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Fulltext Complete Genome Sequences of SARS-CoV-2 Strains Detected in Malaysia

Chong YM, Sam IC, Ponnampalavanar S, Syed Omar SF, Kamarulzaman A, Munusamy V, et al.

Microbiol Resour Announc, 2020 May 14;9(20).
PMID: 32409547 DOI: 10.1128/MRA.00383-20

We sequenced four severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomes from Malaysia during the second wave of infection and found unique mutations which suggest local evolution. Circulating Malaysian strains represent introductions from different countries, particularly during the first wave of infection. Genome sequencing is important for understanding local epidemiology.

Matched MeSH terms: Mutation
Parathyroid hormone-dependent familial hypercalcemia with low measured PTH levels and a presumptive novel pathogenic mutation in CaSR

Mahajan A, Buse J, Kline G

Osteoporos Int, 2020 Jan;31(1):203-207.
PMID: 31641801 DOI: 10.1007/s00198-019-05170-9

Familial hypocalciuric hypercalcemia (FHH) is a benign autosomal dominant condition characterized by lifelong asymptomatic hypercalcemia. FHH is typically caused by a heterozygous inactivating mutation of the calcium-sensing receptor (CaSR) and characterized by moderate hypercalcemia, inappropriately normal or elevated serum parathyroid hormone (PTH), and relative hypocalciuria (FeCa 2%. PTH levels were repeatedly below the mean of the reference range (on two separate assays) and sometimes even below the lower reference limit. Two siblings, one niece, and her son had hypercalcemia without nephrolithiasis. Cinacalcet, used as a PTH-suppression test, normalized serum total and ionized calcium after 7 days of cinacalcet 30 mg BID, confirming her hypercalcemia was PTH-mediated. Given her family history, genetic testing was pursued and discovered a novel pathogenic mutation of the CaSR gene confirming the diagnosis of FHH type 1. Our case represents an atypical presentation of FHH1 with low PTH and FeCa > 2%. This contributes to the expanding clinical and biochemical spectrum of CaSR inactivating mutations and presents an innovative approach to evaluating biochemically uncertain familial hypercalcemia with cinacalcet before pursuing expensive genetic analysis.

Matched MeSH terms: Mutation
Fulltext Mutation of kvrA Causes OmpK35 and OmpK36 Porin Downregulation and Reduced Meropenem-Vaborbactam Susceptibility in KPC-Producing Klebsiella pneumoniae

Dulyayangkul P, Wan Nur Ismah WAK, Douglas EJA, Avison MB

Antimicrob Agents Chemother, 2020 06 23;64(7).
PMID: 32312773 DOI: 10.1128/AAC.02208-19

Meropenem-vaborbactam resistance in Klebsiella pneumoniae isolates is associated with loss-of-function mutations in the OmpK35 and OmpK36 porins. We identify two previously unknown loss-of-function mutations that confer cefuroxime resistance in K. pneumoniae isolates. The proteins lost were NlpD and KvrA; the latter is a transcriptional repressor that controls capsule production. We demonstrate that KvrA loss reduces OmpK35 and OmpK36 porin production, which confers reduced susceptibility to meropenem-vaborbactam in a KPC-3-producing K. pneumoniae isolate.

Matched MeSH terms: Mutation
Fulltext A Hybrid SSA and SMA with Mutation Opposition-Based Learning for Constrained Engineering Problems

Wang S, Liu Q, Liu Y, Jia H, Abualigah L, Zheng R, et al.

Comput Intell Neurosci, 2021;2021:6379469.
PMID: 34531910 DOI: 10.1155/2021/6379469

