun to consider the alignment of these models with Early Intervention systems and whether sufficient infrastructure exists to scale up these training efforts and to sustain their public health impact. This commentary aims to address this gap by reviewing factors that have been found to uniformly impact the scale-up of EBIs across diverse public systems (Fagan 20, 1147–1168, 2019), and to extend this framework to the implementation of EBIs within public Early Intervention systems. These factors include developer and funder capacity, the public's awareness of and support for EBIs, the system's leadership support for EBI use, the capacity for community engagement in implementation efforts, the availability of a skilled workforce capable of delivering EBIs, and the capacity for data monitoring and quality improvement. This commentary discusses how these factors may specifically impact the scale-up of autism EBIs within EI systems to support toddlers and young, autistic children, and implications for autism researchers. [ABSTRACT FROM AUTHOR]

We tested the association between early childcare attendance in the first three years of life and child development at age 3.5 years in the French context, where early childcare is subsidized. In the ELFE (Étude Longitudinale Français depuis l'Enfance) birth cohort study set in metropolitan France, children's development was reported by parents at age 3.5 years (n = 11,033) via the Child Development Inventory (CDI) questionnaire. CDI scores were transformed into a development quotient (DQ), with a DQ < 90 corresponding to possible and a DQ < 85 corresponding to a probable developmental delay. Inverse probability weighted multivariable regression models were used to analyse whether early childcare in the first three years of life (centre-based, childminder, informal or parental care) was associated to development delay. Compared to children in exclusive parental care, those in centre-based childcare (CBC) or with a childminder prior to school entry were significantly less likely to experience possible (OR = 0.56, [95% CI = 0.51–0.61] for CBC and OR = 0.77, [95% CI = 0.72–0.83] for childminder attendance) and probable developmental delay (OR = 0.62, [0.58–0.67] for CBC and OR = 0.80 [0.76–0.83] for childminder). Informal childcare attendance was not significantly associated with children's possible nor probable developmental delay ((OR = 0.97, [0.84–1.12]) and (OR = 0.97, [0.82–1.15]), respectively). Conclusions: Overall, our findings add to the existing scientific literature, showing that in the French context, where childcare can start as early as 3 months of age, early childcare attendance can contribute to child's development. What's Known on This Subject: • Studies on early childcare attendance and child development have shown mixed results, associations with better psychomotor development mainly being observed in Nordic countries, while some studies in other countries such as the USA showed no or negative associations. What This Study Adds: • In a country with broad and subsidized access to childcare such as France, access to early childhood education can positively contribute to children's psychomotor development. However, we found that access to childcare does not appear to reduce social inequalities in children's psychomotor development. [ABSTRACT FROM AUTHOR]

Background: Individuals with intellectual disability, including people with Down syndrome (DS), often exhibit restricted and repetitive behaviours (RRBs). However, RRBs have not been deeply characterised in children and adolescents with DS. Method: The study encompassed a cohort of 151 participants aged 4 to 18 years with DS. RRBs were assessed utilising the Repetitive Behaviour Scale‐Revised. Additionally, data pertaining to cognitive and adaptive functioning, linguistic abilities, sleep patterns and emotional/behavioural issues were gathered. Results: Self‐injurious behaviours were reported less frequently whereas parents most commonly endorsed items related to behaviours associated with the need for sameness and ritualistic behaviours. We observed very few gender differences, whereas some age‐related differences emerged, with adolescents exhibiting higher scores in items related with higher‐level RRBs. The analysis of the association between RRBs and clinical features revealed that RRBs were associated with parent‐reported sleep difficulties, as well as with internalising and externalising problems. We also observed a negative correlation with IQ whereas associations with adaptive skills emerged mainly for lower‐level RRBs, such as motor stereotypies. Finally, RRBs were negatively associated with linguistic abilities, both expressive and receptive. Conclusions: RRBs in children and adolescents with DS are of significant clinical interest due to their associations with various clinical dimensions. Therefore, psychological and neuropsychiatric assessment should include an accurate evaluation of RRBs for young people with DS. [ABSTRACT FROM AUTHOR]

