Analysis of Clinical Laboratory Detecting Challenging Variants from Exome Sequencing Using Simulated Patient-Parent Trio Sample: Pilot Study for Neurodevelopmental Disorder de Novo Variants.

To date, there has been no systematic analysis for the clinical laboratory in detecting technically challenging variants using the trio-based exome sequencing (ES) approach. Here, we present an interlaboratory pilot proficiency testing study that used synthetic patient-parent specimens to assess the detection of challenging variants with de novo dominant inheritance modes for neurodevelopmental disorders using various trio-based ES. In total, 27 clinical laboratories that performed diagnostic exome analyses participated in the survey. One of the 26 challenging variants was identified by all laboratories, whereas all 26 variants were identified by only nine laboratories. The lack of identification of mosaic variants was often due to the bioinformatics analysis that excluded the variant. For missing intended heterozygous variants, probable root causes were related to the technical bioinformatics pipeline and variant interpretation and reporting. For each missing variant, there may be more than one probable reason from the different laboratories. There was considerable variation in interlaboratory performance for detecting challenging variants using trio-based ES. This finding may have important implications for the design and validation of tests for different variant types in clinical laboratories, especially for technically challenging variants, and necessary workflow modification can potentially improve trio-based ES performance.

A latent class analysis of the socio-demographic factors and associations with mental and behavioral disorders among Australian children and adolescents.

BACKGROUND: Previous studies have shown a relationship between socio-demographic variables and the mental health of children and adolescents. However, no research has been found on a model-based cluster analysis of socio-demographic characteristics with mental health. This study aimed to identify the cluster of the items representing the socio-demographic characteristics of Australian children and adolescents aged 11-17 years by using latent class analysis (LCA) and examining the associations with their mental health. METHODS: Children and adolescents aged 11-17 years (n = 3152) were considered from the 2013-2014 Young Minds Matter: The Second Australian Child and Adolescent Survey of Mental Health and Wellbeing. LCA was performed based on relevant socio-demographic factors from three levels. Due to the high prevalence of mental and behavioral disorders, the generalized linear model with log-link binomial family (log-binomial regression model) was used to examine the associations between identified classes, and the mental and behavioral disorders of children and adolescents. RESULTS: This study identified five classes based on various model selection criteria. Classes 1 and 4 presented the vulnerable class carrying the characteristics of "lowest socio-economic status and non-intact family structure" and "good socio-economic status and non-intact family structure" respectively. By contrast, class 5 indicated the most privileged class carrying the characteristics of "highest socio-economic status and intact family structure". Results from the log-binomial regression model (unadjusted and adjusted models) showed that children and adolescents belonging to classes 1 and 4 were about 1.60 and 1.35 times more prevalent to be suffering from mental and behavioral disorders compared to their class 5 counterparts (95% CI of PR [prevalence ratio]: 1.41-1.82 for class 1; 95% CI of PR [prevalence ratio]: 1.16-1.57 for class 4). Although children and adolescents from class 4 belong to a socio-economically advantaged group and shared the lowest class membership (only 12.7%), the class had a greater prevalence (44.1%) of mental and behavioral disorders than did class 2 ("worst education and occupational attainment and intact family structure") (35.2%) and class 3 ("average socio-economic status and intact family structure") (32.9%). CONCLUSIONS: Among the five latent classes, children and adolescents from classes 1 and 4 have a higher risk of developing mental and behavioral disorders. The findings suggest that health promotion and prevention as well as combating poverty are needed to improve mental health in particular among children and adolescents living in non-intact families and in families with a low socio-economic status.

Observational Cohort Study Dedicated to Autism Spectrum Disorder: Milestone Steps, Results Updates, Perspectives.

Autism Spectrum Disorder (ASD) is a neurodevelopmental condition characterized by persistent difficulties in two domains: social communication and interaction, alongside with restricted, repetitive pattern of behaviors. It affects children and persists into adolescence and adulthood. Its causes and underlying psychopathological mechanisms are unknown and remain to be discovered. TEDIS cohort study developed over the decade 2010-2022, in Ile-de-France region, includes 1300 patients' files up to date, with valuable health information drawn from ASD evaluation. It provides researchers and decision makers with reliable data source to improve knowledge and practice in the context of ASD patients.