Based on Salp Swarm Algorithm (SSA) and Slime Mould Algorithm (SMA), a novel hybrid optimization algorithm, named Hybrid Slime Mould Salp Swarm Algorithm (HSMSSA), is proposed to solve constrained engineering problems. SSA can obtain good results in solving some optimization problems. However, it is easy to suffer from local minima and lower density of population. SMA specializes in global exploration and good robustness, but its convergence rate is too slow to find satisfactory solutions efficiently. Thus, in this paper, considering the characteristics and advantages of both the above optimization algorithms, SMA is integrated into the leader position updating equations of SSA, which can share helpful information so that the proposed algorithm can utilize these two algorithms' advantages to enhance global optimization performance. Furthermore, Levy flight is utilized to enhance the exploration ability. It is worth noting that a novel strategy called mutation opposition-based learning is proposed to enhance the performance of the hybrid optimization algorithm on premature convergence avoidance, balance between exploration and exploitation phases, and finding satisfactory global optimum. To evaluate the efficiency of the proposed algorithm, HSMSSA is applied to 23 different benchmark functions of the unimodal and multimodal types. Additionally, five classical constrained engineering problems are utilized to evaluate the proposed technique's practicable abilities. The simulation results show that the HSMSSA method is more competitive and presents more engineering effectiveness for real-world constrained problems than SMA, SSA, and other comparative algorithms. In the end, we also provide some potential areas for future studies such as feature selection and multilevel threshold image segmentation.

Matched MeSH terms: Mutation
Cuticle thickening associated with fenitrothion and imidacloprid resistance and influence of voltage-gated sodium channel mutations on pyrethroid resistance in the tropical bed bug, Cimex hemipterus

Soh LS, Veera Singham G

Pest Manag Sci, 2021 Nov;77(11):5202-5212.
PMID: 34272799 DOI: 10.1002/ps.6561

BACKGROUND: The common bed bug, Cimex lectularius L., and the tropical bed bug, Cimex hemipterus (F.), are now widely regarded as important public health pests following their rapid global resurgence, largely due to insecticide resistance and an increased rate of global travel. The insecticide resistance mechanisms are well documented in C. lectularius, however, only one mechanism is validated in C. hemipterus thus far. This demands further understanding on the resistance mechanisms involved in C. hemipterus.
RESULTS: Here, we identified differences in resistance to fenitrothion (organophosphate) and imidacloprid (neonicotinoid) related cuticle thickness in C. hemipterus. There is evidence of a possible association between cuticle thickness and resistance, but the association can be tenuous, likely because resistance is multifactorial in C. hemipterus. We also discovered a novel T1011 residue in domain IIS6 of the voltage-gated sodium channel that likely enhanced susceptibility to deltamethrin (pyrethroid) despite the presence of a L1014F mutation known to confer pyrethroid resistance in C. hemipterus. Our findings also confirmed that the M918I mutation enhanced resistance to pyrethroid when present with the L1014F mutation, which was consistent with a super-kdr phenotype, as reported previously. Multiple resistance mechanisms can be found within a single C. hemipterus population, and the presence of both M918I + L1014F mutations likely masked the influence of cuticle thickness in conferring resistance against deltamethrin. The elevated metabolic enzyme activities in some strains were not necessarily associated with increased insecticide resistance.
CONCLUSION: This study has enhanced our understanding on the penetration resistance mechanism and target site insensitivity of sodium channels in C. hemipterus.

Matched MeSH terms: Mutation
Decision-making for Risk-reducing Salpingo-oophorectomy (RRSO) in Southeast Asian BRCA Mutation Carriers With Breast Cancer: A Qualitative Study

Sa'at H, Lee YK, Yoon SY, Wong SW, Woo YL, Barlow-Stewart K, et al.

Int J Behav Med, 2022 Feb;29(1):1-13.
PMID: 33791992 DOI: 10.1007/s12529-021-09984-y