• Identification of a novel role for type IV collagen in bone biology. • Col4a1 mutant mouse models of Gould syndrome exhibit skeletal abnormalities. • Elevated TGFβ signaling contributes to skeletal pathogenesis in Col4a1 mutant mice. • Phenotypic and mechanistic overlap between Gould syndrome and other collagen-related ECM disorders. Skeletal defects are hallmark features of many extracellular matrix (ECM) and collagen-related disorders. However, a biological function in bone has never been defined for the highly evolutionarily conserved type IV collagen. Collagen type IV alpha 1 (COL4A1) and alpha 2 (COL4A2) form α1α1α2 (IV) heterotrimers that represent a fundamental basement membrane constituent present in every organ of the body, including the skeleton. COL4A1 and COL4A2 mutations cause Gould syndrome, a variable and clinically heterogenous multisystem disorder generally characterized by the presence of cerebrovascular disease with ocular, renal, and muscular manifestations. We have previously identified elevated TGFβ signaling as a pathological insult resulting from Col4a1 mutations and demonstrated that reducing TGFβ signaling ameliorate ocular and cerebrovascular phenotypes in Col4a1 mutant mouse models of Gould syndrome. In this study, we describe the first characterization of skeletal defects in Col4a1 mutant mice that include a developmental delay in osteogenesis and structural, biomechanical and vascular alterations of mature bones. Using distinct mouse models, we show that allelic heterogeneity influences the presentation of skeletal pathology resulting from Col4a1 mutations. Importantly, we found that TGFβ target gene expression is elevated in developing bones from Col4a1 mutant mice and show that genetically reducing TGFβ signaling partially ameliorates skeletal manifestations. Collectively, these findings identify a novel and unsuspected role for type IV collagen in bone biology, expand the spectrum of manifestations associated with Gould syndrome to include skeletal abnormalities, and implicate elevated TGFβ signaling in skeletal pathogenesis in Col4a1 mutant mice. [ABSTRACT FROM AUTHOR]

Angelman Syndrome (AS) is a neurodevelopmental disorder with severe symptoms and associated comorbidities. It is caused by the inactivity or lack of the UBE3a gene. Symptoms of the syndrome include intellectual disability and developmental delay. The current study investigated sleep disturbances (SD) in children and adolescents with AS, associations between SD and possible predictors of SD. Variables examined included age, gender, newborn and infancy history, challenging behavior, type of therapy received, genetic type of AS, and seizures. The sample included data from 109 participants with a mean age of 8.21, accessed via the Global Angelman Syndrome Registry. Chi-square tests were carried out to assess the associations between the variables and a logistical regression was carried out to assess the possible predictors of SD. Associations were found between SD and certain repetitive behaviors: slapping walls, focal hand movements, and agitation at new situations. From these associations, a regression formed a predictive model for sleep disturbances. The findings of this research demonstrated the importance of investigating the relationship between sleep disturbances and challenging behavior in children and adolescents with AS and the need for further research in this area. • The current study investigated sleep disturbances (SD) in children and adolescents with AS. • The sample included data from 109 participants accessed via the Global Angelman Syndrome Registry. • Associations between sleep disturbances and challenging behavior were examined. • Associations were found between SD and slapping walls, focal hand movements, and agitation at new situations. [ABSTRACT FROM AUTHOR]

Biallelic SUFU variants have originally been linked to Joubert syndrome, comprising cerebellar abnormalities, dysmorphism, and polydactyly. In contrast, heterozygous truncating variants have recently been associated with developmental delay and ocular motor apraxia, but only a limited number of patients have been reported. Here, we aim to delineate further the mild end of the phenotypic spectrum related to SUFU haploinsufficiency. Nine individuals (from three unrelated families) harboring truncating SUFU variants were investigated, including two previously reported individuals (from one family). We provide results from a comprehensive assessment comprising neuroimaging, neuropsychology, video-oculography, and genetic testing. We identified three inherited or de novo truncating variants in SUFU (NM_016169.4): c.895C>T p.(Arg299∗), c.71dup p.(Ala25Glyfs∗23), and c.71del p.(Pro24Argfs∗72). The phenotypic expression showed high variability both between and within families. Clinical features include motor developmental delay (seven of nine), axial hypotonia (five of nine), ocular motor apraxia (three of nine), and cerebellar signs (three of nine). Four of the six reported children had macrocephaly. Neuropsychological and developmental assessments revealed mildly delayed language development in the youngest children, whereas general cognition was normal in all variant carriers. Subtle but characteristic SUFU -related neuroimaging abnormalities (including superior cerebellar dysplasia, abnormalities of the superior cerebellar peduncles, rostrally displaced fastigium, and vermis hypoplasia) were observed in seven of nine individuals. Our data shed further light on the mild but recognizable features of SUFU haploinsufficiency and underline its marked phenotypic variability, even within families. Notably, neurodevelopmental and behavioral abnormalities are mild compared with Joubert syndrome and seem to be well compensated over time. [ABSTRACT FROM AUTHOR]

