Destabilization of mutated human PUS3 protein causes intellectual disability.

Pseudouridine (Ψ) is an RNA base modification ubiquitously found in many types of RNAs. In humans, the isomerization of uridine is catalyzed by different stand-alone pseudouridine synthases (PUS). Genomic mutations in the human pseudouridine synthase 3 gene (PUS3) have been identified in patients with neurodevelopmental disorders. However, the underlying molecular mechanisms that cause the disease phenotypes remain elusive. Here, we utilize exome sequencing to identify genomic variants that lead to a homozygous amino acid substitution (p.[(Tyr71Cys)];[(Tyr71Cys)]) in human PUS3 of two affected individuals and a compound heterozygous substitution (p.[(Tyr71Cys)];[(Ile299Thr)]) in a third patient. We obtain wild-type and mutated full-length human recombinant PUS3 proteins and characterize the enzymatic activity in vitro. Unexpectedly, we find that the p.Tyr71Cys substitution neither affect tRNA binding nor pseudouridylation activity in vitro, but strongly impair the thermostability profile of PUS3, while the p.Ile299Thr mutation causes protein aggregation. Concomitantly, we observe that the PUS3 protein levels as well as the level of PUS3-dependent Ψ levels are strongly reduced in fibroblasts derived from all three patients. In summary, our results directly illustrate the link between the identified PUS3 variants and reduced Ψ levels in the patient cells, providing a molecular explanation for the observed clinical phenotypes.

Homozygous variant of MLC1 results in megalencephalic leukoencephalopathy with subcortical cysts.

BACKGROUND: Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare, inherited disorder that causes epilepsy, intellectual disorders, and early onset macrocephaly. MLC1 has been identified as a main pathogenic gene. METHODS: Clinical data such as magnetic resonance imaging (MRI), routine blood tests, and physical examinations were collected from proband. Trio whole-exome sequencing (WES) of the family was performed, and all variants with a minor allele frequency (<0.01) in the exon and canonical splicing sites were selected for further pathogenic evaluation. Candidate variants were validated using Sanger sequencing. RESULTS: Here, we report a new homozygous variant identified in two children from the same family in the MLC1 gene [NM_015166.4: c.838_843delinsATTTTA, (p.Ser280_Phe281delinsIleLeu)]. This variant is classified as variant of uncertain significance (VUS) according to the ACMG guidelines. Further experiments demonstrate that the newly identified variant causes a decrease of MLC1 protein levels when expressed in a heterologous expression system. CONCLUSION: Our case expands on this genetic variation and provides new evidence for the clinical diagnosis of MLC1-related MLC.

Cancer Risk in Patients with Down Syndrome-A Retrospective Cohort Study from Germany.

BACKGROUND: Individuals with Down syndrome are thought to have a unique tumor profile. METHODS: Using the IQVIA Disease Analyzer database, patients aged ≥18 years diagnosed with Down syndrome in German general practices between 2005 and 2021 were compared with patients without Down syndrome for cancer incidence, adjusting for age, sex, average annual visit frequency, and comorbidity. The 5-year cumulative incidence of cancer overall and specific cancers was analyzed using Kaplan-Meier curves and compared using the log-rank test. In addition, univariable Cox regression analysis was performed. RESULTS: A total of 2438 patients with Down syndrome and 12,190 patients without Down syndrome were included; 3.9% of patients without Down syndrome and 3.1% of patients with Down syndrome were diagnosed with cancer (p = 0.143). Regression analysis showed no significant association between Down syndrome and subsequent cancer in the total population (HR: 0.79; 95% CI: 0.57-1.09), in women (HR: 0.89; 95% CI: 0.56-1.37), or in men (HR: 0.69; 95% CI: 0.43-1.11). Analyses by cancer type and sex showed a strong but not significant negative association between Down syndrome and breast cancer in women (HR: 0.33; 95% CI: 0.12-0.93). CONCLUSIONS: Our results could form the basis for future studies to clarify whether and to what extent an adapted screening program needs to be modified for individuals with Down syndrome due to the particular cancer distribution pattern.

