SLC26A4 is one of the most common genes causing autosomal recessive non-syndromic sensorineural hearing loss (SNHL). It has been reported to cause Pendred Syndrome (PDS) and DFNB4 which is deafness with enlarged vestibular aqueduct (EVA). However, mutated SLC26A4 is not conclusive for having either DFNB4 or PDS. Three unrelated Jordanian families consisting of eight affected individuals with congenital bilateral hearing loss (HL) participated in this study. Whole-exome and Sanger sequencing were performed to investigate the underlying molecular etiology of HL. Further clinical investigations, including laboratory blood workup for the thyroid gland, CT scan for the temporal bone, and thyroid ultrasound were performed. Three disease-causing variants were identified in SLC26A4 in the three families, two of which were novel. Two families had a novel pathogenic homozygous splice-site accepter variant (c.165-1G>C), while the third family had compound heterozygous pathogenic variants (c.1446G>A; p.Trp482* and c.304G>A; p.Gly102Arg). Our approach helped in redirecting the diagnosis of several affected members of three different families from non-syndromic HL to syndromic HL. Two of the affected individuals had typical PDS, one had DFNB4, while the rest had atypical PDS. Our work emphasized the intra- and inter-familial variability of SLC26A4-related phenotypes. In addition, we highlighted the variable phenotypic impact of SLC26A4 on tailoring a personalized healthcare management.

Purpose: Four consanguineous Jordanian families with affected members of unknown gastrointestinal related diseases were recruited to assess the utility and efficiency of whole exome sequencing (WES) in reaching the definitive diagnosis. Patients and Methods: Members from four consanguineous Jordanian families were recruited in this study. Laboratory and imaging tests were used for initial diagnosis, followed by performing WES to test all affected members for the detection of causative variants. Sanger sequencing was used for validation. Results: We had a 100% success rate identifying each case presented in this study. Conclusion: This is the first study applying a WES testing approach in the diagnosis of pediatric diseases in Jordan. Our results strongly suggest the need to implement WES as an evident diagnostic tool in the clinical setting, as it will subsequently allow for proper disease management and genetic counseling.

Adipogenesis is a multi-stage process essential for healthy fat storage and metabolic regulation. While early regulatory mechanisms are well characterized, the control of late-stage adipocyte differentiation remains poorly understood. Integrating CAGE-seq, promoter capture Hi-C, and a high-throughput siRNA screen of druggable genes, we report here that chromatin architecture rewiring promotes gene regulation changes essential for terminal adipogenesis. We identified nine clusters of dynamic promoter-anchored chromosomal interactions, many involving distal enhancers. Functional screening of genes engaged in these interactions revealed 19 novel regulators of late adipogenesis, including proteins with peptidase and ubiquitin ligase activity. Human genetic variant-to-gene mapping, coupled with cross-species chromatin interaction and synteny analyses, highlighted new gene-trait associations relevant to lipid traits (FXYD5, LAP3, SGPP1) and type 2 diabetes (FBXO17, FN3KRP, ZFAND6, TTC3). Our findings define the 3D gene regulatory landscape of late adipogenesis. The molecular links uncovered here provide mechanistic insight into metabolic disease risk and potential interventions.

Background: Wide application of genome sequencing technologies has highlighted extensive genetic diversity in Acute Myeloid Leukemia (AML), yet the specific roles of individual genes remain unclear. This systematic review and meta-analysis aims to provide robust evidence for the prognostic impact of somatic gene mutations in de novo AML patients, while also exploring the prevalence of these mutations. Methods: Eligible studies were identified from PubMed and Scopus, with a focus on those reporting the prognostic influence of somatic gene mutations on overall survival (OS) or relapse-free survival (RFS) when compared to wild-type carriers. We calculated the pooled prevalence with 95% confidence intervals to assess the frequency of these mutations, and the pooled Hazard Ratio (HR) to compare OS and RFS associated with specific gene mutations. Results: We evaluated 53 somatic gene mutations using 80 studies, involving 20,048 de novo AML patients. The analysis revealed that the most prevalent affected genes were NPM1 (27%), DNMT3A (26%), and FLT3-ITD (24%). Mutations in CSF3R, TET2, and TP53 were significantly associated with poorer OS or RFS (p < 0.05). Sensitivity analysis confirmed that ASXL1, DNMT3A, and RUNX1 mutations were consistently linked to inferior OS or RFS. In contrast, CEBPAdm mutations were associated with favorable OS [HR = 0.39 (0.30–0.50)] and RFS [HR = 0.44 (0.37–0.54)]. Subgroup analysis showed that FLT3-ITD mutations were consistently associated with worse OS or RFS across all subgroups, though no significant subgroup differences were noted. No significant impact on OS or RFS was observed for mutations in GATA2, FLT3-TKD, KRAS, NRAS, IDH1, and IDH2. Conclusions: These findings provide critical insights into AML prognosis, aiding clinical decision-making and improving risk stratification strategies.

Non-small cell lung carcinoma (NSCLC) is the second most common cancer type worldwide. It is a type of lung malignancy that initially starts in the lung and may spread to other parts of the human body. Mutations in the epidermal growth factor receptor (EGFR), play a significant role in cell growth and malignancy. EGFR is also considered a major driver oncogene in NSCLC. Thus, several targeted drugs, like tyrosine kinase inhibitors (TKIs), i.e., Gefitinib, have been developed and approved by the FDA against the EGFR. Tyrosine kinase inhibitor (TKI) drug usage has shown an improved survival rate. However, the possibility of drug resistance threatens treatment plans and efficacy. Computational methods, such as, molecular dynamics simulation, have been developed to calculate the binding stability of WT and mutant EGFR. In this study, we investigate the performance of molecular dynamics simulation (MD simulation) tools - GROMACS, NAMD, and BioExcel - on the EGFR-Gefitinib complex, focusing on the catalytic site mutation G719S. The analysis of conformational changes in both WT and mutant EGFR-Gefitinib complexes after simulation revealed structural alterations. Comparative analysis across different time scales highlights the efficacy of NAMD and GROMACS over BioExcel, particularly evident in root mean square deviation and root mean square fluctuations. This investigation sheds light on the optimal use of MD simulation tools for studying large protein complexes, helping in the development of targeted therapies for NSCLC and other cancer types.