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Background: This study aims to explore the association between the quality of life (QoL) in children with Down syndrome (DS) and its relationship with demographic characteristics of both parents and children. The investigation encompasses five domains: physical and psychological well‐being, autonomy and parental relationship, social well‐being, and peers, as well as school and the learning environment. Method: An online questionnaire, the KIDSCREEN‐27, was used to measure the QoL of 112 families with DS in Saudi Arabia, referred to as "Parent‐Reported Measures." Descriptive statistics were analyzed using the Statistical Package for Social Sciences. Results: The study found that the QoL of children with DS showed high scores in the psychological well‐being, autonomy, parental relations, school, and learning environment domains. However, the physical and social well‐being and peer domains had lower scores, although still considered "good scores." Family income had a positively significant influence on all QoL domains. Specifically, higher family income was associated with better QoL outcomes, except for social well‐being. Parental age was found to influence psychological well‐being, while parental education and the relationship between the parent and child influenced social well‐being. Lastly, the child's gender was found to have an impact on the school and learning environment domain. Conclusion: The study highlights the importance of understanding the impact of the demographic variability of children with DS and their parents on the QoL of their children. It emphasizes the need to address the needs of families with lower incomes and the importance of parental education and relationships with their children in improving social well‐being. The findings could aid policymakers and healthcare providers in improving the QoL for families with children who have DS. This study aims to determine the relationship between demographic variables of parents with down syndrome (DS) children and their quality of life (QoL). It is the first time to use the Arabic version KIDSCREEN questionnaire, after validation. This is the first study to measure the demographic variables influence on the reported QoL of children with DS. This study found that family income influenced all QoL domains except social well‐being. Psychological well‐being was influenced by parental age. Social well‐being was influenced by parental education. Finally, the school and learning environment was influenced by the child's gender. [ABSTRACT FROM AUTHOR]

Oxidative stress has been hypothesized to play a crucial role in the complications of type 2 diabetes (T2D). Hyperglycaemia-mediated increases in free radicals have a deleterious effect on cellular compartments and nucleic acids, leading to imbalances between free radicals and antioxidant enzymes. This case–control study comprised two groups with 100 participants (50 T2D and 50 DN patients) and aimed to examine the association between single-nucleotide polymorphisms (SNPs) in the genes encoding nicotinamide adenine dinucleotide phosphate oxidase (NOX), glutathione S-transferase P (GSTP1), and glutathione peroxidase 1(GPX1) and diabetic nephropathy (DN) risk in patients with T2D. An SNP genotyping assay was performed using TaqMan assay and real-time PCR to identify the SNPs (NOX rs4673, GSTP rs1695, GPX1 rs1050450). The Sanger method was used to validate our findings. Fisher chi-square analyses revealed no significant differences in these genes when comparing T2D patients with and without DN. Our findings suggest no association between the rs4673, rs1695, and rs1050450 SNPs and DN in Saudi patients with T2D. [ABSTRACT FROM AUTHOR]

Introduction: One of the complications of diabetes mellitus (DM) is diabetic nephropathy (DN), which plays a significant role in the progression of end‐stage renal disease. Oxidative stress is implicated in DN pathogenesis, and genetic variations in antioxidant enzymes such as superoxide dismutase 2 (SOD2) and catalase (CAT) may contribute to the susceptibility. This study aimed to investigate the potential association between single nucleotide polymorphisms (SNPs) in antioxidant enzymes, specifically SOD2 rs4880 and CAT rs769217, and the risk of T2D and susceptibility to DN within the Saudi population. Methods: This case–control study included 150 participants, comprising 50 patients with T2D without DN (group 1), 50 patients with T2D with DN (group 2), and 50 healthy participants (group 3). The samples were genotyped using real‐time PCR for SOD2 rs4880 and CAT rs769217 SNPs. Sanger sequencing was used for validation. Statistical analyses were performed to explore associations between these SNPs and T2D with or without DN. Results: No significant difference was observed in CAT rs769217 expression between the groups. However, a significant difference was observed in SOD2 rs4880 expression between the healthy controls and patients with T2D with DN (p =.028). Furthermore, SOD2 rs4880 was associated with approximately threefold increased risk of DN in patients with T2D compared to that in healthy participants (odds ratio [OR] = 2.99 [1.31–6.83]). Validation through Sanger sequencing further confirmed these findings. Conclusions: The findings of this study provide evidence that SOD2 rs4880 SNP may contribute to inadequate defence by the antioxidant enzyme, SOD2, against DM‐induced oxidative stress and thus cause DN in Saudi patients with T2D. Therefore, SOD2 rs4880 may serve as a predictive marker to prevent the development and progression of DN in patients with T2D. [ABSTRACT FROM AUTHOR]

