RESUMO
Background: Congenital heart defects (CHDs) are the most common type of birth defects and a major cause of infant mortality. Although knowledge of genetic risk variants for CHDs is scarce, most cases of CHDs are considered to be due to multifactorial inheritance. Objective: To analyze the association of 14 single nucleotide polymorphic variants previously associated with a risk of CHDs in a Mexican population with isolated CHDs. Materials and Methods: DNA samples obtained from healthy subjects and from subjects with isolated atrial, ventricular, or atrioventricular septal defects living in Northeastern Mexico were analyzed by real time-polymerase chain reaction for allelic discrimination of genetic variants of the genes TBX1, TBX20, ASTX-18-AS1, AXIN1, MTHFR, NKX2.5, BMP4, and NFATc1. The odds ratios (ORs) for allele and genotype frequencies and inheritance models were obtained. Results: Forty-two patients and 138 controls were included. Two variants were found to confer a risk of CHDs: variant rs4720169 of TBX20 in which the OR for the heterozygous state was 1.88 (95% confidence interval [CI]: 1.12-3.14, p = 0.010), whereas the OR for the homozygous state was 3.82 (95% CI: 1.18-12.3, p = 0.010); and variant rs12921862 of AXIN1 in which the OR for the heterozygous state was 4.15 (95% CI: 2.42-7.10; p ≤ 0.001), whereas the OR for the homozygous state was 9.2 (95% CI: 1.31-64.7, p = 0.008) for allele A. Conclusion: Genetic variants of the TBX20 and AXIN1 genes confer a significantly increased risk of congenital septal heart defects in a population from Northeastern Mexico.
Assuntos
Proteína Axina/genética , Comunicação Atrioventricular/genética , Defeitos dos Septos Cardíacos/genética , Proteínas com Domínio T/genética , Alelos , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , México , Projetos Piloto , Polimorfismo de Nucleotídeo Único , Estudos ProspectivosRESUMO
Down syndrome occurs more frequently in the offsprings of older pregnant women and may be associated with atrioventricular septal defect. This refers to a broad spectrum of malformations characterized by a deficiency of the atrioventricular septum and abnormalities of the atrioventricular valves caused by an abnormal fusion of the superior and inferior endocardial cushions with the midportion of the atrial septum and the muscular portion of the ventricular septum.
Assuntos
Ablação por Cateter/métodos , Cardiopatias Congênitas/diagnóstico por imagem , Defeitos dos Septos Cardíacos/diagnóstico por imagem , Síndromes de Pré-Excitação/diagnóstico por imagem , Anormalidades Múltiplas/diagnóstico , Adolescente , Bloqueio de Ramo/diagnóstico por imagem , Bloqueio de Ramo/genética , Síndrome de Down/complicações , Síndrome de Down/genética , Eletrocardiografia/métodos , Feminino , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/cirurgia , Defeitos dos Septos Cardíacos/genética , Humanos , Masculino , Idade Materna , Síndromes de Pré-Excitação/genética , Síndromes de Pré-Excitação/cirurgia , Gravidez , Prognóstico , Vetorcardiografia/métodos , Adulto JovemRESUMO
Congenital heart defects (CHD) are found in ~50 % of Down syndrome (DS) patients. Genetic variants have been implicated, including CRELD1 mutations, but no previous study has examined the candidate genes, NKX2-5 and GATA4, in DS patients with secundum atrial defects (ASDII) and ventricular septal defects (VSD). Furthermore, CRELD1 mutations have not yet been studied in Mexican DS patients with atrioventricular septal defects (AVSD). Mexican DS patients (n = 148) with standard trisomy 21 were classified as follows: group I, normal heart; group II, VSD, ASDII, or both; and group III, AVSD. Mexican healthy controls (n = 113) were also included. Sequence analysis was performed on NKX2-5 and GATA4 in all three groups, and on CRELD1 in only group III. Statistical differences in the percentages of functional variants were analyzed by Fisher's exact test. Three non-synonymous variants in NKX2-5 were identified in the heterozygous state: a novel p.Pro5Ser was found in one DS patient without CHD; the p.Glu21Gln was found in one ASDII patient; and the p.Arg25Cys (R25C) was found in three patients (one from each DS study group). The p.Glu21Gln and R25C were also documented in 0.88 % of the controls. No significant difference was observed between the DS groups and healthy controls. Germline mutations in the NKX2-5, GATA4, and CRELD1 genes do not appear to be associated with CHD in Mexican DS patients. Our findings also support the notion that the R25C variant of NKX2-5 is a polymorphism, as it was not significantly different between our DS patients and controls.
