Haploinsufficiency underlies the neurodevelopmental consequences of SLC6A1 variants.

Heterozygous variants in SLC6A1, encoding the GAT-1 GABA transporter, are associated with seizures, developmental delay, and autism. The majority of affected individuals carry missense variants, many of which are recurrent germline de novo mutations, raising the possibility of gain-of-function or dominant-negative effects. To understand the functional consequences, we performed an in vitro GABA uptake assay for 213 unique variants, including 24 control variants. De novo variants consistently resulted in a decrease in GABA uptake, in keeping with haploinsufficiency underlying all neurodevelopmental phenotypes. Where present, ClinVar pathogenicity reports correlated well with GABA uptake data; the functional data can inform future reports for the remaining 72% of unscored variants. Surface localization was assessed for 86 variants; two-thirds of loss-of-function missense variants prevented GAT-1 from being present on the membrane while GAT-1 was on the surface but with reduced activity for the remaining third. Surprisingly, recurrent de novo missense variants showed moderate loss-of-function effects that reduced GABA uptake with no evidence for dominant-negative or gain-of-function effects. Using linear regression across multiple missense severity scores to extrapolate the functional data to all potential SLC6A1 missense variants, we observe an abundance of GAT-1 residues that are sensitive to substitution. The extent of this missense vulnerability accounts for the clinically observed missense enrichment; overlap with hypermutable CpG sites accounts for the recurrent missense variants. Strategies to increase the expression of the wild-type SLC6A1 allele are likely to be beneficial across neurodevelopmental disorders, though the developmental stage and extent of required rescue remain unknown.

Implications of a De Novo Variant in the SOX12 Gene in a Patient with Generalized Epilepsy, Intellectual Disability, and Childhood Emotional Behavioral Disorders.

SRY-box transcription factor (SOX) genes, a recently discovered gene family, play crucial roles in the regulation of neuronal stem cell proliferation and glial differentiation during nervous system development and neurogenesis. Whole exome sequencing (WES) in patients presenting with generalized epilepsy, intellectual disability, and childhood emotional behavioral disorder, uncovered a de novo variation within SOX12 gene. Notably, this gene has never been associated with neurodevelopmental disorders. No variants in known genes linked with the patient's symptoms have been detected by the WES Trio analysis. To date, any MIM phenotype number associated with intellectual developmental disorder has not been assigned for SOX12. In contrast, both SOX4 and SOX11 genes within the same C group (SoxC) of the Sox gene family have been associated with neurodevelopmental disorders. The variant identified in the patient here described was situated within the critical high-mobility group (HMG) functional site of the SOX12 protein. This domain, in the Sox protein family, is essential for DNA binding and bending, as well as being responsible for transcriptional activation or repression during the early stages of gene expression. Sequence alignment within SoxC (SOX12, SOX4 and SOX11) revealed a high conservation rate of the HMG region. The in silico predictive analysis described this novel variant as likely pathogenic. Furthermore, the mutated protein structure predictions unveiled notable changes with potential deleterious effects on the protein structure. The aim of this study is to establish a correlation between the SOX12 gene and the symptoms diagnosed in the patient.

Copy number variants at 4q31.3 affecting the regulatory region of FBXW7 associated with neurodevelopmental delay.

Emerging research has demonstrated that genomic alterations disrupting topologically associated domains (TADs) and chromatin interactions underlie the pathogenic mechanisms of specific copy number variants (CNVs) in neurodevelopmental disorders. We report two patients with a de novo deletion and a duplication in chromosome 4q31, potentially causing FBX-related neurodevelopmental syndrome by affecting the regulatory region of FBXW7. High-throughput chromosome conformation capture (Hi-C) analysis using available capture data in neural progenitor cells revealed the rewiring of the TAD boundary close to FBXW7. Both patients exhibited facial dysmorphisms, cardiac and limb abnormalities, and neurodevelopmental delays, showing significant clinical overlap with previously reported FBXW7-related features. We also included an additional 10 patients with CNVs in the 4q31 region from the literature and the DECIPHER database for Hi-C analysis, which confirmed that disruption of the regulatory region of FBXW7 likely contributes to the developmental defects observed in these patients.

