Maternal risk factors for congenital heart defects in infants with Down syndrome from Western Mexico

Atrioventricular septal defects (AVSDs) have been identified as intriguingly infrequent among Hispanics with Down syndrome (DS) born in the United States. The aim of this study was to evaluate the effect of possible maternal risk factors in the presence of congenital heart defects (CHDs) in Mexican infants with DS. A total of 231 live birth infants born with DS during 2009–2018 at the “Dr. Juan I. Menchaca” Civil Hospital of Guadalajara (Guadalajara, Mexico) were ascertained in a case–control study. Patients with DS with any major CHD were included as cases and those without major CHD as controls. Potential risk factors were analyzed using logistic regression. Of eligible infants with DS, 100 (43.3%) had ≥1 major CHDs (cases) and were compared with a control group of 131 infants (56.7%) with DS without CHDs. Prevalent CHDs were ostium secundum atrial septal defects (ASDs) (46.9%), ventricular septal defects (27.3%), and AVSDs (14%). Lack of folic acid supplementation before pregnancy had a significant risk for CHDs in infants with DS (adjusted odds ratio [aORs] = 2.9 (95% confidence interval [95% CI]: 1.0–8.6) and in the analysis by subtype of CHDs, also, for the occurrence of ASDs (aOR = 11.5, 95% CI: 1.4–94.4). Almost half of the infants with DS in our sample had CHDs, being ASD the commonest subtype and AVSD the rarest. Our ethnic background alone or in concomitance with observed nutritional disadvantages seems to contribute differences in CHD subtype rates in our DS patients.     

Sex differences for major congenital heart defects in Down Syndrome: A population based study

Background

Down syndrome (DS) is the most common autosomal chromosomal anomaly in liveborn infants. About 40% of infants with DS have a major congenital heart defect (CHD). Among them, atrioventricular septal defects (AVSD), atrial septal defects (ASD), ventricular septal defect (VSD) and Tetralogy of Fallot (ToF) are the most common. The aim of this study was to estimate the sex difference in the occurrence of CHD in infants with DS comparing it with non-DS infants.

Consanguineous marriage and congenital heart defects: a case-control study in the neonatal period

The independent effect of consanguinity on the prevalence of congenital heart defects (CHDs), all and specific types, was investigated in newborns admitted to nine hospitals located in Beirut, Lebanon and members of the National Collaborative Perinatal Neonatal Network (NCPNN). Cases were 173 newborns admitted to the Neonatal Intensive Care Units (NICU) of participating hospitals during the 3-year period from January 1, 2000 to December 31, 2002 and diagnosed during their hospital stay as having one or more CHD. Cases with chromosomal abnormalities were excluded. Cases with more than one CHD were assigned one principal malformation. Controls consisted of a random sample of 865 newborns without a CHD admitted to the NICU during the same period. After controlling for confounders, first cousin consanguinity remained significantly associated with an increased risk of CHD: infants born to first cousin marriages had a 1.8 times higher risk of having a CHD diagnosed at birth compared to those born to unrelated parents (95% CI: 1.1-3.1). In particular, first-cousin marriage was a significant risk factor for ventricular septal defect (VSD), atrial septal defect (ASD), hypoplastic left heart (HLH), and single ventricle (SV). No association was found with d-transposition of the great arteries, coarctation, pulmonary atresia (PA), atrioventricular septal defect (AVSD), and tetralogy of Fallot (TOF). The results of this study suggest a familial factor in the multifactorial etiology of CHDs. Additional epidemiologic and family-based genetic studies are needed to understand the complex cause of CHDs.     