The Parkinson disease (PD) is the second most common neurodegenerative disorder affecting the central nervous system and motor functions. The biological complexity of PD is yet to reveal potential targets for intervention or to slow the disease severity. Therefore, this study aimed to compare the fidelity of blood to substantia nigra (SN) tissue gene expression from PD patients to provide a systematic approach to predict role of the key genes of PD pathobiology. Differentially expressed genes (DEGs) from multiple microarray data sets of PD blood and SN tissue from GEO database are identified. Using the theoretical network approach and variety of bioinformatic tools, we prioritized the key genes from DEGs. A total of 540 and 1024 DEGs were identified in blood and SN tissue samples, respectively. Functional pathways closely related to PD such as ERK1 and ERK2 cascades, mitogen-activated protein kinase (MAPK) signaling, Wnt, nuclear factor-κB (NF-κB), and PI3K-Akt signaling were observed by enrichment analysis. Expression patterns of 13 DEGs were similar in both blood and SN tissues. Comprehensive network topological analysis and gene regulatory networks identified additional 10 DEGs functionally connected with molecular mechanisms of PD through the mammalian target of rapamycin (mTOR), autophagy, and AMP-activated protein kinase (AMPK) signaling pathways. Potential drug molecules were identified by chemical-protein network and drug prediction analysis. These potential candidates can be further validated in vitro/in vivo to be used as biomarkers and/or novel drug targets for the PD pathology and/or to arrest or delay the neurodegeneration over the years, respectively. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) is a multifactorial progressive airflow obstruction in the lungs, accounting for high morbidity and mortality across the world. This study aims to identify potential COPD blood-based biomarkers by analyzing the dysregulated gene expression patterns in blood and lung tissues with the help of robust computational approaches. The microarray gene expression datasets from blood (136 COPD and 6 controls) and lung tissues (16 COPD and 19 controls) were analyzed to detect shared differentially expressed genes (DEGs). Then these DEGs were used to construct COPD protein network-clusters and functionally enrich them against gene ontology annotation terms. The hub genes in the COPD network clusters were then queried in GWAS catalog and in several cancer expression databases to explore their pathogenic roles in lung cancers. The comparison of blood and lung tissue datasets revealed 63 shared DEGs. Of these DEGs, 12 COPD hub gene-network clusters (SREK1, TMEM67, IRAK2, MECOM, ASB4, C1QTNF2, CDC42BPA, DPF3, DET1, CCDC74B, KHK, and DDX3Y) connected to dysregulations of protein degradation, inflammatory cytokine production, airway remodeling, and immune cell activity were prioritized with the help of protein interactome and functional enrichment analysis. Interestingly, IRAK2 and MECOM hub genes from these COPD network clusters are known for their involvement in different pulmonary diseases. Additional COPD hub genes like SREK1, TMEM67, CDC42BPA, DPF3, and ASB4 were identified as prognostic markers in lung cancer, which is reported in 1% of COPD patients. This study identified 12 gene network- clusters as potential blood based genetic biomarkers for COPD diagnosis and prognosis. [ABSTRACT FROM AUTHOR]

Background: Familial hypercholesterolemia (FH) is a lipid disorder caused by pathogenic mutations in LDLRAP1 gene. The present study has aimed to deepen our understanding about the pathogenicity predictions of FH causative genetic mutations, as well as their relationship to phenotype changes in LDLRAP1 protein, by utilizing multidirectional computational analysis. Methods: FH linked LDLRAP1 mutations were mined from databases, and the prediction ability of several pathogenicity classifiers against these clinical variants, was assessed through different statistical measures. Furthermore, these mutations were 3D modelled in protein structures to assess their impact on protein phenotype changes. Results: Our findings suggest that Polyphen‐2, when compared with SIFT, M‐CAP and CADD tools, can make better pathogenicity predictions for FH causative LDLRAP1 mutations. Through, 3D simulation and superimposition analysis of LDLRAP1 protein structures, it was found that missense mutations do not create any gross changes in the protein structure, although they could induce subtle structural changes at the level of amino acid residues. Near native molecular dynamic analysis revealed that missense mutations could induce variable degrees of fluctuation differences guiding the protein flexibility. Stability analysis showed that most missense mutations shifts the free energy equilibrium and hence they destabilize the protein. Molecular docking analysis demonstrates the molecular shifts in hydrogen and ionic bonds and Van der waals bonding properties, which further cause differences in the binding energy of LDLR‐LDLRAP1 proteins. Conclusions: The diverse computational approaches used in the present study may provide a new dimension for exploring the structure–function relationship of the novel and deleterious LDLRAP1 mutations linked to FH. [ABSTRACT FROM AUTHOR]