A systematic review of linguistic and metalinguistic studies in Persian-speaking individuals with intellectual disorder.

The purpose of this study is to analyze the Linguistic and Metalinguistic abilities of Persian-speaking individuals with Intellectual disorder to identify the areas and results of the research carried out in order to recognize their main linguistic features, the research gaps, and also guide future research. To this end, first, related keywords were searched and related topics were separated. Then, by reading the abstracts and, if necessary, the entire articles, the unrelated articles were removed. The articles were categorized and studied on linguistic and metalinguistic characters in four areas such as semantics, phonetics and phonology, morphology and syntax, and pragmatics. In addition, to investigate the effect of bilingualism and gender on the linguistic abilities of these individuals, the findings related to studies in the field of bilingualism and gender were examined in a separate section. From the general review of about 39 studies found, we found that in the fewest studies, the field of pragmatics was dealt with. The general results of the investigation were presented in the table of the results section in addition, in phonological studies, there was no significant difference in phonological awareness between girls and boys. In bilinguals, phonological awareness skills were related to their spelling skills.

A national profile of substance use disorder among Medicaid enrollees on the autism spectrum or with intellectual disability.

BACKGROUND: Recent research has questioned the assumption that people with intellectual disability (ID) or autism spectrum disorder (ASD) are less at risk of substance use disorders (SUDs). Overall, little is known about SUDs among people with intellectual and developmental disabilities (/IDDs). OBJECTIVE: This study aimed to estimate prevalence of SUD among Medicaid enrollees with ASD, ID, or ASD + ID; characterize these groups and types of SUDs; and identify risk of SUD by demographic and clinical characteristics within groups. METHODS: We used 2008-2012 national Medicaid data to identify enrollees with ASD, ID, ASD + ID and a sample without ASD/ID and identified SUDs within these individuals. We used descriptive statistics to characterize enrollee groups and types of SUDs, calculated SUD prevalence, and used modified Poisson regression to examine adjusted relative risk of SUD within disability groups. RESULTS: SUD prevalence increased yearly across disability groups to 1-2.2%, increasing most quickly among those with ASD. Alcohol abuse was the most common SUD among those with ID-only (57%) versus cannabis abuse among the ASD-only group (41%). Risk of SUD was higher among those with co-occurring psychiatric disorders - notably, depression. CONCLUSIONS: Results highlight increasing prevalence of SUD among Medicaid enrollees with ASD-only and ASD + ID and higher risk of SUD among those with depression and other psychiatric disorders. Understanding access to screening, diagnosis and treatment of SUD among people with I/DDs is a highly important question for future research.

Identification of two novel variants of the BCL11B gene in two Chinese pedigrees associated with neurodevelopmental disorders.

Objective: According to a recent report, the mutation of transcription factor gene BCL11B is associated with the development of neurodevelopmental disorders and immune deficiency. By analyzing both clinical features and genetic variations, this study aims to reveal the genetic etiology of four patients with neurodevelopmental disorders from two unrelated Chinese pedigrees. Methods: From the 4 cases, the clinical data were collected. The potential pathogenic gene variations were analyzed by means of based-trio whole exome sequencing (Trio-WES) and then validated through Sanger sequencing in their respective pedigrees. Furthermore, both the in vitro minigene assay and the NMD assay were performed to evaluate the impact of splicing and frameshift variants. Results: The 4 patients displayed mild-to-severe intellectual developmental disorder, which was accompanied by speech delay, dysmorphic facies, and serious caries. In addition, the extended phenotype of developmental regression was observed in the proband from Family 1, which has been unreported previously. Molecular analysis was conducted to identify two novel heterozygous variants in the BCL11B gene: a maternal splicing variant c.427 + 1G > A in Family 1 and a de novo frameshift variant c.2461_2462insGAGCCACACCGGCG (p.Glu821Glyfs*28) in Family 2. As revealed by the in vitro minigene assay, the c.427 + 1G > A variant activated a new cryptic splice site. As confirmed by an overexpression assay, there was no significant difference in the level of mRNA and protein expression between the mutate-BCL11B (p.Glu821Glyfs*28) and the wild type. It confirms that p.Glu821Glyfs*28 variant could be an NMD escaping variant. Conclusion: The extended phenotype of BCL11B-related disorders is reported in this study to reveal the clinical and genetic heterogeneity of the disease. The study starts by identifying a splicing variant and a novel frameshift variant of the BCL11B gene, thus confirming its aberrant translation. The findings of this study expand the mutation spectrum of the genetic BCL11B gene, which not only improves the understanding of the associated neurodevelopmental disorders from a clinical perspective but also provides guidance on diagnosis and genetic counseling for patients.