Maternal age and prevalence of isolated congenital heart defects in an urban area of the United States

Although maternal age has been associated with a number of birth defects in several reports, the literature on the association of maternal age with isolated congenital heart defect (CHD) phenotypes has been limited. We evaluated CHD prevalence based on a cohort of 5,289 infants and fetuses with isolated CHDs born during the period 1968–2005 and ascertained by the Metropolitan Atlanta Congenital Defects Program (MACDP) among residents of five central counties in Atlanta. For our denominator, we obtained information on births to residents of the same counties from vital records (n = 1,301,143). We calculated prevalence ratios for 23 CHD phenotypes by several maternal age categories, using the group 25–29 years of age as a reference group. We used Poisson regression models to estimate adjusted prevalence ratios (aPRs) and 95% confidence intervals (CIs), controlling for maternal race, infant sex, and birth cohort. A maternal age of 35 years or older was associated with an increased prevalence for several CHD phenotypes: laterality defects (aPR = 2.06; CI 1.22–3.48), all conotruncal defects (aPR = 1.30; CI 1.03–1.65), and specifically for dextro‐transposition of the great arteries (aPR = 1.65; CI 1.10–2.48), coarctation of the aorta (aPR = 1.54; CI 1.10–2.16), ventricular septal defects (aPR = 1.20; CI 1.06–1.36), and atrial septal defects (aPR = 1.36; CI 1.05–1.77). Our findings suggest that the birth prevalence of specific isolated CHDs varies with maternal age. Further studies are warranted to corroborate these observations, taking into account potential confounding by known modifiable risk factors. Published 2011 Wiley‐Liss, Inc.     

Parental consanguinity increases congenital heart diseases in South India

BACKGROUND: Congenital heart diseases (CHDs) are the commonest single group of congenital abnormalities with a prevalence ranging from 1.0 to 50.89 per 1000 live births in the world population including India, whereas Mysore has a prevalence of 11.08 per 1000 live births. One of the risk factors for the occurrence of CHDs is parental consanguinity, in particular first-cousin marriage between parents. AIM: The present study examined the role of consanguineous marriages in causing CHDs in Mysore, South India. SUBJECTS AND METHODS: A total of 144 confirmed CHD cases with an age range of 1 day to 23 years and a control group of 200 families from different localities of Mysore city were considered for the present study. Methods included the establishment of a genetic register and pedigree analysis followed by statistical analysis by logistic regression. RESULTS: The findings revealed that first-cousin marriages (44.68%) and uncle-niece marriages (46.81%) are equally significant in increasing CHDs. The subtypes of CHDs associated with consanguinity were found to be atrial septal defect (ASD) and patent ductus arteriosus (PDA). These findings emphasize the important role played by segregation of recessive genes in the offspring resulting in the causation of CHDs. CONCLUSION: Therefore, for every incidence of parental consanguinity, the risk (odds) of birth of a child with CHD increases. There is an urgent need to educate the public on the deleterious effects of inbreeding, especially in India, which has high overall consanguinity.     

Maternal and offspring MTHFR gene C677T polymorphism as predictors of congenital atrial septal defect and patent ductus arteriosus

To observe the association of MTHFR gene C677T locus polymorphism with occurrence of congenital heart defects (CHDs), 21 patients with atrial septal defect (ASD), 35 patients with patent ductus arteriosus (PDA), one patient with both conditions combined, and their biological parents were collected as the case group. Another 104 normal individuals and their biological parents without a family history of birth defects were selected as the control group. MTHFR C677T genotypes of each sample were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The results showed for the occurrence of ASD, the odds ratio (OR) of TT genotype was 4.08 [95% confidence interval (95% CI) = 1.28-13.24] compared with CT genotype. For the occurrence of PDA, the ORs of TT were 3.44 (95% CI = 0.89-16.13) and 2.38 (95% CI = 0.92-6.14) compared with CC and CT genotypes, respectively. Author as meant? Compared with CC + CT genotype combination, the ORs of TT were 3.95 (95% CI = 1.38-11.44) and 2.60 (95% CI = 1.02-6.36) for ASD and PSD respectively. The results also had sex differences and the statistical significance was only observed in male ASD and female PDA. The ORs of T allele carriers were 2.29 (95% CI = 1.08-4.92) and 1.88 (95% CI = 1.02-3.47) compared with C allele for the occurrences of ASD and PDA respectively. The analysis of parents genotype showed that the OR of TT mothers was 2.31 (95% CI = 0.96-5.59, P < 0.05) compared with (CC + CT) for the occurrence of PDA in offspring. So this study could give a clue that MTHFR C677T locus variation was related with occurrence of ASD and PDA, and the carriers of TT genotype and T allele had higher risk of diseases. The mother carrying TT genotype was associated with occurrence of PDA in offspring.     

