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SCN5A mutation status increases the risk of major arrhythmic events in Asian populations with Brugada syndrome: systematic review and meta-analysis.
Rattanawong, P, Chenbhanich, J, Mekraksakit, P, Vutthikraivit, W, Chongsathidkiet, P, Limpruttidham, N, Prasitlumkum, N, Chung, EH
Annals of noninvasive electrocardiology : the official journal of the International Society for Holter and Noninvasive Electrocardiology, Inc. 2019;(1):e12589
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Abstract
BACKGROUND Brugada syndrome (BrS) is an inherited arrhythmic disease linked to SCN5A mutations. It is controversial whether SCN5A mutation carriers possess a greater risk of major arrhythmic events (MAE). We examined the association of SCN5A mutations and MAE in BrS patients. METHODS We comprehensively searched the databases of MEDLINE and EMBASE from inception to September 2017. Included studies were published cohort and case-control studies that compared MAE in BrS patients with and without SCN5A mutations. Data from each study were combined using the random-effects model. Generic inverse variance method of DerSimonian and Laird was employed to calculate the risk ratios (RR) and 95% confidence intervals (CI). RESULTS Seven studies from March 2002 to October 2017 were included (1,049 BrS subjects). SCN5A mutations were associated with MAE in Asian populations (RR = 2.03, 95% CI: 1.37-3.00, p = 0.0004, I2 = 0.0%), patients who were symptomatic (RR = 2.66, 95% CI: 1.62-4.36, p = 0.0001, I2 = 23.0%), and individuals with spontaneous type-1 Brugada pattern (RR = 1.84, 95% CI: 1.05-3.23, p = 0.03, I2 = 0.0%). CONCLUSIONS SCN5A mutations in BrS increase the risk of MAE in Asian populations, symptomatic BrS patients, and individuals with spontaneous type-1 Brugada pattern. Our study suggests that SCN5A mutation status should be an important tool for risk assessment in BrS patients.
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Epilepsy in hemiplegic migraine: Genetic mutations and clinical implications.
Prontera, P, Sarchielli, P, Caproni, S, Bedetti, C, Cupini, LM, Calabresi, P, Costa, C
Cephalalgia : an international journal of headache. 2018;(2):361-373
Abstract
Objective We performed a systematic review on the comorbidities of familial/sporadic hemiplegic migraine (F/SHM) with seizure/epilepsy in patients with CACNA1A, ATP1A2 or SCN1A mutations, to identify the genotypes associated and investigate for the presence of mutational hot spots. Methods We performed a search in MEDLINE and in the Human Gene Mutation and Leiden Open Variation Databases for mutations in the CACNA1A, ATP1A2 and SCN1A genes. After having examined the clinical characteristics of the patients, we selected those having HM and seizures, febrile seizures or epilepsy. For each gene, we determined both the frequency and the positions at protein levels of these mutations, as well as the penetrance of epilepsy within families. Results Concerning F/SHM-Epilepsy1 (F/SHME1) and F/SHME2 endophenotypes, we observed a prevalent involvement of the transmembrane domains, and a strong correlation in F/SHME1 when the positively charged amino acids were involved. The penetrance of epilepsy within the families was highest for patients carrying mutation in the CACNA1A gene (60%), and lower in those having SCN1A (33.3%) and ATP1A2 (30.9%) mutations. Conclusion Among the HM cases with seizure/epilepsy, we observed mutational hot spots in the transmembrane domains of CACNA1A and ATP1A2 proteins. These findings could lead to a better understanding of the pathological mechanisms underlying migraine and epilepsy, therein guaranteeing the most appropriate therapeutic approach.
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Impact of the H3K27M mutation on survival in pediatric high-grade glioma: a systematic review and meta-analysis.
