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1.
Int Heart J ; 60(5): 1113-1122, 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31484864

RESUMO

Occurring in about 1% of all live births, congenital heart defects (CHDs) represent the most frequent type of developmental abnormality and account for remarkably increased infant morbidity and mortality. Aggregating studies demonstrate that genetic components have a key role in the occurrence of CHDs. Nevertheless, due to pronounced genetic heterogeneity, the genetic causes of CHDs remain unclear in most patients. In this research, 114 unrelated patients affected with CHDs and 218 unrelated individuals without CHDs served as controls were recruited. The coding regions and splicing donors/acceptors of the ISL1 gene, which codes for a transcription factor required for proper cardiovascular development, were screened for mutations by sequencing in all study participants. The functional characteristics of an identified ISL1 mutation were delineated with a dual-luciferase reporter assay system. As a result, a new heterozygous ISL1 mutation, NM_002202.2: c.225C>G; p. (Tyr75*), was discovered in an index patient with double outlet right ventricle and ventricular septal defect. Analysis of the proband's family unveiled that the mutation co-segregated with the CHD phenotype. The nonsense mutation was absent in the 436 control chromosomes. Biological analysis showed that the mutant ISL1 protein had no transcriptional activity. Furthermore, the mutation nullified the synergistic activation between ISL1 and TBX20, another CHD-associated transcription factor. This research for the first time links an ISL1 loss-of-function mutation to double outlet right ventricle in humans, which adds insight to the molecular pathogenesis underpinning CHDs, suggesting potential implications for timely personalized management of CHD patients.


Assuntos
Dupla Via de Saída do Ventrículo Direito/genética , Genes Reporter/genética , Predisposição Genética para Doença/epidemiologia , Proteínas com Homeodomínio LIM/genética , Mutação com Perda de Função/genética , Fatores de Transcrição/genética , Estudos de Casos e Controles , Causalidade , Pré-Escolar , China/epidemiologia , Dupla Via de Saída do Ventrículo Direito/diagnóstico por imagem , Feminino , Cardiopatias Congênitas/diagnóstico por imagem , Cardiopatias Congênitas/epidemiologia , Cardiopatias Congênitas/genética , Heterozigoto , Hospitais Universitários , Humanos , Incidência , Lactente , Masculino , Mutação , Linhagem , Prognóstico , Estudos Retrospectivos , Medição de Risco
2.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(8): 837-840, 2019 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-31400141

RESUMO

OBJECTIVE: To analyze the clinical and molecular genetic characteristics of patient with Kleefstra syndrome 1. METHODS: Clinical data, chromosomal karyotype and whole genome copy number variations (CNVs) of the patient were analyzed. RESULTS: The patient was found to have a karyotype of 45,XX,-9[4]/46,XX,r(9)(p24q34)[56]. Whole-genome CNVs detection revealed that she has carried a heterozygous deletion of approximately 670 kb at 9q34.3, which encompassed the entire EHMT1 gene. The region is strongly associated with Kleefstra syndrome (1/9q telomere deletion). In addition, the patient also had heterozygous deletion of 9pter, which may predispose to formation of ring chromosome 9. CONCLUSION: The child was diagnosed with Kleefstra syndrome type 1 in conjunct with ring chromosome 9.


Assuntos
Cromossomos Humanos Par 9/genética , Anormalidades Craniofaciais/genética , Cardiopatias Congênitas/genética , Deficiência Intelectual/genética , Cromossomos em Anel , Criança , Deleção Cromossômica , Variações do Número de Cópias de DNA , Feminino , Humanos
3.
Medicine (Baltimore) ; 98(33): e16822, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31415400

RESUMO

Fetal cardiovascular malformations is widely focused and screened, but the accuracy of screening is not satisfactory. In this study, we compared the types of congenital heart malformation, accompanying diseases and fetal outcomes in the first and second trimesters of pregnancy to clarify the advantage of early screening.From January 2013 to June 2018, 230 fetuses were diagnosed with congenital heart malformations using ultrasound method in Qilu Hospital of Shandong University, and divided into 2 groups:the first trimester fetuses (group A) and the second trimester fetuses (group B). In addition, we collected and organized medical data of 347 cases diagnosed with congenital heart disease during 1998 to 2005 (group C). We compared the spectrum of congenital heart disease, associated comorbidities and outcome of fetuses diagnosed with congenital heart disease.There were differences in the types and incidence of cardiac malformations between the first and second trimesters of pregnancy. The number of cases of non-cardiac malformation, congenital heart disease with single ventricular circulation, fetal intrauterine death and premature pregnancy termination was significantly lower in the late stage (group A and group B) than that in the early stage (group C). More patients were screened for trisomy 21, 18, 13 syndromes and Turner syndrome in group A than group B (P <.001). More fetuses with a 22q11 deletion were screened in group B than group C.Early pregnancy screening using ultrasound diagnosis is very important for fetuses with congenital heart disease.