Background: Impaired visuomotor integration (VMI) is commonly observed in children with developmental delay (DD). This pilot study aimed to evaluate the effects of tablet computer-based cognitive training on the VMI in children with DD. Methods: This study included children aged 4 to under 18 years diagnosed with DD. The children participated in a 12-week tablet computer-based visual-spatial and visuomotor training program. They were administered the Mind Rx Kids Program (Brain Academy, Seoul, South Korea). The participants underwent daily 30-min tablet computer-based training for 12 weeks. The primary visuomotor function was measured using the Beery-Buktenica Developmental Test of Visual-Motor Integration, 6th Edition (VMI-6). For secondary outcomes, measurements were taken before and after 12-week treatment using the Quality of Upper Extremity Skills Test (QUEST), Functional Independence Measure for Children (WeeFIM), Childhood Autism Rating Scale (CARS), Attention deficit hyperactivity disorder Rating Scale (ARS), and Child Smartphone Addiction Observer Scale. The Wilcoxon signed-rank test was used to compare the pre- and post-treatment outcomes. Results: Ten children with DD participated in this study. The results of the 12-week tablet computer-based cognitive training showed significant improvements in the raw score, standard score, percentile score, and equivalent age of the Beery VMI-6. Additionally, there were significant improvements in QUEST and WeeFIM scores. Although there were improvements in the CARS, ARS, and smartphone addiction observer scale, these were not statistically significant. Conclusion: This pilot study confirmed that applying tablet computer-based cognitive training to children with DD not only improves VMI, but also enhances fine motor skills and activities of daily living. Furthermore, the results of this study indicate that tablet computer-based cognitive training does not increase digital media addiction. Therefore, children with DD can engage in tablet computer-based cognitive training at home without concerns about digital media addiction. [ABSTRACT FROM AUTHOR]

The synergistic integration of tourism, the economy, and the ecological environment within a region is crucial for promoting its sustainable development. Tourism acts as a catalyst for green economic growth, yet varying levels of tourism development can intensify the strain on the ecological environment. Thus, achieving a Pareto optimal balance among the benefits of these three entities holds significant theoretical and practical relevance. This research utilizes statistical data spanning from 2000 to 2021 to devise a tourism-economy-ecological environment (TEE) indicator system for Xinjiang. The study employs a coupled coordination model to analyze the spatial and temporal coupling dynamics between subsystems and to classify the types of coupled coordination. The analysis also identifies obstacles that impede the degree of coordination. The findings indicate that during the period under investigation, the TEE system in Xinjiang experienced consistent growth. However, the tourism subsystem exhibited disparate development and pronounced resource monopolization, which stimulated the economic subsystem's growth, albeit with noticeable developmental lags in the latter stages. Spatially, economic performance demonstrated a declining trend from core urban centers like Urumqi City and Karamay City towards peripheral areas. From an ecological perspective, the distribution of resources exhibited a heterogeneous "M-V-W" pattern, characterized by significant disparities in the availability of natural resources and the occurrence of localized ecological deterioration. There is a notable and increasing degree of coupled coordination in regional synergistic development, which is primarily manifested in the delayed development of tourism. The combined development of the three subsystems is influenced by some factors, including environmental pollution, resources, economic quality, and industrial structure. Soot emissions, green space per capita in parks, and sulfur dioxide emissions are identified as key constraints. This study provides theoretical backing and empirical evidence for economic growth, the optimization of industrial structure, and the preservation of the ecological environment in arid and semi-arid regions globally. [ABSTRACT FROM AUTHOR]