De novo variants in GATAD2A in individuals with a neurodevelopmental disorder: GATAD2A-related neurodevelopmental disorder.

GATA zinc finger domain containing 2A (GATAD2A) is a subunit of the nucleosome remodeling and deacetylase (NuRD) complex. NuRD is known to regulate gene expression during neural development and other processes. The NuRD complex modulates chromatin status through histone deacetylation and ATP-dependent chromatin remodeling activities. Several neurodevelopmental disorders (NDDs) have been previously linked to variants in other components of NuRD's chromatin remodeling subcomplex (NuRDopathies). We identified five individuals with features of an NDD that possessed de novo autosomal dominant variants in GATAD2A. Core features in affected individuals include global developmental delay, structural brain defects, and craniofacial dysmorphology. These GATAD2A variants are predicted to affect protein dosage and/or interactions with other NuRD chromatin remodeling subunits. We provide evidence that a GATAD2A missense variant disrupts interactions of GATAD2A with CHD3, CHD4, and CHD5. Our findings expand the list of NuRDopathies and provide evidence that GATAD2A variants are the genetic basis of a previously uncharacterized developmental disorder.

Early markers of neurodevelopmental disorders based on general movements for very preterm infants: study protocol for a multicentre prospective cohort study in a clinical setting in China.

INTRODUCTION: Very preterm (VPT) infants may experience varying degrees of neurodevelopmental challenges. Lack of early markers for neurodevelopmental disorders may delay referral to early interventions. The detailed General Movements Assessment (GMA) could help us to identify early markers for VPT infants at risk of atypical neurodevelopmental clinical phenotype in the very early stage of life as soon as possible. Preterm infants with high risk of atypical neurodevelopmental outcomes will have the best possible start to life if early precise intervention in critical developmental windows is allowed. METHODS AND ANALYSIS: This is a nationwide, multicentric prospective cohort study that will recruit 577 infants born <32 weeks of age. This study will determine the diagnostic value of the developmental trajectory of general movements (GMs) at writhing and fidgety age with qualitative assessment for different atypical developmental outcomes at 2 years evaluated by the Griffiths Development Scales-Chinese. The difference in the General Movement Optimality Score (GMOS) will be used to distinguish normal (N), poor repertoire (PR) and cramped sychronised (CS) GMs. We plan to build the percentile rank of GMOS (median, 10th, 25th, 75th and 90th percentile rank) in N, PR and CS of each global GM category and analyse the relationship between GMOS in writhing movements and Motor Optimality Score (MOS) in fidgety movements based on the detailed GMA. We explore the subcategories of the GMOS list, and MOS list that may identify specific early markers that help us to identify and predict different clinical phenotypes and functional outcomes in VPT infants. ETHICS AND DISSEMINATION: The central ethical approval has been confirmed from the Research Ethical Board of Children's Hospital of Fudan University (ref approval no. 2022(029)) and the local ethical approval has been also obtained by the corresponding ethics committees of the recruitment sites. Critical analysis of the study results will contribute to providing a basis for hierarchical management and precise intervention for preterm infants in very early life. TRIAL REGISTRATION NUMBER: ChiCTR2200064521.

Targeting Sigma Receptors for the Treatment of Neurodegenerative and Neurodevelopmental Disorders.

The sigma-1 receptor is a 223 amino acid-long protein with a recently identified structure. The sigma-2 receptor is a genetically unrelated protein with a similarly shaped binding pocket and acts to influence cellular activities similar to the sigma-1 receptor. Both proteins are highly expressed in neuronal tissues. As such, they have become targets for treating neurological diseases, including Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), multiple sclerosis (MS), Rett syndrome (RS), developmental and epileptic encephalopathies (DEE), and motor neuron disease/amyotrophic lateral sclerosis (MND/ALS). In recent years, there have been many pre-clinical and clinical studies of sigma receptor (1 and 2) ligands for treating neurological disease. Drugs such as blarcamesine, dextromethorphan and pridopidine, which have sigma-1 receptor activity as part of their pharmacological profile, are effective in treating multiple aspects of several neurological diseases. Furthermore, several sigma-2 receptor ligands are under investigation, including CT1812, rivastigmine and SAS0132. This review aims to provide a current and up-to-date analysis of the current clinical and pre-clinical data of drugs with sigma receptor activities for treating neurological disease.

