Copy number variations in autistic children.

Autism spectrum disorder (ASD) manifests as a neurodevelopmental condition marked by challenges in social communication, interaction and the performing of repetitive behaviors. The prevalence of autism increases markedly on an annual basis; however, the etiology remains incompletely understood. Cytogenetically visible chromosomal abnormalities, including copy number variations (CNVs), have been shown to contribute to the pathogenesis of ASD. More than 1% of ASD conditions can be explained based on a known genetic locus, whereas CNVs account for 5-10% of cases. However, there are no studies on the Saudi Arabian population for the detection of CNVs linked to ASD, to the best of our knowledge. Therefore, the aim of the present study was to explore the prevalence of CNVs in autistic Saudi Arabian children. Genomic DNA was extracted from the peripheral blood of 14 autistic children along with four healthy control children and then array-based comparative genomic hybridization (aCGH) was used to detect CNVs. Bioinformatics analysis of the aCGH results showed the presence of recurrent and non-recurrent deletion/duplication CNVs in several regions of the genome of autistic children. The most frequent CNVs were 1q21.2, 3p26.3, 4q13.2, 6p25.3, 6q24.2, 7p21.1, 7q34, 7q11.1, 8p23.2, 13q32.3, 14q11.1-q11.2 and 15q11.1-q11.2. In the present study, CNVs in autistic Saudi Arabian children were identified to improve the understanding of the etiology of autism and facilitate its diagnosis. Additionally, the present study identified certain possible pathogenic genes in the CNV region associated with several developmental and neurogenetic diseases.

Herpesvirus Entry Mediator as an Immune Checkpoint Target and a Potential Prognostic Biomarker in Myeloid and Lymphoid Leukemia.

Herpesvirus entry mediator (HVEM) is a molecular switch that can modulate immune responses against cancer. The significance of HVEM as an immune checkpoint target and a potential prognostic biomarker in malignancies is still controversial. This study aims to determine whether HVEM is an immune checkpoint target with inhibitory effects on anti-tumor CD4+ T cell responses in vitro and whether HVEM gene expression is dysregulated in patients with acute lymphocytic leukemia (ALL). HVEM gene expression in tumor cell lines and peripheral blood mononuclear cells (PBMCs) from ALL patients and healthy controls was measured using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Tumor cells were left untreated (control) or were treated with an HVEM blocker before co-culturing with CD4+ T cells in vitro in a carboxyfluorescein succinimidyl ester (CFSE)-dependent proliferation assay. HVEM expression was upregulated in the chronic myelogenous leukemia cell line (K562) (FC = 376.3, p = 0.086) compared with normal embryonic kidney cells (Hek293). CD4+ T cell proliferation was significantly increased in the HVEM blocker-treated K562 cells (p = 0.0033). Significant HVEM differences were detected in ALL PBMCs compared with the controls, and these were associated with newly diagnosed ALL (p = 0.0011) and relapsed/refractory (p = 0.0051) B cell ALL (p = 0.0039) patients. A significant differentiation between malignant ALL and the controls was observed in a receiver operating characteristic (ROC) curve analysis with AUC = 0.78 ± 0.092 (p = 0.014). These results indicate that HVEM is an inhibitory molecule that may serve as a target for immunotherapy and a potential ALL biomarker.

Multiple Recurrent Copy Number Variations (CNVs) in Chromosome 22 Including 22q11.2 Associated with Autism Spectrum Disorder.

Introduction: Autism spectrum disorder (ASD) is a developmental disorder that can cause substantial social, communication, and behavioral challenges. Genetic factors play a significant role in ASD, where the risk of ASD has been increased for unclear reasons. Twin studies have shown important evidence of both genetic and environmental contributions in ASD, where the level of contribution of these factors has not been proven yet. It has been suggested that copy number variation (CNV) duplication and the deletion of many genes in chromosome 22 (Ch22) may have a strong association with ASD. This study screened the CNVs in Ch22 in autistic Saudi children and assessed the candidate gene in the CNVs region of Ch22 that is most associated with ASD. Methods: This study included 15 autistic Saudi children as well as 4 healthy children as controls; DNA was extracted from samples and analyzed using array comparative genomic hybridization (aCGH) and DNA sequencing. Results: The aCGH detected (in only 6 autistic samples) deletion and duplication in many regions of Ch22, including some critical genes. Moreover, DNA sequencing determined a genetic mutation in the TBX1 gene sequence in autistic samples. This study, carried out using aCGH, found that six autistic patients had CNVs in Ch22, and DNA sequencing revealed mutations in the TBX1 gene in autistic samples but none in the control. Conclusion: CNV deletion and the duplication of the TBX1 gene could be related to ASD; therefore, this gene needs more analysis in terms of expression levels.