Assuntos
Feto/diagnóstico por imagem , Cardiopatias Congênitas/diagnóstico por imagem , Primeiro Trimestre da Gravidez , Segundo Trimestre da Gravidez , Ultrassonografia Pré-Natal/estatística & dados numéricos , Aberrações Cromossômicas/estatística & dados numéricos , Feminino , Cardiopatias Congênitas/embriologia , Cardiopatias Congênitas/genética , Humanos , Incidência , Gravidez , Cuidado Pré-Natal/estatística & dados numéricos
4.
Life Sci ; 232: 116635, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31283925

RESUMO

AIMS: The pathological cardiac hypertrophy will develop into heart failure, which has no effective treatment currently. Previous studies have proved that microRNAs (miRNAs) participate in the development of cardiac hypertrophy and regulate the pathological progress. In this study, we want to investigate the role of microRNA-92b-3p (miR-92b-3p) in cardiomyocyte hypertrophy and the mechanisms involved. MATERIALS AND METHODS: Neonatal mouse ventricular cells (NMVCs) were isolated from the hearts of 1-3-d-old newborn C57BL6 mice. The isolated NMVCs were induced hypertrophic phenotype by Angiotensin-II (Ang-II) and the cell size was examined by FITC-phalloidin staining assay. The expression of miR-92b-3p was determined by quantitative real-time PCR (qRT-qPCR). MRNA and protein level of ß-MHC, ACTA1 and HAND2 in NMVCs transfected with miR-92b-3p mimic and inhibition were assessed by RT-qPCR assay and western blot assay, respectively. Dual luciferase assay was used to verify the interaction between miR-92b-3p and the 3'-untranslated region (UTR) of HAND2 gene. KEY FINDINGS: MiR-92b-3p and HAND2 were significantly increased in Ang-II-induced NMVCs. Overexpression of miR-92b-3p can ameliorate Ang-II-induced cardiomyocyte hypertrophy. MiR-92b-3p negatively regulated HAND2 expression at the transcriptional level. Both miR-92b-3p mimic and HAND2 siRNA could efficiently inhibit Ang-II-induced hypertrophy in mouse cardiomyocytes. SIGNIFICANCE: MiR-92b-3p inhibits Ang-II-induced cardiomyocyte hypertrophy via targeting HAND2.


Assuntos
Angiotensina II/farmacologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Cardiomiopatia Hipertrófica/tratamento farmacológico , Cardiomiopatia Hipertrófica/metabolismo , MicroRNAs/metabolismo , Miócitos Cardíacos/patologia , Regiões 3' não Traduzidas , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/patologia , Modelos Animais de Doenças , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/metabolismo , Cardiopatias Congênitas/patologia , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Ventrículos do Coração/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genética , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima
5.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(7): 708-711, 2019 Jul 10.
Artigo em Chinês | MEDLINE | ID: mdl-31302917

RESUMO

OBJECTIVE: To correlate genotype with clinical phenotype of a child featuring multiple congenital malformations. METHODS: Clinical examination of the patient was carried out. Chromosome microarray analysis (CMA) was employed to detect genomic copy number variations (CNVs), and quantitative PCR (qPCR) was used for verifying the result. RESULTS: The child had congenital heart disease (ventricular septal defect, atrial septal defect, pulmonary arterial hypertension, and tricuspid regurgitation), psychomotor retardation, agenesis of corpus callosum, hypospadias and scoliosis. CMA has detected a 1.8 Mb deletion at 7p22.3, a 1.8 Mb duplication at 7p22.3p22.2 and a 23.5 Mb duplication at 7q33q36.3 in the fetus, all of which were de novo in origin. CONCLUSION: CMA can precisely detect microdeletion/duplications and facilitate the genotype-phenotype correlation analysis.


Assuntos
Anormalidades Múltiplas/genética , Cromossomos Humanos Par 7/genética , Variações do Número de Cópias de DNA , Cardiopatias Congênitas/genética , Criança , Testes Genéticos , Humanos , Masculino , Fenótipo , Deleção de Sequência
6.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(7): 727-730, 2019 Jul 10.
Artigo em Chinês | MEDLINE | ID: mdl-31302922

RESUMO

OBJECTIVE: To analyze the clinical and molecular genetics features of a family affected with Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS). METHODS: High-throughput sequencing was used to detect copy number variations (CNVs) and pathogenic variant within the whole exome of the affected child. RESULTS: No pathogenic CNV was found in the child, while exome sequencing identified a heterozygous c.3367_c.3370delAGAA (p.Arg1123Argfs*6) frameshifting variant in the exon 16 of the KAT6B gene. The same variant was not found in either parent. CONCLUSION: The c.3367_c.3370delAGAA (p.R1123Rfs*6) probably underlies the disease in the affected child. Above finding has facilitated genetic counseling and prenatal diagnosis for the family.


Assuntos
Blefarofimose/genética , Hipotireoidismo Congênito/genética , Variações do Número de Cópias de DNA , Cardiopatias Congênitas/genética , Histona Acetiltransferases/genética , Deficiência Intelectual/genética , Instabilidade Articular/genética , Criança , Facies , Feminino , Humanos , Mutação , Fenótipo , Gravidez
7.
Medicine (Baltimore) ; 98(30): e16556, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31348278

RESUMO

Polycyclic aromatic hydrocarbons (PAHs) may be 1 of etiologic factors responsible for congenital heart diseases (CHDs). Variations of the microsomal epoxide hydrolase (EPHX1) gene, as well as their possible interactions with PAHs exposure, may increase susceptibility to CHDs.This case-control study investigated the risk of CHDs in relation to the EPHX1 polymorphisms and assessed the interactions between these polymorphisms and PAHs exposure in 357 mothers of CHDs fetuses and 270 control mothers. Logistic regression models for the risk of CHDs were applied to determine the effect of genetic polymorphisms using additive, recessive, and dominant genetic models, as well as gene-exposure interactions. Multiple testing was adjusted by applying the false discovery rate (FDR).None of the maternal genetic polymorphisms of EPHX1 was associated with CHDs occurrence. Only the single nucleotide polymorphism rs1051740 was associated with an increased risk of right-sided obstructive malformations under the recessive model (adjusted odds ratio [aOR] = 1.852, 95% confidence interval [CI]: 1.065, 3.22) before FDR correction. A possible modifying effect of PAHs exposure on genetic polymorphisms of EPHX1 was found in susceptibility to CHDs, though no multiplicative-scale interactions between maternal exposure to PAHs and polymorphisms of EPHX1 gene were seento affect the risk of CHDs.The role of EPHX1 gene polymorphisms for CHDs need to be further evaluated, in particularly by interacting with PAHs exposure.