Severe manifestation of Rauch-Azzarello syndrome associated with biallelic deletion of CTNND2.

CTNND2 encodes δ-catenin, a component of an adherens junction complex, and plays an important role in neuronal structure and function. To date, only heterozygous loss-of-function CTNND2 variants have been associated with mild neurodevelopmental delay and behavioral anomalies, a condition, which we named Rauch-Azzarello syndrome. Here, we report three siblings of a consanguineous family of Syrian descent with a homozygous deletion encompassing the last 19 exons of CTNND2 predicted to disrupt the transcript. All presented with severe neurodevelopmental delay with absent speech, profound motor delay, stereotypic behavior, microcephaly, short stature, muscular hypotonia with lower limb hypertonia, and variable eye anomalies. The parents and the fourth sibling were heterozygous carriers of the deletion and exhibited mild neurodevelopmental impairment resembling that of the previously described heterozygous individuals. The present study unveils a severe manifestation of CTNND2-associated Rauch-Azzarello syndrome attributed to biallelic loss-of-function aberrations, clinically distinct from the already described mild presentation of heterozygous individuals. Furthermore, we demonstrate novel clinical features in homozygous individuals that have not been reported in heterozygous cases to date.

Expanding the clinical phenotype and variant spectrum associated with RFX7.

RFX7 encodes a transcription factor that is ubiquitously expressed and important for neural development. Haploinsufficiency of RFX7 is associated with intellectual disability, developmental delay, and diverse malformations of brain structures. Currently, there are only 16 clinically described individuals who have variants in RFX7. A recognizable pattern of malformation associated with mutation in RFX7 has not yet been uncovered. Here we describe the phenotypic presentation of two additional individuals who have novel de novo variants in RFX7. One of the individuals we describe is from an under-represented Afro-Caribbean population.

A milder form of NSRP1-associated neurodevelopmental disorder, caused by a missense variant in the nuclear localization signal.

Nuclear Speckle Splicing Regulator Protein 1 (NSRP1) is a splice factor found in nuclear speckles, which are small membrane-free organelles implicated in epigenetic regulation, chromatin organization, DNA repair, and RNA modification. Bi-allelic loss-of-function variants in NSRP1 have recently been identified in patients suffering from a severe neurodevelopmental disorder, presenting with neurodevelopmental delay, epilepsy, microcephaly, hypotonia, and spastic cerebral palsy. Described patients acquired neither independent walking nor speech and often showed anomalies on cerebral MRI. Here we describe the case of a 14-year-old girl with motor and language delay as well as intellectual disability, who presents an ataxic gait but walks without assistance and speaks in short sentences. Whole-genome sequencing revealed the compound heterozygous NSRP1 variants c.114 + 2T > G and c.1595T > A (p.Val532Glu). Functional validation using HEK293T cells transfected with either wild-type or mutated GFP-tagged Nsrp1 suggests that the Val532Glu variant interferes with the function of the nuclear localization signal, and leads to mislocalization of NSRP1 in the cytosol, thus confirming the pathogenicity of the observed variant. This case helps to expand the phenotypic and genetic spectrum associated with pathogenic NSRP1 variants and indicates that this diagnosis should also be suspected in patients with milder phenotypes.

A case report of a patient with neurodevelopmental disorder with impaired speech and hyperkinetic movements: A biallelic variant in the ZNF142 gene.

Biallelic pathogenic variations in the zinc finger protein 142 (ZNF142) gene are associated with neurodevelopmental disorder with impaired speech and hyperkinetic movements (NEDISHM). This disorder is characterized by developmental delay, intellectual disability, speech delay, and movement disorders such as dystonia, tremor, ataxia, and chorea. Here, we report a patient who exhibited common neurological features and rarely reported brain MRI findings. Exome sequencing identified a novel biallelic variant in ZNF142 (c.3528_3529delTG; p.C1176fs*5 (NM_001105537.4)). NEDISHM was first described by Khan et al. (2019) and has been reported in 39 patients to date. Furthermore, upon reviewing our in-house data covering 750 individuals, we identified three different pathogenic ZNF142 variants. It appears that the frequency of ZNF142 alleles is not as low as initially thought, suggesting that this gene should be included in new generation sequencing panels for similar clinical scenarios. Our goal is to compile and expand upon the clinical features observed in NEDISHM, providing novel insights and presenting a new variant to the literature. We also aim to demonstrate that ZNF142 pathogenic variants should be considered in neurodevelopmental diseases.

