Global developmental delay (GDD) and intellectual disability (ID) are relatively common neurodevelopmental disorders that significantly impact affected children, their families, and society. The etiology of GDD/ID is notably diverse, encompassing both genetic and acquired factors. Although the precise cause of most GDD/ID cases remains unclear, an estimated half of all cases can be attributed to genetic factors. Thus, a detailed medical history and comprehensive physical examination remain pivotal for guiding diagnostic investigations into the underlying causes of GDD/ID. Advancements in genetic testing have supplanted traditional methods such as karyotyping and fluorescence in situ hybridization with chromosomal microarrays, which are now the primary genetic tests for children with idiopathic GDD/ID. Moreover, the evaluation of Fragile X and Rett syndrome should be an integral component of initial diagnostic assessments. In recent years, whole-exome sequencing and whole-genome sequencing have emerged as important diagnostic tools for evaluating children with GDD/ID and have substantially enhanced the diagnostic yield rates. Gene therapy has emerged as a promising avenue and is poised to become a cornerstone in addressing various genetic developmental and epilepsy disorders. Early intervention facilitated by a proficient multidisciplinary team can markedly enhance the prognosis and outcomes of GDD/ID, particularly when parents or caregivers are actively engaged in the interventional process. This review discusses risk factors and common underlying causes, explores recent evidence and recommendations for genetic evaluation, and offers management strategies for children with GDD/ID.

OBJECTIVE: This study aims to report a severe phenotype of Arboleda-Tham syndrome in a 20-month-old girl, characterized by global developmental delay, distinct facial features, intellectual disability. Arboleda-Tham syndrome is known for its wide phenotypic spectrum and is associated with truncating variants in the KAT6A gene.
METHODS: To diagnose this case, a combination of clinical phenotype assessment and whole-exome sequencing technology was employed. The genetic analysis involved whole-exome sequencing, followed by confirmation of the identified variant through Sanger sequencing.
RESULTS: The whole-exome sequencing revealed a novel de novo frameshift mutation c.3048del (p.Leu1017Serfs*17) in the KAT6A gene, which is classified as likely pathogenic. This mutation was not found in the ClinVar and HGMD databases and was not present in her parents. The mutation leads to protein truncation or activation of nonsense-mediated mRNA degradation. The mutation is located within exon 16, potentially leading to protein truncation or activation of nonsense-mediated mRNA degradation. Protein modeling suggested that the de novo KAT6A mutation might alter hydrogen bonding and reduce protein stability, potentially damaging the protein structure and function.
CONCLUSIONS: This study expands the understanding of the genetic basis of Arboleda-Tham syndrome, highlighting the importance of whole-exome sequencing in diagnosing cases with varied clinical presentations. The discovery of the novel KAT6A mutation adds to the spectrum of known pathogenic variants and underscores the significance of this gene in the syndrome\'s pathology.

患儿，男，1岁1个月，主诉\"转氨酶反复升高6月余\"。主要临床表现为整体发育迟缓，精神运动发育落后，小头畸形，肌张力低；实验室检查表现为反复肝功能异常，铜蓝蛋白降低；头颅影像学显示胼胝体薄，脑室系统扩大，脑沟裂池变深、增宽；肝脏病理表现为肝细胞轻度小泡性脂肪变性伴肝纤维化；基因检测结果提示空泡蛋白分选相关蛋白51基因变异。.

Global developmental delay (GDD)/intellectual disability (ID) is common in children and its etiology is unknown in many cases. Chromosomal abnormalities are predominant genetic causes of GDD/ID. The aim of this study is to determine the genetic risk factors that may be involved in the etiology of GDD/ID. In this study, 810 children with moderate to severe, clinically unexplained GDD/ID for whom cytogenetic analysis were performed were retrospectively rescreened. The results showed that GDD/ID affected more females than males (2 girls:1 boy). A total of 54 children (6.7%) with GDD showed chromosomal aberrations (CAs): 59.3% of these CAs were structural aberrations, and the rest were numerical aberrations (40.7%). Specifically, inversions, deletions, and reciprocal and robertsonian translocations, which were detected in 1, 0.7, 0.8, and 0.4% of the children, respectively, constituted important categories of structural CAs. Among numerical CAs, classic Turner and mosaics were detected in 1.2% of all children. Trisomy 21 and mosaic trisomy 21 were detected in 1% of the children. Marker chromosomes and 47,XXY karyotypes were found in two children each. Our results suggest that female sex is more affected by CAs among GDD/ID cases, and cytogenetic analysis is useful in the etiological diagnosis of GDD/ID.

