A Comprehensive Overview on COVID-19: Future Perspectives

The outbreak of COVID-19 has proven to be an unprecedented disaster for the whole world. The virus has inflicted billion of lives across the globe in all aspects—physically, psychologically, as well as socially. Compared to the previous strains of β-CoV genera- MERS and SARS, SARS-CoV-2 has significantly higher transmissibility and worst post-recovery implications. A frequent mutation in the initial SARS-CoV-2 strain has been a major cause of mortalities (approx. 3 million deaths) and uncontrolled virulence (approx. 1 billion positive cases). As far as clinical manifestations are concerned, this particular virus has exhibited deleterious impacts on systems other than the respiratory system (primary target organ), such as the brain, hematological system, liver, kidneys, endocrine system, etc. with no promising curatives to date. Lack of emergency treatments and shortage of life-saving drugs has promoted the repurposing of existing therapeutics along with the emergence of vaccines with the combined efforts of scientists and industrial experts in this short span. This review summarizes every detail on COVID-19 and emphasizes undermining the future approaches to minimize its prevalence to the remaining lives.

Molecular Characterization of α- and β-Thalassaemia Among Children From 1 to 10 Years of Age in Guangxi, A Multi-Ethnic Region in Southern China

Background: Thalassemia is one of the most common genetic diseases in southern China. Howerver, population in different regions or different population has their own spectrums of thalassemia. To investigate the prevalence and spectrum features of thalassemia among children in Guangxi. Hematology and genetic analysis were performed on 71,459 children aged 1–10 years in various regions of Guangxi.Results: A total of 11,821 children were diagnoses with thalassemia including 7,615 (10.66%) subjects of α-thalassemia, 3,507 (4.90%) subjects of β-thalassemia, and 699 (0.98%) cases with both α- and β-thalassemia. Nine α-thalassemia mutations and 30 genotypes were identified among the α-thalassemia children. The - -SEA and - -SEA/αα were the most frequent mutation and genotype, respectively. One α-thalassemia fusion gene and a rare 2.4 kb deletion both causing α+-thalassemia were identified, respectively. Thirteen β-thalassemia mutations and 31 genotypes were characterized among the β-thalassemia children, with the most common mutation CD41-42 (-CTTT) accounting for 46.05% of the β-mutations. Two rare mutations IVS-II-5 (G>C), and IVS-I-2 (T>C) were firstly identified. Furthermore, 92 genotypes were identified among 699 children with both α- and β-thalassemia.Conclusions: Our findings highlight the great heterogeneity and the extensive spectrum of thalassemia among children in Guangxi, which provide an available reference for prevention of thalassemia in this area.

Case Report: Pathogenic MYH9 c.5797delC Mutation in a Patient With Apparent Thrombocytopenia and Nephropathy

MYH9-related disease or disorder (MYH9-RD) is an autosomal dominant disease caused by mutations in the MYH9 gene. Mutations in this gene initially affect the hemic system, and other manifestations may evolve with age. Here, we report the case of a 46-year-old Chinese woman with MYH9-RD who was primarily misdiagnosed with idiopathic thrombocytopenia purpura. Exome sequencing of the patient, and the mother and son of the patient revealed a deletion mutation c.5797delC (p. R1933Efs*15) in exon 41 (encoding non-helical tailpiece, NHT) of the MYH9 gene, which consequently led to a frameshift mutation. To the best of our knowledge, this mutation has been reported in Italy once, while the substitution mutation c.5797 C>T is the most frequent mutation. Mutations that affect the NHT region cause thrombocytopenia throughout life; however, our patient presented with a more severe phenotype than previously reported, including thrombocytopenia, inclusion bodies in neutrophils, sensorineural hearing loss, nephropathy, and abnormal liver enzymes. Our goal in the current case is to prevent further progression of renal involvement and to identify other affected members in this family to provide early intervention. This case may raise awareness of MYH9-RD when diagnosing thrombocytopenia and improve our understanding of this condition.

Connexin 26 (GJB2) Gene Mutations Linked With Autosomal Recessive Nonsyndromic Sensorineural Hearing Loss in Iraqi Population.

