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1.
Cell Physiol Biochem ; 42(5): 2021-2029, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28803248

RESUMO

BACKGROUND/AIMS: Congenital Sick Sinus Syndrome (SSS) is a disorder associated with sudden cardiac death due to severe bradycardia and prolonged pauses. Mutations in HCN4, the gene encoding inward Na+/K+ current (If), have been described as a cause of congenital SSS. The objective of this study is to develop an SSS model in embryonic zebrafish, and use zebrafish as a moderate-throughput assay to functionally characterize HCN4 variants. METHODS: To determine the function of hcn4 in zebrafish, embryos were either bathed in the If -specific blocker (ZD-7288), or endogenous hcn4 expression was knocked down using splice-blocking morpholinos. To assess whether the zebrafish model discriminates benign from pathogenic variants, we tested four HCN4 mutations known to cause human SSS and four variants of unknown significance (VUS). RESULTS: Pharmacological blockade and knockdown of hcn4 in zebrafish phenocopied human SSS, displaying bradycardia and cardiac pauses in intact embryos and explanted hearts. The zebrafish assay correctly identified all disease-causing variants. Of the VUS, the assay predicted 2 as benign and 2 as hypomorphic variants. CONCLUSIONS: We conclude that our embryonic zebrafish assay is a novel and effective tool to functionally characterize human HCN4 variants, which can be translated into important clinical prognostic information.


Assuntos
Variação Genética , Síndrome do Nó Sinusal/patologia , Animais , Animais Geneticamente Modificados , Bradicardia/etiologia , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/metabolismo , Genótipo , Coração/efeitos dos fármacos , Coração/fisiologia , Frequência Cardíaca/efeitos dos fármacos , Humanos , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/antagonistas & inibidores , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/genética , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/metabolismo , Hibridização In Situ , Morfolinos/metabolismo , Proteínas Musculares/antagonistas & inibidores , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Mutação , Técnicas de Patch-Clamp , Fenótipo , Canais de Potássio/genética , Canais de Potássio/metabolismo , Pirimidinas/farmacologia , Síndrome do Nó Sinusal/genética , Peixe-Zebra/metabolismo
2.
Am J Med Genet A ; 173(8): 2176-2188, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28653806

RESUMO

Congenital left-sided cardiac lesions (LSLs) are a significant contributor to the mortality and morbidity of congenital heart disease (CHD). Structural copy number variants (CNVs) have been implicated in LSL without extra-cardiac features; however, non-penetrance and variable expressivity have created uncertainty over the use of CNV analyses in such patients. High-density SNP microarray genotyping data were used to infer large, likely-pathogenic, autosomal CNVs in a cohort of 1,139 probands with LSL and their families. CNVs were molecularly confirmed and the medical records of individual carriers reviewed. The gene content of novel CNVs was then compared with public CNV data from CHD patients. Large CNVs (>1 MB) were observed in 33 probands (∼3%). Six of these were de novo and 14 were not observed in the only available parent sample. Associated cardiac phenotypes spanned a broad spectrum without clear predilection. Candidate CNVs were largely non-recurrent, associated with heterozygous loss of copy number, and overlapped known CHD genomic regions. Novel CNV regions were enriched for cardiac development genes, including seven that have not been previously associated with human CHD. CNV analysis can be a clinically useful and molecularly informative tool in LSLs without obvious extra-cardiac defects, and may identify a clinically relevant genomic disorder in a small but important proportion of these individuals.


Assuntos
Variações do Número de Cópias de DNA/genética , Cardiopatias Congênitas/genética , Coração/fisiopatologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Genômica , Genótipo , Cardiopatias Congênitas/fisiopatologia , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Adulto Jovem
3.
Development ; 140(19): 4102-9, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24046323

RESUMO

Heparan sulfate proteoglycans (HSPGs) control many cellular processes and have been implicated in the regulation of left-right (LR) development by as yet unknown mechanisms. Using lineage-targeted knockdowns, we found that the transmembrane HSPG Syndecan 2 (Sdc2) regulates LR patterning through cell-autonomous functions in the zebrafish ciliated organ of asymmetry, Kupffer's vesicle (KV), including regulation of cell proliferation and adhesion, cilia length and asymmetric fluid flow. Exploring downstream pathways, we found that the cell signaling ligand Fgf2 is exclusively expressed in KV cell lineages, and is dependent on Sdc2 and the transcription factor Tbx16. Strikingly, Fgf2 controls KV morphogenesis but not KV cilia length, and KV morphogenesis in sdc2 morphants can be rescued by expression of fgf2 mRNA. Through an Fgf2-independent pathway, Sdc2 and Tbx16 also control KV ciliogenesis. Our results uncover a novel Sdc2-Tbx16-Fgf2 pathway that regulates epithelial cell morphogenesis.