Human voltage-gated potassium (Kv) channels are expressed by a 40-member gene family that is essential for normal electrical activity and is closely linked to various excitability disorders. Function-altering sequence variants in the KCNB1 gene, which encodes the neuronally expressed Kv2.1 channel, are associated with neurodevelopmental disorders including developmental delay with or without epileptic activity. In this study, we describe a 40-monthold fraternal twin who presented with severe neurodevelopmental delay. Electroencephalogram recordings at 19 months of age revealed poor sleep architecture and the presence of multifocal epileptiform discharges. The individual's fraternal twin was neurotypical, and there was no family history of neurodevelopmental delay or seizures. Whole genome sequencing at 33 months of age for the proband revealed a de novo variant in KCNB1 [c.1154C > T/p. Pro385Leu], encoding a proline-to-leucine substitution at residue 385, in the extracellular region immediately preceding Kv2.1 transmembrane segment 6 (S6). Cellular electrophysiological analysis of the effects of the gene variant in heterologously expressed Kv2.1 demonstrated that homozygous Kv2.1-P385L channels were completely non-functional. Channels generated by a 50/50 expression of wild-type Kv2.1 and Kv2.1-P385L, designed to mimic the proband's heterozygous status, revealed a partially dominant-negative effect, resulting in an 81% reduction in current magnitude. The dramatic loss of function in Kv2.1 is the most likely cause of the severe developmental delay and seizure activity in the proband, further enriching our phenotypic understanding of KCNB1 developmental encephalopathies. [ABSTRACT FROM AUTHOR]

Background: TRIM8-related neuro-renal syndrome (NRS), caused by pathogenic variants of the TRIM8 gene, is characterized by epilepsy, developmental delay (DD) and renal disorders. The severity of the neurological effects as well as the presence of renal disorders is variable among patients. Here, we report three additional patients with clinical features compatible with NRS and summarize the association between the variants’ loci and phenotype of TIRM8-related NRS. Methods: A retrospective analysis was conducted for three Chinese children with NRS due to TRIM8 variants identified through whole-exome sequencing (WES). Previous reports of patients with TRIM8-related NRS were reviewed systematically. Demographic and clinical data were collected from these patients Results: Two de novo TRIM8 truncating variants in three NRS patients were identified in our study, including c.1327_c.1328delCCinsTG (p. Arg443*) and c.1375C>T (p.Gln459*). Our three patients all exhibited drug-resistant epilepsy and early-onset DD, and two of whom developed electrical status epilepticus during sleep (ESES). Brain magnetic resonance imaging (MRI) showed periventricular leukomalacia in one patient and normal in the other two. All three patients demonstrated nephrotic range proteinuria (NRP) or nephrotic syndrome (NS) with normal renal function during follow-up. There was a total of 27 patients with TRIM8-related NRS have been identified to date. The most common clinical features are renal diseases (89%), DD (89%), followed by epilepsy (78%). 67% of patients eventually progressed to end-stage renal disease (ESRD). Focal seizure was the most frequent seizure type (57%). 52% of patients presented drug-resistant epilepsy. 64% of patients exhibited non-specific brain MRI abnormalities. Brain atrophy was the most common change (50%). Two patients with TRIM8 variants closer to the N-terminal had neurological diseases without renal damage. Five patients with TRIM8 variants closer to the C-terminal had no severe neurological diseases. Seven patients had Gln459* variant which is the most common variant (7/27, 25.9%). The severity of the renal and neurological damage of the seven patients was variable. Conclusion: This study expands the number of individuals with confirmed NRS due to pathogenic variants in TRIM8. Neurological and renal phenotype with the same variant locus differed in their severity. Further research is needed to explore the relationship between genotype and phenotype of TRIM8 variants. [ABSTRACT FROM AUTHOR]

Introduction: Severe childhood obesity can be caused by pathogenic variants in several genes involved in monogenic and syndromic obesity. Recently, heterozygous variants in pleckstrin homology domain interacting protein (PHIP) have been identified in patients with obesity as part of Chung-Jansen syndrome. Case Presentation: The index patient is a 5-year-old boy with severe obesity since 1 year of age, developmental delay, facial dysmorphism, and behavior problems. Whole-exome sequencing identified a novel missense variant in PHIP (c.3182C>A, p.Ala1061Glu) in the index patient. Further genetic testing in family members revealed segregation of the same PHIP variant in the brother and mother, who both presented with severe childhood obesity and developmental delay or learning difficulties. The PHIP missense variant was predicted pathogenic by multiple in silico tools and affects a highly conserved residue. Conclusion: Early-onset obesity may be monogenic. Our finding expands the spectrum of disease-causing variants in PHIP and demonstrates variable intrafamilial clinical expressivity and severity. Screening for PHIP variants should be included in genetic testing in patients with severe early-onset obesity. [ABSTRACT FROM AUTHOR]