Assuntos
Moléculas de Adesão Celular/genética , Síndrome de Down/genética , Comunicação Atrioventricular/genética , Proteínas da Matriz Extracelular/genética , Fator de Transcrição GATA4/genética , Mutação em Linhagem Germinativa , Defeitos dos Septos Cardíacos/genética , Proteínas de Homeodomínio/genética , Fatores de Transcrição/genética , Adolescente , Criança , Pré-Escolar , Síndrome de Down/complicações , Feminino , Predisposição Genética para Doença , Proteína Homeobox Nkx-2.5 , Humanos , Lactente , Recém-Nascido , Masculino , México , Polimorfismo GenéticoRESUMO
Rho/Rho-kinase pathway plays a critical role in the regulation of cellular functions such as proliferation and migration. One of the possible theories of the development of ventricular septal defects is cell migration disorder. The aim of this study was to analyze the genotype distributions and allele frequencies for the ROCK2 gene Thr431Asn polymorphisms in the development of cardiac septal defects in a Turkish population. In this case-control study, 300 patients with cardiac defects (150 patients with ventricular and 150 patients with atrial septal defects) and control group (150 healthy control subjects) were investigated. A single-nucleotide polymorphism in ROCK2 gene Thr431Asn was analyzed by real-time PCR using a Light-Cycler. Neither genotype distributions nor the allele frequencies for the Thr431Asn polymorphism showed a significant difference between the groups. These results suggest that there is no association of the ROCK2 gene Thr431Asn polymorphism with the development of cardiac septal defects in pediatric patients.
Assuntos
Predisposição Genética para Doença , Defeitos dos Septos Cardíacos/genética , Quinases Associadas a rho/genética , Criança , Pré-Escolar , Feminino , Frequência do Gene , Defeitos dos Septos Cardíacos/patologia , Humanos , Lactente , Masculino , Polimorfismo de Nucleotídeo Único , TurquiaRESUMO
Há vários anos, a oclusão percutânea do canal arterial persistente é uma técnica factível e eficaz na maioria das variantes morfológicas descritas por Krishenko. O tipo B, em janela, caracterizado por ser curto, permanece um desafio, devido ao maior risco de embolizações das próteses e das oclusões incompletas. Descrevemos aqui o uso bem-sucedido de oclusores septais AMPLATZER® em três pacientes com canal arterial em janela, dois casos tratados com dispositivos de 5 mm e um com o de 7 mm. O dispositivo AMPLATZER® desenhado para a oclusão da comunicação interatrial mostrou-se eficaz para o tratamento percutâneo dessa variante morfológica de canal arterial persistente.
For several years the percutaneous closure of patent ductus arteriosus has been a reliable and effective technique for most of the morphologic variants described by Krichenko. Type B, or window-type, patent ductus arteriosus remains a challenge due to the higher risk of device embolizations and incomplete occlusions. We report the successful use of AMPLATZERTM septal occluder in three patients with window-type patent ductus arteriosus, two cases treated with a 5-mm device and one case with a 7-mm device. The AMPLATZERTM device designed for the occlusion of atrial septal defects is effective for the percutaneous treatment of this morphological variant of patent ductus arteriosus.
Assuntos
Humanos , Masculino , Feminino , Criança , Adolescente , Adulto , Implante de Prótese Vascular , Permeabilidade do Canal Arterial/cirurgia , Permeabilidade do Canal Arterial/genética , Angiografia/métodos , Comunicação Interatrial/cirurgia , Comunicação Interatrial/genética , Defeitos dos Septos Cardíacos/cirurgia , Defeitos dos Septos Cardíacos/genéticaRESUMO
High prevalence of somatic mutations in the cardiac transcription factor genes NKX2.5 and GATA4 have been reported in the affected cardiovascular tissue of patients with isolated cardiac septal defects, suggesting a role of somatic mutations in the pathogenesis of these congenital heart defects (CHDs). However, all somatic mutations have been identified in DNA extracted from an archive of formalin-fixed cardiac tissues. In the present study, to address the hypothesis that somatic mutations are important in isolated CHDs, we analyzed the GATA4 and NKX2.5 genes in the fresh-frozen pathologic cardiac tissue specimen and corresponding non-diseased tissue obtained from a series of 62 CHD patients, including 35 patients with cardiac septal defects and 27 with other cardiac anomalies. We identified one variant and two common polymorphisms in the NKX2.5 gene, and six variants and two common polymorphisms in the GATA4 gene. All identified variants were seen in both the fresh-frozen pathologic cardiac tissue and the corresponding non-diseased tissue, which indicates that they all were constitutional variants. The present study has identified NKX2.5 and GATA4 constitutional variants in our CHD cohort, but was unable to replicate the previously published findings of high prevalence of somatically derived sequence mutations in patients with cardiac septal defects using fresh-frozen cardiac tissues rather than formalin-fixed tissues.
