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1.
Circ Res ; 126(7): 811-821, 2020 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-32078439

RESUMO

RATIONALE: Transposition of the great arteries (TGA) is one of the most severe types of congenital heart diseases. Understanding the clinical characteristics and pathogenesis of TGA is, therefore, urgently needed for patient management of this severe disease. However, the clinical characteristics and genetic cause underlying TGA remain largely unexplored. OBJECTIVE: We sought to systematically examine the clinical characteristics and genetic cause for isolated nonsyndromic TGA. METHODS AND RESULTS: We recruited 249 patients with TGA (66 family trios) and performed whole-exome sequencing. The incidence of patent ductus arteriosus in dextro-TGA (52.7%) and dextrocardia/mesocardia in congenitally corrected TGA (32.8%) were significantly higher than that in other subtypes. A high prevalence of bicuspid pulmonic valve (9.6%) was observed in patients with TGA. Similar results were observed in a replication group of TGA (n=132). Through a series of bioinformatics filtering steps, we obtained 82 candidate genes harboring potentially damaging de novo, loss of function, compound heterozygous, or X-linked recessive variants. Established congenital heart disease-causing genes, such as FOXH1, were found among the list of candidate genes. A total of 19 ciliary genes harboring rare potentially damaging variants were also found; for example, DYNC2LI1 with a de novo putatively damaging variant. The enrichment of ciliary genes supports the roles of cilia in the pathogenesis of TGA. In total, 33% of the TGA probands had >1 candidate gene hit by putatively deleterious variants, suggesting that a portion of the TGA cases were probably affected by oligogenic or polygenic inheritance. CONCLUSIONS: The findings of clinical characteristic analyses have important implications for TGA patient stratification. The results of genetic analyses highlight the pathogenic role of ciliary genes and a complex genetic architecture underlying TGA.

2.
Sci Rep ; 9(1): 16515, 2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31712678

RESUMO

Congenital heart disease is the most common birth defect in newborns and the leading cause of death in infancy, affecting nearly 1% of live births. A locus in chromosome 4p16, adjacent to MSX1 and STX18, has been associated with atrial septal defects (ASD) in multiple European and Chinese cohorts. Here, genotyping data from the UK Biobank was used to test for associations between this locus and congenital heart disease in adult survivors of left ventricular outflow tract obstruction (n = 164) and ASD (n = 223), with a control sample of 332,788 individuals, and a meta-analysis of the new and existing ASD data was performed. The results show an association between the previously reported markers at 4p16 and risk for either ASD or left ventricular outflow tract obstruction, with effect sizes similar to the published data (OR between 1.27-1.45; all p < 0.05). Differences in allele frequencies remained constant through the studied age range (40-70 years), indicating that the variants themselves do not drive lethal genetic defects. Meta-analysis shows an OR of 1.35 (95% CI: 1.25-1.46; p < 10-4) for the association with ASD. The findings show that the genetic associations with ASD can be generalized to adult survivors of both ASD and left ventricular lesions. Although the 4p16 associations are statistically compelling, the mentioned alleles confer only a small risk for disease and their frequencies in this adult sample are the same as in children, likely limiting their clinical significance. Further epidemiological and functional studies may elicit factors triggering disease in interaction with the risk alleles.

3.
Cell Rep ; 28(5): 1346-1361.e4, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31365875

RESUMO

Cardiac outflow tract (OFT) is a major hotspot for congenital heart diseases. A thorough understanding of the cellular diversity, transitions, and regulatory networks of normal OFT development is essential to decipher the etiology of OFT malformations. We performed single-cell transcriptomic sequencing of 55,611 mouse OFT cells from three developmental stages that generally correspond to the early, middle, and late stages of OFT remodeling and septation. Known cellular transitions, such as endothelial-to-mesenchymal transition, have been recapitulated. In particular, we identified convergent development of the vascular smooth muscle cell (VSMC) lineage where intermediate cell subpopulations were found to be involved in either myocardial-to-VSMC trans-differentiation or mesenchymal-to-VSMC transition. Finally, we uncovered transcriptional regulators potentially governing cellular transitions. Our study provides a single-cell reference map of cell states for normal OFT development and paves the way for further studies of the etiology of OFT malformations at the single-cell level.