Assuntos
Poluentes Atmosféricos/toxicidade , Epóxido Hidrolases/genética , Cardiopatias Congênitas/genética , Exposição Materna/efeitos adversos , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Adulto , Estudos de Casos e Controles , China , Feminino , Feto/metabolismo , Predisposição Genética para Doença/embriologia , Predisposição Genética para Doença/genética , Cardiopatias Congênitas/embriologia , Humanos , Modelos Logísticos , Mães , Razão de Chances , Polimorfismo de Nucleotídeo Único , Gravidez
8.
Nat Commun ; 10(1): 3043, 2019 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-31292440

RESUMO

There are established associations between advanced paternal age and offspring risk for psychiatric and developmental disorders. These are commonly attributed to genetic mutations, especially de novo single nucleotide variants (dnSNVs), that accumulate with increasing paternal age. However, the actual magnitude of risk from such mutations in the male germline is unknown. Quantifying this risk would clarify the clinical significance of delayed paternity. Using parent-child trio whole-exome-sequencing data, we estimate the relationship between paternal-age-related dnSNVs and risk for five disorders: autism spectrum disorder (ASD), congenital heart disease, neurodevelopmental disorders with epilepsy, intellectual disability and schizophrenia (SCZ). Using Danish registry data, we investigate whether epidemiologic associations between each disorder and older fatherhood are consistent with the estimated role of dnSNVs. We find that paternal-age-related dnSNVs confer a small amount of risk for these disorders. For ASD and SCZ, epidemiologic associations with delayed paternity reflect factors that may not increase with age.


Assuntos
Testes Genéticos , Modelos Genéticos , Idade Paterna , Adulto , Fatores Etários , Transtorno do Espectro Autista/epidemiologia , Transtorno do Espectro Autista/genética , Criança , Dinamarca/epidemiologia , Epilepsia/epidemiologia , Epilepsia/genética , Feminino , Cardiopatias Congênitas/epidemiologia , Cardiopatias Congênitas/genética , Humanos , Incidência , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/genética , Masculino , Pessoa de Meia-Idade , Mutação , Polimorfismo de Nucleotídeo Único , Prevalência , Sistema de Registros/estatística & dados numéricos , Medição de Risco/métodos , Esquizofrenia/epidemiologia , Esquizofrenia/genética , Sequenciamento Completo do Exoma
9.
Cytogenet Genome Res ; 158(3): 121-125, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31315107

RESUMO

VACTERL association is defined by the occurrence of congenital malformations: vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula with esophageal atresia, radial and renal dysplasia, and limb defects. No genetic alterations have been discovered except for some sporadic chromosomal rearrangements and gene mutations. We report a boy with VACTERL association and shawl scrotum with bifid scrotum who presented with a de novo Yq11.223q11.23 microdeletion identified by array CGH. The deletion spans 3.1 Mb and encompasses several genes in the AZFc region, frequently deleted in infertile men with severe oligozoospermia or azoospermia. Herein, we discuss the possible explanation for this unusual genotype-phenotype correlation. We suggest that the deletion of the BPY2 (previously VCY2) gene, located in the AZFc region and involved in spermatogenesis, contributed to the genesis of the phenotype. In fact, BPY2 interacts with a ubiquitin-protein ligase, involved in the SHH pathway which is known to be implicated in the genesis of VACTERL association.


Assuntos
Canal Anal/anormalidades , Deleção Cromossômica , Cromossomos Humanos Y/genética , Esôfago/anormalidades , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/patologia , Rim/anormalidades , Deformidades Congênitas dos Membros/genética , Deformidades Congênitas dos Membros/patologia , Proteínas/genética , Escroto/patologia , Coluna Vertebral/anormalidades , Traqueia/anormalidades , Canal Anal/patologia , Hibridização Genômica Comparativa , Esôfago/patologia , Estudos de Associação Genética , Humanos , Lactente , Rim/patologia , Masculino , Coluna Vertebral/patologia , Traqueia/patologia , Ubiquitina-Proteína Ligases/metabolismo , Incerteza
10.
Med. infant ; 26(2): 92-98, Junio 2019. tab, ilus
Artigo em Espanhol | LILACS | ID: biblio-1009182

RESUMO

Introducción: El síndrome de deleción 22q11.2, también llamado síndrome Velo-Cardio-Facial (VCFS/del22q11.2) o síndrome de DiGeorge, es una entidad causada por una anomalía cromosómica, deleción en la región q11.2 (brazo largo) del cromosoma 22. Se trata de una enfermedad multisistémica de expresión variable que afecta el aparato cardiovascular, la inmunidad, las funciones endocrinológicas, la cavidad oral, el desarrollo neurocognitivo, con una expresión facial particular. La prevalencia estimada es de 1:2000/4000. Objetivos: Identificar y describir las cardiopatías congénitas más frecuentemente asociadas a pacientes con síndrome de microdeleción 22q11.2. Materiales y métodos: Estudio descriptivo, transversal y retrospectivo que analiza los pacientes con diagnóstico de microdeleción 22q11.2 atendidos en el Hospital Garrahan desde Octubre de 1998 hasta Febrero 2018. El criterio diagnóstico fueron signos clínicos compatibles y la presencia de la microdeleción 22q11.2 por técnica de FISH o MLPA. Resultados: Población: 321 pacientes, 151 Femeninos (47%) 170 Masculinos (53%). Rango etario: 0 a 197 meses (1 día a 16,4 años). Mediana de edad al diagnóstico clínico: 31 meses. El 74,4% (239/321) de los pacientes evaluados con microdeleción 22q11.2 tuvieron cardiopatías congénitas asociadas a facies peculiar. Las cardiopatías congénitas más frecuentemente asociadas fueron conotroncales. De los pacientes con cardiopatías congénitas el 68,6% requirió cirugía cardiovascular. Fallecieron 24 pacientes (10%) con cardiopatías congénitas asociadas y en el 93% la causa de muerte estuvo relacionada a la afección cardiológica. Conclusiones: Los pacientes con microdeleción 22q11.2 se asocian con un alto porcentaje de cardiopatías congénitas, la gran mayoría son complejas (conotroncales) y requieren resolución quirúrgica en los primeros años de vida. Es de vital importancia la evaluación multidisciplinaria de este grupo especial de pacientes con cardiopatía asociada a otras alteraciones extra cardíacas para el diagnóstico precoz y tratamiento oportuno (AU)


