The mediator complex subunit 23 (MED23) gene encodes a protein that acts as a tail module mediator complex, a multi-subunit co-activator involved in several cellular activities. MED23 has been shown to have substantial roles in myogenesis and other molecular mechanisms. The functions of MED23 in the neurological system remain unclear and the clinical phenotype is not thoroughly described. Whole exome sequencing was used to identify a novel mutation in the MED23 gene. DNA capture probes using next-generation sequencing-based copy number variation analysis with Illumina array were performed. The clinical, demographic, neuroimaging, and electrophysiological data of the patients were collected, and similarly, the data of all reported cases in the literature were extracted to compare findings. Screening a total of 9,662 articles, we identified 22 main regulatory processes for the MED23 gene, including suppressive activity for carcinogenic processes. MED23 is also involved in the brain\'s neurogenesis and functions. The identified cases mainly presented with intellectual disability (87.5%) and developmental delay (50%). Seizures were present in only 18.75% of the patients. Slow backgrounds and spike and sharp-wave complexes were reported on the electroencephalogram (EEG) of a few patients and delayed myelination, thin corpus callosum, and pontine hypoplasia on magnetic resonance imaging (MRI). The MED23 gene regulates several processes in which its understanding promotes considerable therapeutic potential for patients. It is crucial to consider genetic and laboratory testing, particularly when encountering potential carriers. Intellectual disability and developmental delay are the most notable clinical signs with heterogeneous features on EEG and MRI.

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.

OBJECTIVE: Many barriers to implementation of developmental screening in primary care exist, especially for children from under-resourced communities. Developmental screening is vital to early detection of developmental delay and autism spectrum disorder, and early intervention (EI) referral. This study sought to examine whether implementation of a standardized clinical workflow using electronic screening tools improved both rates of developmental screening, and the number of children identified at risk for developmental delay, in a federally qualified health center (FQHC).
METHODS: A retrospective study was conducted at an academic-affiliated FQHC. Electronic versions of the Ages and Stages Questionnaire 3 (ASQ-3) and Modified Checklist in Autism for Toddlers Revised (M-CHAT-R) were implemented at well-child visits. New clinical workflow training on developmental screening and EI referral was provided. Chi-square and Fisher\'s Exact analyses were conducted.
RESULTS: ASQ-3 screening rates increased from 62.7 to 73.6% pre- to post-intervention. Post-intervention, there was a significant decrease in paper screens (p < .001), and a significant increase in the percentage of children with ASQ-3 results in the below cutoff range from 14.7 to 18.2% (p < .002). M-CHAT-R screening rates increased from 56.4 to 59.4% pre- to post-intervention. Post-intervention, there was a significant increase in electronic screens (p < .001).
CONCLUSIONS: Implementation of electronic screening tools improved universal developmental screening in a FQHC. To decrease barriers in under-resourced communities, the use of electronic tools may decrease the rate of screening error seen with paper screening and have the potential to better identify children at risk for developmental delay.

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.

UNASSIGNED: Inherited 5-oxoprolinase (OPLAH) deficiency is a rare inborn condition characterized by 5-oxoprolinuria. The inherited condition of 5-oxoprolinuria, or pyroglutamic aciduria, is primarily caused by mutations in the genes that encode glutathione synthetase (GSS) and 5-oxoprolinase (OPLAH), which are enzymes involved in the gamma-glutamyl cycle in glutathione metabolism. We report a 3-year-old male patient with epilepsy and speech difficulty diagnosed as primary 5-oxoprolinuria due to a novel OPLAH gene mutation.
UNASSIGNED: A 3-year-old boy who was delivered at full term in an uncomplicated birth to consanguineous parents presented with epilepsy at the age of 2 years. He did not speak fluently. He was using 5-10 words with decreased language fluency. His past medical history revealed postnatal macrocephaly, hydrocephalus, and well-controlled epilepsy with levetiracetam. Progressive cerebral atrophy, hypomyelination, ventriculomegaly, and corpus callosum hypoplasia were striking features in brain MRI. A urine sample was sent for organic acid analysis by gas chromatography-mass spectrometry (GC-MS); quantitation of 5-oxoproline by stable isotope dilution gave a value of 177.9 mmol/mol creatinine (reference values 25.8-92.2). Molecular genetic analysis of the OPLAH gene revealed a novel homozygous variant (OPLAH (NM_017570.5): c.1909C>T p.Arg637Trp).
UNASSIGNED: We conclude that inherited 5-oxoprolinase deficiency is not a benign biochemical condition, and patients with 5-oxoprolinuria should be screened for it. The nature of this inherited metabolic disorder must be determined through long-term observation. We wish to emphasize the significance of molecular genetic analysis in symptomatic patients with persistently elevated levels of 5-oxoproline in the urine, as measured by organic acid analysis.