Assuntos
Cílios/metabolismo , Embrião não Mamífero/metabolismo , Células Epiteliais/citologia , Fator 2 de Crescimento de Fibroblastos/metabolismo , Sindecana-2/metabolismo , Proteínas com Domínio T/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/embriologia , Animais , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Células Epiteliais/metabolismo , Fator 2 de Crescimento de Fibroblastos/genética , Imuno-Histoquímica , Hibridização In Situ , Sindecana-2/genética , Proteínas com Domínio T/genética , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/genética
4.
Am J Med Genet A ; 167A(12): 2975-84, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26284702

RESUMO

Wolff-Parkinson-White (WPW) syndrome is a common cause of supraventricular tachycardia that carries a risk of sudden cardiac death. To date, mutations in only one gene, PRKAG2, which encodes the 5'-AMP-activated protein kinase subunit γ-2, have been identified as causative for WPW. DNA samples from five members of a family with WPW were analyzed by exome sequencing. We applied recently designed prioritization strategies (VAAST/pedigree VAAST) coupled with an ontology-based algorithm (Phevor) that reduced the number of potentially damaging variants to 10: a variant in KCNE2 previously associated with Long QT syndrome was also identified. Of these 11 variants, only MYH6 p.E1885K segregated with the WPW phenotype in all affected individuals and was absent in 10 unaffected family members. This variant was predicted to be damaging by in silico methods and is not present in the 1,000 genome and NHLBI exome sequencing project databases. Screening of a replication cohort of 47 unrelated WPW patients did not identify other likely causative variants in PRKAG2 or MYH6. MYH6 variants have been identified in patients with atrial septal defects, cardiomyopathies, and sick sinus syndrome. Our data highlight the pleiotropic nature of phenotypes associated with defects in this gene.


Assuntos
Exoma , Síndrome de Wolff-Parkinson-White/genética , Proteínas Quinases Ativadas por AMP/genética , Adulto , Miosinas Cardíacas/genética , Feminino , Loci Gênicos , Humanos , Masculino , Cadeias Pesadas de Miosina/genética , Linhagem , Canais de Potássio de Abertura Dependente da Tensão da Membrana/genética , Síndrome de Wolff-Parkinson-White/etiologia
5.
Pediatr Cardiol ; 35(1): 38-46, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23797157

RESUMO

Patients with heterotaxy syndrome (HS) have significant cardiac and extracardiac anomalies that impact outcome. To improve the management of this complex patient population, we performed a comprehensive analysis of their anatomic and clinical features along with an evaluation of resource utilization data. The objectives were to describe anatomic and clinical features of patients with HS syndrome treated at a single center from 1992 to 2011 focusing on the impact of ventricular morphology (univentricular [UV] vs. biventricular [BV]) on clinical outcomes and resource utilization. Clinical and echocardiographic data from patients with HS were abstracted from medical records. Health care costs were indexed to inflation. Seventy-eight patients were identified with HS ranging in age from 1 day to 29 years old. UV morphology was present in 46 patients (59 %), most commonly with right-ventricular dominance (36 of 46). The presence of extra cardiac anomalies did not differ between the UV and BV groups (82 vs. 78 %) nor did morbidities, such as need for enteral tube feedings (47 vs. 25 %) or pacemaker placement (24 vs. 25 %). Mortality was 28 % in the entire cohort: 39 % in univentricuar patients versus 10.5 % in those with biventricular anatomy. Hospital length of stay for medical illnesses was similar in both groups, but length of stay after surgery was significantly longer in UV than BV patients. Among survivors, UV patients had greater median hospital costs (TeX 67,732, p < 0.001), but when this was adjusted for mortality and variable follow-up, there were no differences in health care costs within the first year of life. Significant health care dollars are used to manage children with HS, the majority of which involve expenses related to surgical care. Although patients with biventricular morphology have better survival, morbidity and resource utilization are similar to those for UV patients especially within the first year of life.