Introduction: 22q11.2 deletion syndrome, also called velocardiofacial syndrome (VCFS/del22q11.2) or DiGeorge syndrome, is a condition caused by chromosomal abnormality, a deletion in the q11.2 region (long arm) of chromosome 22. VCFS is a multisystem disease of variable expression that affects the cardiovascular, immune, and endocrine systems, the oral cavity, neurocognitive development, and is associated with specific facial features. The estimated prevalence is 1:2000/4000. Objectives: To identify and describe the most common congenital heart defects associated with 22q11.2 micro-deletion syndrome. Materials and methods: Descriptive, cross-sectional, and retrospective study analyzing patients diagnosed with a 22q11.2 microdeletion seen at Garrahan Hospital from October 1998 to February 2018. Diagnostic criteria were compatible clinical signs and the presence of a 22q11.2 microdeletion identified by FISH or MLPA. Results: Population: 321 patients, 151 female (47%) and 170 Male (53%). Age range: 0 to 197 months (1 day to 16.4 years). Median age at clinical diagnosis: 31 months. Overall, 74.4% (239/321) of patients with a 22q11.2 microdeletion had congenital heart defects associated with a peculiar facies. The most commonly associated congenital heart defects were conotruncal. Of the patients with congenital heart defects, 68.6% required cardiovascular surgery. Of the patients with congenital heart defects 24 patients died (10%) and in 93% the cause of death was related to the heart disease (p 0.002). Conclusions: A high percentage of patients with a 22q11.2 microdeletion have congenital heart defects, which are complex (conotruncal) in the majority, requiring surgical treatment in the first years of life. Multidisciplinary evaluation of this special group of patients with heart defects associated with other extracardiac disorders is essential for an early diagnosis and timely treatment (AU)


Assuntos
Humanos , Recém-Nascido , Lactente , Pré-Escolar , Criança , Adolescente , Cromossomos Humanos Par 22/genética , Deleção Cromossômica , Síndrome de DiGeorge/diagnóstico , Síndrome de DiGeorge/genética , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/genética , Tetralogia de Fallot/etiologia , Tetralogia de Fallot/genética , Estudos Transversais , Estudos Retrospectivos , Cardiopatias Congênitas/cirurgia , Comunicação Interventricular/etiologia , Comunicação Interventricular/genética
11.
Med. infant ; 26(2): 99-106, Junio 2019. tab, ilus
Artigo em Espanhol | LILACS | ID: biblio-1009227

RESUMO

Introducción: Las cardiopatías congénitas (CC) son las anomalías congénitas más frecuentes. Representan el 0,8-1,2% de todos los defectos del nacimiento y tienen una prevalencia de alrededor de 5,8 por cada 1000 personas. El Servicio de Cardiología del Hospital Garrahan es un centro de referencia nacional y de países limítrofes donde se realizan 18000 consultas anuales. Los pacientes que concurren por primera vez se atienden en el consultorio de orientación. Objetivo: Describir la epidemiologia y perfil de los pacientes que asisten diariamente al consultorio de orientación de cardiología infantil en un hospital pediátrico de tercer nivel de Buenos Aires. Métodos: Entre septiembre de 2017 y febrero de 2018 se recolectaron los datos de 1000 pacientes atendidos en forma consecutiva en el consultorio de orientación de cardiología. A la totalidad de los pacientes se les realizó anamnesis, examen físico cardiovascular, electrocardiograma, y en los casos en los que se consideró necesario, saturometría, radiografía de tórax y/o ecocardiograma. Las variables a considerar fueron edad, procedencia, presencia o ausencia de cardiopatías congénitas o adquiridas, soplo, cianosis, insuficiencia cardíaca, estado nutricional, síndromes genéticos asociados, métodos diagnósticos e indicaciones terapéuticas implementadas. Se subdividió la población en cinco grupos: Grupo A (pacientes con cardiopatía congénita), Grupo B (cardiopatías operadas), Grupo C (miocardiopatías), Grupo D (arritmias), Grupo E (corazón sano). Resultados: La edad mediana fue 4.86 años (0.03 a 18.9 años). El 64% de los pacientes procedían de la provincia de Buenos Aires. Los motivos de consulta fueron: interconsultas internas 29.5%, derivación por cardiopatía 27.2%, soplo 17.6%, síncope 7%, segunda opinión 5.1%, arritmias 4.8%, precordialgia 3.1%, palpitaciones 2.6%, episodio paroxístico 1.4%, cardiomegalia 0.7%, disnea 0.5%, mal progreso de peso 0.3%. El 10.6% tenían un síndrome genético. Grupo A: 252 pacientes con una edad mediana de 1.9 años. Las cardiopatías acianóticas con hiperflujo pulmonar fueron las más frecuentes (66.66%, 168/252). Grupo B: 51 pacientes, 23.52%(12/51) fueron Fallot reparados en otra institución. Grupo C: 22 pacientes, siendo la miocardiopatía hipertrófica la más frecuente. Grupo D: 47 pacientes, la preexcitación ventricular fue el hallazgo más frecuente (34,04%, 16/47). Grupo E: 628 pacientes, 45.70% (287/628) derivados por pediatras del área ambulatoria, principalmente para valoración de pacientes con enfermedades sistémicas o síndromes genéticos. Conclusión: Los motivos de derivación al consultorio de orientación de cardiología fueron muy diversos. La mayoría de los pacientes provenían de provincia de Buenos Aires. Solamente el 37.2% presentó algún problema cardiológico de base. El 91% de los pacientes que consultaron por soplo, no tuvieron cardiopatía. El grupo correspondiente a los pacientes con cardiopatías no operadas (grupo A) fue el de menor edad (mediana de 1.9 años) y las cardiopatías simples no cianóticas con hiperflujo pulmonar representaron el 66.66% de las cardiopatías. La implementación del ecocardiograma portátil en el consultorio de orientación permitió confirmar el diagnóstico y definir la conducta terapéutica en el 29.4% de los pacientes durante la primer consulta (AU)