4.
Nat Commun ; 10(1): 3111, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31308376

RESUMO

Biomedical repositories such as the UK Biobank provide increasing access to prospectively collected cardiac imaging, however these data are unlabeled, which creates barriers to their use in supervised machine learning. We develop a weakly supervised deep learning model for classification of aortic valve malformations using up to 4,000 unlabeled cardiac MRI sequences. Instead of requiring highly curated training data, weak supervision relies on noisy heuristics defined by domain experts to programmatically generate large-scale, imperfect training labels. For aortic valve classification, models trained with imperfect labels substantially outperform a supervised model trained on hand-labeled MRIs. In an orthogonal validation experiment using health outcomes data, our model identifies individuals with a 1.8-fold increase in risk of a major adverse cardiac event. This work formalizes a deep learning baseline for aortic valve classification and outlines a general strategy for using weak supervision to train machine learning models using unlabeled medical images at scale.


Assuntos
Valva Aórtica/anormalidades , Doenças das Valvas Cardíacas/patologia , Aprendizado de Máquina , Valva Aórtica/diagnóstico por imagem , Valva Aórtica/patologia , Cardiopatias/patologia , Doenças das Valvas Cardíacas/diagnóstico por imagem , Humanos , Imagem por Ressonância Magnética , Aprendizado de Máquina Supervisionado
5.
Circulation ; 139(16): 1889-1899, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30813762

RESUMO

BACKGROUND: Although lower-complexity cardiac malformations constitute the majority of adult congenital heart disease (ACHD), the long-term risks of adverse cardiovascular events and relationship with conventional risk factors in this population are poorly understood. We aimed to quantify the risk of adverse cardiovascular events associated with lower-complexity ACHD that is unmeasured by conventional risk factors. METHODS: A multitiered classification algorithm was used to select individuals with lower-complexity ACHD and individuals without ACHD for comparison among >500 000 British adults in the UK Biobank. ACHD diagnoses were subclassified as isolated aortic valve and noncomplex defects. Time-to-event analyses were conducted for the primary end points of fatal or nonfatal acute coronary syndrome, ischemic stroke, heart failure, and atrial fibrillation and a secondary combined end point for major adverse cardiovascular events. Maximum follow-up time for the study period was 22 years with retrospectively and prospectively collected data from the UK Biobank. RESULTS: We identified 2006 individuals with lower-complexity ACHD and 497 983 unexposed individuals in the UK Biobank (median age at enrollment, 58 [interquartile range, 51-63] years). Of the ACHD-exposed group, 59% were male, 51% were current or former smokers, 30% were obese, and 69%, 41%, and 7% were diagnosed or treated for hypertension, hyperlipidemia, and diabetes mellitus, respectively. After adjustment for 12 measured cardiovascular risk factors, ACHD remained strongly associated with the primary end points, with hazard ratios ranging from 2.0 (95% CI, 1.5-2.8; P<0.001) for acute coronary syndrome to 13.0 (95% CI, 9.4-18.1; P<0.001) for heart failure. ACHD-exposed individuals with ≤2 cardiovascular risk factors had a 29% age-adjusted incidence rate of major adverse cardiovascular events, in contrast to 13% in individuals without ACHD with ≥5 risk factors. CONCLUSIONS: Individuals with lower-complexity ACHD had a higher burden of adverse cardiovascular events relative to the general population that was unaccounted for by conventional cardiovascular risk factors. These findings highlight the need for closer surveillance of patients with mild to moderate ACHD and further investigation into management and mechanisms of cardiovascular risk unique to this growing population of high-risk adults.


Assuntos
Síndrome Coronariana Aguda/epidemiologia , Cardiopatias Congênitas/epidemiologia , Insuficiência Cardíaca/epidemiologia , Adulto , Algoritmos , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Estados Unidos/epidemiologia
6.
Birth Defects Res ; 111(11): 640-648, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-30920163