[Display omitted] • A novel heterozygous de novo mutation in LRP1 was identified. • LRP1 variant was predicted to be pathogenic, resulting in potential changes in the properties, stability and the structure of the protein. • The findings in this study postulate that LRP1 variant has a role in TOF pathogenesis and facilitate accurate diagnosis as well as the understanding of underlying molecular mechanisms and pathophysiology of the disease. • High throughput genetic technologies and bioinformatic tools have improved the discovery of many implicated genes related to congenital heart defects (CHD) and TOF. Tetralogy of Fallot (TOF) is a rare, complex congenital heart defect caused by genetic and environmental interactions that results in abnormal heart development during the early stages of pregnancy. Genetic basis of TOF in Saudi populations is not yet studied. Therefore, the objective of this study is to screen for the molecular defects causing TOF in Saudi patients. A family with non-syndromic TOF was recruited from the Western region of Saudi Arabia. Whole exome sequencing (WES) was performed on the proband and her parents. The identified candidate variant was verified by sanger sequencing. Also, different computational biology tools were used to figure out how candidate variants affect the structure and function of candidate protein involved in TOF. A novel heterozygous de novo mutation in LRP1 (p. G3311D) gene was identified in the index case. Also, this variant was absent in the in-house exome sequencing data of 80 healthy Saudi individuals. This variant was predicted to be likely pathogenic, as it negatively affects the biophysical chemical properties and stability of the protein. Furthermore, functional biology data from knock out mouse models confirms that molecular defects in LRP1 gene leads to cardiac defects and lethality. This variant was not previously reported in both Arab and global population genetic databases. The findings in this study postulate that the LRP1 variant has a role in TOF pathogenesis and facilitate accurate diagnosis as well as the understanding of underlying molecular mechanisms and pathophysiology of the disease. [ABSTRACT FROM AUTHOR]

Background: Hereditary spastic paraplegias (HSP), a group of genetically heterogeneous neurological disorders with more than 56 documented loci (SPG1-56), are described either as uncomplicated (or pure), or complicated where in addition to spasticity and weakness of lower extremeties, additional neurological symptoms are present, including dementia, loss of vision, epilepsy, mental retardation and ichthyosis. We identified a large consanguineous family of Indian descent with four affected members with childhood onset HSP (SPG54), presenting with upper and lower limb spasticity, mental retardation and agenesis of the corpus callosum. Results: A common region of homozygosity on chromosome 8 spanning seven megabases (Mb) was identified in the affected individuals using the Illumina human cytoSNP-12 DNA Analysis BeadChip Kit. Exome sequencing identified a homozygous stop gain mutation (pR287X) in the phospholipase A, gene DDHD2, in the affected individuals, resulting in a premature stop codon and a severely truncated protein lacking the SAM and DDHD domains crucial for phosphoinositide binding and phospholipase activity. Conclusion: This mutation adds to the knowledge of HSP, suggests a possible founder effect for the pR287X mutation, and adds to the list of genes involved in lipid metabolism with a role in HSP and other neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Background: Syndactyly is a clinical feature of split‐hand foot malformation (SHFM), ectodermal‐dysplasia‐syndactyly (EDSS1) and Cenani–Lenz syndactyly syndromes (CLSS). In EDSS1, only cutaneous syndactyly is observed, with sparse hair, abnormal nails and dentition. In SHFM, bony syndactyly may vary from hypoplasia of one phalanx to aplasia of central digits, extending to complete fusion of all fingers and toes in CLSS. Several genes have been assigned to these syndromes. Performing a single step molecular diagnostics becomes a challenge when a phenotype has overlaps with several syndromes or when some of the clinical features are not fully expressed in patients. Methods: Whole exome sequencing (WES) analysis on one sample derived from a consanguineous family was performed. A causative variant in WES data was prioritized via standard bioinformatics tools. The selected variant was Sanger sequenced in all the available family members for autosomal recessive segregation. Results: A novel missense variant (c.1151A>G; p.Tyr384Cys) was identified in the LRP4 gene. Sanger validation confirmed that all affected individuals were homozygous and the obligate carriers were heterozygous for this variant. The variant is neither reported in 1000 human genomes, nor in 60 706 exomes databases, and is predicted as "pathogenic" by SIFT, Polyphen‐2 and MutationTaster software. Conclusions: The present study broadens the pathogenic spectrum of the LRP4 gene in syndactyly syndromes. WES is a powerful tool for genetic analysis in research and can be readily used as a first‐line diagnostic test in syndactyly and related phenotypes. [ABSTRACT FROM AUTHOR]