Congenital central hypoventilation syndrome in korea: 20 years of clinical observation and evaluation of the ventilation strategy in a single center.

Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder characterized by hypoventilation due to impaired breathing control by the central nervous system and other symptoms of autonomic dysfunction. Mutations in paired-like homeobox 2 B (PHOX2B) are responsible for most cases of CCHS. Patients with CCHS have various phenotypes and severities, making the diagnosis difficult. This study aimed to present a comprehensive single-center experience of patients with CCHS, including key clinical features, treatment strategies, and outcomes. A retrospective chart review was performed for patients diagnosed with CCHS between January 2001 and July 2023 at Seoul National University Children's Hospital. Finally, we selected 24 patients and collected their demographic data, genotypes, ventilation methods, and clinical features related to autonomic dysfunction. The relationship between the clinical manifestations and genotypes was also examined. All patients used home ventilators, and tracheostomy was performed in 87.5% of patients. Fifteen (62.5%) patients had constipation and nine (37.5%) were diagnosed with Hirschsprung disease. Arrhythmia, endocrine dysfunction, and subclinical hypothyroidism were present in nine (37.5%), six patients (25.0%), and two patients (16.7%), respectively. A significant number of patients exhibited neurodevelopmental delays (19 patients, 79.2%). There was a correlation between the phenotype and genotype of PHOX2B in patients with CCHS. (r = 0.71, p < 0.001).   Conclusion: There was a positive correlation between paired-like homeobox 2 B mutations (especially the number of GCN repeats in the polyalanine repeat mutations sequence) and clinical manifestations. This study also demonstrated how initial treatment for hypoventilation affects neurodevelopmental outcomes in patients with CCHS. What is Known: • Congenital central hypoventilation syndrome is a rare genetic disorder characterized by hypoventilation and dysfunction of autonomic nervous system. • The disease-defining gene of CCHS is PHOX2B gene - most of the cases have heterozygous PARMs and the number of GCN triplets varies among the patients(20/24 - 20/33). What is New: • We have noted in the Korean patients with CCHS that there is a correlation between genotype (number of GCN repeats) and severity of phenotype. • National support for rare diseases allowed for a prompter diagnosis of patients with CCHS in Korean population.

Association between the COVID-19 pandemic and childhood development aged 30 to 36 months in South Korea, based on the National health screening program for infants and children database.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has had a significant impact on the neurodevelopment of children. However, the precise effects of the virus and the social consequences of the pandemic on pediatric neurodevelopment are not yet fully understood. We aimed to compare the neurodevelopment of children between before and during the COVID-19 pandemic, as well as examine the impact of socioeconomic status (SES) and regional differences on the development. METHODS: The study used the Korean Developmental Screening Test to compare the difference in the risk of neurodevelopmental delay between before and during the COVID-19 pandemic. Multivariable logistic regression analysis was conducted to identify the relationship between experiencing the COVID-19 pandemic and the risk of neurodevelopmental delay. Stratified analyses were performed to determine whether the developmental delays caused by the pandemic's impact varied depending on SES or regional inequality. RESULTS: This study found an association between the experience of COVID-19 and a higher risk of neurodevelopmental delay in communication (adjusted OR [aOR]: 1.21, 95% confidence interval [CI]: 1.19, 1.22; P-value: < 0.0001) and social interaction (aOR: 1.15, 95% CI: 1.13, 1.17; P-value: < 0.0001) domains among children of 30-36 months' ages. Notably, the observed association in the Medicaid group of children indicates a higher risk of neurodevelopmental delay compared to those in the non-Medicaid group. CONCLUSIONS: These findings highlight the need to be concerned about the neurodevelopment of children who experienced the COVID-19 pandemic. The study also calls for increased training and support for Medicaid children, parents, teachers, and healthcare practitioners. Additionally, policy programs focused on groups vulnerable to developmental delays are required.

Gestational Age and Neurodevelopmental Delay in Term Births at 6 and 12 Months: The Japan Environment and Children's Study (JECS).