RESUMO

BACKGROUND: Congenital heart disease (CHD) is the most common birth defect group and a significant contributor to neonatal and infant death. CHD with single ventricle anatomy, including hypoplastic left heart syndrome (HLHS), tricuspid atresia (TA), and various double-inlet ventricle (DIV) malformations, is the most complex with the highest mortality. Prenatal risk factors associated with HLHS have been studied, but such data for DIV are lacking. METHODS: We analyzed DIV cases and nonmalformed controls in the National Birth Defects Prevention Study, a case-control, multicenter population-based study of birth defects. Random forest analysis identified potential predictor variables for DIV, which were included in multivariable models to estimate effect magnitude and directionality. RESULTS: Random forest analysis identified pre-pregnancy diabetes, history of maternal insulin use, maternal total lipid intake, paternal race, and intake of several foods and nutrients as potential predictors of DIV. Logistic regression confirmed pre-pregnancy diabetes, maternal insulin use, and paternal race as risk factors for having a child with DIV. Additionally, higher maternal total fat intake was associated with a reduced risk. CONCLUSIONS: Maternal pre-pregnancy diabetes and history of insulin use were associated with an increased risk of having an infant with DIV, while maternal lipid intake had an inverse association. These novel data provide multiple metabolic pathways for investigation to identify better the developmental etiologies of DIV and suggest that public health interventions targeting diabetes prevention and management in women of childbearing age could reduce CHD risk.

7.
Genet Epidemiol ; 43(2): 215-226, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30511478

RESUMO

Loss of function variants in NOTCH1 cause left ventricular outflow tract obstructive defects (LVOTO). However, the risk conferred by rare and noncoding variants in NOTCH1 for LVOTO remains largely uncharacterized. In a cohort of 49 families affected by hypoplastic left heart syndrome, a severe form of LVOTO, we discovered predicted loss of function NOTCH1 variants in 6% of individuals. Rare or low-frequency missense variants were found in 16% of families. To make a quantitative estimate of the genetic risk posed by variants in NOTCH1 for LVOTO, we studied associations of 400 coding and noncoding variants in NOTCH1 in 1,085 cases and 332,788 controls from the UK Biobank. Two rare intronic variants in strong linkage disequilibrium displayed significant association with risk for LVOTO amongst European-ancestry individuals. This result was replicated in an independent analysis of 210 cases and 68,762 controls of non-European and mixed ancestry. In conclusion, carrying rare predicted loss of function variants in NOTCH1 confer significant risk for LVOTO. In addition, the two intronic variants seem to be associated with an increased risk for these defects. Our approach demonstrates the utility of population-based data sets in quantifying the specific risk of individual variants for disease-related phenotypes.


Assuntos
Predisposição Genética para Doença , Cardiopatias Congênitas/genética , Íntrons/genética , Mutação com Perda de Função/genética , Mutação de Sentido Incorreto/genética , Receptor Notch1/genética , Obstrução do Fluxo Ventricular Externo/genética , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Humanos , Masculino , Linhagem , Fatores de Risco , Sequenciamento Completo do Exoma
8.
Circulation ; 138(21): e653-e711, 2018 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-30571578

RESUMO

This review provides an updated summary of the state of our knowledge of the genetic contributions to the pathogenesis of congenital heart disease. Since 2007, when the initial American Heart Association scientific statement on the genetic basis of congenital heart disease was published, new genomic techniques have become widely available that have dramatically changed our understanding of the causes of congenital heart disease and, clinically, have allowed more accurate definition of the pathogeneses of congenital heart disease in patients of all ages and even prenatally. Information is presented on new molecular testing techniques and their application to congenital heart disease, both isolated and associated with other congenital anomalies or syndromes. Recent advances in the understanding of copy number variants, syndromes, RASopathies, and heterotaxy/ciliopathies are provided. Insights into new research with congenital heart disease models, including genetically manipulated animals such as mice, chicks, and zebrafish, as well as human induced pluripotent stem cell-based approaches are provided to allow an understanding of how future research breakthroughs for congenital heart disease are likely to happen. It is anticipated that this review will provide a large range of health care-related personnel, including pediatric cardiologists, pediatricians, adult cardiologists, thoracic surgeons, obstetricians, geneticists, genetic counselors, and other related clinicians, timely information on the genetic aspects of congenital heart disease. The objective is to provide a comprehensive basis for interdisciplinary care for those with congenital heart disease.