ABSTRACT De novo heterozygous variants in RNU4‐2, a component of the major spliceosome, were recently found to cause a novel neurodevelopmental disorder. Preliminary evidence suggests that this newly discovered syndrome is one of the most common monogenic causes of neurodevelopmental disorders. It is characterised by developmental delay and intellectual disability, microcephaly, short stature and hypotonia. However, much remains to be elucidated regarding the phenotype of the affected individuals. We report on four novel individuals affected by the condition, two of which were identified following targeted sequencing based solely on the facial features that were similar to those of the first patient we identified. This strongly suggests that this syndrome entails a recognisable morphological phenotype, which is particularly relevant for resource‐limited regions where whole genome sequencing is not readily available, and in view of retro‐active selection/prioritisation of individuals with hitherto negative genetic testing. [ABSTRACT FROM AUTHOR]

Mathematical algorithms known as "epigenetic clocks" use methylation values at a set of CpG sites to estimate the biological age of an individual in a tissue-specific manner. These clocks have demonstrated both acceleration and delays in epigenetic aging in multiple neuropsychiatric conditions, including schizophrenia and neurodevelopmental disorders such as autism spectrum disorder. However, no study to date has examined epigenetic aging in ADHD despite its status as one of the most prevalent neurodevelopmental conditions, with 1 in 9 children having ever received an ADHD diagnosis in the US. Only a handful of studies have examined epigenetic age in brain tissue from neurodevelopmental conditions, with none focused on ADHD, despite the obvious relevance to pathogenesis. Thus, here we asked if post-mortem brain tissue in those with lifetime histories of ADHD would show accelerated or delayed epigenetic age, as has been found for other neurodevelopmental conditions. We applied four different epigenetic clocks to estimate epigenetic age in individuals with ADHD and unaffected controls from cortical (anterior cingulate cortex, N = 55) and striatal (caudate, N = 56) post-mortem brain tissue, as well as peripheral blood (N = 84) and saliva (N = 112). After determining which epigenetic clock performed best in each tissue, we asked if ADHD was associated with altered biological aging in corticostriatal brain and peripheral tissues. We found that a range of epigenetic clocks accurately predicted chronological age in all tissues. We also found that a diagnosis of ADHD was not significantly associated with differential epigenetic aging, neither for the postmortem ACC or caudate, nor for peripheral tissues. These findings held when accounting for comorbid psychiatric diagnoses, substance use, and stimulant medication. Thus, in this study of epigenetic clocks in ADHD, we find no evidence of altered epigenetic aging in corticostriatal brain regions nor in peripheral tissue. We consider reasons for this unexpected finding, including the limited sampling of brain regions, the age range of individuals studied, and the possibility that processes that accelerate epigenetic age may be counteracted by the developmental delay posited in some models of ADHD. [ABSTRACT FROM AUTHOR]

Background: Genetic disorders could also contribute to intellectual disability. Using whole exome sequencing (WES), several variants have been identified as autosomal-dominant inheritance intellectual disability. Thus, the application of WES has demonstrated its critical role in distinguishing intellectual disability in children patients, which provides essential diagnosis and promotes therapeutic strategy. Case presentation: The proband, an 18-month-old female patient, presented with a complex clinical profile characterized by profound developmental delay, epilepsy, and neurological developmental impairment. WES identified a heterozygous c.913A>G variant in exon 2 of NACC1, resulting in disease caused by a change in the amino acid sequence, affecting the protein features and resulting in splice site changes, as revealed by MutationTaster analysis. The protein structure of NAC1 was built and named AF-Q96RE7-F1, and the mutant site was beyond the BTB/POZ, NLS, and BEN domains. Subsequently, PyMOL software was used to illustrate the molecular structure between the wild type and the mutant type of NAC1. The residues around the 304 site of amino acid changed in NAC1 p.T304A with an altered hydrogen bond, indicating an unstable structure. The patient was diagnosed with intellectual disability and profound developmental delay with epilepsy harboring a novel de novo NACC1 variant. Upon hospital admission, a comprehensive treatment regimen was initiated, including antiseizure medications, nutritional supplements, and rehabilitation training. As a result, the patient's movement performance improved. However, recurrent epilepsy attacks still occurred. Conclusion: This is the first case revealing a novel NACC1 c.903A>G variant that induced a neurological impairment in an infant. This report expanded the understanding of the non-domain-associated variant of NACC1 and developmental disorder. [ABSTRACT FROM AUTHOR]

