EDMUNDO ARTEAGA FERNANDEZ
Projetos de Pesquisa
Unidades Organizacionais
Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina - Médico
LIM/11 - Laboratório de Cirurgia Cardiovascular e Fisiopatologia da Circulação, Hospital das Clínicas, Faculdade de Medicina
LIM/11 - Laboratório de Cirurgia Cardiovascular e Fisiopatologia da Circulação, Hospital das Clínicas, Faculdade de Medicina
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- Clinical predictors of a positive genetic test in hypertrophic cardiomyopathy in the Brazilian population(2014) MARSIGLIA, Julia Daher Carneiro; CREDIDIO, Flavia Laghi; OLIVEIRA, Theo Gremen Mimary de; REIS, Rafael Ferreira; ANTUNES, Murillo de Oliveira; ARAUJO, Aloir Queiroz de; PEDROSA, Rodrigo Pinto; BARBOSA-FERREIRA, Joao Marcos Bemfica; MADY, Charles; KRIEGER, Jose Eduardo; ARTEAGA-FERNANDEZ, Edmundo; PEREIRA, Alexandre CostaBackground: Hypertrophic cardiomyopathy is a genetic autosomal dominant disease characterized by left ventricular hypertrophy. The molecular diagnosis is important but still expensive. This work aimed to find clinical predictors of a positive genetic test in a Brazilian tertiary centre cohort of index cases with HCM. Methods: In the study were included patients with HCM clinical diagnosis. For genotype x phenotype comparison we have evaluated echocardiographic, electrocardiographic, and nuclear magnetic resonance measures. All patients answered a questionnaire about familial history of HCM and/or sudden death. beta myosin heavy chain, myosin binding protein C, and troponin T genes were sequenced for genetic diagnosis. Results: The variables related to a higher probability of a positive genetic test were familial history of HCM, higher mean heart frequency, presence of NSVT and lower age. Probabilities of having a positive molecular genetic test were calculated from the final multivariate logistic regression model and were used to identify those with a higher probability of a positive molecular diagnosis. Conclusions: We developed an easy and fast screening method that takes into account only clinical data that can help to select the patients with a high probability of positive genetic results from molecular sequencing of Brazilian HCM patients.
- A Variant Detection Pipeline for Inherited Cardiomyopathy-Associated Genes Using Next-Generation Sequencing(2015) OLIVEIRA, Theo G. M.; MITNE-NETO, Miguel; CERDEIRA, Louise T.; MARSIGLIA, Julia D. C.; ARTEAGA-FERNANDEZ, Edmundo; KRIEGER, Jose E.; PEREIRA, Alexandre C.In inherited cardiomyopathies, genetic testing is recognized as an enriching procedure in the diagnostic closure of a cardiac condition. Many genetic mutations have been described as pathogenically related to cardiomyopathies, turning next-generation sequencing into an extremely reliable scenario. Here we describe the validation process of a pipeline constructed with a target panel of 74 cardiomyopathy-related genes sequenced using a next-generation sequencing system. Fifty-two samples from a hypertrophic cardiomyopathy casuistic with previous molecular diagnostics (Sanger-sequenced for MYH7, MYBCP3, and TNNT2; 19 positives and 33 negatives) were processed in parallel with a HapMap reference sample (NA12878) applied for a complete panel assessment. Sequencing coverage values were satisfactory, with a mean of 250x (95% CI, 226.03-273.91) and 95.2% of target bases with a coverage of >= 10x. With a total of 567 variants, variant call sensitivity was tested in five scenarios of coverage and variant allele frequency cutoffs. Maximum achieved sensitivity was 96.7% for single-nucleotide variants and 28.5% for indels, and positive predictive values remained above 0.959 during the whole process. Inter- and intra-assay reproducibility values were 89.5% and 87.3%, respectively. After a careful assessment of analytical performance, we infer that the assay presents potential feasibility for application in diagnostic routines, with minimal time requirements and a simple bioinformatics structure.