Lu, VM, Alvi, MA, McDonald, KL, Daniels, DJ
Journal of neurosurgery. Pediatrics. 2018;(3):308-316
Abstract
OBJECTIVE Pediatric high-grade gliomas (pHGGs), including diffuse intrinsic pontine glioma, present a prognostic challenge given their lethality and rarity. A substitution mutation of lysine for methionine at position 27 in histone H3 (H3K27M) has been shown to be highly specific to these tumors. Data are accumulating regarding the poor outcomes of patients with these tumors; however, the quantification of pooled outcomes has yet to be done, which could assist in prioritizing management. The aim of this study was to quantitatively pool data in the current literature on the H3K27M mutation as an independent prognostic factor in pHGG. METHODS Searches of seven electronic databases from their inception to March 2018 were conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Data were extracted and pooled using a meta-analysis of proportions. Meta-regression was used to identify potential sources of heterogeneity. RESULTS Six observational studies satisfied the selection criteria for inclusion. They reported the survival outcomes of a pooled cohort of 474 pHGG patients, with 258 (54%) and 216 (46%) patients positive and negative, respectively, for the H3K27M mutation. Overall, the presence of the mutation was independently and significantly associated with a worse prognosis (HR 3.630, p < 0.001). Overall survival was significantly shorter (by 2.300 years; p = 0.008) when the H3K27M mutation was present in pHGG. Meta-regression did not identify any study covariates of heterogeneous concern. CONCLUSIONS According to the current literature, pHGG patients positive for the H3K27M mutation are more than 3 times more susceptible to succumbing to this disease by more than 2 years, compared to patients negative for the mutation. More robust outcome data are required to improve our quantitative understanding of this pathological entity in order to assist in prioritizing clinical management. Future larger prospective studies are required to overcome inherent biases in the current literature to validate the quantitative findings of this study. ABBREVIATIONS CI = confidence interval; GRADE = Grades of Recommendation Assessment, Development and Evaluation; HR = hazard ratio; MD = mean difference; NOS = Newcastle-Ottawa Scale; OS = overall survival; pHGG = pediatric high-grade glioma; PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-Analyses; RE = random effects.
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Significantly mutated genes and regulatory pathways in SCLC-a meta-analysis.
Sundaresan, V, Lin, VT, Liang, F, Kaye, FJ, Kawabata-Iwakawa, R, Shiraishi, K, Kohno, T, Yokota, J, Zhou, L
Cancer genetics. 2017;:20-28
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Abstract
Small cell lung cancer (SCLC) accounts for approximately 15% of all lung cancers and demands effective targeted therapeutic strategies. In this meta-analysis study, we aim to identify significantly mutated genes and regulatory pathways to help us better understand the progression of SCLC and to identify potential biomarkers. Besides ranking genes based on their mutation frequencies, we sought to identify statistically significant mutations in SCLC with the MutSigCV software. Our analysis identified several genes with relatively low mutation frequency, including PTEN, as highly significant (p < 0.001), suggesting these genes may play an important role in the progression of SCLC. Our results also indicated mutations in genes involved in the axon guidance pathways likely play an important role in SCLC progression. In addition, we observed that the mutation rate was significantly higher in samples with RB1 gene mutated when compared to samples with wild type RB1, suggesting that RB1 status has significant impact on the mutation profile and disease progression in SCLC.
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Effects of Mutations of 3 Amino Acids on Hepatocellular Carcinoma: A Systematic Review and Meta-analysis.
Lin, LL, Wang, W, Chang, J, Song, X, Yu, R, Qiu, DM
Technology in cancer research & treatment. 2015;(3):262-9
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Abstract
In recent years, over 1000 reports have been published on the association between hepatic diseases and gene mutations which may result in pathogenic amino acids. Most of the studies focus on the hepatocellular carcinoma (HCC). The aim was to systematically examine the published literature on the association between the mutations of arginine, serine, and threonine and hepatic diseases, particularly HCC. The Biosciences information service database was systematically searched before July 10, 2012. Of the initially selected 471 publications, 112 articles were included in this study. Meta-analyses were conducted for 3 amino acids. Risk ratios were used to analyze the association between amino acids and liver diseases. We analyze the literature on the association between gene mutations and hepatic diseases, especially in patients with HCC. Full-text articles were analyzed by 4 independent researchers. Some amino acid mutations were found only in people with liver diseases--not in the general population. Arginine and threonine mutations occurred more frequently in patients with hepatic diseases, compared to the normal population. There is a statistically significant association between arginine mutations and the risk of HCC and serine mutations and the risk of HCC.
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Interferon-α combined with lamivudine versus lamivudine monotherapy for the emergence of YMDD mutations in chronic hepatitis B infection: a meta-analysis of randomized controlled trials.