Parental consanguinity increases congenital heart diseases in South India

Background: Congenital heart diseases (CHDs) are the commonest single group of congenital abnormalities with a prevalence ranging from 1.0 to 50.89 per 1000 live births in the world population including India, whereas Mysore has a prevalence of 11.08 per 1000 live births. One of the risk factors for the occurrence of CHDs is parental consanguinity, in particular first-cousin marriage between parents.

Aim: The present study examined the role of consanguineous marriages in causing CHDs in Mysore, South India.

Subjects and methods: A total of 144 confirmed CHD cases with an age range of 1 day to 23 years and a control group of 200 families from different localities of Mysore city were considered for the present study. Methods included the establishment of a genetic register and pedigree analysis followed by statistical analysis by logistic regression.

Results: The findings revealed that first-cousin marriages (44.68%) and uncle–niece marriages (46.81%) are equally significant in increasing CHDs. The subtypes of CHDs associated with consanguinity were found to be atrial septal defect (ASD) and patent ductus arteriosus (PDA). These findings emphasize the important role played by segregation of recessive genes in the offspring resulting in the causation of CHDs.

Conclusion: Therefore, for every incidence of parental consanguinity, the risk (odds) of birth of a child with CHD increases. There is an urgent need to educate the public on the deleterious effects of inbreeding, especially in India, which has high overall consanguinity.     

Hyperhomocysteinemia and MTHFR polymorphisms in association with orofacial clefts and congenital heart defects: a meta-analysis

Several studies have reported an association between hyperhomocysteinemia, 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphisms and cleft lip with or without cleft palate (CLP), and congenital heart defects (CHDs). However, findings have been inconsistent. A meta-analysis was performed of published studies until September 2006 investigating these associations in both mothers and children. Homocysteine data were provided in two CLP and three CHD studies, and MTHFR polymorphisms were reported in ten CLP and eight CHD studies. Data were analyzed using the random effects model in the Cochrane Review Manager. The pooled odds ratio (OR) of maternal hyperhomocysteinemia was 2.3 (95% CI 0.4-11.9) for CLP, and 4.4 (2.6-7.3) for CHDs. The MTHFR C677T polymorphism and CLP showed pooled ORs of 1.2 (0.9-1.5) in mothers and 1.0 (0.9-1.2) in children, whereas these estimates for the A1298C polymorphism were 1.0 (0.7-1.2) in mothers and 0.9 (0.6-1.2) in children. The MTHFR C677T polymorphism in CHD studies demonstrated a pooled OR of 1.0 (0.8-1.3) for mothers and 1.1 (0.9-1.5) for children. Two studies investigating the maternal A1298C polymorphism in CHDs demonstrated a pooled OR of 1.2 (0.8-1.8). Only one CHD study reported an OR of 1.3 (0.8-2.1) for this polymorphism in children. In conclusion, this meta-analysis demonstrates that maternal hyperhomocysteinemia is a risk factor for CHDs. The MTHFR polymorphisms C677T and A1298C in both mothers and children are not independently associated with CLP or CHDs. Future studies should be performed to investigate the interactions between maternal hyperhomocysteinemia, B-vitamin intake, related polymorphisms and the risk of CLP and CHDs.     