OBJECTIVE: To determine the benefits of cochlear implantation in hearing loss children with multiple disabilities (MD) in terms of auditory outcomes, speech performance, and their quality of life.
METHODS: This was a cross sectional study from January 2019 to December 2020 in which thirty-one children with hearing loss and multiple disabilities were evaluated. Their improvement in auditory and speech performances were assessed using Categories of Auditory Performance version II (CAP-II) and the Speech Intelligibility Rating (SIR) scales. The assessment was done at 6-month intervals, with the baseline evaluation done at least six months after activation of the implant. Parents were asked to fill the Parents Evaluation of Aural/Oral Performance of Children (PEACH) diary and Perceived Benefit Questionnaire (PBQ) to evaluate the child\'s quality of life.
RESULTS: All 31 children have Global Developmental Delay (GDD), with 11 having an additional disability. Both mean CAP-II and SIR scores showed significant improvement with increased hearing age (p < 0.05) after 6-month intervals. In addition, 20 out of 31 children (64.5%) have achieved verbal communication after implantation. The mean PEACH score in quiet was significantly better than in noise (p = 0.007) and improved with the increased of hearing age. The majority of parents (96%‒100%) perceived a cochlear implant as beneficial to their child in terms of auditory response, awareness, interaction, communication, and speech development.
CONCLUSIONS: Cochlear implantation had shown benefits in children with multiple disabilities. Outcome measures should not only focus on auditory and speech performances but the improvement in quality of life. Hence, individualized each case with realistic expectation from families must be emphasized in this group of children.
METHODS: Level 3.

The most severe form of spastic cerebral palsy (CP), which affects the arms and legs and often the face, is known as spastic quadriplegia. In addition to other developmental disabilities such as intellectual disability and seizures, it can cause difficulty in walking. Children with CP often have seizures as a result of brain injury, and spastic quadriplegic CP is typically associated with global developmental delay. For the purpose of addressing the unique motor and functional challenges associated with spastic quadriplegia, neurophysiotherapy is essential. This treatment includes neurodevelopmental techniques, posture and balance training, and activities aimed at improving gait. The purpose of this case study is to demonstrate how early and continuous physical therapy interventions can maximize a child\'s functional abilities and prevent further complications. In this instance, a five-year-old boy with a documented history of spastic quadriplegia, seizure disorder, and global developmental delay reported experiencing challenges with sitting, walking, and speech. He had three episodes of fever, which led to his hospital admission. The child\'s medical history included acute hemorrhagic encephalitis, mild hydroureteronephrosis on the left side, and persistent convulsions that affected only one side of the body. Bilateral thalamic altered signal intensities were observed in the brain\'s MRI, and multiple calcifications were detected in the periventricular cortex, thalamus, and basal ganglia on the brain\'s CT scan. To enhance the independence, strength, and coordination of voluntary movement in individuals with CP, a variety of techniques are used in addition to physical therapy, such as occupational therapy, speech therapy, aquatic therapy, constraint-induced movement therapy, functional electrical stimulation, orthotic devices, injections of botulinum toxin, and hippotherapy.

BACKGROUND: Global developmental delay or intellectual disability usually accompanies various genetic disorders as a part of the syndrome, which may include seizures, autism spectrum disorder and multiple congenital abnormalities. Next-generation sequencing (NGS) techniques have improved the identification of pathogenic variants and genes related to developmental delay. This study aimed to evaluate the yield of whole exome sequencing (WES) and neurodevelopmental disorder gene panel sequencing in a pediatric cohort from Ukraine. Additionally, the study computationally predicted the effect of variants of uncertain significance (VUS) based on recently published genetic data from the country\'s healthy population.
METHODS: The study retrospectively analyzed WES or gene panel sequencing findings of 417 children with global developmental delay, intellectual disability, and/or other symptoms. Variants of uncertain significance were annotated using CADD-Phred and SIFT prediction scores, and their frequency in the healthy population of Ukraine was estimated.
RESULTS: A definitive molecular diagnosis was established in 66 (15.8%) of the individuals. WES diagnosed 22 out of 37 cases (59.4%), while the neurodevelopmental gene panel identified 44 definitive diagnoses among the 380 tested patients (12.1%). Non-diagnostic findings (VUS and carrier) were reported in 350 (83.2%) individuals. The most frequently diagnosed conditions were developmental and epileptic encephalopathies associated with severe epilepsy and GDD/ID (associated genes ARX, CDKL5, STXBP1, KCNQ2, SCN2A, KCNT1, KCNA2). Additionally, we annotated 221 VUS classified as potentially damaging, AD or X-linked, potentially increasing the diagnostic yield by 30%, but 18 of these variants were present in the healthy population of Ukraine.
CONCLUSIONS: This is the first comprehensive study on genetic causes of GDD/ID conducted in Ukraine. This study provides the first comprehensive investigation of the genetic causes of GDD/ID in Ukraine. It presents a substantial dataset of diagnosed genetic conditions associated with GDD/ID. The results support the utilization of NGS gene panels and WES as first-line diagnostic tools for GDD/ID cases, particularly in resource-limited settings. A comprehensive approach to resolving VUS, including computational effect prediction, population frequency analysis, and phenotype assessment, can aid in further reclassification of deleterious VUS and guide further testing in families.