Assuntos
Procedimentos Cirúrgicos Cardíacos/economia , Recursos em Saúde/estatística & dados numéricos , Ventrículos do Coração , Síndrome de Heterotaxia , Tempo de Internação , Adulto , Fatores Etários , Procedimentos Cirúrgicos Cardíacos/estatística & dados numéricos , Criança , Ecocardiografia/economia , Ecocardiografia/estatística & dados numéricos , Feminino , Custos de Cuidados de Saúde/estatística & dados numéricos , Pesquisa sobre Serviços de Saúde , Ventrículos do Coração/anormalidades , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/cirurgia , Síndrome de Heterotaxia/diagnóstico , Síndrome de Heterotaxia/economia , Síndrome de Heterotaxia/mortalidade , Síndrome de Heterotaxia/terapia , Humanos , Recém-Nascido , Tempo de Internação/economia , Tempo de Internação/estatística & dados numéricos , Masculino , Registros Médicos Orientados a Problemas/estatística & dados numéricos , Estudos Retrospectivos , Estados Unidos/epidemiologia
6.
Circulation ; 123(21): 2353-62, 2011 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-21576655

RESUMO

BACKGROUND: We investigated the effect of polymorphisms in the renin-angiotensin-aldosterone system (RAAS) genes on ventricular remodeling, growth, renal function, and response to enalapril in infants with single ventricle. METHODS AND RESULTS: Single ventricle infants enrolled in a randomized trial of enalapril were genotyped for polymorphisms in 5 genes: angiotensinogen, angiotensin-converting enzyme, angiotensin II type 1 receptor, aldosterone synthase, and chymase. Alleles associated with renin-angiotensin-aldosterone system upregulation were classified as risk alleles. Ventricular mass, volume, somatic growth, renal function using estimated glomerular filtration rate, and response to enalapril were compared between patients with ≥2 homozygous risk genotypes (high risk), and those with <2 homozygous risk genotypes (low risk) at 2 time points: before the superior cavopulmonary connection (pre-SCPC) and at age 14 months. Of 230 trial subjects, 154 were genotyped: Thirty-eight were high risk, and 116 were low risk. Ventricular mass and volume were elevated in both groups pre-SCPC. Ventricular mass and volume decreased and estimated glomerular filtration rate increased after SCPC in the low-risk (P<0.05), but not the high-risk group. These responses were independent of enalapril treatment. Weight and height z-scores were lower at baseline, and height remained lower in the high-risk group at 14 months, especially in those receiving enalapril (P<0.05). CONCLUSIONS: Renin-angiotensin-aldosterone system-upregulation genotypes were associated with failure of reverse remodeling after SCPC surgery, less improvement in renal function, and impaired somatic growth, the latter especially in patients receiving enalapril. Renin-angiotensin-aldosterone system genotype may identify a high-risk subgroup of single ventricle patients who fail to fully benefit from volume-unloading surgery. Follow-up is warranted to assess long-term impact. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT00113087.


Assuntos
Ventrículos do Coração/anormalidades , Ventrículos do Coração/metabolismo , Sistema Renina-Angiotensina/genética , Função Ventricular/genética , Remodelação Ventricular/genética , Aldosterona/genética , Angiotensinas/genética , Estudos de Coortes , Método Duplo-Cego , Feminino , Genótipo , Transtornos do Crescimento/genética , Transtornos do Crescimento/metabolismo , Transtornos do Crescimento/fisiopatologia , Humanos , Lactente , Recém-Nascido , Testes de Função Renal , Masculino , Peptidil Dipeptidase A/genética , Polimorfismo Genético/genética , Renina/genética , Regulação para Cima/genética
7.
Development ; 136(18): 3143-52, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19700618