BACKGROUND: In the recent years, a high risk of developmental delay not only in very low birth weight infants and late preterm infants but also in early term infants (37-38 weeks) have increasingly been reported. However, in Japan, there are virtually no studies regarding the development delays in early term infants. METHODS: This study used the data from the Japan Environment and Children's Study (JECS), a birth cohort study conducted in Japan. Data were selected for analysis from the records of 104,065 fetal records. The risk of neurodevelopmental delays at 6 months and 12 months after birth was evaluated using multivariate analysis for infants of various gestational ages, using the 40th week of pregnancy as a reference value. Neurodevelopment was evaluated at 6 months and 12 months after birth using the Ages and Stages Questionnaires, Japanese translation (J-ASQ-3). RESULTS: The proportion of infants born at a gestational age of 37 to 38 weeks who did not reach the J-ASQ-3 score cutoff value was significantly higher in all areas at both 6 months and 12 months after birth, when compared to that of infants born at 40 weeks. The odds ratio decreased at 12 months after birth compared to that at 6 months after birth. CONCLUSION: Early term infants in Japan are at an increased risk of neurodevelopmental delay at 12 months after birth.

GNB1 Encephalopathy: Clinical Case Report and Literature Review.

GNB1 encephalopathy is a rare genetic disease caused by pathogenic variants in the G Protein Subunit Beta 1 (GNB1) gene, with only around 68 cases documented worldwide. Although most cases had been caused by de novo germline mutations, in this case, the pathogenic variant was inherited from patient's mother, indicating an autosomal dominant inheritance pattern. The patient presented at 25 years of age with mild developmental delay and cognitive impairment, prominent generalized dystonia, and horizontal nystagmus which are all characterizing symptoms of GNB1 encephalopathy. Electroencephalography (EEG) showed no epileptiform patterns, and magnetic resonance imaging (MRI) revealed hypointensities in globus pallidus and dentate nucleus areas. The main theory for GNB1 encephalopathy pathogenesis is neuronal hyperexcitability caused by impaired ion channel regulation. Due to low specificity of symptoms, diagnosis relies on genetic testing. As there are no standardized GNB1 encephalopathy treatment guidelines, evaluation of different treatment options is based on anecdotal cases. Reviewing different treatment options, deep brain stimulation and intrathecal baclofen pump, as well as some other medications still in preclinical trials, seem to be the most promising.

EPHA4 Genetic Variant in a Patient with Epilepsy, Ophthalmological Anomalies, and Neurodevelopmental Delay.

We present the findings of a Whole Exome Sequencing in a 2-year-old boy, conceived via In Vitro Fertilization with donor sperm, who suffers from an undiagnosed neurological syndrome. The following heterozygous variant in the EPHA4 gene was identified and classified as likely pathogenic: c.1655_1656, p.(Ser552CysfsTer23). Subsequent segregation analysis showed that the variant was not inherited from the mother and the sperm donor is not accessible for genetic testing. The presented results can further expand upon the genetic variants considered when diagnosing complex neurological syndromes and shows the importance of access to biological samples from donor banks in genetically ambiguous cases.

Evaluation of Neurological and Auditory Development in Children with Congenital Heart Disease using Essence Q Questionnaire and Auditory Brainstem Response (ABR) Test.

Objectives: The progress of cardiac surgery in children and the increase in the survival of children with Congenital Heart Disease (CHD) has led to consider another issue called a neurodevelopmental disorder. In this study, 53 children with CHD were evaluated in terms of development with the Essence Q questionnaire, Otoacoustic Emission (OAE), and Auditory Brainstem Response (ABR) regarding these patients' hearing and risk factors. The Essence Q scores were also examined. Materials & Methods: In this prospective, cross-sectional study, the researchers included 53 children diagnosed with CHD. Initially, each child underwent ABR and OAE tests. Subsequently, data on potential risk factors associated with neurodevelopmental delay were collected. A trained project associate administered the Essence Q questionnaire, using parents' information as a guide. Following data collection, this study proceeded with an in-depth analysis of the information. Results: Thirty-six boys (67.92%) and 17 girls (32.08%) with CHD were included in the study. The mean age of children was 26.98±10.64 months. The mean Essence Q score for boys was 7.48±2.57. Moreover, the average score for girls was 2.23 ± 8.11. According to this questionnaire, 39 patients (73.58%) had hyperactivity disorder, 46 patients (86.79%) had behavioral disorders, and ten patients (16.98%) had a motor delay. Unlike previous studies, all patients had normal OAE and ABR hearing. Conclusion: This study demonstrated that factors such as developmental delay in the first year, a known genetic disease, and a history of seizures significantly impacted the Essence Q score. However, elements like prematurity, the use of ventilation, abnormalities on the dorsum, and the number of days post-surgery did not significantly affect the Essence Q score. Essence Q can be a reliable tool in screening for neurodevelopment in children with CHD.