Assuntos
Cardiopatias Congênitas/diagnóstico , American Heart Association , Aneuploidia , Variações do Número de Cópias de DNA , Síndrome de Down/diagnóstico , Síndrome de Down/genética , Variação Genética , Cardiopatias Congênitas/epidemiologia , Cardiopatias Congênitas/genética , Humanos , Polimorfismo de Nucleotídeo Único , Estados Unidos/epidemiologia
9.
Circ Genom Precis Med ; 11(6): e002054, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29875125

RESUMO

BACKGROUND: Low birthweight has been associated with a higher risk of hypertension, type 2 diabetes mellitus (T2D), and cardiovascular disease. The Barker hypothesis posits that intrauterine growth restriction resulting in lower birthweight is causal for these diseases, but causality is difficult to infer from observational studies. METHODS: We performed regression analyses to assess associations of birthweight with cardiovascular disease and T2D in 237 631 individuals from the UK Biobank. Further, we assessed the causal relationship of such associations using Mendelian randomization. RESULTS: In the observational analyses, birthweight showed inverse associations with systolic and diastolic blood pressure (ß, -0.83 and -0.26; per raw unit in outcomes and SD change in birthweight; 95% confidence interval [CI], -0.90 to -0.75 and -0.31 to -0.22, respectively), T2D (odds ratio, 0.83; 95% CI, 0.79-0.87), lipid-lowering treatment (odds ratio, 0.84; 95% CI, 0.81-0.86), and coronary artery disease (hazard ratio, 0.85; 95% CI, 0.78-0.94), whereas the associations with adult body mass index and body fat (ß, 0.04 and 0.02; per SD change in outcomes and birthweight; 95% CI, 0.03-0.04 and 0.01-0.02, respectively) were positive. The Mendelian randomization analyses indicated inverse causal associations of birthweight with low-density lipoprotein cholesterol, 2-hour glucose, coronary artery disease, and T2D and positive causal association with body mass index but no associations with blood pressure. CONCLUSIONS: Our study indicates that lower birthweight, used as a proxy for intrauterine growth retardation, is causally related with increased susceptibility to coronary artery disease and T2D. This causal relationship is not mediated by adult obesity or hypertension.


Assuntos
Peso ao Nascer/genética , Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Análise da Randomização Mendeliana/métodos , Adulto , Idoso , Glicemia/análise , Pressão Sanguínea , Índice de Massa Corporal , Doenças Cardiovasculares/genética , Diabetes Mellitus Tipo 2/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Observacionais como Assunto , Fatores de Risco , Estados Unidos/epidemiologia
11.
J Pediatr ; 195: 275-278, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29254757

RESUMO

In a retrospective study of 19 171 mother-child dyads, elevated random plasma glucose values during early pregnancy were directly correlated with increased risk for congenital heart disease in offspring. Plasma glucose levels proximal to the period of cardiac development may represent a modifiable risk factor for congenital heart disease in expectant mothers without diabetes.


Assuntos
Glicemia/metabolismo , Cardiopatias Congênitas/etiologia , Hiperglicemia/diagnóstico , Complicações na Gravidez/diagnóstico , Primeiro Trimestre da Gravidez/sangue , Adolescente , Adulto , Biomarcadores/sangue , Feminino , Humanos , Hiperglicemia/sangue , Recém-Nascido , Gravidez , Complicações na Gravidez/sangue , Estudos Retrospectivos , Fatores de Risco , Adulto Jovem
12.
Curr Opin Pediatr ; 29(5): 513-519, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28786837

RESUMO

PURPOSE OF REVIEW: Genome sequencing is now available as a clinical diagnostic test. There is a significant knowledge and translation gap for nongenetic specialists of the processes necessary to generate and interpret clinical genome sequencing. The purpose of this review is to provide a primer on contemporary clinical genome sequencing for nongenetic specialists describing the human genome project, current techniques and applications in genome sequencing, limitations of current technology, and techniques on the horizon. RECENT FINDINGS: As currently implemented, genome sequencing compares short pieces of an individual's genome with a reference sequence developed by the human genome project. Genome sequencing may be used for obtaining timely diagnostic information, cancer pharmacogenomics, or in clinical cases when previous genetic testing has not revealed a clear diagnosis. At present, the implementation of clinical genome sequencing is limited by the availability of clinicians qualified for interpretation, and current techniques in used clinical testing do not detect all types of genetic variation present in a single genome. SUMMARY: Clinicians considering a genetic diagnosis have wide array of testing choices which now includes genome sequencing. Although not a comprehensive test in its current form, genome sequencing offers more information than gene-panel or exome sequencing and has the potential to replace targeted single-gene or gene-panel testing in many clinical scenarios.