RESUMO

One of the first steps in zebrafish heart and gut organogenesis is the migration of bilateral primordia to the midline to form cardiac and gut tubes. The mechanisms that regulate this process are poorly understood. Here we show that the proteoglycan syndecan 2 (Sdc2) expressed in the extra-embryonic yolk syncytial layer (YSL) acts locally at the YSL-embryo interface to direct organ primordia migration, and is required for fibronectin and laminin matrix assembly throughout the embryo. Surprisingly, neither endogenous nor exogenous sdc2 expressed in embryonic cells can compensate for knockdown of sdc2 in the YSL, indicating that Sdc2 expressed in extra-embryonic tissues is functionally distinct from Sdc2 in embryonic cells. The effects of sdc2 knockdown in the YSL can be rescued by extra-embryonic Sdc2 lacking an extracellular proteolytic cleavage (shedding) site, but not by extra-embryonic Sdc2 lacking extracellular glycosaminoglycan (GAG) addition sites, suggesting that distinct GAG chains on extra-embryonic Sdc2 regulate extracellular matrix assembly, cell migration and epithelial morphogenesis of multiple organ systems throughout the embryo.


Assuntos
Movimento Celular/fisiologia , Morfogênese/fisiologia , Sindecana-2/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra , Animais , Linhagem da Célula , Polaridade Celular , Gema de Ovo/metabolismo , Embrião não Mamífero/anatomia & histologia , Embrião não Mamífero/fisiologia , Endocárdio/citologia , Endocárdio/metabolismo , Endoderma/citologia , Endoderma/metabolismo , Técnicas de Silenciamento de Genes , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Sindecana-2/genética , Peixe-Zebra/anatomia & histologia , Peixe-Zebra/embriologia , Proteínas de Peixe-Zebra/genética
8.
Am J Med Genet A ; 158A(12): 3137-47, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23165927

RESUMO

Congenital diaphragmatic hernia (CDH) is a developmental defect of the diaphragm that causes high newborn mortality. Isolated or non-syndromic CDH is considered a multifactorial disease, with strong evidence implicating genetic factors. As low heritability has been reported in isolated CDH, family-based genetic methods have yet to identify the genetic factors associated with the defect. Using the Utah Population Database, we identified distantly related patients from several extended families with a high incidence of isolated CDH. Using high-density genotyping, seven patients were analyzed by homozygosity exclusion rare allele mapping (HERAM) and phased haplotype sharing (HapShare), two methods we developed to map shared chromosome regions. Our patient cohort shared three regions not previously associated with CDH, that is, 2q11.2-q12.1, 4p13 and 7q11.2, and two regions previously involved in CDH, that is, 8p23.1 and 15q26.2. The latter regions contain GATA4 and NR2F2, two genes implicated in diaphragm formation in mice. Interestingly, three patients shared the 8p23.1 locus and one of them also harbored the 15q26.2 segment. No coding variants were identified in GATA4 or NR2F2, but a rare shared variant was found in intron 1 of GATA4. This work shows the role of heritability in isolated CDH. Our family-based strategy uncovers new chromosomal regions possibly associated with disease, and suggests that non-coding variants of GATA4 and NR2F2 may contribute to the development of isolated CDH. This approach could speed up the discovery of the genes and regulatory elements causing multifactorial diseases, such as isolated CDH.


Assuntos
Cromossomos Humanos , Hérnias Diafragmáticas Congênitas , Adulto , Fator II de Transcrição COUP/genética , Estudos de Casos e Controles , Criança , Estudos de Coortes , DNA/sangue , DNA/genética , Diafragma/anormalidades , Saúde da Família , Feminino , Fator de Transcrição GATA4/genética , Dosagem de Genes , Predisposição Genética para Doença , Genótipo , Hérnia Diafragmática/sangue , Hérnia Diafragmática/genética , Humanos , Masculino , Linhagem , Polimorfismo de Nucleotídeo Único
9.
J Pediatr ; 159(2): 243-7.e1, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21450305

RESUMO

OBJECTIVE: To determine the prevalence of patent foramen ovale (PFO) in children with migraine. STUDY DESIGN: Children aged 6.0 to 18.0 years with migraine headache were evaluated for PFO and right-to-left shunting with color-flow Doppler scanning, saline solution contrast transthoracic echocardiography, and contrast transcranial Doppler scanning. RESULTS: The population consisted of 109 children with migraine; 38 (35%) with aura and 71 (65%) without aura. The overall PFO prevalence was 35%, similar to the general population (35% vs 25%; P = .13). However, compared with the general population (25%), the PFO prevalence was significantly greater in subjects with aura (50%, P = .0004) but similar in those without aura (27%, P = .73). Atrial shunt size was not associated with the presence or absence of aura. CONCLUSION: Children with migraine with aura have a significantly higher prevalence of PFO compared with those without aura or the general population. These data suggest that PFO may contribute to the pathogenesis of migraine with aura in children and have implications for clinical decision making.