The brain on time: links between development and neurodegeneration.

Neurodegenerative diseases are characterized by the progressive loss of structure or function of neurons. In this Spotlight, we explore the idea that genetic forms of neurodegenerative disorders might be rooted in neural development. Focusing on Alzheimer's, Parkinson's and Huntington's disease, we first provide a brief overview of the pathology for these diseases. Although neurodegenerative diseases are generally thought of as late-onset diseases, we discuss recent evidence promoting the notion that they might be considered neurodevelopmental disorders. With this view in mind, we consider the suitability of animal models for studying these diseases, highlighting human-specific features of human brain development. We conclude by proposing that one such feature, human-specific regulation of neurogenic time, might be key to understanding the etiology and pathophysiology of human neurodegenerative disease.

Altered Purinergic Signaling in Neurodevelopmental Disorders: Focus on P2 Receptors.

With the umbrella term 'neurodevelopmental disorders' (NDDs) we refer to a plethora of congenital pathological conditions generally connected with cognitive, social behavior, and sensory/motor alterations. Among the possible causes, gestational and perinatal insults have been demonstrated to interfere with the physiological processes necessary for the proper development of fetal brain cytoarchitecture and functionality. In recent years, several genetic disorders caused by mutations in key enzymes involved in purine metabolism have been associated with autism-like behavioral outcomes. Further analysis revealed dysregulated purine and pyrimidine levels in the biofluids of subjects with other NDDs. Moreover, the pharmacological blockade of specific purinergic pathways reversed the cognitive and behavioral defects caused by maternal immune activation, a validated and now extensively used rodent model for NDDs. Furthermore, Fragile X and Rett syndrome transgenic animal models as well as models of premature birth, have been successfully utilized to investigate purinergic signaling as a potential pharmacological target for these diseases. In this review, we examine results on the role of the P2 receptor signaling in the etiopathogenesis of NDDs. On this basis, we discuss how this evidence could be exploited to develop more receptor-specific ligands for future therapeutic interventions and novel prognostic markers for the early detection of these conditions.

New Insights in 9q21.13 Microdeletion Syndrome: Genotype-Phenotype Correlation of 28 Patients.

The implementation of array comparative genomic hybridisation (array-CGH) allows us to describe new microdeletion/microduplication syndromes which were previously not identified. 9q21.13 microdeletion syndrome is a genetic condition due to the loss of a critical genomic region of approximately 750kb and includes several genes, such as RORB and TRPM6. Here, we report a case of a 7-year-old boy affected by 9q21.13 microdeletion syndrome. He presents with global developmental delay, intellectual disability, autistic behaviour, seizures and facial dysmorphism. Moreover, he has severe myopia, which was previously reported in only another patient with 9q21.13 deletion, and brain anomalies which were never described before in 9q21.13 microdeletion syndrome. We also collect 17 patients from a literature search and 10 cases from DECIPHER database with a total number of 28 patients (including our case). In order to better investigate the four candidate genes RORB, TRPM6, PCSK5, and PRUNE2 for neurological phenotype, we make, for the first time, a classification in four groups of all the collected 28 patients. This classification is based both on the genomic position of the deletions included in the 9q21.3 locus deleted in our patient and on the different involvement of the four-candidate gene. In this way, we compare the clinical problems, the radiological findings, and the dysmorphic features of each group and of all the 28 patients in our article. Moreover, we perform the genotype-phenotype correlation of the 28 patients to better define the syndromic spectrum of 9q21.13 microdeletion syndrome. Finally, we propose a baseline ophthalmological and neurological monitoring of this syndrome.