Genetic and lifestyle factors related to the periconception vitamin B12 status and congenital heart defects: a Dutch case-control study

Maternal hyperhomocysteinemia is associated with congenital heart defects (CHDs) in the offspring. A low periconception vitamin B12 status is determined by genetic and lifestyle factors and causes hyperhomocysteinemia. We investigated methionine synthase reductase (MTRR) and transcobalamin II (TC) genes and maternal intake and serum concentrations of vitamin B12 in association with CHD risk. Seventeen months after the index-pregnancy, we studied 230 children with a CHD and 251 non-malformed children and their parents. Data were collected on current and periconception maternal vitamin supplement use and maternal dietary vitamin B12 intake of the month before the study moment. Blood samples were taken for the determination of MTRR A66G and TC C776G genotypes in families and maternal serum vitamin B12 concentrations. Transmission disequilibrium tests and univariate and multivariate analyses were applied. Allele transmissions were not significantly distorted. The MTRR and TC genotypes did not significantly affect CHD risk. Neither polymorphisms in mothers and/or children revealed significant interactions nor in combination with low vitamin B12 intake. Low maternal serum vitamin B12 combined with the maternal or child's MTRR 66 GG genotype resulted in odds ratios of 1.4 (95% confidence interval 0.6-3.5) and 1.3 (0.5-3.4), respectively. The TC 776 GG genotype in mothers and children revealed risk estimates of 2.2 (0.7-7.1) and 1.9 (0.5-7.4), respectively. In conclusion, MTRR 66 GG and TC 776 GG genotypes in mothers and children may contribute to the risk of CHDs, particularly when the maternal vitamin B12 status is low. The future enlargement of our sample size might demonstrate significant associations.     

结合珠蛋白基因1/2多态性与中国人冠心病易感性的关联研究

目的 通过分析冠心病患者及冠脉正常组中结合珠蛋白(haptoglobin,HP)基因1/2多态性分布,初步探讨HP基因1/2多态性与冠心病易感性的关系.方法 经冠脉造影确诊冠心病组189例,冠脉正常对照组242名;采用聚合酶链反应-限制性片段长度多态性技术检测所有受试者HP基因型.结果 冠心病组HP基因型分布与对照组相比差异有统计学意义(P=0.002),表现为HP2-2基因型在冠心病组的频率明显高于对照组(0.54vs.0.35,P=0.000),单因素分析显著增加冠心病的风险(OR=2.166,95%CI:1.467～3.196),HP2等位基因的频率也明显高于对照组(0.74 vs.0.61).同时,多因素Logistic回归分析表明HP2-2基因型是冠心病的独立危险因素(P=0.002;OR=2.101,95%CI:1.311～3.367).结论 HP2-2基因型与冠心病的发生相关,可能是冠心病发病的独立危险因子;HP2等位基因可能是中国人冠心病的易感基因.

Abstract：

Objective To assess the association of haptoglobin (HP)1/2 polymorphism with coronary heart disease (CHD) in Chinese Hans. Methods One hundred and eighty-nine CHD patients and 242 healthy controls confirmed with angiography were recruited. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was utilized to genotype the HP1 and HP2 alleles and genotype frequencies in cases and controls were compared. Results The frequency of HP2-2 genotype was significantly higher in CHDs than in controls (0. 54 vs. 0.35, P=0.000). The HP2-2 genotype significantly increased the risk for CHD in univariable analysis (OR= 2. 165, 95% CI: 1. 467-3. 196). Multifactor Logistic regression analysis indicated that HP2-2 genotype is an independent risk factor to CHD (P=0.002;OR=2. 101, 95% CI: 1. 311-3. 367). Similarly, the HP2 allele frequency in the CHD group was significantly higher than that in the control subjects (0.74 vs. 0. 61, P= 0. 000). Conclusion The HP2-2genotype is associated with CHD in Chinese. HP2-2 genotype may be an independent risk factor to CHD,and HP2 allele may be a genetic susceptibility factor to CHD in Chinese.     