Assuntos
Forame Oval Patente/epidemiologia , Transtornos de Enxaqueca/complicações , Adolescente , Criança , Ecocardiografia Doppler em Cores , Feminino , Seguimentos , Forame Oval Patente/complicações , Forame Oval Patente/diagnóstico por imagem , Humanos , Masculino , Transtornos de Enxaqueca/diagnóstico por imagem , Transtornos de Enxaqueca/epidemiologia , Prevalência , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Ultrassonografia Doppler Transcraniana , Estados Unidos/epidemiologia
10.
Am J Med Genet A ; 155A(10): 2578-83, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21910241

RESUMO

Timothy syndrome type 1 (TS-1) is a rare disorder that affects multiple organ systems and has a high incidence of sudden death due to profound QT prolongation and resultant ventricular arrhythmias. All previously described cases of TS-1 are the result of a missense mutation in exon 8A (p.G406R), an alternatively spliced variant of the L-type calcium channel gene (Ca(v)1.2, CACNA1C). Most patients reported in the literature represent highly affected individuals who present early in life with severe cardiac and neurological manifestations. Here, we describe somatic mosaicism in TS-1 patients with less severe manifestations than the typical TS-1 patient. These findings suggest that the TS prognosis may not be as dismal as previously reported. Moreover, our findings have implications for genetic counseling in that previously described de novo TS mutations may represent cases of parental mosaicism and warrant careful genotyping of parental tissue other than peripheral blood lymphocytes.


Assuntos
Síndrome do QT Longo/genética , Síndrome do QT Longo/patologia , Mosaicismo , Fenótipo , Sindactilia/genética , Sindactilia/patologia , Adolescente , Transtorno Autístico , Sequência de Bases , Canais de Cálcio Tipo L/genética , Eletrocardiografia , Éxons/genética , Feminino , Genótipo , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Dados de Sequência Molecular , Análise de Sequência de DNA
11.
Nat Commun ; 12(1): 6442, 2021 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-34750360

RESUMO

The genetic architecture of atrial fibrillation (AF) encompasses low impact, common genetic variants and high impact, rare variants. Here, we characterize a high impact AF-susceptibility allele, KCNQ1 R231H, and describe its transcontinental geographic distribution and history. Induced pluripotent stem cell-derived cardiomyocytes procured from risk allele carriers exhibit abbreviated action potential duration, consistent with a gain-of-function effect. Using identity-by-descent (IBD) networks, we estimate the broad- and fine-scale population ancestry of risk allele carriers and their relatives. Analysis of ancestral migration routes reveals ancestors who inhabited Denmark in the 1700s, migrated to the Northeastern United States in the early 1800s, and traveled across the Midwest to arrive in Utah in the late 1800s. IBD/coalescent-based allele dating analysis reveals a relatively recent origin of the AF risk allele (~5000 years). Thus, our approach broadens the scope of study for disease susceptibility alleles to the context of human migration and ancestral origins.


Assuntos
Fibrilação Atrial/genética , Predisposição Genética para Doença/genética , Canal de Potássio KCNQ1/genética , Mutação de Sentido Incorreto , Polimorfismo de Nucleotídeo Único , Potenciais de Ação , Alelos , Dinamarca , Emigrantes e Imigrantes , Feminino , Genótipo , Geografia , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Masculino , Pessoa de Meia-Idade , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/fisiologia , Linhagem , Fatores de Risco , Utah
12.
Am J Cardiol ; 102(5): 629-31, 2008 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-18721526

RESUMO

Mutations in the genes encoding transforming growth factor-beta receptor types I and II (TGFBR1 and TGFBR2, respectively) are commonly identified in patients with Loeys-Dietz syndrome, as well as some patients with Marfan's syndrome or familial thoracic aortic aneurysms and dissections. This suggests that there is considerable phenotypic heterogeneity associated with mutations in these genes. Because bicuspid aortic valve (BAV) is a congenital heart defect in patients with Loeys-Dietz syndrome, this study was conducted to investigate whether variants in TGFBR1 or TGFBR2 are responsible for sporadic BAV. Analysis of these genes in 35 patients with BAVs identified only known single-nucleotide polymorphisms or novel synonymous or intronic substitutions. In conclusion, mutations in TGFBR1 and TGFBR2 rarely cause sporadic BAV.