Assuntos
Testes Genéticos/métodos , Sequenciamento Completo do Genoma , Projeto Genoma Humano , Humanos
13.
Dev Cell ; 39(4): 491-507, 2016 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-27840109

RESUMO

Embryonic gene expression intricately reflects anatomical context, developmental stage, and cell type. To address whether the precise spatial origins of cardiac cells can be deduced solely from their transcriptional profiles, we established a genome-wide expression database from 118, 949, and 1,166 single murine heart cells at embryonic day 8.5 (e8.5), e9.5, and e10.5, respectively. We segregated these cells by type using unsupervised bioinformatics analysis and identified chamber-specific genes. Using a random forest algorithm, we reconstructed the spatial origin of single e9.5 and e10.5 cardiomyocytes with 92.0% ± 3.2% and 91.2% ± 2.8% accuracy, respectively (99.4% ± 1.0% and 99.1% ± 1.1% if a ±1 zone margin is permitted) and predicted the second heart field distribution of Isl-1-lineage descendants. When applied to Nkx2-5-/- cardiomyocytes from murine e9.5 hearts, we showed their transcriptional alteration and lack of ventricular phenotype. Our database and zone classification algorithm will enable the discovery of novel mechanisms in early cardiac development and disease.


Assuntos
Perfilação da Expressão Gênica , Coração/embriologia , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Análise de Célula Única , Algoritmos , Animais , Biomarcadores/metabolismo , Linhagem da Célula/genética , Separação Celular , Embrião de Mamíferos/citologia , Corpos Embrioides/citologia , Regulação da Expressão Gênica no Desenvolvimento , Integrases/metabolismo , Camundongos , Modelos Biológicos , Miocárdio/metabolismo , Reação em Cadeia da Polimerase , Reprodutibilidade dos Testes , Análise de Sequência de RNA
15.
PLoS Genet ; 12(4): e1005963, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27058611

RESUMO

Congenital heart disease (CHD) has a complex genetic etiology, and recent studies suggest that high penetrance de novo mutations may account for only a small fraction of disease. In a multi-institutional cohort surveyed by exome sequencing, combining analysis of 987 individuals (discovery cohort of 59 affected trios and 59 control trios, and a replication cohort of 100 affected singletons and 533 unaffected singletons) we observe variation at novel and known loci related to a specific cardiac malformation the atrioventricular septal defect (AVSD). In a primary analysis, by combining developmental coexpression networks with inheritance modeling, we identify a de novo mutation in the DNA binding domain of NR1D2 (p.R175W). We show that p.R175W changes the transcriptional activity of Nr1d2 using an in vitro transactivation model in HUVEC cells. Finally, we demonstrate previously unrecognized cardiovascular malformations in the Nr1d2tm1-Dgen knockout mouse. In secondary analyses we map genetic variation to protein-interaction networks suggesting a role for two collagen genes in AVSD, which we corroborate by burden testing in a second replication cohort of 100 AVSDs and 533 controls (p = 8.37e-08). Finally, we apply a rare-disease inheritance model to identify variation in genes previously associated with CHD (ZFPM2, NSD1, NOTCH1, VCAN, and MYH6), cardiac malformations in mouse models (ADAM17, CHRD, IFT140, PTPRJ, RYR1 and ATE1), and hypomorphic alleles of genes causing syndromic CHD (EHMT1, SRCAP, BBS2, NOTCH2, and KMT2D) in 14 of 59 trios, greatly exceeding variation in control trios without CHD (p = 9.60e-06). In total, 32% of trios carried at least one putatively disease-associated variant across 19 loci,suggesting that inherited and de novo variation across a heterogeneous group of loci may contribute to disease risk.