Using second trimester ultrasound and maternal serum biomarker data to help detect congenital heart defects in pregnancies with positive triple-marker screening results

Congenital heart defects (CHDs) are the most common of all birth defects. For many newborns with a CHD, prenatal versus postnatal detection is associated with substantially decreased morbidity and mortality risks. Although technological advances in fetal echocardiography have led to an increased capacity to detect CHDs prenatally, pregnancies without an identified risk factor are not routinely screened. With the aim of identifying pregnancies at increased risk for CHDs, this study examined the relationship between CHDs and typically collected second trimester biomarker data collected on a large population-based sample of singleton pregnancies with one or more second trimester screen positive result for Down syndrome, trisomy 18 (T-18), Smith-Lemli-Opitz syndrome (SLOS), or a neural tube defect (NTD). Where possible, logistic models for cases and controls were built and potential referral models were tested among study subsamples with information on the presence or absence of CHDs reported pre- and perinatally. When considered in combination, screen positive for T-18, screen positive for SLOS, nuchal fold measurement > or = 5 mm, and/or having an adjusted hCG multiple of the median > or = the 95th centile detected 42.7% of all pregnancies with a CHD in the combined subsample (where co-occurrence with chromosomal defects was not considered) and detected 29.7% of all pregnancies with a CHD in the no-chromosomal defect subsample. A nuchal fold measurement > or = 5 mm detected 18.2% of those with a CHD in the Down syndrome subsample and an adjusted hCG multiple of the median (MoM) < or = 5th centile detected 92.9% of those with a CHD in the T-18 subsample.     

Association between VEGF polymorphisms (936c/t, -460t/c and -634g/c) with haplotypes and coronary heart disease susceptibility

Aim: Our aim was to investigate the association between single nucleotide polymorphisms (SNPs) of vascular endothelial growth factor (VEGF) and coronary heart disease (CHD) susceptibility in Chinese Han population. Methods: 144 CHD patients and 150 healthy individuals were enrolled in the study. Three SNPs (936C/T, -460T/C and -634G/C) of VEGF were chose and then were genotyped with Sequenom time-of-flight mass spectrometry (TOFMS). Odds ratio (OR) with 95% confidence interval (CI) were used to evaluate the association of genotypes and haplotypes and CHD susceptibility. Results: The frequencies of -460T/C CC genotype (13.6%) was found higher in the case group than that of control group (6.7%), which indicated that CC genotype was a risk factor for CHD (OR=2.50, 95% CI=1.10-5.68). Correspondently, the C allele appeared to increase the risk of CHD (OR=1.54, 95% CI=1.07-2.22). For -634G/C polymorphism, the risk of the CC genotype carrier for CHD increased 2.24 fold compared to the wild genotype. Moreover, -634G/CC allele was significantly associated with CHD susceptibility (OR=1.65, 95% CI=1.15-2.36). In addition, +936C/T CT genotype and C allele appeared to be a genetic-susceptibility factors for CHD (OR=2.43, 95% CI=1.44-4.10; OR=1.95, 95% CI=1.26-3.02). The haplotype analysis showed that T-C-T, C-C-C and C-G-C haplotypes all could increase the risk for CHD (OR: 2.43, 2.77 and 2.33). Conclusion: we concluded VEGF polymorphisms were associated with CHD susceptibility. Moreover, the haplotypes of T-C-T, C-C-C and C-G-C all could increase the risk for CHD.     