Assuntos
Aorta Torácica , Valva Aórtica/anormalidades , DNA/genética , Cardiopatias Congênitas/genética , Mutação , Proteínas Serina-Treonina Quinases/genética , Receptores de Fatores de Crescimento Transformadores beta/genética , Adolescente , Adulto , Criança , Pré-Escolar , Dilatação Patológica/etiologia , Feminino , Humanos , Lactente , Masculino , Reação em Cadeia da Polimerase , Prognóstico , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptor do Fator de Crescimento Transformador beta Tipo II , Fator de Crescimento Transformador beta
13.
J Electrocardiol ; 40(6): 484-8, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17673249

RESUMO

BACKGROUND AND PURPOSE: The electrocardiogram (ECG) is commonly used as a screening tool for diagnosis of the ostium secundum atrial septal defect (ASD). We sought to analyze the utility of conventional ECG criteria in detecting right ventricular enlargement (RVE) due to the presence of an ASD. METHODS: Patients who underwent transcatheter or surgical closure of an isolated ASD between 1997 and 2004 were included if an ECG was performed less than 9 months before ASD closure and had echocardiographic RVE. RESULTS: Of 99 children (aged 6.8 +/- 4.7 years; range, 1-18 years) with RVE and ASD, 57% had an ECG that met 1 or more RVE criteria. The sensitivity of ECG increased to 70% in younger patients and to 80% for the largest defects. CONCLUSIONS: Electrocardiographic criteria for RVE are present in just more than over half of young patients with large ASDs. Although ECG is more sensitive in younger patients, it is unreliable as a screen for this lesion.


Assuntos
Eletrocardiografia/métodos , Comunicação Interatrial/diagnóstico , Programas de Rastreamento/métodos , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
15.
Circ Arrhythm Electrophysiol ; 8(2): 400-8, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25717017

RESUMO

BACKGROUND: Recent genome-wide association studies have demonstrated an association between MYH6, the gene encoding α-myosin heavy chain (α-MHC), and sinus node function in the general population. Moreover, a rare MYH6 variant, R721W, predisposing susceptibility to sick sinus syndrome has been identified. However, the existence of disease-causing MYH6 mutations for familial sick sinus syndrome and their underlying mechanisms remain unknown. METHODS AND RESULTS: We screened 9 genotype-negative probands with sick sinus syndrome families for mutations in MYH6 and identified an in-frame 3-bp deletion predicted to delete one residue (delE933) at the highly conserved coiled-coil structure within the binding motif to myosin-binding protein C in one patient. Co-immunoprecipitation analysis revealed enhanced binding of delE933 α-MHC to myosin-binding protein C. Irregular fluorescent speckles retained in the cytoplasm with substantially disrupted sarcomere striation were observed in neonatal rat cardiomyocytes transfected with α-MHC mutants carrying delE933 or R721W. In addition to the sarcomere impairments, delE933 α-MHC exhibited electrophysiological abnormalities both in vitro and in vivo. The atrial cardiomyocyte cell line HL-1 stably expressing delE933 α-MHC showed a significantly slower conduction velocity on multielectrode array than those of wild-type α-MHC or control plasmid transfected cells. Furthermore, targeted morpholino knockdown of MYH6 in zebrafish significantly reduced the heart rate, which was rescued by coexpressed wild-type human α-MHC but not by delE933 α-MHC. CONCLUSIONS: The novel MYH6 mutation delE933 causes both structural damage of the sarcomere and functional impairments on atrial action propagation. This report reinforces the relevance of MYH6 for sinus node function and identifies a novel pathophysiology underlying familial sick sinus syndrome.