BACKGROUND: The uptake of risk-reducing salpingo-oophorectomy (RRSO) in Asian countries is variable despite being the most effective option for ovarian cancer risk reduction in BRCA mutation carriers. Exploration of factors which may impact the RRSO decision-making of BRCA mutation carriers from Malaysia, a developing country in Southeast Asia, was undertaken.
METHODS: In-depth interviews with 28 Malaysian BRCA mutation carriers with a history of breast cancer were conducted in addition to observing their RRSO decision-making consultations in the clinic.
RESULTS: The decision-making considerations among the carriers were centered around the overarching theme of "Negotiating cancer risk and womanhood priorities," with the following themes: (1) risk perception, (2) self-preservation, (3) motherhood obligation, and (4) the preciousness of marriage. Cognitive knowledge of BRCA risk was often conceptualized based on personal and family history of cancer, personal beliefs, and faith. Many women reported fears that RRSO would affect them physically and emotionally, worrying about the post-surgical impact on their motherhood responsibilities. Nevertheless, some reported feeling obliged to choose RRSO for the sake of their children. For some, their husband's support and approval were critical, with emotional well-being and sexuality reportedly perceived as important to sustaining married life. Despite reporting hesitancy toward RRSO, women's decisions about choosing this option evolved as their priorities changed at different stages of life.
CONCLUSIONS: Recognizing during clinic encounters with Malaysian women that RRSO decision-making involves negotiating the likelihood of developing cancer with the societal priorities of being a woman, mother, and wife may serve to support their decision-making.

Matched MeSH terms: Mutation
Fulltext Genomic Comparisons Reveal Microevolutionary Differences in Mycobacterium abscessus Subspecies

Tan JL, Ng KP, Ong CS, Ngeow YF

Front Microbiol, 2017;8:2042.
PMID: 29109707 DOI: 10.3389/fmicb.2017.02042

Mycobacterium abscessus, a rapid-growing non-tuberculous mycobacterium, has been the cause of sporadic and outbreak infections world-wide. The subspecies in M. abscessus complex (M. abscessus, M. massiliense, and M. bolletii) are associated with different biologic and pathogenic characteristics and are known to be among the most frequently isolated opportunistic pathogens from clinical material. To date, the evolutionary forces that could have contributed to these biological and clinical differences are still unclear. We compared genome data from 243 M. abscessus strains downloaded from the NCBI ftp Refseq database to understand how the microevolutionary processes of homologous recombination and positive selection influenced the diversification of the M. abscessus complex at the subspecies level. The three subspecies are clearly separated in the Minimum Spanning Tree. Their MUMi-based genomic distances support the separation of M. massiliense and M. bolletii into two subspecies. Maximum Likelihood analysis through dN/dS (the ratio of number of non-synonymous substitutions per non-synonymous site, to the number of synonymous substitutions per synonymous site) identified distinct genes in each subspecies that could have been affected by positive selection during evolution. The results of genome-wide alignment based on concatenated locally-collinear blocks suggest that (a) recombination has affected the M. abscessus complex more than mutation and positive selection; (b) recombination occurred more frequently in M. massiliense than in the other two subspecies; and (c) the recombined segments in the three subspecies have come from different intra-species and inter-species origins. The results lead to the identification of possible gene sets that could have been responsible for the subspecies-specific features and suggest independent evolution among the three subspecies, with recombination playing a more significant role than positive selection in the diversification among members in this complex.

Matched MeSH terms: Mutation
Insights and future directions of potential genetic therapy for Apert syndrome: A systematic review

Al-Namnam NM, Jayash SN, Hariri F, Rahman ZAA, Alshawsh MA

Gene Ther, 2021 Nov;28(10-11):620-633.
PMID: 33619359 DOI: 10.1038/s41434-021-00238-w

Apert syndrome is a genetic disorder characterised by craniosynostosis and structural discrepancy of the craniofacial region as well as the hands and feet. This condition is closely linked with fibroblast growth factor receptor-2 (FGFR2) gene mutations. Gene therapies are progressively being tested in advanced clinical trials, leading to a rise of its potential clinical indications. In recent years, research has made great progress in the gene therapy of craniosynostosis syndromes and several studies have investigated its influences in preventing/diminishing the complications of Apert syndrome. This article reviewed and exhibited different techniques of gene therapy and their influences in Apert syndrome progression. A systematic search was executed using electronic bibliographic databases including PubMed, EMBASE, ScienceDirect, SciFinder and Web of Science for all studies of gene therapy for Apert syndrome. The primary outcomes measurements vary from protein to gene expressions. According to the findings of included studies, we conclude that the gene therapy using FGF in Apert syndrome was critical in the regulation of suture fusion and patency, occurred via alterations in cellular proliferation. The superior outcome could be brought by biological therapies targeting the FGF/FGFR signalling. More studies in molecular genetics in Apert syndrome are recommended. This study reviews the current literature and provides insights to future possibilities of genetic therapy as intervention in Apert syndrome.