Assuntos
Defeitos dos Septos Cardíacos/genética , Animais , Feminino , Heterozigoto , Homozigoto , Humanos , Masculino , Camundongos , Camundongos Knockout , Mutação , Linhagem
16.
Genome Med ; 8(1): 24, 2016 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-26932475

RESUMO

BACKGROUND: As whole exome sequencing (WES) and whole genome sequencing (WGS) transition from research tools to clinical diagnostic tests, it is increasingly critical for sequencing methods and analysis pipelines to be technically accurate. The Genome in a Bottle Consortium has recently published a set of benchmark SNV, indel, and homozygous reference genotypes for the pilot whole genome NIST Reference Material based on the NA12878 genome. METHODS: We examine the relationship between human genome complexity and genes/variants reported to be associated with human disease. Specifically, we map regions of medical relevance to benchmark regions of high or low confidence. We use benchmark data to assess the sensitivity and positive predictive value of two representative sequencing pipelines for specific classes of variation. RESULTS: We observe that the accuracy of a variant call depends on the genomic region, variant type, and read depth, and varies by analytical pipeline. We find that most false negative WGS calls result from filtering while most false negative WES variants relate to poor coverage. We find that only 74.6% of the exonic bases in ClinVar and OMIM genes and 82.1% of the exonic bases in ACMG-reportable genes are found in high-confidence regions. Only 990 genes in the genome are found entirely within high-confidence regions while 593 of 3,300 ClinVar/OMIM genes have less than 50% of their total exonic base pairs in high-confidence regions. We find greater than 77 % of the pathogenic or likely pathogenic SNVs currently in ClinVar fall within high-confidence regions. We identify sites that are prone to sequencing errors, including thousands present in publicly available variant databases. Finally, we examine the clinical impact of mandatory reporting of secondary findings, highlighting a false positive variant found in BRCA2. CONCLUSIONS: Together, these data illustrate the importance of appropriate use and continued improvement of technical benchmarks to ensure accurate and judicious interpretation of next-generation DNA sequencing results in the clinical setting.


Assuntos
Genética Médica , Genoma Humano , Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Biologia Computacional/métodos , Biologia Computacional/normas , Bases de Dados de Ácidos Nucleicos , Exoma , Variação Genética , Genética Médica/métodos , Genética Médica/normas , Genômica/métodos , Genômica/normas , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Sequenciamento de Nucleotídeos em Larga Escala/normas , Humanos , Reprodutibilidade dos Testes
17.
JAMA Pediatr ; 169(12): 1112-6, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26457543

RESUMO

IMPORTANCE: There is a well-described association between maternal diabetes mellitus and risk of congenital heart disease (CHD) in offspring. Although the clinical diagnoses of type 2 diabetes or gestational diabetes are strong risk factors for CHD, subclinical abnormalities of glucose and insulin metabolism are common within the general population and could also confer risk for CHD. We hypothesize that continuous measures of blood analytes related to maternal diabetes are related to odds of cardiac malformations. OBJECTIVE: To explore the potential association of 2 different CHD phenotypes in offspring with maternal midpregnancy measures of glucose and insulin. DESIGN, SETTING, AND PARTICIPANTS: Case-control study from a population-based cohort of 277 pregnant women in southern and central California carrying infants with tetralogy of Fallot (TOF) (n = 55), dextrotransposition of the great arteries (dTGA) (n = 42), or healthy infants without CHD (n = 180). Serum samples were collected from 2003 through 2007. The analysis was conducted from March through June 2015. MAIN OUTCOMES AND MEASURES: Blood analytes related to maternal glucose metabolism were measured from random nonfasting second-trimester blood samples. We measured serum insulin levels by a validated radioimmunoassay, and we measured glucose levels. Multivariable logistic regression models estimated the association between these levels and case status. RESULTS: Serum glucose values were elevated in the maternal samples for offspring with TOF (median, 97.0 mg/dL [to convert to millimoles per liter, multiply by 0.0555]) relative to controls (median, 91.5 mg/dL) (P = .01, Wilcoxon rank sum test), a phenomenon not observed in the maternal samples for offspring with dTGA (median, 90.0 mg/dL) relative to controls (P = .18, Wilcoxon rank sum test). Serum insulin levels were significantly different between controls (median, 18.8 µIU/mL [to convert to picomoles per liter, multiply by 6.945]) and maternal samples for offspring with dTGA (median, 13.1 µIU/mL; P = .048, Wilcoxon rank sum test) but not with TOF (median, 14.3 µIU/mL; P = .35, Wilcoxon rank sum test). Relative to maternal blood glucose levels of infants without cardiac malformations, we observed that maternal blood glucose levels in models including insulin were strongly associated with odds of TOF (adjusted odds ratio = 7.54; 95% CI, 2.30-24.69) but not with dTGA (adjusted odds ratio = 1.16; 95% CI, 0.28-4.79). CONCLUSIONS AND RELEVANCE: These results represent a direct correlation of glucose as a continuous variable to odds of specific cardiac malformations. The association between serum glucose and odds of TOF indicates the need for additional epidemiological and mechanistic investigations into the risk conferred by insulin signaling and glucose metabolism during early pregnancy.