Alterations in Immune-Related Defensin Alpha 4 (DEFA4) Gene Expression in Health and Disease.

Defensin Alpha 4 (DEFA4) is the fourth member of the Alpha Defensins family known as a part of antimicrobial peptides in the innate immune system. DEFA4 has a strong preference to kill Gram-negative bacteria more than Gram-positive bacteria. In addition, DEFA4 exhibits antiviral activity against human immunodeficiency virus type 1 (HIV-1) in vitro. Moreover, DEFA4 can act as an inhibitor of corticosterone production (Corticostatin). On the other hand, alternations in DEFA4 gene expression have been reported in different disorders such as diseases related to inflammation and immunity dysfunction, brain-related disorders, and various cancers. The up-regulation of DEFA4 appears to be involved in the malignant transformation or aggressive form of cancer. Interestingly, the modified version of DEFA4 fragment (1-11) was potent and efficient against antibiotic-resistant bacteria. This review provides a general background abSaudi Arabia out DEFA4 and sheds light on changes in DEFA4 gene expression in different diseases. The paper also discusses other aspects related to DEFA4 as an antimicrobial and antiviral agent. The research was conducted based on available articles obtained from databases starting from 1988 to the present.

DNA Methylation Level of Transcription Factor Binding Site in the Promoter Region of Acyl-CoA Synthetase Family Member 3 (ACSF3) in Saudi Autistic Children.

BACKGROUND: DNA methylation (DNAm) is one of the main epigenetic mechanisms that affects gene expression without changing the underlying DNA sequence. Aberrant DNAm has an implication in different human diseases such as cancer, schizophrenia, and autism spectrum disorder (ASD). ASD is a neurodevelopmental disorder that affects behavior, learning, and communication skills. Acyl-CoA synthetase family member 3 (ACSF3) encodes malonyl-CoA synthetase that is involved in the synthesis and oxidation of fatty acids. The dysregulation in such gene has been reported in combined malonic and methylmalonic aciduria associated with neurological symptoms such as memory problems, psychiatric diseases, and/or cognitive decline. This research aims to study DNAm in the transcription factor (TF) binding site of ACSF3 in Saudi autistic children. To determine whether the DNAm of the TF-binding site is a cause or a consequence of transcription regulation of ACSF3. METHODS: RT-qPCR and DNA methylight qPCR were used to determine the expression and DNAm level in the promoter region of ACSF3, respectively. DNA and RNA were extracted from 19 cases of ASD children and 18 control samples from their healthy siblings. RESULTS: The results showed a significant correlation between the gene expression of ACSF3 and specificity protein 1 (SP1) in 17 samples of ASD patients, where both genes were upregulated in 9 samples and downregulated in 8 samples. CONCLUSION: Although this study found no DNAm in the binding site of SP1 within the ACSF3 promoter, the indicated correlation highlights a possible role of ACSF3 and SP1 in ASD patients.

Effect of e-cigarette flavoring agents on the neural retina of chick embryo: histological and gene expression study.

BACKGROUND: An electronic cigarette (e-cigarette) is initially marketed as an assistant product to quit smoking or limit its use. However, recent studies suggest the opposite, describing it as a product that lacks adequate quality and user safety. The present study aimed to investigate the effect of e-cigarette flavoring agent (cinnamon flavor) on the neural retina development of chick embryos and apoptosis induction after the early and late apoptosis stages by quantitative detection of gene expression CASP-3 at both embryonic days E9 and E17. METHODS: Fertilized chicken eggs were divided into two groups: control and treatment, and each group included two embryonic days; E9 and E17. For each treatment stage, two dosages of the treatment were applied, 2% and 5%. The neural retinas were dissected from the sclera and retinal pigment epithelium for subsequent RNA extraction and histological examination. RESULTS: This study indicated that aerosol of the subtle cinnamon flavor e-liquid causes downregulated expression of CASP3 in neural retina development. In addition, the hematoxylin and eosin (H&E)-stained sections showed multiple structural changes in the retinal layers and evidence of apoptotic cell death. CONCLUSION: Cell death was visible and abundant in E9, and E17 concludes that flavor vapor condensate treatment caused neuronal cell death. CASP-3 was downregulated, which indicates that cell death occurred independently of CASP-3.