Diagnostic accuracy of ASQ for screening of neurodevelopmental delays in low resource countries.

OBJECTIVE: The Bayley Scales of Infant Development (BSID) is the most used diagnostic tool to identify neurodevelopmental disorders in children under age 3 but is challenging to use in low-resource countries. The Ages and Stages Questionnaire (ASQ) is an easy-to-use, low-cost clinical tool completed by parents/caregivers that screens children for developmental delay. The objective was to determine the performance of ASQ as a screening tool for neurodevelopmental impairment when compared with BSID second edition (BSID-II) for the diagnosis of moderate-to-severe neurodevelopmental impairment among infants at 12 and 18 months of age in low-resource countries. METHODS: Study participants were recruited as part of the First Bites Complementary Feeding trial from the Democratic Republic of Congo, Zambia, Guatemala and Pakistan between October 2008 and January 2011. Study participants underwent neurodevelopmental assessment by trained personnel using the ASQ and BSID-II at 12 and 18 months of age. RESULTS: Data on both ASQ and BSID-II assessments of 1034 infants were analysed. Four of five ASQ domains had specificities greater than 90% for severe neurodevelopmental delay at 18 months of age. Sensitivities ranged from 23% to 62%. The correlations between ASQ communications subscale and BSID-II Mental Development Index (MDI) (r=0.38) and between ASQ gross motor subscale and BSID-II Psychomotor Development Index (PDI) (r=0.33) were the strongest correlations found. CONCLUSION: At 18 months, ASQ had high specificity but moderate-to-low sensitivity for BSID-II MDI and/or PDI <70. ASQ, when administered by trained healthcare workers, may be a useful screening tool to detect severe disability in infants from rural low-income to middle-income settings. TRIAL REGISTRATION NUMBER: NCT01084109.

A novel 1p13.2 deletion associates with neurodevelopmental disorders in a three-generation pedigree.

BACKGROUND: A multitude of studies have highlighted that copy number variants (CNVs) are associated with neurodevelopmental disorders (NDDs) characterized by a wide range of clinical characteristics. Benefiting from CNV calling from WES data, WES has emerged as a more powerful and cost-effective molecular diagnostic tool, which has been widely used for the diagnosis of genetic diseases, especially NDDs. To our knowledge, isolated deletions on chromosome 1p13.2 are rare. To date, only a few patients were reported with 1p13.2 deletions and most of them were sporadic. Besides, the correlation between 1p13.2 deletions and NDDs remained unclear. CASE PRESENTATION: Here, we first reported five members in a three-generation Chinese family who presented with NDDs and carried a novel 1.41 Mb heterozygous 1p13.2 deletion with precise breakpoints. The diagnostic deletion contained 12 protein-coding genes and was observed to segregate with NDDs among the members of our reported family. Whether those genes contribute to the patient's phenotypes is still inconclusive. CONCLUSIONS: We hypothesized that the NDD phenotype of our patients was caused by the diagnostic 1p13.2 deletion. However, further in-depth functional experiments are still needed to establish a 1p13.2 deletion-NDDs relationship. Our study might supplement the spectrum of 1p13.2 deletion-NDDs.

Genomic Diagnosis of Rare Pediatric Disease in the United Kingdom and Ireland.