Assuntos
Miosinas Cardíacas/genética , Mutação , Cadeias Pesadas de Miosina/genética , Síndrome do Nó Sinusal/genética , Potenciais de Ação , Animais , Animais Recém-Nascidos , Miosinas Cardíacas/metabolismo , Estimulação Cardíaca Artificial , Análise Mutacional de DNA , Eletrocardiografia Ambulatorial , Feminino , Técnicas de Silenciamento de Genes , Estudos de Associação Genética , Predisposição Genética para Doença , Células HeLa , Humanos , Pessoa de Meia-Idade , Morfolinos/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Cadeias Pesadas de Miosina/metabolismo , Linhagem , Fenótipo , Ratos , Ratos Sprague-Dawley , Sarcômeros/metabolismo , Sarcômeros/patologia , Síndrome do Nó Sinusal/diagnóstico , Síndrome do Nó Sinusal/metabolismo , Síndrome do Nó Sinusal/fisiopatologia , Síndrome do Nó Sinusal/terapia , Transfecção , Peixe-Zebra , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
16.
PLoS One ; 10(6): e0131514, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26121141

RESUMO

Most isolated congenital heart defects are thought to be sporadic and are often ascribed to multifactorial mechanisms with poorly understood genetics. Total Anomalous Pulmonary Venous Return (TAPVR) occurs in 1 in 15,000 live-born infants and occurs either in isolation or as part of a syndrome involving aberrant left-right development. Previously, we reported causative links between TAVPR and the PDGFRA gene. TAPVR has also been linked to the ANKRD1/CARP genes. However, these genes only explain a small fraction of the heritability of the condition. By examination of phased single nucleotide polymorphism genotype data from 5 distantly related TAPVR patients we identified a single 25 cM shared, Identical by Descent genomic segment on the short arm of chromosome 12 shared by 3 of the patients and their obligate-carrier parents. Whole genome sequence (WGS) analysis identified a non-synonymous variant within the shared segment in the retinol binding protein 5 (RBP5) gene. The RBP5 variant is predicted to be deleterious and is overrepresented in the TAPVR population. Gene expression and functional analysis of the zebrafish orthologue, rbp7, supports the notion that RBP5 is a TAPVR susceptibility gene. Additional sequence analysis also uncovered deleterious variants in genes associated with retinoic acid signaling, including NODAL and retinol dehydrogenase 10. These data indicate that genetic variation in the retinoic acid signaling pathway confers, in part, susceptibility to TAPVR.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala/métodos , Síndrome de Cimitarra/genética , Transdução de Sinais , Tretinoína/metabolismo , Animais , Cromossomos Humanos Par 12/genética , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Frequência do Gene/genética , Técnicas de Silenciamento de Genes , Variação Genética , Coração/embriologia , Coração/fisiologia , Humanos , Masculino , Morfolinos/farmacologia , Linhagem , Software , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
17.
Ann Thorac Surg ; 98(3): 1098-101, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25193198

RESUMO

Flail tricuspid valve in the neonate is a rare and often fatal condition requiring early diagnosis and intervention. We report 3 infants born without antenatal signs of cardiovascular compromise. Severe hypoxemia developed within hours of birth due to disruption of the anterior leaflet of the tricuspid valve. Each patient was stabilized and required differing levels of acute care including prostaglandin-E2 alone, prostaglandin-E2 plus nitric oxide and milrinone, or extracorporeal membrane oxygenation. All patients underwent successful tricuspid valve repair.


Assuntos
Doenças das Valvas Cardíacas/diagnóstico , Doenças das Valvas Cardíacas/cirurgia , Valva Tricúspide , Humanos , Recém-Nascido
18.
J Thorac Cardiovasc Surg ; 148(6): 2560-6, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25282659

RESUMO

OBJECTIVE: Apolipoprotein E (APOE) genotype is a determinant of neurologic recovery after brain ischemia and traumatic brain injury. The APOE ε2 allele has been associated with worse neurodevelopmental (ND) outcome after repair of congenital heart defects (CHD) in infancy. Replication of this finding in an independent cohort is essential to validate the observed genotype-phenotype association. METHODS: The association of APOE genotype with ND outcomes was assessed in a combined cohort of patients with single-ventricle CHD enrolled in the Single Ventricle Reconstruction and Infant Single Ventricle trials. ND outcome was assessed at 14 months using the Psychomotor Development Index (PDI) and Mental Development Index (MDI) of the Bayley Scales of Infant Development-II. Stepwise multivariable regression was performed to develop predictive models for PDI and MDI scores. RESULTS: Complete data were available for 298 of 435 patients. After adjustment for preoperative and postoperative covariates, the APOE ε2 allele was associated with a lower PDI score (P = .038). Patients with the ε2 allele had a PDI score approximately 6 points lower than those without the risk allele, explaining 1.04% of overall PDI variance, because the ε2 allele was present in only 11% of the patients. There was a marginal effect of the ε2 allele on MDI scores (P = .058). CONCLUSIONS: These data validate the association of the APOE ε2 allele with adverse early ND outcomes after cardiac surgery in infants, independent of patient and operative factors. Genetic variants that decrease neuroresilience and impair neuronal repair after brain injury are important risk factors for ND dysfunction after surgery for CHD.