Zhang, YL, Zhang, J, Cui, LY
Hepato-gastroenterology. 2015;(137):133-9
Abstract
BACKGROUND/AIMS: Tyrosine-methionine-aspartate-aspartate (YMDD) mutations were the main limitation of lamivudine (LAM) for treating chronic hepatitis B (CHB). The aim of this study was to evaluate whether LAM combined with IFN-α offer advantage over lamivudine monotherapy for the occurrence of YMDD mutations in CHB using a meta-analysis. METHODOLOGY We searched electronic databases and calculated the odds ratios (OR) with their 95% confidence intervals (CI) and pooled the results. RESULTS Our meta-analysis indicated that the difference of YMDD mutation rates between the combination therapy of IFN-α2b, IFN-α2a and Peg-IFN-α2a respectively plus LAM and LAM monotherapy (95% CI, 3.25-9.70, 95% CI, 5.77-17.51, 95% CI, 6.79-26.13, respectively). The rate of YMDD mutations in LAM monotherapy was increased when compared with combination and sequential combination group (95% CI, 6.79-22.16, and 95% CI, 2.69-7.75, respectively). The YMDD mutation rate in combination therapy was lower than that of LAM monotherapy in HBeAg positive patients (95% CI, 4.98-13.23). CONCLUSIONS Our present meta-analysis suggests that different types of IFN-a in combination with LAM can significantly reduce the rate of YMDD mutation compared to LAM monotherapy.
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Mutations in the HFE gene and sporadic amyotrophic lateral sclerosis risk: a meta-analysis of observational studies.
Li, M, Wang, L, Wang, W, Qi, XL, Tang, ZY
Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas. 2014;(3):215-22
Abstract
Iron homeostasis dysregulation has been regarded as an important mechanism in neurodegenerative diseases. The H63D and C282Y polymorphisms in the HFE gene may be involved in the development of sporadic amyotrophic lateral sclerosis (ALS) through the disruption of iron homeostasis. However, studies investigating the relationship between ALS and these two polymorphisms have yielded contradictory outcomes. We performed a meta-analysis to assess the roles of the H63D and C282Y polymorphisms of HFE in ALS susceptibility. PubMed, MEDLINE, EMBASE, and Cochrane Library databases were systematically searched to identify relevant studies. Strict selection criteria and exclusion criteria were applied. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of associations. A fixed- or random-effect model was selected, depending on the results of the heterogeneity test. Fourteen studies were included in the meta-analysis (six studies with 1692 cases and 8359 controls for C282Y; 14 studies with 5849 cases and 13,710 controls for H63D). For the C282Y polymorphism, significant associations were observed in the allele model (Y vs C: OR=0.76, 95%CI=0.62-0.92, P=0.005) and the dominant model (YY+CY vs CC: OR=0.75, 95%CI=0.61-0.92, P=0.006). No associations were found for any genetic model for the H63D polymorphism. The C282Y polymorphism in HFE could be a potential protective factor for ALS in Caucasians. However, the H63D polymorphism does not appear to be associated with ALS.
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Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: a gradient of severity in cognitive impairments.
Leblond, CS, Nava, C, Polge, A, Gauthier, J, Huguet, G, Lumbroso, S, Giuliano, F, Stordeur, C, Depienne, C, Mouzat, K, et al
PLoS genetics. 2014;(9):e1004580
Abstract
SHANK genes code for scaffold proteins located at the post-synaptic density of glutamatergic synapses. In neurons, SHANK2 and SHANK3 have a positive effect on the induction and maturation of dendritic spines, whereas SHANK1 induces the enlargement of spine heads. Mutations in SHANK genes have been associated with autism spectrum disorders (ASD), but their prevalence and clinical relevance remain to be determined. Here, we performed a new screen and a meta-analysis of SHANK copy-number and coding-sequence variants in ASD. Copy-number variants were analyzed in 5,657 patients and 19,163 controls, coding-sequence variants were ascertained in 760 to 2,147 patients and 492 to 1,090 controls (depending on the gene), and, individuals carrying de novo or truncating SHANK mutations underwent an extensive clinical investigation. Copy-number variants and truncating mutations in SHANK genes were present in ∼1% of patients with ASD: mutations in SHANK1 were rare (0.04%) and present in males with normal IQ and autism; mutations in SHANK2 were present in 0.17% of patients with ASD and mild intellectual disability; mutations in SHANK3 were present in 0.69% of patients with ASD and up to 2.12% of the cases with moderate to profound intellectual disability. In summary, mutations of the SHANK genes were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment. Given the rare frequency of SHANK1 and SHANK2 deleterious mutations, the clinical relevance of these genes remains to be ascertained. In contrast, the frequency and the penetrance of SHANK3 mutations in individuals with ASD and intellectual disability-more than 1 in 50-warrant its consideration for mutation screening in clinical practice.