Matched MeSH terms: Mutation
Prevalence, comorbidities and mortality of generalized pustular psoriasis: A literature review

Prinz JC, Choon SE, Griffiths CEM, Merola JF, Morita A, Ashcroft DM, et al.

J Eur Acad Dermatol Venereol, 2023 Feb;37(2):256-273.
PMID: 36331364 DOI: 10.1111/jdv.18720

Generalized pustular psoriasis (GPP) is a rare auto-inflammatory skin disease characterised by acute episodes of sterile pustule formation. Diagnosis and treatment of the disease have historically been complicated by a lack of awareness, and no consistent global definition or clinical coding standards. Now acknowledged as a distinct clinical entity with a recognised genetic component, GPP can take a serious and life-threatening course due to systemic inflammatory complications and its association with various comorbidities. As with other rare diseases, there are significant challenges to understanding the epidemiology of GPP, notably a small patient population, non-standardised study methodologies and ethnic differences in its presentation. A clearer understanding of GPP is therefore required for clinicians to better manage patients with this rare condition. In this review article, we present an overview of the available data on GPP prevalence estimates in key demographics and report the frequency of genetic mutations associated with the disease. We detail the incidence of known comorbidities and summarise the data on mortality and assigned causes of death. Lastly, we discuss the various factors that impact the collection, interpretation and comparison of these data.

Matched MeSH terms: Mutation
Fulltext Alternative antiviral approaches to combat influenza A virus

Wong KH, Lal SK

Virus Genes, 2023 Feb;59(1):25-35.
PMID: 36260242 DOI: 10.1007/s11262-022-01935-3

Influenza A (IAV) is a major human respiratory pathogen that contributes to a significant threat to health security, worldwide. Despite vaccinations and previous immunisations through infections, humans can still be infected with influenza several times throughout their lives. This phenomenon is attributed to the antigenic changes of hemagglutinin (HA) and neuraminidase (NA) proteins in IAV via genetic mutation and reassortment, conferring antigenic drift and antigenic shift, respectively. Numerous findings indicate that slow antigenic drift and reassortment-derived antigenic shift exhibited by IAV are key processes that allow IAVs to overcome the previously acquired host immunity, which eventually leads to the annual re-emergence of seasonal influenza and even pandemic influenza, in rare occasions. As a result, current therapeutic options hit a brick wall quickly. As IAV remains a constant threat for new outbreaks worldwide, the underlying processes of genetic changes and alternative antiviral approaches for IAV should be further explored to improve disease management. In the light of the above, this review discusses the characteristics and mechanisms of mutations and reassortments that contribute to IAV's evolution. We also discuss several alternative RNA-targeting antiviral approaches, namely the CRISPR/Cas13 systems, RNA interference (RNAi), and antisense oligonucleotides (ASO) as potential antiviral approaches against IAV.

Matched MeSH terms: Mutation
Mutations in atpG2 may confer resistance to gentamicin in Listeria monocytogenes

Ng JML, Ngeow YF, Saw SH, Ng HF, Zin T

J Med Microbiol, 2022 Dec;71(12).
PMID: 36748567 DOI: 10.1099/jmm.0.001618

Introduction Listeriosis, a foodborne infection caused by Listeria monocytogenes, could lead to febrile listerial gastroenteritis and a more invasive form which is often associated with a high mortality and hospitalisation rate. Gentamicin, used as an adjunct therapy with ampicillin, remains the treatment of choice for this life-threatening and invasive infection.Gap statement Nevertheless, there is little data on gentamicin resistance determinants in L. monocytogenes.Aim In this study, we selected and characterised B2b, a gentamicin-resistant mutant derived from L. monocytogenes ATCC 19115 to determine the target(s) of resistance in L. monocytogenes after exposure to gentamicin.Methodology Whole-genome sequencing was carried out to identify the mutation site(s) and possible mechanism(s) of resistance. The mutant was characterised using antimicrobial susceptibility testing and PCR. For biological verifications, complementation and allelic exchange mutagenesis were carried out.Results We found that the gentamicin resistance in B2b was caused by a 10 bp deletion in atpG2 which encodes a gamma subunit of the ATP synthase in L. monocytogenes. Using atpG2 PCR, various other mutations were identified in other gentamicin resistant mutants derived from ATCC 19115. In addition, the mutation from B2b, when introduced into L. ivanovii, also caused gentamicin resistance in this Listeria species.Conclusion Hence, atpG2 mutations appear to be important determinants of gentamicin resistance not only in L. monocytogenes but possibly also in other Listeria species.