BACKGROUND: Pediatric disorders include a range of highly penetrant, genetically heterogeneous conditions amenable to genomewide diagnostic approaches. Finding a molecular diagnosis is challenging but can have profound lifelong benefits. METHODS: We conducted a large-scale sequencing study involving more than 13,500 families with probands with severe, probably monogenic, difficult-to-diagnose developmental disorders from 24 regional genetics services in the United Kingdom and Ireland. Standardized phenotypic data were collected, and exome sequencing and microarray analyses were performed to investigate novel genetic causes. We developed an iterative variant analysis pipeline and reported candidate variants to clinical teams for validation and diagnostic interpretation to inform communication with families. Multiple regression analyses were performed to evaluate factors affecting the probability of diagnosis. RESULTS: A total of 13,449 probands were included in the analyses. On average, we reported 1.0 candidate variant per parent-offspring trio and 2.5 variants per singleton proband. Using clinical and computational approaches to variant classification, we made a diagnosis in approximately 41% of probands (5502 of 13,449). Of 3599 probands in trios who received a diagnosis by clinical assertion, approximately 76% had a pathogenic de novo variant. Another 22% of probands (2997 of 13,449) had variants of uncertain significance in genes that were strongly linked to monogenic developmental disorders. Recruitment in a parent-offspring trio had the largest effect on the probability of diagnosis (odds ratio, 4.70; 95% confidence interval [CI], 4.16 to 5.31). Probands were less likely to receive a diagnosis if they were born extremely prematurely (i.e., 22 to 27 weeks' gestation; odds ratio, 0.39; 95% CI, 0.22 to 0.68), had in utero exposure to antiepileptic medications (odds ratio, 0.44; 95% CI, 0.29 to 0.67), had mothers with diabetes (odds ratio, 0.52; 95% CI, 0.41 to 0.67), or were of African ancestry (odds ratio, 0.51; 95% CI, 0.31 to 0.78). CONCLUSIONS: Among probands with severe, probably monogenic, difficult-to-diagnose developmental disorders, multimodal analysis of genomewide data had good diagnostic power, even after previous attempts at diagnosis. (Funded by the Health Innovation Challenge Fund and Wellcome Sanger Institute.).

Current Best Practices for Analysis of Dendritic Spine Morphology and Number in Neurodevelopmental Disorder Research.

Quantitative methods for assessing neural anatomy have rapidly evolved in neuroscience and provide important insights into brain health and function. However, as new techniques develop, it is not always clear when and how each may be used to answer specific scientific questions posed. Dendritic spines, which are often indicative of synapse formation and neural plasticity, have been implicated across many brain regions in neurodevelopmental disorders as a marker for neural changes reflecting neural dysfunction or alterations. In this Perspective we highlight several techniques for staining, imaging, and quantifying dendritic spines as well as provide a framework for avoiding potential issues related to pseudoreplication. This framework illustrates how others may apply the most rigorous approaches. We consider the cost-benefit analysis of the varied techniques, recognizing that the most sophisticated equipment may not always be necessary for answering some research questions. Together, we hope this piece will help researchers determine the best strategy toward using the ever-growing number of techniques available to determine neural changes underlying dendritic spine morphology in health and neurodevelopmental disorders.

A review of the cognitive impact of neurodevelopmental and neuropsychiatric associated copy number variants.

The heritability of intelligence or general cognitive ability is estimated at 41% and 66% in children and adults respectively. Many rare copy number variants are associated with neurodevelopmental and neuropsychiatric conditions (ND-CNV), including schizophrenia and autism spectrum disorders, and may contribute to the observed variability in cognitive ability. Here, we reviewed studies of intelligence quotient or cognitive function in ND-CNV carriers, from both general population and clinical cohorts, to understand the cognitive impact of ND-CNV in both contexts and identify potential genotype-specific cognitive phenotypes. We reviewed aggregate studies of sets ND-CNV broadly linked to neurodevelopmental and neuropsychiatric conditions, and genotype-first studies of a subset of 12 ND-CNV robustly associated with schizophrenia and autism. Cognitive impacts were observed across ND-CNV in both general population and clinical cohorts, with reports of phenotypic heterogeneity. Evidence for ND-CNV-specific impacts were limited by a small number of studies and samples sizes. A comprehensive understanding of the cognitive impact of ND-CNVs would be clinically informative and could identify potential educational needs for ND-CNV carriers. This could improve genetic counselling for families impacted by ND-CNV, and clinical outcomes for those with complex needs.

Common sleep disorders in children: assessment and treatment.

Pediatric sleep disorders are a common, mainly among children with pre-existing disabilities, neurological conditions, and neurodevelopmental disorders. The consequences are variable, and sleep disorders may be associated with deficits in neurocognitive performance and growth failure. Rising awareness about sleep disorders among pediatricians will improve the early diagnosis and management of these disorders. This review describes normal sleep patterns in infants and children and provide a recent update on common sleep disorders that improve the diagnosis and treatment of children with sleep disorders.