Introduction: Congenital heart defects (CHD) are the most common congenital abnormalities. They account for 0.8-1.2% of all birth defects and have a prevalence of around 5.8 per 1000 people. The Department of Cardiology of Garrahan Hospital is a national and bordering-country reference center, receiving 18000 consultations annually. Patients seen for the first time are assessed at the cardiology guidance clinic. Objective: To describe the epidemiology and profile of patients who seen daily at the child cardiology guidance clinic of a third-level pediatric hospital in Buenos Aires. Methods: Between September 2017 and February 2018, data from 1000 patients consecutively seen at the cardiology guidance clinic were collected. All patients underwent anamnesis, cardiovascular physical examination, electrocardiogram and, if considered necessary, pulse oximetry, chest x-ray, and/or echocardiogram. The variables considered were age, place of origin, presence or absence of congenital or acquired heart disease, murmur, cyanosis, heart failure, nutritional status, associated genetic syndromes, diagnostic methods, and treatment. The population was divided into five groups: Group A (patients with congenital heart defects), Group B (operated cardiopathies), Group C (myocardiopathies), Group D (arrhythmias), Group E (healthy heart). Results: Median age was 4.86 years (0.03 to 18.9 years). Overall, 64% of patients came from the province of Buenos Aires. The reasons for consultation were: internal consultations 29.5%, cardiac shunt 27.2%, murmur 17.6%, syncope 7%, second opinion 5.1%, arrhythmias 4.8%, precordialgia 3.1%, palpitations 2.6%, paroxysmal episode 1.4%, cardiomegaly 0.7%, dyspnea 0.5%, 0.3% poor weight gain. A genetic syndrome was identified in 10.6%. Group A: 252 patients with a median age of 1.9 years. Acyanotic congenital heart defect with pulmonary hyperflow was the most common (66.66%, 168/252). Group B: 51 patients, 23.52% (12/51) had tetralogy of Fallot repaired at another institution. Group C: 22 patients, in whom hypertrophic cardiomyopathy was the most common. Group D: 47 patients, in whom ventricular preexcitation was the most common finding (34.04%, 16/47). Group E: 628 patients, 45.70% (287/628) referred by pediatricians from the outpatient clinics, mainly for the assessment of systemic diseases or genetic syndromes. Conclusion: The reasons for referral to the cardiology guidance clinic were varied. Most of the patients came from the province of Buenos Aires. Only 37.2% had an underlying heart disease. Of the patients who consulted because of a murmur, 91% did not suffer from heart disease. The group of patients with congenital heart disease who had not undergone surgery (group A) was the youngest (median 1.9 years) and simple non-cyanotic heart disease with pulmonary hyperflow accounted for 66.66% of heart diseases. The implementation of the portable echocardiography in the guidance clinic confirmed the diagnosis and defined the management in 29.4% of patients during the first consultation (AU)


Assuntos
Humanos , Recém-Nascido , Lactente , Pré-Escolar , Criança , Adolescente , Serviço Hospitalar de Cardiologia/estatística & dados numéricos , Assistência Ambulatorial/estatística & dados numéricos , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/epidemiologia , Cardiopatias/diagnóstico , Cardiopatias/epidemiologia , Encaminhamento e Consulta , Prevalência , Estudos Retrospectivos , Sopros Cardíacos/diagnóstico , Sopros Cardíacos/epidemiologia , Estudo Observacional
12.
Environ Sci Pollut Res Int ; 26(21): 21983-21992, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31144180

RESUMO

The development of congenital heart disease (CHD) is a complicated process and affected by multiple environmental factors, as genetic factors, and the interactions among those factors. Previous studies have shown that intrauterine hypoxic environment exposure is a risk factor of CHD, but the genetic factors involved in the process are not clear. In this study, given that tetralogy of Fallot (TOF) is a CHD with hypoxemia as its primary pathophysiological manifestation, an in silico analysis was performed to reveal the relationship between potential target genes (miR-124) with the energy metabolism in non-syndromic TOF patients' cardiomyocyte. Furthermore, the study investigated the correlation between the primary miR-124 (rs531564) polymorphism and CHD susceptibility in 432 sporadic patients and 450 controls from two different altitude provinces (city) in China. Our study indicated that the minor C allele of rs531564 correlated with reduced risk of CHD in the low altitude city. Besides, the C allele has elevated frequency in the high-altitude group. Therefore, our findings suggest that the minor C allele of rs531564 SNP may be involved in the reduction of the risk of CHD in a way that interacts with the intrauterine hypoxic environmental factors.