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Epilepsy, hippocampal sclerosis and febrile seizures linked by common genetic variation around SCN1A.
Kasperaviciute, D, Catarino, CB, Matarin, M, Leu, C, Novy, J, Tostevin, A, Leal, B, Hessel, EV, Hallmann, K, Hildebrand, MS, et al
Brain : a journal of neurology. 2013;(Pt 10):3140-50
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Abstract
Epilepsy comprises several syndromes, amongst the most common being mesial temporal lobe epilepsy with hippocampal sclerosis. Seizures in mesial temporal lobe epilepsy with hippocampal sclerosis are typically drug-resistant, and mesial temporal lobe epilepsy with hippocampal sclerosis is frequently associated with important co-morbidities, mandating the search for better understanding and treatment. The cause of mesial temporal lobe epilepsy with hippocampal sclerosis is unknown, but there is an association with childhood febrile seizures. Several rarer epilepsies featuring febrile seizures are caused by mutations in SCN1A, which encodes a brain-expressed sodium channel subunit targeted by many anti-epileptic drugs. We undertook a genome-wide association study in 1018 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 7552 control subjects, with validation in an independent sample set comprising 959 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 3591 control subjects. To dissect out variants related to a history of febrile seizures, we tested cases with mesial temporal lobe epilepsy with hippocampal sclerosis with (overall n = 757) and without (overall n = 803) a history of febrile seizures. Meta-analysis revealed a genome-wide significant association for mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures at the sodium channel gene cluster on chromosome 2q24.3 [rs7587026, within an intron of the SCN1A gene, P = 3.36 × 10(-9), odds ratio (A) = 1.42, 95% confidence interval: 1.26-1.59]. In a cohort of 172 individuals with febrile seizures, who did not develop epilepsy during prospective follow-up to age 13 years, and 6456 controls, no association was found for rs7587026 and febrile seizures. These findings suggest SCN1A involvement in a common epilepsy syndrome, give new direction to biological understanding of mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures, and open avenues for investigation of prognostic factors and possible prevention of epilepsy in some children with febrile seizures.
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Precore mutation of hepatitis B virus may contribute to hepatocellular carcinoma risk: evidence from an updated meta-analysis.
Liao, Y, Hu, X, Chen, J, Cai, B, Tang, J, Ying, B, Wang, H, Wang, L
PloS one. 2012;(6):e38394
Abstract
BACKGROUND Studies focused on the correlation of mutations in the genome of Hepatitis B Virus (HBV) like Pre-S mutation, Basal Core promoter (BCP), Enhancer II (EnhII), especially Precore mutation, with the risk of hepatocellular carcinoma (HCC) have triggered stiff controversies. With an increasing number of studies in this field recently, we conducted this meta-analysis to appraise the correlations. METHODS We searched the commonly used databases both in English and Chinese till February 1(st), 2012. Meta-analysis was performed in fixed/random-effects models using STATA 10.0. Publication bias was examined through Egger's test and Begg's funnel plot. RESULTS In total, 85 case-control studies were included involving 16745 HBV-infected patients, of whom 5781 had HCC. Statistically significant correlations were observed in Precore mutation G1896A (OR = 1.46, 95% confidence interval [CI] = 1.15-1.85, P(OR) = 0.002), G1899A (OR = 3.13, 95%CI = 2.38-4.13, P(OR)<0.001) and Pre-S mutation especially Pre-S1 deletion (OR = 2.94, 95%CI = 2.22 to 3.89) and Pre-S2 deletion (OR = 3.02, 95%CI = 2.03 to 4.50). Similar correlation existed between BCP double mutation A1762T/G1764A, T1753V, C1653T and HCC. In subgroup analysis, the Asians, genotype C or HBeAg positive patients with certain above mutations may be more susceptible to HCC. Besides, the mutations like G1896A and BCP double mutation may be associated with the progression of the liver diseases. CONCLUSIONS Precore mutation G1896A, G1899A, deletions in Pre-S region as well as the other commonly seen mutations correlated with the increased risk of HCC, especially in Asians and may predict the progression of the liver disease.