Introduction Methods Results Conclusion Cohen syndrome is a rare disease associated with neurodevelopmental disorders, especially intellectual disability (ID), neutropenia and recurrent infections are consistently reported in cases. Neutropenia is an important part of the syndrome, as well as ID. Homozygous variants in the VPS13B gene, located on chromosome 8q22 and containing 62 exons, have been found to cause Cohen syndrome. Cohen syndrome is commonly diagnosed when dysmorphological findings and developmental delay become more apparent. However, the identification of some findings with increasing age has caused the diagnosis of Cohen syndrome to be delayed.Cases diagnosed with ID were evaluated using whole‐exome sequencing/clinical exome sequencing method. Family segregation analysis was performed using Sanger sequencing. We presented the clinical and genetic findings of three cases diagnosed with Cohen syndrome and their parents in detail.In this study, we presented the occurrence of symptoms in different age groups, and the prognosis of three cases carrying the VPS13B gene variants, including three different variant types: missense, frameshift and nonsense. Although our cases had different variant types, they shared important similarities on the onset period and prognosis of the symptoms. All cases presented hypotonia, difficulties in swallowing, recurrent respiratory tract infections, neutropenia, delay in motor development, ID and hyperactivity. Our cases did not have a diagnosis of autism spectrum disorder. All cases had increased willingness to engage in social communication.We emphasize the importance of early‐onset recurrent infections and hypotonia for early diagnosis and preventive genetic counselling in Cohen syndrome. [ABSTRACT FROM AUTHOR]

Biallelic pathogenic variants in TARS2 lead to combined oxidative phosphorylation deficiency, subtype 21 (COXPD21, MIM #615918), which is a rare mitochondrial encephalomyopathy (ME) characterized by early-onset severe axial hypotonia, limb hypertonia, psychomotor developmental delay, epilepsy and brain anomalies. To date, approximately 28 individuals with COXPD21 and 28 TARS2 variants have been identified. In this study, we reported additional four individuals from three unrelated Chinese families with mitochondrial encephalomyopathy caused by pathogenic variants in TARS2, and described the novel clinical phenotypes and genotypic information. In addition to two novel variants (c.512G > A, p.Arg171Lys; c.988dup, p.Arg330Lysfs*4), one previously reported variant (c.470 C > G, p.Thr157Arg) recurred in six Chinese individuals with COXPD21 but was not present in populations of other races. Our findings expanded the mutation spectrum of TARS2 and confirmed that c.470 C > G is a Chinese-specific founder mutation. The novel phenotypes, including reduced fetal movement, eye anomalies and sleep irregularities, observed in our patients enriched the clinical characteristics of COXPD21. [ABSTRACT FROM AUTHOR]

ABSTRACT Rearrangements of the p‐arm of Chromosome 8 can result in a spectrum of neurodevelopmental challenges, along with increased risk of epilepsy, structural brain and cardiac malformations, persisting developmental delays, and other health challenges. The majority of patients reported on in this sample are characterized by an inverted‐duplication deletion rearrangement, but deletions, duplications, and mosaic ring changes in 8p result in similar phenotype. In this report, we add to the phenotypic and functional description of these patients according to their specific chromosomal rearrangement, share neuro‐psychometric values, and propose surveillance care guidelines for caregivers and medical providers of patients with Chromosome 8p Syndromes. Observations from clinical experience with 24 patients seen at our 8p‐dedicated Multi‐Disciplinary Neurogenetics program are shared. [ABSTRACT FROM AUTHOR]