- Screening of MYH7, MYBPC3, and TNNT2 genes in Brazilian patients with hypertrophic cardiomyopathy(2013) MARSIGLIA, Julia Daher Carneiro; CREDIDIO, Flavia Laghi; OLIVEIRA, Theo Gremen Mimary de; REIS, Rafael Ferreira; ANTUNES, Murillo de Oliveira; ARAUJO, Aloir Queiroz de; PEDROSA, Rodrigo Pinto; BARBOSA-FERREIRA, Joao Marcos Bemfica; MADY, Charles; KRIEGER, Jose Eduardo; ARTEAGA-FERNANDEZ, Edmundo; PEREIRA, Alexandre da CostaBackground Hypertrophic cardiomyopathy (HC) is the most prevalent genetic cardiac disease caused by a mutation in sarcomeres, Z-disks, or calcium-handling genes and is characterized by unexplained left ventricular hypertrophy. The aim of this study was to determine the genetic profile of Brazilian patients with HC and correlate the genotype with the phenotype. Methods We included 268 index patients from Sao Paulo city and 3 other cities in Brazil and extracted their DNA from whole blood. We amplified the coding sequencing of MYH7, MYBPC3, and TNNT2 genes and sequenced them with an automatic sequencer. Results We identified causal mutations in 131 patients (48.8%). Seventy-eight (59.5%) were in the MYH7 gene, 50 (38.2%) in the MYBPC3 gene, and 3 (2.3%) in the TNNT2 gene. We identified 69 mutations, 24 not previously described. Patients with an identified mutation were younger at diagnosis and at current age, had a higher mean heart rate and higher nonsustained ventricular tachycardia frequency compared with those without a mutation. Patients with MYH7 gene mutations had a larger left atrium and higher frequency of atrial fibrillation than did patients with MYBPC3 gene mutations. Conclusion The presence of a mutation in one of the genes suggests a worse prognosis. Mutations in the MYH7 gene, rather than in the MYBPC3 gene, were also related to a worse prognosis. This is the first work characterizing HC molecular epidemiology in the Brazilian population for the 3 most important genes.
- Plasma Pro-B-Type Natriuretic Peptide Testing as a Screening Method for Hypertrophic Cardiomyopathy(2012) FERNANDES, Fabio; ARTEAGA-FERNANDEZ, Edmundo; ANTUNES, Murillo de Oliveira; BUCK, Paula; MARSIGLIA, Julia Daher Carneiro; MATSUMOTO, Afonso; NASTARI, Luciano; KRIEGER, Jose Eduardo; PEREIRA, Alexandre Costa; MADY, CharlesBackground: Clinical multistage risk assessment associated with electrocardiogram (ECG) and NT-proBNP may be a feasible strategy to screen hypertrophic cardiomyopathy (HCM). We investigated the effectiveness of a screening based on ECG and NT-proBNP in first-degree relatives of patients with HCM. Methods and Results: A total of 106 first-degree relatives were included. All individuals were evaluated by echocardiography, ECG, NT-proBNP, and molecular screening (available for 65 individuals). From the 106 individuals, 36 (34%) had diagnosis confirmed by echocardiography. Using echocardiography as the gold standard, ECG criteria had a sensitivity of 0.71, 0.42, and 0.52 for the Romhilt-Estes, Sokolow-Lyon, and Cornell criteria, respectively. Mean values of NT-ProBNP were higher in affected as compared with nonaffected relatives (26.1 vs. 1290.5, P < .001). The AUC of NT-proBNP was 0.98. Using a cutoff value of 70 pg/mL, we observed a sensitivity of 0.92 and specificity of 0.96. Using molecular genetics as the gold standard, ECG criteria had a sensitivity of 0.67, 0.37, and 0.42 for the Romhilt-Estes, Sokolow-Lyon, and Cornell criteria, respectively. Using a cutoff value of 70 pg/mL, we observed a sensitivity of 0.83 and specificity of 0.98. Conclusion: Values of NT-proBNP above 70 pg/mL can be used to effectively select high-risk first-degree relatives for HCM screening. (J Cardiac Fail 2012;18:564-568)