The Approach to a Child with Dysmorphic Features: What the Pediatrician Should Know.

The advancement of genetic knowledge and the discovery of an increasing number of genetic disorders has made the role of the geneticist progressively more complex and fundamental. However, most genetic disorders present during childhood; thus, their early recognition is a challenge for the pediatrician, who will be also involved in the follow-up of these children, often establishing a close relationship with them and their families and becoming a referral figure. In this review, we aim to provide the pediatrician with a general knowledge of the approach to treating a child with a genetic syndrome associated with dysmorphic features. We will discuss the red flags, the most common manifestations, the analytic collection of the family and personal medical history, and the signs that should alert the pediatrician during the physical examination. We will offer an overview of the physical malformations most commonly associated with genetic defects and the way to describe dysmorphic facial features. We will provide hints about some tools that can support the pediatrician in clinical practice and that also represent a useful educational resource, either online or through apps downloaded on a smartphone. Eventually, we will offer an overview of genetic testing, the ethical considerations, the consequences of incidental findings, and the main indications and limitations of the principal technologies.

γ-Aminobutyric acid transporter and GABAA receptor mechanisms in Slc6a1+/A288V and Slc6a1+/S295L mice associated with developmental and epileptic encephalopathies.

We have previously characterized the molecular mechanisms for variants in γ-aminobutyric acid transporter 1-encoding solute carrier family 6-member 1 (SLC6A1) in vitro and concluded that a partial or complete loss of γ-aminobutyric acid uptake due to impaired protein trafficking is the primary aetiology. Impairment of γ-aminobutyric acid transporter 1 function could cause compensatory changes in the expression of γ-aminobutyric acid receptors, which, in turn, modify disease pathophysiology and phenotype. Here we used different approaches including radioactive 3H γ-aminobutyric acid uptake in cells and synaptosomes, immunohistochemistry and confocal microscopy as well as brain slice surface protein biotinylation to characterize Slc6a1+/A288V and Slc6a1+/S295L mice, representative of a partial or a complete loss of function of SLC6A1 mutations, respectively. We employed the γ-aminobutyric acid transporter 1-specific inhibitor [3H]tiagabine binding and GABAA receptor subunit-specific radioligand binding to profile the γ-aminobutyric acid transporter 1 and GABAA receptor expression in major brain regions such as cortex, cerebellum, hippocampus and thalamus. We also determined the total and surface expression of γ-aminobutyric acid transporter 1, γ-aminobutyric acid transporter 3 and expression of GABAA receptor in the major brain regions in the knockin mice. We found that γ-aminobutyric acid transporter 1 protein was markedly reduced in cortex, hippocampus, thalamus and cerebellum in both mutant mouse lines. Consistent with the findings of reduced γ-aminobutyric acid uptake for both γ-aminobutyric acid transporter 1(A288V) and γ-aminobutyric acid transporter 1(S295L), both the total and the γ-aminobutyric acid transporter 1-mediated 3H γ-aminobutyric acid reuptake was reduced. We found that γ-aminobutyric acid transporter 3 is only abundantly expressed in the thalamus and there was no compensatory increase of γ-aminobutyric acid transporter 3 in either of the mutant mouse lines. γ-Aminobutyric acid transporter 1 was reduced in both somatic regions and nonsomatic regions in both mouse models, in which a ring-like structure was identified only in the Slc6a1+/A288V mouse, suggesting more γ-aminobutyric acid transporter 1 retention inside endoplasmic reticulum in the Slc6a1+/A288V mouse. The [3H]tiagabine binding was similar in both mouse models despite the difference in γ-aminobutyric acid uptake function and γ-aminobutyric acid transporter 1 protein expression for both mutations. There were no differences in GABAA receptor subtype expression, except for a small increase in the expression of α5 subunits of GABAA receptor in the hippocampus of Slc6a1S295L homozygous mice, suggesting a potential interaction between the expression of this GABAA receptor subtype and the mutant γ-aminobutyric acid transporter 1. The study provides the first comprehensive characterization of the SLC6A1 mutations in vivo in two representative mouse models. Because both γ-aminobutyric acid transporter 1 and GABAA receptors are targets for anti-seizure medications, the findings from this study can help guide tailored treatment options based on the expression and function of γ-aminobutyric acid transporter 1 and GABAA receptor in SLC6A1 mutation-mediated neurodevelopmental and epileptic encephalopathies.