Matched MeSH terms: Mutation
Fulltext International Trade Path with Multi-Polarization based on Multidirectional Mutation Genetic Algorithm Enabled Neural Network

Zhang Q, Chong CW, Abdullah AR, Ali MH

Comput Intell Neurosci, 2021;2021:1370180.
PMID: 34691167 DOI: 10.1155/2021/1370180

At present, the development speed of international trade cannot catch up with the economic development speed, and the insufficient development speed of international trade will directly affect the rapid development of national economy. In order to solve the problem of international trade, the overall optimal scheduling of trade vehicles and the optimal planning of trade transportation path are very important to improve enterprise services, reduce enterprise costs, increase enterprise benefits, and enhance enterprise competitiveness. The second development of the program is based on the programming interface provided by Baidu map. This paper proposes a neural network algorithm for genetic optimization of multiple mutations, which overcomes the shortcoming of traditional genetic algorithm population "ten" character distribution by mixing multiple coding methods, and enhances the local search ability of genetic algorithm by introducing a new large-mutation small-range search population. The example application shows that the optimization method can realize the optimization of international trade path under real road conditions and greatly improve the work efficiency of actual trade.

Matched MeSH terms: Mutation
Utility of public knowledge bases for the interpretation of comprehensive tumor molecular profiling results

Lebedeva A, Timokhin G, Ignatova E, Kavun A, Veselovsky E, Sharova M, et al.

Clin Exp Med, 2023 Oct;23(6):2663-2674.
PMID: 36752890 DOI: 10.1007/s10238-023-01011-6

With the growing use of comprehensive tumor molecular profiling (CTMP), the therapeutic landscape of cancer is rapidly evolving. NGS produces large amounts of genomic data requiring complex analysis and subsequent interpretation. We sought to determine the utility of publicly available knowledge bases (KB) for the interpretation of the cancer mutational profile in clinical practice. Analysis was performed across patients who previously underwent CTMP. Independent interpretation of the CTMP was performed manually, and then, the recommendations were compared to ones present in KBs (OncoKB, CIViC, CGI, CGA, VICC, MolecularMatch). A total of 222 CTMP reports from 222 patients with 932 genomic alterations (GA) were identified. For 368 targetable GA identified in 171 (77%) of the patients, 1381 therapy recommendations were compiled. Except for CGA, therapy ESCAT LOE I, II, IIIA and IIIB therapy options were equally represented in the majority of KB. Personalized treatment options with ESCAT LOE I-II were provided for 35 patients (16%); MolecularMatch/CIViC allowed to collect ESCAT I-II treatment options for 34 of them (97%), OncoKB/CGI-for 33 of them (94%). Employing VICC and CGA 6 (17%) and 20 (57%) of patients were left without ESCAT I or II treatment options. For 88 patients with ESCAT level III-B therapy recommendations: only 2 (2%), 3 (3%), 4 (5%) and 6 (7%) of patients were left without options with CIViC, MolecularMatch, CGI and OncoKB, and with VICC-12 (14%). Highest overlap ratio was observed for IIIA (0.81) biomarkers, with the comparable results for LOE I-II. Meanwhile, overlap ratio for ESCAT LOE IV was 0.22. Public KBs provide substantial information on ESCAT-I/R1 biomarkers, but the information on ESCAT II-IV and resistance biomarkers is underrepresented. Manual curation should be considered the gold standard for the CTMP interpretation.