Ion channels mediate voltage fluxes or action potentials that are central to the functioning of excitable cells such as neurons. The KCNB family of voltage-gated potassium channels (Kv) consists of two members (KCNB1 and KCNB2) encoded by KCNB1 and KCNB2, respectively. These channels are major contributors to delayed rectifier potassium currents arising from the neuronal soma which modulate overall excitability of neurons. In this study, we identified several mono-allelic pathogenic missense variants in KCNB2, in individuals with a neurodevelopmental syndrome with epilepsy and autism in some individuals. Recurrent dysmorphisms included a broad forehead, synophrys, and digital anomalies. Additionally, we selected three variants where genetic transmission has not been assessed, from two epilepsy studies, for inclusion in our experiments. We characterized channel properties of these variants by expressing them in oocytes of Xenopus laevis and conducting cut-open oocyte voltage clamp electrophysiology. Our datasets indicate no significant change in absolute conductance and conductance-voltage relationships of most disease variants as compared to wild type (WT), when expressed either alone or co-expressed with WT-KCNB2. However, variants c.1141A>G (p.Thr381Ala) and c.641C>T (p.Thr214Met) show complete abrogation of currents when expressed alone with the former exhibiting a left shift in activation midpoint when expressed alone or with WT-KCNB2. The variants we studied, nevertheless, show collective features of increased inactivation shifted to hyperpolarized potentials. We suggest that the effects of the variants on channel inactivation result in hyper-excitability of neurons, which contributes to disease manifestations.

This study reports on biallelic homozygous and monoallelic de novo variants in SLITRK3 in three unrelated families presenting with epileptic encephalopathy associated with a broad neurological involvement characterized by microcephaly, intellectual disability, seizures, and global developmental delay. SLITRK3 encodes for a transmembrane protein that is involved in controlling neurite outgrowth and inhibitory synapse development and that has an important role in brain function and neurological diseases. Using primary cultures of hippocampal neurons carrying patients\' SLITRK3 variants and in combination with electrophysiology, we demonstrate that recessive variants are loss-of-function alleles. Immunostaining experiments in HEK-293 cells showed that human variants C566R and E606X change SLITRK3 protein expression patterns on the cell surface, resulting in highly accumulating defective proteins in the Golgi apparatus. By analyzing the development and phenotype of SLITRK3 KO (SLITRK3-/-) mice, the study shows evidence of enhanced susceptibility to pentylenetetrazole-induced seizure with the appearance of spontaneous epileptiform EEG as well as developmental deficits such as higher motor activities and reduced parvalbumin interneurons. Taken together, the results exhibit impaired development of the peripheral and central nervous system and support a conserved role of this transmembrane protein in neurological function. The study delineates an emerging spectrum of human core synaptopathies caused by variants in genes that encode SLITRK proteins and essential regulatory components of the synaptic machinery. The hallmark of these disorders is impaired postsynaptic neurotransmission at nerve terminals; an impaired neurotransmission resulting in a wide array of (often overlapping) clinical features, including neurodevelopmental impairment, weakness, seizures, and abnormal movements. The genetic synaptopathy caused by SLITRK3 mutations highlights the key roles of this gene in human brain development and function.

The mitochondrial disorder-Leigh syndrome is a neurodegenerative disorder often manifested with brainstem abnormalities. The case report highlights the auditory brainstem response in a child with medical findings suggestive of Leigh syndrome. The case report also emphasizes the importance of ruling out any underlying neural pathology before making a clinical impression in children with developmental delays.