Predictability of the neurodevelopmental assessment based on the Kyoto Scale of Psychological Development 2001 at 18-24 months of corrected age and 3 years of age in identifying cognitive impairment at 6 years of age in very preterm infants: A retrospective study at a Japanese tertiary center.

BACKGROUND: It is unknown how accurately the current Japanese classification system for neurodevelopmental delay based on the assessment with the Kyoto Scale of Psychological Development (KSPD) at toddlerhood and pre-school periods predicts cognitive impairment at school age. METHODS: This single-center retrospective cohort study enrolled infants born at 22-29 weeks of gestational age. At 18-24 months of corrected age and 3 years of age, the patients were categorized according to the current Japanese criteria for neurodevelopmental delay based on their overall developmental quotient calculated using the KSPD-2001. Cognitive impairment at 6 years of age was classified according to the calculated or estimated full-scale intelligence quotient. The predictability of the current Japanese classification of neurodevelopmental delay for cognitive impairment at 6 years of age was investigated. RESULTS: Of 566 eligible patients, 364 (64 %) completed the protocol. The current classification for the neurodevelopmental delay showed significant agreement with the severity of cognitive impairment at 6 years of age. The sensitivity and specificity of the KSPD-2001-based assessment for any cognitive impairment at 6 years of age were 0.64 and 0.74 at 18-24 months of corrected age and 0.83 and 0.70 at 3 years of age. The corresponding sensitivity and specificity for moderate/severe cognitive impairment were 0.51 and 0.96 at 18-24 months of corrected age and 0.68 and 0.95 at 3 years of age. CONCLUSION: The KSPD-2001 is a useful tool to predict the severity of cognitive impairment at school age.

Comparative Transcriptomics Data Profiling Reveals E2F Targets as an Important Biological Pathway Overexpressed in Intellectual Disability Disorder.

Intellectual disability (ID) is an early childhood neurodevelopmental disorder that is characterized by impaired intellectual functioning and adaptive behavior. It is one of the major concerns in the field of neurodevelopmental disorders across the globe. Diversified approaches have been put forward to overcome this problem. Among all these approaches, high throughput transcriptomic analysis has taken an important dimension. The identification of genes causing ID rapidly increased over the past 3 to 5 years owing to the use of sophisticated high throughput sequencing platforms. Early monitoring and preventions are much important for such disorder as their progression occurs during fetal development. This study is an attempt to identify differentially expressed genes (DEGs) and upregulated biological processes involved in development of ID patients through comparative analysis of available transcriptomics data. A total of 7 transcriptomic studies were retrieved from National Center for Biotechnology Information (NCBI) and were subjected to quality check and trimming prior to alignment. The normalization and differential expression analysis were carried out using DESeq2 and EdgeR packages of Rstudio to identify DEGs in ID. In progression of the study, functional enrichment analysis of the results obtained from both DESeq2 and EdgeR was done using gene set enrichment analysis (GSEA) tool to identify major upregulated biological processes involved in ID. Our findings concluded that monitoring the level of E2F targets, estrogen, and genes related to oxidative phosphorylation, DNA repair, and glycolysis during the developmental stage of an individual can help in the early detection of ID disorder.

Phenotypic and genetic analysis of children with unexplained neurodevelopmental delay and neurodevelopmental comorbidities in a Chinese cohort using trio-based whole-exome sequencing.