Assuntos
Fator de Transcrição GATA4/genética , Defeitos dos Septos Cardíacos/genética , Proteínas de Homeodomínio/genética , Mutação , Fatores de Transcrição/genética , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Secções Congeladas , Proteína Homeobox Nkx-2.5 , Humanos , Lactente , Recém-Nascido , Masculino , Mutação de Sentido Incorreto , Miocárdio/metabolismo , Miocárdio/patologia , Polimorfismo de Nucleotídeo Único , Adulto JovemRESUMO
BACKGROUND: Cardiac development is a complex and multifactorial biological process. Heterozygous mutations in the transcription factor NKX2.5 are between the first evidence of a genetic cause for congenital heart defects in human beings. In this study, we evaluated the presence and frequency of mutations in the NKX2.5 gene on 159 unrelated patients with a diverse range of non-syndromic congenital heart defects (conotruncal anomalies, septal defects, left-sided lesions, right-sided lesions, patent ductus arteriosus and Ebstein's anomaly). METHODS: The coding region of the NKX2.5 locus was amplified by polymerase chain reaction and mutational analysis was performed using denaturing high performance liquid chromatography (DHPLC) and DNA sequencing. RESULTS: We identified two distinct mutations in the NKX2.5 coding region among the 159 (1.26%) individuals evaluated. An Arg25Cys mutation was identified in a patient with Tetralogy of Fallot. The second mutation found was an Ala42Pro in a patient with Ebstein's anomaly. CONCLUSIONS: The association of NKX2.5 mutations is present in a small percentage of patients with non-syndromic congenital heart defects and may explain only a few cases of the disease. Screening strategies considering the identification of germ-line molecular defects in congenital heart disease are still unwarranted and should consider other genes besides NKX2.5.
Assuntos
Deformidades Congênitas da Mão/genética , Proteínas de Homeodomínio/genética , Mutação Puntual , Fatores de Transcrição/genética , Sequência de Aminoácidos , Análise Mutacional de DNA , Permeabilidade do Canal Arterial/genética , Anomalia de Ebstein/genética , Defeitos dos Septos Cardíacos/genética , Proteína Homeobox Nkx-2.5 , Humanos , Reação em Cadeia da Polimerase , Tetralogia de Fallot/genéticaRESUMO
In this study, we have identified and evaluated the cardiovascular anomalies associated with Williams-Beuren syndrome in children.In a retrospective, lineal, and observational study, we reviewed the files of children who were seen from 1980 through 2005 (25 years) after a clinical diagnosis of Williams-Beuren syndrome.Forty children were diagnosed with this syndrome at the National Institute of Pediatrics in Mexico City. Of these, 32 (80%) were found to have congenital heart defects. The male-to-female ratio was 1.3:1 and ages ranged from 6 months to 15 years (mean, 4.4 years) at the time of diagnosis. All of the patients had morphologic and genetic characteristics typical of the syndrome.We emphasize the cardiovascular aspects from a clinical point of view. Supravalvular aortic stenosis was our most frequent finding, in 18 of 32 patients (56%); gradient differences in these patients ranged from 14 to 81 mmHg. Five patients showed combined lesions, the most frequent being supravalvular aortic stenosis in combination with pulmonary artery brachial stenosis, or with atrial and ventricular defects. Patients with incomplete atrioventricular defect and bicuspid aortic valve, as were seen at our hospital, have not to our knowledge been reported in other studies.One of the patients was scheduled for balloon dilation; another was scheduled for surgery; a 3rd patient was operated on twice for the placement of an aorto-aortic bridge; another underwent ventricular septal defect closure; and yet another underwent aortoplasty, this last dying shortly after surgery.