Assuntos
Glicemia/análise , Diabetes Mellitus Tipo 2/sangue , Diabetes Gestacional/sangue , Cardiopatias Congênitas/epidemiologia , Adulto , California , Estudos de Casos e Controles , Feminino , Cardiopatias Congênitas/etiologia , Humanos , Insulina/sangue , Razão de Chances , Gravidez , Fatores de Risco , Adulto Jovem
18.
PLoS Genet ; 11(10): e1005496, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26448358

RESUMO

High throughput sequencing has facilitated a precipitous drop in the cost of genomic sequencing, prompting predictions of a revolution in medicine via genetic personalization of diagnostic and therapeutic strategies. There are significant barriers to realizing this goal that are related to the difficult task of interpreting personal genetic variation. A comprehensive, widely accessible application for interpretation of whole genome sequence data is needed. Here, we present a series of methods for identification of genetic variants and genotypes with clinical associations, phasing genetic data and using Mendelian inheritance for quality control, and providing predictive genetic information about risk for rare disease phenotypes and response to pharmacological therapy in single individuals and father-mother-child trios. We demonstrate application of these methods for disease and drug response prognostication in whole genome sequence data from twelve unrelated adults, and for disease gene discovery in one father-mother-child trio with apparently simplex congenital ventricular arrhythmia. In doing so we identify clinically actionable inherited disease risk and drug response genotypes in pre-symptomatic individuals. We also nominate a new candidate gene in congenital arrhythmia, ATP2B4, and provide experimental evidence of a regulatory role for variants discovered using this framework.


Assuntos
Arritmias Cardíacas/genética , Predisposição Genética para Doença , ATPases Transportadoras de Cálcio da Membrana Plasmática/genética , Análise de Sequência de DNA , Arritmias Cardíacas/patologia , Sequência de Bases , Mapeamento Cromossômico , Variação Genética , Genoma Humano , Genótipo , Humanos , Fenótipo
19.
Hum Mutat ; 36(11): 1080-7, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26173643

RESUMO

The RASopathies constitute a family of autosomal-dominant disorders whose major features include facial dysmorphism, cardiac defects, reduced postnatal growth, variable cognitive deficits, ectodermal and skeletal anomalies, and susceptibility to certain malignancies. Noonan syndrome (NS), the commonest RASopathy, is genetically heterogeneous and caused by functional dysregulation of signal transducers and regulatory proteins with roles in the RAS/extracellular signal-regulated kinase (ERK) signal transduction pathway. Mutations in known disease genes account for approximately 80% of affected individuals. Here, we report that missense mutations altering Son of Sevenless, Drosophila, homolog 2 (SOS2), which encodes a RAS guanine nucleotide exchange factor, occur in a small percentage of subjects with NS. Four missense mutations were identified in five unrelated sporadic cases and families transmitting NS. Disease-causing mutations affected three conserved residues located in the Dbl homology (DH) domain, of which two are directly involved in the intramolecular binding network maintaining SOS2 in its autoinhibited conformation. All mutations were found to promote enhanced signaling from RAS to ERK. Similar to NS-causing SOS1 mutations, the phenotype associated with SOS2 defects is characterized by normal development and growth, as well as marked ectodermal involvement. Unlike SOS1 mutations, however, those in SOS2 are restricted to the DH domain.


Assuntos
Estudos de Associação Genética , Mutação , Síndrome de Noonan/genética , Domínios e Motivos de Interação entre Proteínas/genética , Proteínas Son Of Sevenless/genética , Adolescente , Adulto , Alelos , Substituição de Aminoácidos , Criança , Análise Mutacional de DNA , Exoma , Facies , Feminino , Genótipo , Humanos , Masculino , Modelos Moleculares , Síndrome de Noonan/diagnóstico , Fenótipo , Conformação Proteica , Proteínas Son Of Sevenless/química , Adulto Jovem
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