BACKGROUND: Trio-based whole-exome sequencing (trio-WES) enables identification of pathogenic variants, including copy-number variants (CNVs), in children with unexplained neurodevelopmental delay (NDD) and neurodevelopmental comorbidities (NDCs), including autism spectrum disorder (ASD), epilepsy, and attention deficit hyperactivity disorder. Further phenotypic and genetic analysis on trio-WES-tested NDD-NDCs cases may help to identify key phenotypic factors related to higher diagnostic yield of using trio-WES and novel risk genes associated with NDCs in clinical settings. METHODS: In this study, we retrospectively performed phenotypic analysis on 163 trio-WES-tested NDD-NDCs children to determine the phenotypic differences between genetically diagnosed and non-genetically diagnosed groups. Additionally, we conducted genetic analysis of ASD genes with the help of Simons Foundation for Autism Research Institute (SFARI) Gene database to identify novel possible ASD-risk genes underlying genetic NDD conditions. RESULTS: Among these 163 patients, pathogenic variants were identified in 82 cases (82/163, 50.3%), including 20 cases with CNVs. By comparing phenotypic variables between genetically diagnosed group (82 cases) and non-genetically diagnosed group (81 cases) with multivariate binary logistic regression analysis, we revealed that NDD-NDCs cases presenting with severe-profound NDD [53/82 vs 17/81, adjusted-OR (95%CI): 4.865 (2.213 - 10.694), adjusted-P < 0.001] or having multiple NDCs [26/82 vs 8/81, adjusted-OR (95%CI): 3.731 (1.399 - 9.950), adjusted-P = 0.009] or accompanying ASD [64/82 vs 35/81, adjusted-OR (95%CI): 3.256 (1.479 - 7.168), adjusted-P = 0.003] and head circumference abnormality [33/82 vs 11/81, adjusted-OR (95%CI): 2.788 (1.148 - 6.774), adjusted-P = 0.024] were more likely to have a genetic diagnosis using trio-WES. Moreover, 37 genes with monogenetic variants were identified in 48 patients genetically diagnosed with NDD-ASD, and 15 dosage-sensitive genes were identified in 16 individuals with NDD-ASD carrying CNVs. Most of those genes had been proven to be ASD-related genes. However, some of them (9 genes) were not proven sufficiently to correlate with ASD. By literature review and constructing protein-protein interaction networks among these 9 candidate ASD-risk genes and 102 established ASD genes obtained from the SFARI Gene database, we identified CUL4B, KCNH1, and PLA2G6 as novel possible ASD-risk genes underlying genetic NDD conditions. CONCLUSIONS: Trio-WES testing is recommended for patients with unexplained NDD-NDCs that have severe-profound NDD or multiple NDCs, particularly those with accompanying ASD and head circumference abnormality, as these independent factors may increase the likelihood of genetic diagnosis using trio-WES. Moreover, NDD patients with pathogenic variants in CUL4B, KCNH1 and PLA2G6 should be aware of potential risks of developing ASD during their disease courses.

Duplication at 19q13.32q13.33 Segregating with Neuropsychiatric Phenotype in a Three-Generation Family: Towards the Definition of a Critical Region.

Chromosomal submicroscopic imbalances represent well-known causes of neurodevelopmental disorders. In some cases, these can cause specific autosomal dominant syndromes, with high-to-complete penetrance and de novo occurrence of the variant. In other cases, they result in non-syndromic neurodevelopmental disorders, often acting as moderate-penetrance risk factors, possibly inherited from unaffected parents. We describe a three-generation family with non-syndromic neuropsychiatric features segregating with a novel 19q13.32q13.33 microduplication. The propositus was a 28-month-old male ascertained for psychomotor delay, with no dysmorphic features or malformations. His mother had Attention-Deficit/Hyperactivity Disorder and a learning disability. The maternal uncle had an intellectual disability. Chromosomal microarray analysis identified a 969 kb 19q13.32q13.33 microduplication in the proband. The variant segregated in the mother, the uncle, and the maternal grandmother of the proband, who also presented neuropsychiatric disorders. Fragile-X Syndrome testing was negative. Exome Sequencing did not identify Pathogenic/Likely Pathogenic variants. Imbalances involving 19q13.32 and 19q13.33 are associated with neurodevelopmental delay. A review of the reported microduplications allowed to propose BICRA (MIM *605690) and KPTN (MIM *615620) as candidates for the neurodevelopmental delay susceptibility in 19q13.32q13.33 copy number gains. The peculiarities of this case are the small extension of the duplication, the three-generation segregation, and the full penetrance of the phenotype.