Assuntos
Apolipoproteína E2/genética , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Deficiências do Desenvolvimento/genética , Cardiopatias Congênitas/cirurgia , Sistema Nervoso/crescimento & desenvolvimento , Fatores Etários , Desenvolvimento Infantil , Deficiências do Desenvolvimento/fisiopatologia , Deficiências do Desenvolvimento/psicologia , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Recém-Nascido , Masculino , Análise Multivariada , Testes Neuropsicológicos , Fenótipo , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Fatores de Risco
19.
Future Cardiol ; 9(4): 507-18, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23834692

RESUMO

Congenital heart defects (CHDs) are the most common congenital abnormalities. Analysis of large multigenerational families has led to the identification of a number of genes for CHDs. However, identifiable variations in these genes are the cause of a small proportion of cases of CHDs, suggesting significant genetic heterogeneity. In addition, large families with CHDs are rare, making the identification of additional genes difficult. Next-generation sequencing technologies will provide an opportunity to identify more genes in the future. However, the significant genetic variation between individuals will present a challenge to distinguish between 'pathogenic' and 'benign' variants. We have demonstrated that the analysis of multiple individuals in small families using combinations of algorithms can reduce the number of candidate variants to a small, manageable number. Thus, the analysis of small nuclear families or even distantly related 'sporadic' cases may begin to uncover the 'dark matter' of CHD genetics.


Assuntos
Predisposição Genética para Doença , Testes Genéticos/métodos , Variação Genética , Cardiopatias Congênitas/genética , Humanos , Linhagem
20.
Pediatr Neurol ; 49(6): 393-6, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24095578

RESUMO

BACKGROUND: The etiology and clinical importance of white matter lesions in migraine remain poorly understood. To understand these issues more fully, we reviewed the brain magnetic resonance imaging scans of pediatric patients and assessed the relationships between white matter lesions, migraine type, patent foramen ovale, and right-to-left shunting. METHODS: The magnetic resonance imaging scans of a cohort of children (n = 89) and adolescents, ages 6 to 18 years, who participated in a study of migraine and patent foramen ovale were reviewed. All children in the cohort had undergone saline contrast transthoracic echocardiography and transcranial Doppler studies. RESULTS: White matter lesions were detected in 15 of the 89 patients (17%). White matter lesions were small (<5 mm) in the majority (10/15; 66%). We observed no relationship between the presence of white matter lesions and (1) migraine type (six patients with white matter lesions among 35 with migraine with aura [17%] vs. nine with white matter lesions among 54 without aura [17%]; P = 1.0); (2) patent foramen ovale (five with white matter lesions among 35 with patent foramen ovale [14%] vs. 10 with white matter lesions among 54 without patent foramen ovale [19%]; P = 0.77); or (3) shunt size (two large shunts in 15 with white matter lesions [13%] vs. nine large shunts among 72 without white matter lesions [13%]; P = 1.0). CONCLUSIONS: These results indicate that small white matter lesions are not infrequent in children and adolescents with migraine. However, no relationships between white matter lesions and migraine type, patent foramen ovale, or degree of right-to-left shunting were observed.


Assuntos
Encéfalo/patologia , Leucoencefalopatias/complicações , Transtornos de Enxaqueca/complicações , Fibras Nervosas Mielinizadas/patologia , Adolescente , Criança , Ecocardiografia , Feminino , Seguimentos , Humanos , Leucoencefalopatias/diagnóstico , Leucoencefalopatias/epidemiologia , Imageamento por Ressonância Magnética , Masculino , Transtornos de Enxaqueca/diagnóstico , Transtornos de Enxaqueca/epidemiologia , Ultrassonografia Doppler Transcraniana
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