Impact of School Closures due to COVID-19 on Children with Neurodevelopmental Disorders in Japan.

In March 2020, many schools were closed to prevent the spread of COVID-19 in Japan, and it is predicted that many children, especially those with neurodevelopmental disorders (NDDs), will be affected emotionally and behaviorally. Here, we examined the impact of school closures due to COVID-19 on school-aged children with NDDs using the Child Behavior Checklist. Totally, data on 121 children diagnosed with autism spectrum disorder, attention-deficit hyperactivity disorder, and/or intellectual disorder were analyzed and it was found that externalizing and aggressive behavior increased in all NDDs, regardless of the type of diagnosis. A clear prospect is important for children with NDDs children to lead a stable life, and more generous supports for children with NDDs and their families are needed.

Advanced theory of mind in children with mild intellectual disability and deaf or hard of hearing children: A two-year longitudinal study in middle childhood.

The present study investigates the development of advanced theory of mind (AToM) among typically developing (TD) children, children with mild intellectual disability (MID), and deaf or hard of hearing (DHH) children. The 2-year longitudinal study comprised three waves and included a large sample of children from Poland in middle childhood aged around 7.5-9.5 years (N = 779; M = 7.7, SD = 0.92 at wave 1). The analysis of children's understanding of second-order false belief and the Faux-Pas Recognition Test showed that TD children outperformed children with MID and DHH children on both measures. At 7.5 years, almost 60% of the TD children correctly solved the second-order false belief task; correct performance at 7.5 years in children with MID and DHH children was 27 and 38% respectively. Two years later, correct performance rose to 80% (TD children), 45% (children with MID), and 63% (DHH children). Despite these differences, the speed of AToM development did not differ across the groups. The development of faux-pas recognition followed a non-linear pattern, with TD children showing no further significant development after mid-elementary school. Our findings show differences in AToM development between TD children, children with MID, and DHH children, and they suggest that children's development of AToM may follow different developmental pathways, depending on the aspect of AToM under study.

Cluster Analysis of the Child Behavior Checklist 1.5-5 for Preschool Children Diagnosed With a Mental Disorder.

Research on the relationship between the Child Behavior Checklist (CBCL) and Diagnostic and Statistical Manual for Mental Disorder diagnoses for preschool children is scarce. Cluster analysis can be useful for investigating characteristics of a clinical group by using CBCL subscales and classifying subtypes of a Diagnostic and Statistical Manual for Mental Disorder diagnosis group. This study conducted a cluster analysis of the CBCL 1.5-5 for preschool children diagnosed with a mental disorder. Participants were 333 children (255 males and 78 females) aged 1.5 to 5 years who were diagnosed with a mental disorder. The CBCL 1.5-5 and Bayley Scales of Infant Development II were used as assessment instruments. Three clusters were extracted and then compared with CBCL 1.5-5 profiles of each Diagnostic and Statistical Manual for Mental Disorder-5 subject group to determine their clusters. Cluster 1 was named "intellectual disorder cluster." Cluster 2 was referred to as "other mental disorders cluster," and Cluster 3 was called "autism spectrum disorder cluster." When differences in profiles of behavior problems distinguished by CBCL 1.5-5 scales were examined among different clusters, discriminant validity was found to be high.