Validación de la PDMS-2 en población española. Evaluación de la intervención de fisioterapia y la participación de los padres en el tratamiento de niños con trastornos del neurodesarrollo / Validation of the PDMS-2 scale in the Spanish population. Evaluation of physiotherapy intervention and parental involvement in the treatment of children with neurodevelopmental disorders

Objetivo: Adaptar transculturalmente la escala del desarrollo motor de Peabody, segunda edición (PDMS-2), del español mexicano al español de España y evaluar su validez. Determinar la eficacia del tratamiento fisioterápico (número de sesiones de fisioterapia y actividades propuestas por el fisioterape uta y realizadas por los padres) en niños con trastornos del neurodesarrollo de 0 a 3 años.Sujetos y métodos: Un primer estudio descriptivo prospectivo de validación de la PDMS-2, que incluyó a 74 sujetos con trastorno del neurodesarrollo con edades comprendidas entre 0 y 3 años. Un segundo ensayo clínico aleatorio para evaluar la intervención de fisioterapia (concepto Bobath) en el grupo experimental (n = 37), que recibió sesiones únicas de 30 minutos semanales durante ocho semanas frente al grupo de control (n = 37), que no recibió fisioterapia y utilizó la PDMS-2 para su evaluación. Resultados: Se encontró una adecuada confiabilidad interagente (coeficiente de correlación intraclase = 0,76). La escala mostró también una muy buena consistencia interna (alfa = 0,99). Hubo diferencias significativas entre ambos grupos a las ocho semanas. El grupo experimental obtuvo mejores puntuaciones en el postest después de administrar el tratamiento de fisioterapia (p < 0,001). Se encontraron coeficientes de correlación moderados y significativos entre el número de sesiones de fisioterapia y el cociente motor total (r = 0,38; p < 0,05) y las actividades realizadas en casa con el cociente motor total (r = 0,46; p = 0,005). Conclusiones: La PDMS-2 es un instrumento válido y fiable para medir el desarrollo motor grueso y fino en niños con trastorno del neurodesarrollo de 0 a 3 años. La fisioterapia es útil en la mejoría en niños con retraso del neurodesarrollo...(AU)

Aim: Cross-culturally adapt the PDMS-2 scale from Spanish-Mexican to Spanish-Spanish and evaluate its validity. To determine the efficacy of physiotherapy treatment (number of physiotherapy sessions and activities proposed by the physiotherapist and performed by the parents) in children with neurodevelopmental disorders between the ages of 0 and 3 years. Subjects and methods: A first prospective descriptive study of validation of the PDMS-2 scale including 74 subjects with neurodevelopmental disorder with aged from 0 and 3 years old. A second randomized clinical trial to evaluate the physiotherapy (Bobath concept) intervention in the experimental group (EG) (n = 37) who received unique 30-minute weekly sessions for 8 weeks against the control group (CG) (n = 37) that did not receive physiotherapy using the PDMS-2 scale for evaluation. Results: An adequate inter-rater reliablity was found (ICC = 0.76). The scale showed also a very good internal consistency (alpha = 0,99). Significant differences between both groups at 8 weeks. EG obtained better scores in the postest after administrating the physiotherapy treatment (p < 0.001) Moderate and significant correlation coefficients were found between the number of physiotherapy sessions and Total Motor Quotient (TMQ) (r = 0.38; p < 0.05) and the home actitvities with TMQ (r = 0.46; p = 0.005). Conclusions: The Peabody PDMS-2 scale is a valid and reliable instrument to measure gross and fine motor development in children with neurodevelopmental disorder aged from 0 and 3 years old. Physiotherapy is useful for helping children with delayed neurodevelopment improve. The number of physiotherapy sessions and the activities proposed by the physiotherapist and performed at home by the parents show a direct and positive relationship with the results obtained in motor development.(AU)