Objectives: The ARNSHL wasn’t been studied enough in Iraq, this study aimed to detect the prevalence of the three most common mutations of Connexin 26 gene in Iraqi population. This study was conducted in order to detect c.35delG, c.235delC and c.167delT mutations in GJB2 gene, we were employed PCR-RFLP assays.Results: The current case-control study was conducted from January 2018 to January 2020, The study was included 95 deaf patients (55 males and 40 females) their age range between 11-40 years and 21.5 ± 6.3 year (mean ± SD) and 110 healthy control group, their ages range between 10-40 years and 20.1 ± 5.9 year (mean ± SD), these two groups were matched in age and gender. From 95 deaf patients with ARNSHL who were participated in this study, c.35delG was the main frequent mutation encountered with GJB2 gene, The second frequent mutation was c.235delC, None of 95 deaf patients were showed the c.167delT mutation, these variants were not detected in healthy control group which was studied parallel with patients group. Our data conclude that GJB2 c.35delG and c.235delC gene mutations were the main cause of ARNSHL in Iraqi deaf population.

Partial Rescue of F508del-CFTR Stability and Trafficking Defects by Double Corrector Treatment

Deletion of phenylalanine at position 508 (F508del) in the CFTR chloride channel is the most frequent mutation in cystic fibrosis (CF) patients. F508del impairs the stability and folding of the CFTR protein, thus resulting in mistrafficking and premature degradation. F508del-CFTR defects can be overcome with small molecules termed correctors. We investigated the efficacy and properties of VX-445, a newly developed corrector, which is one of the three active principles present in a drug (Trikafta®/Kaftrio®) recently approved for the treatment of CF patients with F508del mutation. We found that VX-445, particularly in combination with type I (VX-809, VX-661) and type II (corr-4a) correctors, elicits a large rescue of F508del-CFTR function. In particular, in primary bronchial epithelial cells of CF patients, the maximal rescue obtained with corrector combinations including VX-445 was close to 60–70% of CFTR function in non-CF cells. Despite this high efficacy, analysis of ubiquitylation, resistance to thermoaggregation, protein half-life, and subcellular localization revealed that corrector combinations did not fully normalize F508del-CFTR behavior. Our study indicates that it is still possible to further improve mutant CFTR rescue with the development of corrector combinations having maximal effects on mutant CFTR structural and functional properties.

Multiomics Analysis of Transcriptome, Epigenome, and Genome Uncovers Putative Mechanisms for Dilated Cardiomyopathy

Objective. Multiple genes have been identified to cause dilated cardiomyopathy (DCM). Nevertheless, there is still a lack of comprehensive elucidation of the molecular characteristics for DCM. Herein, we aimed to uncover putative molecular features for DCM by multiomics analysis. Methods. Differentially expressed genes (DEGs) were obtained from different RNA sequencing (RNA-seq) datasets of left ventricle samples from healthy donors and DCM patients. Furthermore, protein-protein interaction (PPI) analysis was then presented. Differentially methylated genes (DMGs) were identified between DCM and control samples. Following integration of DEGs and DMGs, differentially expressed and methylated genes were acquired and their biological functions were analyzed by the clusterProfiler package. Whole exome sequencing of blood samples from 69 DCM patients was constructed in our cohort, which was analyzed the maftools package. The expression of key mutated genes was verified by three independent datasets. Results. 1407 common DEGs were identified for DCM after integration of the two RNA-seq datasets. A PPI network was constructed, composed of 171 up- and 136 downregulated genes. Four hub genes were identified for DCM, including C3 ( degree = 24 ), GNB3 ( degree = 23 ), QSOX1 ( degree = 21 ), and APOB ( degree = 17 ). Moreover, 285 hyper- and 321 hypomethylated genes were screened for DCM. After integration, 20 differentially expressed and methylated genes were identified, which were associated with cell differentiation and protein digestion and absorption. Among single-nucleotide variant (SNV), C>T was the most frequent mutation classification for DCM. MUC4 was the most frequent mutation gene which occupied 71% across 69 samples, followed by PHLDA1, AHNAK2, and MAML3. These mutated genes were confirmed to be differentially expressed between DCM and control samples. Conclusion. Our findings comprehensively analyzed molecular characteristics from the transcriptome, epigenome, and genome perspectives for DCM, which could provide practical implications for DCM.

Evaluation of Fused Pyrrolothiazole Systems as Correctors of Mutant CFTR Protein

Cystic fibrosis (CF) is a genetic disease caused by mutations that impair the function of the CFTR chloride channel. The most frequent mutation, F508del, causes misfolding and premature degradation of CFTR protein. This defect can be overcome with pharmacological agents named “correctors”. So far, at least three different classes of correctors have been identified based on the additive/synergistic effects that are obtained when compounds of different classes are combined together. The development of class 2 correctors has lagged behind that of compounds belonging to the other classes. It was shown that the efficacy of the prototypical class 2 corrector, the bithiazole corr-4a, could be improved by generating conformationally-locked bithiazoles. In the present study, we investigated the effect of tricyclic pyrrolothiazoles as analogues of constrained bithiazoles. Thirty-five compounds were tested using the functional assay based on the halide-sensitive yellow fluorescent protein (HS-YFP) that measured CFTR activity. One compound, having a six atom carbocyle central ring in the tricyclic pyrrolothiazole system and bearing a pivalamide group at the thiazole moiety and a 5-chloro-2-methoxyphenyl carboxamide at the pyrrole ring, significantly increased F508del-CFTR activity. This compound could lead to the synthesis of a novel class of CFTR correctors.