Matched MeSH terms: Mutation
Purine Nucleoside Phosphorylase Deficient Severe Combined Immunodeficiencies: A Case Report and Systematic Review (1975-2022)

Habib Dzulkarnain SM, Hashim IF, Zainudeen ZT, Taib F, Mohamad N, Nasir A, et al.

J Clin Immunol, 2023 Oct;43(7):1623-1639.
PMID: 37328647 DOI: 10.1007/s10875-023-01532-5

Purine nucleoside phosphorylase deficient severe combined immunodeficiency (PNP SCID) is one of the rare autosomal recessive primary immunodeficiency disease, and the data on epidemiology and outcome are limited. We report the successful management of a child with PNP SCID and present a systematic literature review of published case reports, case series, and cohort studies on PNP SCID listed in PubMed, Web of Science, and Scopus from 1975 until March 2022. Forty-one articles were included from the 2432 articles retrieved and included 100 PNP SCID patients worldwide. Most patients presented with recurrent infections, hypogammaglobulinaemia, autoimmune manifestations, and neurological deficits. There were six reported cases of associated malignancies, mainly lymphomas. Twenty-two patients had undergone allogeneic hematopoietic stem cell transplantation with full donor chimerism seen mainly in those receiving matched sibling donors and/or conditioning chemotherapy before the transplant. This research provides a contemporary, comprehensive overview on clinical manifestations, epidemiology, genotype mutations, and transplant outcome of PNP SCID. These data highlight the importance of screening for PNP SCID in cases presented with recurrent infections, hypogammaglobulinaemia, and neurological deficits.

Matched MeSH terms: Mutation
Fulltext A systematic review on physical mutagens in rice breeding in Southeast Asia

Baadu R, Chong KP, Gansau JA, Mohamed Zin MR, Dayou J

PeerJ, 2023;11:e15682.
PMID: 37868055 DOI: 10.7717/peerj.15682

In the 1920s, Lewis Stadler initiated the introduction of permanent improvements to the genetic makeup of irradiated plants. Since then, studies related to breeding mutations have grown, as efforts have been made to expand and improve crop productivity and quality. Stadler's discovery began with x-rays on corn and barley and later extended to the use of gamma-rays, thermal, and fast neutrons in crops. Radiation has since been shown to be an effective and unique method for increasing the genetic variability of species, including rice. Numerous systematic reviews have been conducted on the impact of physical mutagens on the production and grain quality of rice in Southeast Asia. However, the existing literature still lacks information on the type of radiation used, the rice planting materials used, the dosage of physical mutagens, and the differences in mutated characteristics. Therefore, this article aims to review existing literature on the use of physical mutagens in rice crops in Southeast Asian countries. Guided by the PRISMA Statement review method, 28 primary studies were identified through a systematic review of the Scopus, Science Direct, Emerald Insight, Multidisciplinary Digital Publishing, and MDPI journal databases published between 2016 and 2020. The results show that 96% of the articles used seeds as planting materials, and 80% of the articles focused on gamma-rays as a source of physical mutagens. The optimal dosage of gamma-rays applied was around 100 to 250 Gy to improve plant development, abiotic stress, biochemical properties, and nutritional and industrial quality of rice.

Matched MeSH terms: Mutation
Identification and mechanism determination of the efflux pump subunit amrB gene mutations linked to gentamicin susceptibility in clinical Burkholderia pseudomallei from Malaysian Borneo

Hussin A, Nathan S, Shahidan MA, Nor Rahim MY, Zainun MY, Khairuddin NAN, et al.