Developmental delays (DD) and congenital anomalies (CA) are prevalent yet often remain undiagnosed despite comprehensive genetic testing. This study aims to investigate the diagnostic yield of trio whole-genome sequencing (WGS) in children presenting with DD or CA who remained undiagnosed after previous genetic testing. A prospective cohort study was conducted on children with undiagnosed DD or CA at a single tertiary hospital. All participants suspected of genetic conditions had undergone chromosome analysis, chromosome microarray analysis (CMA), and clinical exome sequencing (CES); however, a subset remained undiagnosed. The WGS test was administered to both the affected children and their parents. A total of 52 children were included, and 10 (19.2%) had undergone a genetic diagnosis through WGS. Eight of these cases were associated with autosomal dominant and de novo variants. WGS led to successful diagnosis due to several factors, including small structural variants, genes not covered in the CES panel, the discovery of newly implicated genes, issues related to coverage depth, low variant allele frequency, challenges in variant interpretation, and differences in the interpretation of variants of unknown significance among clinicians. This study highlights the clinical value of trio WGS testing in undiagnosed children with DD or CA. Notably, an additional 19.2% of affected children were diagnosed through this method.

BACKGROUND: Global developmental delay with speech and behavioral abnormalities (OMIM: 619243) is an autosomal dominant disease caused by variants in TNRC6B gene.
METHODS: We reviewed and summarized clinical manifestations and genotypes in patients previously reported with TNRC6B gene variants. We used several prediction tools to predict pathogenicity and performed minigene assays to verify the function of the synonymous variant affecting RNA splicing.
RESULTS: The patient presented with convulsive seizures and developmental delay. WES combined with functional studies diagnosed a child with a synonymous variant in TNRC6B gene. Through minigene assay and Sanger sequencing, we demonstrated that c.3141G > A variant induced exon 7 skipping and the synonymous variant was pathogenic.
CONCLUSIONS: Synonymous variants do not change the amino acids encoded by the codon, so we usually consider synonymous variants to be benign and ignore their pathogenicity. Minigene assay is a valuable tool to identify the effect of variation on RNA splicing and identify synonymous variants\' benign or pathogenic. We showed that the synonymous variant was pathogenic by minigene assay. WES combined with minigene assay establishes a robust basis for genetic counseling and diagnosing diseases.

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.
METHODS: 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.

UNASSIGNED: Heterozygous variants in Transient receptor potential melastatin type 7 (TRPM7), encoding an essential and ubiquitously expressed cation channel, may cause hypomagnesemia, but current evidence is insufficient to draw definite conclusions and it is unclear whether any other phenotypes can occur.
UNASSIGNED: Individuals with unexplained hypomagnesemia underwent whole-exome sequencing which identified TRPM7 variants. Pathogenicity of the identified variants was assessed by combining phenotypic, functional and in silico analyses.
UNASSIGNED: We report three new heterozygous missense variants in TRPM7 (p.Met1000Thr, p.Gly1046Arg, p.Leu1081Arg) in individuals with hypomagnesemia. Strikingly, autism spectrum disorder and developmental delay, mainly affecting speech and motor skills, was observed in all three individuals, while two out of three also presented with seizures. The three variants are predicted to be severely damaging by in silico prediction tools and structural modeling. Furthermore, these variants result in a clear loss-of-function of TRPM7-mediated magnesium uptake in vitro, while not affecting TRPM7 expression or insertion into the plasma membrane.
UNASSIGNED: This study provides additional evidence for the association between heterozygous TRPM7 variants and hypomagnesemia and adds developmental delay to the phenotypic spectrum of TRPM7-related disorders. Considering that the TRPM7 gene is relatively tolerant to loss-of-function variants, future research should aim to unravel by what mechanisms specific heterozygous TRPM7 variants can cause disease.

Studies have reported inconsistent results regarding associations between parental depression and offspring neurodevelopmental disorders, such as developmental delay and autism spectrum disorder (ASD). In all, 7,593 children who were born between 1996 and 2010 in Taiwan and had at least one parent with major depressive disorder and 75,930 birth-year- and sex-matched children of parents without major depressive disorder were followed from 1996 or time of birth to the end of 2011. Intergroup differences in neurodevelopmental conditions-including ASD, attention-deficit hyperactivity disorder (ADHD), tic disorder, developmental delay, and intellectual disability (ID)-were assessed. Compared with the children in the control group, the children of parents with major depression were more likely [hazard ratio (HR), 95% confidence interval (CI)] to develop ADHD (1.98, 1.80-2.18), ASD (1.52, 1.16-1.94), tic disorder (1.40, 1.08-1.81), developmental delay (1.32, 1.20-1.45), and ID (1.26, 1.02-1.55). Parental depression was associated with offspring neurodevelopmental disorders, specifically ASD, ADHD, developmental delay, ID, and tic disorder. Therefore, clinicians should closely monitor the neurodevelopmental conditions of children of parents with depression.