The Identity of PDGFRA D842V-Mutant Gastrointestinal Stromal Tumors (GIST)

The majority of gastrointestinal stromal tumors (GIST) carry a sensitive primary KIT mutation, but approximately 5% to 10% of cases harbor activating mutations of platelet-derived growth factor receptor (PDGFRA), mainly involving the A-loop encoded by exon 18 (~5%), or more rarely the JM domain, encoded by exon 12 (~1%), or the ATP binding domain encoded by exon 14 (<1%). The most frequent mutation is the substitution at position 842 in the A-loop of an aspartic acid (D) with a valine (V) in exon 18, widely recognized as D842V. This mutation, as well known, provides primary resistance to imatinib and sunitinib. Thus, until few years ago, no active drugs were available for this subtype of GIST. Conversely, recent years have witnessed the development of a new specific inhibitor—avapritinib—that has been studied in in vitro and clinical setting with promising results. In light of this primary resistance to conventional therapies, the biological background of D842V-mutant GIST has been deeply investigated to better understand what features characterize this peculiar subset of GIST, and some promising insights have emerged. Hereinafter, we present a comprehensive overview on the clinical features and the molecular background of this rare subtype of GIST.

Analysis of the Dynamics and Distribution of SARS-CoV-2 Mutations and its Possible Structural and Functional Implications

ABSTRACTAfter eight months of the pandemic declaration, COVID-19 has not been globally controlled. Several efforts to control SARS-CoV-2 dissemination are still running including vaccines and drug treatments. The effectiveness of these procedures depends, in part, that the regions to which these treatments are directed do not vary considerably. Although, it is known that the mutation rate of SARS-CoV-2 is relatively low it is necessary to monitor the adaptation and evolution of the virus in the different stages of the pandemic. Thus, identification, analysis of the dynamics, and possible functional and structural implication of mutations are relevant. Here, we first estimate the number of COVID-19 cases with a virus with a specific mutation and then calculate its global relative frequency (NRFp). Using this approach in a dataset of 100 924 genomes from GISAID, we identified 41 mutations to be present in viruses in an estimated number of 750 000 global COVID-19 cases (0.03 NRFp). We classified these mutations into three groups: high-frequent, low-frequent non-synonymous, and low-frequent synonymous. Analysis of the dynamics of these mutations by month and continent showed that high-frequent mutations appeared early in the pandemic, all are present in all continents and some of them are almost fixed in the global population. On the other hand, low-frequent mutations (non-synonymous and synonymous) appear late in the pandemic and seems to be at least partially continent-specific. This could be due to that high-frequent mutation appeared early when lockdown policies had not yet been applied and low-frequent mutations appeared after lockdown policies. Thus, preventing global dissemination of them. Finally, we present a brief structural and functional review of the analyzed ORFs and the possible implications of the 25 identified non-synonymous mutations.

The Rise of the GRN C157KfsX97 Mutation in Southern Italy: Going Back to the Fall of the Western Roman Empire

Background: Frontotemporal lobar degeneration (FTLD) designates a group of neurodegenerative diseases with remarkable clinical, pathological, and genetic heterogeneity. Mutations in progranulin gene (GRN) are among the most common causes of familial FTLD. The GRN C157KfsX97 mutation is the most frequent mutation occurring in Southern Italy and has been already described in a previous work. Objective: In this study, we reported on additional cases carrying the same mutation and performed a genetic study on the whole cohort, aiming at demonstrating the existence of a founder effect and estimating the age of this mutation. Methods/Results: Based on the haplotype sharing analysis, a founder effect was highly probable, while the age of the mutation, estimated by means of DMLE+ software, resulted in a range between 52 and 82 generations, with the highest frequency at about 62 generations, 1,550 years ago. Conclusion: This is the first study that reports the age estimation of the most recent common ancestor for the GRN C157KfsX97 mutation recurring in Southern Italy. Mutation dating in a geographically restricted population may be useful in order to plan genetic counseling and screening programs in the field of public health.