Assuntos
Altitude , Predisposição Genética para Doença/epidemiologia , Cardiopatias Congênitas/genética , MicroRNAs/genética , Adulto , Idoso , Alelos , Grupo com Ancestrais do Continente Asiático , Estudos de Casos e Controles , China/epidemiologia , Simulação por Computador , Feminino , Cardiopatias Congênitas/epidemiologia , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Fatores de Risco
13.
BMC Genomics ; 20(1): 386, 2019 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-31101013

RESUMO

BACKGROUND: Adenovirus protein, Gam1, triggers the proteolytic destruction of the E1 SUMO-activating enzyme. Microinjection of an empirically determined amount of Gam1 mRNA into one-cell Xenopus embryos can reduce SUMOylation activity to undetectable, but nonlethal, levels, enabling an examination of the role of this post-translational modification during early vertebrate development. RESULTS: We find that SUMOylation-deficient embryos consistently exhibit defects in neural tube and heart development. We have measured differences in gene expression between control and embryos injected with Gam1 mRNA at three developmental stages: early gastrula (immediately following the initiation of zygotic transcription), late gastrula (completion of the formation of the three primary germ layers), and early neurula (appearance of the neural plate). Although changes in gene expression are widespread and can be linked to many biological processes, three pathways, non-canonical Wnt/PCP, snail/twist, and Ets-1, are especially sensitive to the loss of SUMOylation activity and can largely account for the predominant phenotypes of Gam1 embryos. SUMOylation appears to generate different pools of a given transcription factor having different specificities with this post-translational modification involved in the regulation of more complex, as opposed to housekeeping, processes. CONCLUSIONS: We have identified changes in gene expression that underlie the neural tube and heart phenotypes resulting from depressed SUMOylation activity. Notably, these developmental defects correspond to the two most frequently occurring congenital birth defects in humans, strongly suggesting that perturbation of SUMOylation, either globally or of a specific protein, may frequently be the origin of these pathologies.


Assuntos
Embrião de Mamíferos/patologia , Regulação da Expressão Gênica no Desenvolvimento , Cardiopatias Congênitas/genética , Defeitos do Tubo Neural/genética , Sumoilação , Proteínas de Xenopus/metabolismo , Animais , Embrião de Mamíferos/metabolismo , Feminino , Perfilação da Expressão Gênica , Cardiopatias Congênitas/patologia , Masculino , Defeitos do Tubo Neural/patologia , Proteínas Virais/administração & dosagem , Xenopus laevis
14.
Eur J Endocrinol ; 180(6): 397-406, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30991358

RESUMO

Objective Turner Syndrome is associated with several phenotypic conditions associated with a higher risk of subsequent comorbidity. We aimed to evaluate the prevalence of congenital malformations and the occurrence of age-related comorbid conditions and to determine whether the frequencies of congenital and acquired conditions depend on X chromosome gene dosage, as a function of karyotype subgroup. Design and methods This national retrospective observational cohort study includes 1501 patients. We evaluated the prevalence of congenital malformations and the cumulative incidence of subsequent specific comorbidities at five-year intervals, from the ages of 10 to 30 years, with stratification by karyotype subgroup: 45,X (n = 549), 45,X/46,isoXq (n = 280), 46,X,r(X)/46,XX (n = 106), 45,X/46,XX (n = 221), presence of Y (n = 87). Results Median age was 9.4 (3.7-13.7) years at first evaluation and 16.8 (11.2-21.4) years at last evaluation. Congenital heart (18.9%) malformations were more frequent in 45,X patients, and congenital renal (17.2%) malformations were more frequent in 45,X, 45,X/46,isoXq and 46,X,r(X)/46,XX patients than in those with 45,X/46,XX mosaicism or a Y chromosome (P < 0.0001). The cumulative incidence of subsequent acquired conditions, such as thyroid disease, hearing loss, overweight/obesity, dyslipidemia and, to a lesser extent, celiac disease, glucose intolerance/type 2 diabetes, hypertension and liver dysfunction increased with age, but less markedly for patients with mosaicism than for those with other karyotypes. Patients with a ring chromosome were more prone to metabolic disorders. Conclusion These data suggest that X gene chromosome dosage, particularly for Xp genes, contributes to the risk of developing comorbidities.


Assuntos
Cromossomos Humanos X/genética , Anormalidades Congênitas/genética , Dosagem de Genes , Síndrome de Turner/genética , Adolescente , Adulto , Fatores Etários , Criança , Estudos de Coortes , Comorbidade , Anormalidades Congênitas/epidemiologia , Feminino , Cardiopatias Congênitas/epidemiologia , Cardiopatias Congênitas/genética , Humanos , Cariótipo , Rim/anormalidades , Nefropatias/congênito , Nefropatias/epidemiologia , Nefropatias/genética , Mosaicismo , Estudos Retrospectivos , Fatores de Risco , Síndrome de Turner/classificação , Síndrome de Turner/complicações , Adulto Jovem
15.
DNA Cell Biol ; 38(6): 521-531, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31013439

RESUMO

Transcriptional factors and signaling factors in the second heart field (SHF) contribute to cardiac development. However, the associations of intronic gene variants in the SHF with congenital heart disease (CHD) remain ununderstood. Ten single nucleotide polymorphisms (SNPs) from our previous sequencing data were selected and then genotyped in 383 CHD patients and 384 healthy controls in a Chinese population. Genotype analyses revealed that minor alleles in TBX1: rs12165908 C > G [odds ratio (OR) = 2.64; 95% confidence interval (CI) = 1.87-3.73, p = 3.03 × 10-8] and GATA6: rs143085291 C > T (OR = 2.49; 95% CI = 1.18-5.29, p = 0.01) increased CHD risk significantly. Meanwhile, FGF10: rs78454549 T > C and GATA4: rs13275657 A>G polymorphisms were significantly associated with increased risk of simple CHDs. The minor allele C in GATA4: rs17153694 T > C increased the risk of tetralogy of Fallot, whereas minor alleles in TBX1: rs41298006 G>A, FGF10: rs75629618 C>T, FGF10: rs10461755 G>A, FGF10: rs75632187 A>G, and FGF10: rs12518964 G > A were associated with increased risk of single ventricle. The minor allele T in rs143085291 in GATA6 enhancer decreased the transcription level in luciferase assay. Our findings suggest that intronic SNPs in transcriptional factors and signaling factors in the SHF are significantly associated with increased risk of different CHD types.