Deficiency of AP1 Complex Ap1g1 in Zebrafish Model Led to Perturbation of Neurodevelopment, Female and Male Fertility; New Insight to Understand Adaptinopathies.

In vertebrates, two homologous heterotetrameric AP1 complexes regulate the intracellular protein sorting via vesicles. AP-1 complexes are ubiquitously expressed and are composed of four different subunits: γ, ß1, µ1 and σ1. Two different complexes are present in eukaryotic cells, AP1G1 (contains γ1 subunit) and AP1G2 (contains γ2 subunit); both are indispensable for development. One additional tissue-specific isoform exists for µ1A, the polarized epithelial cells specific to µ1B; two additional tissue-specific isoforms exist for σ1A: σ1B and σ1C. Both AP1 complexes fulfil specific functions at the trans-Golgi network and endosomes. The use of different animal models demonstrated their crucial role in the development of multicellular organisms and the specification of neuronal and epithelial cells. Ap1g1 (γ1) knockout mice cease development at the blastocyst stage, while Ap1m1 (µ1A) knockouts cease during mid-organogenesis. A growing number of human diseases have been associated with mutations in genes encoding for the subunits of adaptor protein complexes. Recently, a new class of neurocutaneous and neurometabolic disorders affecting intracellular vesicular traffic have been referred to as adaptinopathies. To better understand the functional role of AP1G1 in adaptinopathies, we generated a zebrafish ap1g1 knockout using CRISPR/Cas9 genome editing. Zebrafish ap1g1 knockout embryos cease their development at the blastula stage. Interestingly, heterozygous females and males have reduced fertility and showed morphological alterations in the brain, gonads and intestinal epithelium. An analysis of mRNA profiles of different marker proteins and altered tissue morphologies revealed dysregulated cadherin-mediated cell adhesion. These data demonstrate that the zebrafish model organism enables us to study the molecular details of adaptinopathies and thus also develop treatment strategies.

Serious Games in the new era of digital-health interventions: A narrative review of their therapeutic applications to manage neurobehavior in neurodevelopmental disorders.

Children and adolescents with neurodevelopmental disorders generally show adaptive, cognitive and motor skills impairments associated with behavioral problems, i.e., alterations in attention, anxiety and stress regulation, emotional and social relationships, which strongly limit their quality of life. This narrative review aims at providing a critical overview of the current knowledge in the field of serious games (SGs), known as digital instructional interactive videogames, applied to neurodevelopmental disorders. Indeed, a growing number of studies is drawing attention to SGs as innovative and promising interventions in managing neurobehavioral and cognitive disturbs in children with neurodevelopmental disorders. Accordingly, we provide a literature overview of the current evidence regarding the actions and the effects of SGs. In addition, we describe neurobehavioral alterations occurring in some specific neurodevelopmental disorders for which a possible therapeutic use of SGs has been suggested. Finally, we discuss findings obtained in clinical trials using SGs as digital therapeutics in neurodevelopment disorders and suggest new directions and hypotheses for future studies to bridge the gaps between clinical research and clinical practice.

DHX30-Associated Neurodevelopmental Disorder with Severe Motor Impairment and Absent Language: First Korean Case in Two Siblings and Literature Review.

DHX30 variants have recently been reported in patients with neurodevelopmental disorders with severe motor impairment and absent language (NEDMIAL). We report the first Korean siblings presenting with NEDMIAL and previously unreported clinical features harboring a rare de novo DHX30 missense variant. The proband was a 10-year-old boy presenting with intellectual disability with severe motor impairment, absent language, facial dysmorphism, strabismus, sleep disturbances, and feeding difficulties. We performed whole-exome sequencing using genomic deoxyribonucleic acid isolated from buccal swabs, which revealed a heterozygous missense variant of DHX30: (c.2344C>T, p.Arg782Trp). Sanger sequencing was conducted for the proband, the affected sister, and each parent. The same variant was confirmed in two siblings but not in their parents, suggesting the possibility of de novo germline mosaicism.