Mol Genet Genomics, 2024 Feb 21;299(1):12.
PMID: 38381232 DOI: 10.1007/s00438-024-02105-w

The bacterium Burkholderia pseudomallei is typically resistant to gentamicin but rare susceptible strains have been isolated in certain regions, such as Thailand and Sarawak, Malaysia. Recently, several amino acid substitutions have been reported in the amrB gene (a subunit of the amrAB-oprA efflux pump gene) that confer gentamicin susceptibility. However, information regarding the mechanism of the substitutions conferring the susceptibility is lacking. To understand the mechanism of amino acid substitution that confers susceptibility, this study identifies the corresponding mutations in clinical gentamicin-susceptible B. pseudomallei isolates from the Malaysian Borneo (n = 46; Sarawak: 5; Sabah: 41). Three phenotypically confirmed gentamicin-susceptible (GENs) strains from Sarawak, Malaysia, were screened for mutations in the amrB gene using gene sequences of gentamicin-resistant (GENr) strains (QEH 56, QEH 57, QEH20, and QEH26) and publicly available sequences (AF072887.1 and BX571965.1) as the comparator. The effect of missense mutations on the stability of the AmrB protein was determined by calculating the average energy change value (ΔΔG). Mutagenesis analysis identified a polymorphism-associated mutation, g.1056 T > G, a possible susceptible-associated in-frame deletion, Delta V412, and a previously confirmed susceptible-associated amino acid substitution, T368R, in each of the three GENs isolates. The contribution of Delta V412 needs further confirmation by experimental mutagenesis analysis. The mechanism by which T368R confers susceptibility, as elucidated by in silico mutagenesis analysis using AmrB-modeled protein structures, is proposed to be due to the location of T368R in a highly conserved region, rather than destabilization of the AmrB protein structure.

Matched MeSH terms: Mutation
Common genes and recurrent causative variants in 957 Asian patients with pediatric epilepsy

Kim SH, Seo J, Kwon SS, Teng LY, Won D, Shin S, et al.

Epilepsia, 2024 Mar;65(3):766-778.
PMID: 38073125 DOI: 10.1111/epi.17857

OBJECTIVE: We aimed to identify common genes and recurrent causative variants in a large group of Asian patients with different epilepsy syndromes and subgroups.
METHODS: Patients with unexplained pediatric-onset epilepsy were identified from the in-house Severance Neurodevelopmental Disorders and Epilepsy Database. All patients underwent either exome sequencing or multigene panels from January 2017 to December 2019, at Severance Children's Hospital in Korea. Clinical data were extracted from the medical records.
RESULTS: Of the 957 patients studied, 947 (99.0%) were Korean and 570 were male (59.6%). The median age at testing was 4.91 years (interquartile range, 1.53-9.39). The overall diagnostic yield was 32.4% (310/957). Clinical exome sequencing yielded a diagnostic rate of 36.9% (134/363), whereas the epilepsy panel yielded a diagnostic rate of 29.9% (170/569). Diagnostic yield differed across epilepsy syndromes. It was high in Dravet syndrome (87.2%, 41/47) and early infantile developmental epileptic encephalopathy (60.7%, 17/28), but low in West syndrome (21.8%, 34/156) and myoclonic-atonic epilepsy (4.8%, 1/21). The most frequently implicated genes were SCN1A (n = 49), STXBP1 (n = 15), SCN2A (n = 14), KCNQ2 (n = 13), CDKL5 (n = 11), CHD2 (n = 9), SLC2A1 (n = 9), PCDH19 (n = 8), MECP2 (n = 6), SCN8A (n = 6), and PRRT2 (n = 5). The recurrent genetic abnormalities included 15q11.2 deletion/duplication (n = 9), Xq28 duplication (n = 5), PRRT2 deletion (n = 4), MECP2 duplication (n = 3), SCN1A, c.2556+3A>T (n = 3), and 2q24.3 deletion (n = 3).
SIGNIFICANCE: Here we present the results of a large-scale study conducted in East Asia, where we identified several common genes and recurrent variants that varied depending on specific epilepsy syndromes. The overall genetic landscape of the Asian population aligns with findings from other populations of varying ethnicities.

Matched MeSH terms: Mutation
Fulltext Surge of severe acute respiratory syndrome coronavirus 2 infections linked to single introduction of a virus strain in Myanmar, 2020

Nyunt MH, Soe HO, Aye KT, Aung WW, Kyaw YY, Kyaw AK, et al.