Assuntos
Cardiopatias Congênitas/genética , Polimorfismo de Nucleotídeo Único , Fatores de Transcrição/genética , Alelos , Criança , Pré-Escolar , China , Feminino , Fator 10 de Crescimento de Fibroblastos/genética , Fator de Transcrição GATA4/genética , Fator de Transcrição GATA6/genética , Células HEK293 , Coração/embriologia , Humanos , Lactente , Íntrons , Masculino , Fatores de Risco , Proteínas com Domínio T/genética , Tetralogia de Fallot/genética , Transcrição Genética
16.
Nat Rev Endocrinol ; 15(5): 299-311, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30842651

RESUMO

Overgrowth syndromes are a heterogeneous group of rare disorders characterized by generalized or segmental excessive growth commonly associated with additional features, such as visceromegaly, macrocephaly and a large range of various symptoms. These syndromes are caused by either genetic or epigenetic anomalies affecting factors involved in cell proliferation and/or the regulation of epigenetic markers. Some of these conditions are associated with neurological anomalies, such as cognitive impairment or autism. Overgrowth syndromes are frequently associated with an increased risk of cancer (embryonic tumours during infancy or carcinomas during adulthood), but with a highly variable prevalence. Given this risk, syndrome-specific tumour screening protocols have recently been established for some of these conditions. Certain specific clinical traits make it possible to discriminate between different syndromes and orient molecular explorations to determine which molecular tests to conduct, despite the syndromes having overlapping clinical features. Recent advances in molecular techniques using next-generation sequencing approaches have increased the number of patients with an identified molecular defect (especially patients with segmental overgrowth). This Review discusses the clinical and molecular diagnosis, tumour risk and recommendations for tumour screening for the most prevalent generalized and segmental overgrowth syndromes.


Assuntos
Neoplasias/epidemiologia , Neoplasias/genética , Arritmias Cardíacas/epidemiologia , Arritmias Cardíacas/genética , Arritmias Cardíacas/patologia , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/epidemiologia , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Gigantismo/epidemiologia , Gigantismo/genética , Gigantismo/patologia , Cardiopatias Congênitas/epidemiologia , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/patologia , Humanos , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Megalencefalia/epidemiologia , Megalencefalia/genética , Megalencefalia/patologia , Neoplasias/patologia , Gravidez , Fatores de Risco , Síndrome de Sotos/epidemiologia , Síndrome de Sotos/genética , Síndrome de Sotos/patologia , Síndrome
17.
Mediators Inflamm ; 2019: 7305028, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30881226

RESUMO

Macrophage migration inhibitory factor (MIF) plays an important pathophysiological role in pulmonary hypertension (PHT). Previously, we demonstrated that serum MIF is increased in pediatric PHT associated with congenital heart disease (CHD). In the present study, we determined possible associations between MIF levels, hemodynamic and histological parameters, and mitochondrial carbamyl-phosphate synthetase I (CPSI) T1405N polymorphism in a similar population. The asparagine 1405 variant (related to A alleles in the C-to-A transversion) has been shown to be advantageous in pediatric PHT compared to the threonine 1405 variant (C alleles). Forty-one patients were enrolled (aged 2-36 months) and subsequently divided into 2 groups after diagnostic evaluation: the high-pulmonary blood flow (high PBF) group (pulmonary-to-systemic blood flow ratio 2.58 (2.21-3.01), geometric mean with 95% CI) and the high-pulmonary vascular resistance (high PVR) group (pulmonary vascular resistance 6.12 (4.78-7.89) Wood units × m2). Serum MIF was measured using a chemiluminescence assay. The CPSI polymorphism was analyzed by polymerase chain reaction followed by high-resolution melting analysis. Medial hypertrophy of pulmonary arteries was assessed by the histological examination of biopsy specimens. Serum MIF was elevated in patients compared to controls (p = 0.045), particularly in the high-PVR group (n = 16) (p = 0.022) and in subjects with the AC CPSI T1405N genotype (n = 16) compared to those with the CC genotype (n = 25) (p = 0.017). Patients with high-PVR/AC-genotype profile (n = 9) had the highest MIF levels (p = 0.030 compared with the high-PBF/CC-genotype subgroup, n = 18). In high-PVR/AC-genotype patients, the medial wall thickness of intra-acinar pulmonary arteries was directly related to MIF levels (p = 0.033). There were no patients with the relatively rare AA genotype in the study population. Thus, in the advantageous scenario of the asparagine 1405 variant (AC heterozygosity in this study), heightened pulmonary vascular resistance in CHD-PHT is associated with medial hypertrophy of pulmonary arteries where MIF chemokine very likely plays a biological role.