Sci Rep, 2021 May 13;11(1):10203.
PMID: 33986354 DOI: 10.1038/s41598-021-89361-7

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a major health concern globally. Genomic epidemiology is an important tool to assess the pandemic of coronavirus disease 2019 (COVID-19). Several mutations have been reported by genome analysis of the SARS-CoV-2. In the present study, we investigated the mutational and phylogenetic analysis of 30 whole-genome sequences for the virus's genomic characteristics in the specimens collected in the early phase of the pandemic (March-June, 2020) and the sudden surge of local transmission (August-September, 2020). The four samples in the early phase of infection were B.6 lineage and located within a clade of the samples collected at the same time in Singapore and Malaysia, while five returnees by rescue flights showed the lineage B. 1.36.1 (three from India), B.1.1 (one from India) and B.1.80 (one from China). However, there was no evidence of local spread from these returnees. Further, all 19 whole-genome sequences collected in the sudden surge of local transmission showed lineage B.1.36. The surge of the second wave on SARS-CoV-2 infection was linked to the single-introduction of a variant (B.1.36) that may result from the strict restriction of international travel and containment efforts. These genomic data provides the useful information to disease control and prevention strategy.

Matched MeSH terms: Mutation
Fulltext Computational modelling of potentially emerging SARS-CoV-2 spike protein RBDs mutations with higher binding affinity towards ACE2: A structural modelling study

Khan A, Hussain S, Ahmad S, Suleman M, Bukhari I, Khan T, et al.

Comput Biol Med, 2022 Feb;141:105163.
PMID: 34979405 DOI: 10.1016/j.compbiomed.2021.105163

The spike protein of SARS-CoV-2 and the host ACE2 receptor plays a vital role in the entry to the cell. Among which the hotspot residue 501 is continuously subjected to positive selection pressure and induces unusual virulence. Keeping in view the importance of the hot spot residue 501, we predicted the potentially emerging structural variants of 501 residue. We analyzed the binding pattern of wild type and mutants (Spike RBD) to the ACE2 receptor by deciphering variations in the amino acids' interaction networks by graph kernels along with evolutionary, network metrics, and energetic information. Our analysis revealed that N501I, N501T, and N501V increase the binding affinity and alter the intra and inter-residue bonding networks. The N501T has shown strong positive selection and fitness in other animals. Docking results and repeated simulations (three times) confirmed the structural stability and tighter binding of these three variants, correlated with the previous results following the global stability trend. Consequently, we reported three variants N501I, N501T, and N501V could worsen the situation further if they emerged. The relations between the viral fitness and binding affinity is a complicated game thus the emergence of high affinity mutations in the SARS-CoV-2 RBD brings up the question of whether or not positive selection favours these mutations or not?

Matched MeSH terms: Mutation
The clinical severity of beta-thalassemia mutations in West Malaysia

George E

Southeast Asian J Trop Med Public Health, 1995;26 Suppl 1:225-8.
PMID: 8629111

Beta-thalassemia in West Malaysia is caused by 14 molecular defects with differing clinical severity. In Chinese patients from West Malaysia, the main beta-thalassemia mutations seen were (a) a 4 base pair-TCTT deletion in codon 41-42 [frameshift mutation (FSC 41-42)]; (b) a C to T substitution at the second intervening sequence (IVS2-654); (c) an A to G substitution in the TATA box [-28 (A to G)], and (d) an A to T substitution in codon 17[17 A to T]. In the Malays, the main mutations seen were (a) a G to C in nucleotide 5 at the intervening sequence I [IVS1-5 (G to C)]; (b) G to T substitution in nucleotide I at the intervening sequence I [IVS1-1 (G to T)]; (c) a A to T substitution in codon 17 (17 A to T); (d) removal of C from codon 35 [codon 35 (-C)], and (e) a 4 base pairs-TCTT deletion in codon 41-42 [frameshift mutation (FSC 41-42)]. A scoring system (Tha1 CS) has been formulated to predict clinical severity. It is the type of beta-thalassemia mutation present that decides on the clinical phenotype. The most severe beta-thalassemia mutation is assigned a score of 4. A score of 8 indicates severe thalassemia.

Matched MeSH terms: Frameshift Mutation*; Point Mutation*

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