Assuntos
Cardiopatias Congênitas/sangue , Cardiopatias Congênitas/genética , Hipertensão Pulmonar/sangue , Oxirredutases Intramoleculares/sangue , Fatores Inibidores da Migração de Macrófagos/sangue , Pré-Escolar , Predisposição Genética para Doença/genética , Genótipo , Hemodinâmica/genética , Hemodinâmica/fisiologia , Humanos , Hipertensão Pulmonar/genética , Lactente
18.
Mol Med Rep ; 19(5): 3831-3840, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30896870

RESUMO

Congenital heart disease (CHD), and cleft lip and palate (CLP) are currently the most common types of structural malformation in infants. Various methods have been used to identify the disease­associated genes. However, targeted next­generation sequencing (NGS) is not yet considered an option for routine use. Thus, the present study aimed to assess the safety and feasibility of using targeted NGS in patients with CHD concomitant with CLP. Between November 2015 and May 2017, a total of 17 patients with CHD concomitant with CLP, who were excluded from a diagnosis of trisomy syndrome, were selected at The Second Xiangya Hospital of Central South University (Changsha, China). Genomic DNA was extracted from peripheral blood samples of the patients. The copy number variants (CNVs) were determined by conducting a single nucleotide polymorphism (SNP) array with Illumina HumanOmni1­Quad Beadchip, while information on other gene mutations was obtained from targeted sequencing. The functions of gene mutations were then predicted using the PolyPhen­2, SIFT and Mutation Taster tools. Finally, Sanger sequencing was used to verify the mutations. The results identified no pathogenic mutations in CNVs analyzed by high­throughput SNP sequencing. Targeted NGS results demonstrated that 10 patients (58.8%) carried gene mutations, including 4 (23.5%) genetically diagnosed cases and 6 (35.3%) cases with unknown etiology. The 4 known diseases were Opitz G/BBB syndrome caused by MID1 gene mutation, Loeys­Dietz syndrome caused by TGFBR1 gene mutation, Ritscher­Schinzel/3C syndrome caused by KIAA0196 gene mutation and CHARGE syndrome caused by CHD7 gene mutation. The remaining 6 cases were not genetically diagnosed, although they carried candidate genes. In conclusion, the present study demonstrated that targeted NGS was an effective and accurate candidate gene detection method in patients with CHD concomitant with CLP.


Assuntos
Biomarcadores/sangue , Fenda Labial/diagnóstico , Fissura Palatina/diagnóstico , Cardiopatias Congênitas/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Polimorfismo de Nucleotídeo Único , Criança , Pré-Escolar , Fenda Labial/sangue , Fenda Labial/complicações , Fenda Labial/genética , Fissura Palatina/sangue , Fissura Palatina/complicações , Fissura Palatina/genética , Feminino , Cardiopatias Congênitas/sangue , Cardiopatias Congênitas/complicações , Cardiopatias Congênitas/genética , Humanos , Lactente , Masculino
19.
Pediatr Cardiol ; 40(4): 762-767, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30868185

RESUMO

Congenital heart defect (CHD) is one of the most common birth defects in China, while pulmonary atresia with intact ventricular septum (PA-IVS) is the life-threatening form of CHD. Numerous previous studies revealed that rare copy number variants (CNVs) play important roles in CHD, but little is known about the prevalence and role of rare CNVs in PA-IVS. In this study, we conducted a genome-wide scanning of rare CNVs in an unselected cohort consisted of 54 Chinese patients with PA-IVS and 20 patients with pulmonary atresia with ventricular septal defect (PA-VSD). CNVs were identified in 6/20 PA-VSD patients (30%), and three of these CNVs (15%) were considered potentially pathogenic. Two pathogenic CNVs occurred at a known CHD locus (22q11.2) and one likely pathogenic deletion located at 13q12.12. However, no rare CNVs were detected in patients with PA-IVS. Potentially pathogenic CNVs were more enriched in PA-VSD patients than in PA-IVS patients (p = 0.018). No rare CNVs were detected in patients with PA-IVS in our study. PA/IVS might be different from PA/VSD in terms of genetics as well as anatomy.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Variações do Número de Cópias de DNA/genética , Cardiopatias Congênitas/genética , Comunicação Interventricular/genética , Atresia Pulmonar/genética , Criança , Pré-Escolar , China , Feminino , Estudo de Associação Genômica Ampla/métodos , Cardiopatias Congênitas/etnologia , Humanos , Lactente , Recém-Nascido , Masculino , Fenótipo , Prevalência , Atresia Pulmonar/etnologia
20.
J Hum Genet ; 64(5): 499-504, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30842599

RESUMO

The genotype-phenotype correlation in BRAF variant in cardio-facio-cutaneous (CFC) syndrome is not clearly defined. Here we report a case with a severe clinical phenotype and a novel BRAF variant, p.Leu485del. The present case showed severe intellectual disability, impaired awareness, hyperekplexia, involuntary movements, early onset refractory seizures, and delayed myelination on brain magnetic resonance imaging as well as a polycystic and dysplastic kidney, which are previously unreported anomalies in CFC or RAS/mitogen-activated protein kinase syndromes related to BRAF variant. CFC syndrome, especially caused by BRAF variant, should be included in the differential diagnosis of patients with developmental and epileptic encephalopathies and hyperekplexia. Furthermore, we need to keep in mind that missense variants or the deletion of Leucine-485 may be associated with severe symptoms.


Assuntos
Sequência de Aminoácidos , Displasia Ectodérmica/genética , Insuficiência de Crescimento/genética , Cardiopatias Congênitas/genética , Proteínas Proto-Oncogênicas B-raf/genética , Deleção de Sequência , Pré-Escolar , Displasia Ectodérmica/patologia , Facies , Insuficiência de Crescimento/patologia , Cardiopatias Congênitas/patologia , Humanos , Leucina , Masculino , Índice de Gravidade de Doença
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