纤溶酶原激活剂抑制物-1基因启动子区-6754G/5G多态性与中国人冠心病的关联研究

目的　研究纤溶酶原激活剂抑制物 - 1(plasminogen activator inhibitor- 1,PAI- 1)基因启动子区 - 6 75 4 G/ 5 G多态性与中国人冠状动脉粥样硬化性心脏病 (coronary heartdisease,CHD,简称冠心病 )发病的关系。方法　应用聚合酶链反应 -限制性片段长度多态性分析 ,对 12 1名健康人和 12 6例冠心病患者(其中急性心肌梗塞 4 7例 ,陈旧性心肌梗塞 39例 ,心绞痛 4 0例 )进行了 PAI- 1基因 4 G/ 5 G多态性分析。结果　 PAI- 1基因 4 G等位基因频率冠心病组 (0 .6 0 )显著高于正常对照组 (0 .4 8) (χ2 =7.6 3,P<0 .0 1) ;4 G/4 G基因型基因频率冠心病组 (0 .397)显著高于正常对照组 (0 .190 ) (χ2 =12 .6 7,P<0 .0 1) ,与 5 G/ 5 G基因型相比 ,对冠心病的比数比 (odds ratio,OR)为 2 .5 4 ,95 %的可信区间 (confidence interval,CI) :1.2 2～ 5 .2 7(P<0 .0 5 ) ,差异有显著性 ,而 4 G/ 5 G基因型对冠心病的 OR为 1.2 8,95 % CI:1.4 5～ 2 .38(P>0 .0 5 ) ,差异无显著性。结论　PAI- 1基因 4 G/ 4 G基因型与中国汉族人冠心病的发病有关联 ,4 G/ 4 G基因型个体易发生冠心病     

孕前半年父亲铅暴露与子代先天性心脏病病因的关联

目的探讨孕前半年父亲环境危险因素暴露与子代先天性心脏病的病因学关联,为CHD的预防提供依据。方法采用统一制定的调查表,按1:2进行匹配,对先心病例组和对照组的父母分别进行面对面结构式访谈,调查相关的影响因素。结果孕前半年父亲铅暴露(OR=4.516)、母亲自然流产史(OR=5.656)、孕前和孕早期夫妻经常争吵(OR=3.557)与子代CHD的发生存在显著相关性(P0.05)。结论父亲的职业环境和母亲的精神因素应给予高度关注,积极寻找自然流产史夫妇的高危因素,对预防子代CHD的发生尤为重要。     

Population-based study of congenital heart defects in Down syndrome

Mental retardation and hypotonia are found in virtually all Down syndrome (DS) individuals, whereas congenital heart defects (CHDs) are only present in a subset of cases. Although there have been numerous reports of the frequency of CHDs in DS, few of the studies have had complete ascertainment of DS in a defined geographic area. The Atlanta Down Syndrome Project, a population-based study of infants born with trisomy 21, provides such a resource. In the first 6.5 years of the study, 243 trisomy 21 livebirths were identified in the five-county Atlanta area (birth prevalence: 9.6/10,000). Cardiac diagnoses were available on 227 (93%) of the cases and 89% of these evaluations were made by echocardiography, cardiac catheterization, surgery, or autopsy. Of the 227 DS infants, 44% had CHDs including 45% atrioventricular septal defect (with or without other CHDs), 35% ventricular septal defect (with or without other CHDs), 8% isolated secundum atrial septal defect, 7% isolated persistent patent ductus arteriosus, 4% isolated tetralogy of Fallot, and 1% other. This report is unique in that it contains the largest number of trisomy 21 infants ascertained in a population-based study where modern techniques for diagnosing cardiac abnormalities predominate. Am. J. Med. Genet. 80:213–217, 1998. © 1998 Wiley-Liss, Inc.     

P-selectin gene polymorphism associates with pulmonary hypertension in congenital heart disease

Objective: To investigate the relationship between P-selectin gene polymorphism and congenital heart disease (CHD) with pulmonary hypertension (PAH). Methods: 58 CHD patients with PAH (PAH-CHD), 43 CHD patients without PAH and 205 healthy subjects were included in this study. The concentration of plasma P-selectin was determined by ELISA kits; the direct sequencing of PCR products was used to analyze the P-selectin genotypes. Results: The concentration of plasma P-selectin was markedly higher in PAH-CHD patients than that in CHD subjects and controls, while no difference was observed between CHD group and control. A significant difference of P-selectin genotype -825T/C polymorphism was observed between patients with PAH-CHD and healthy subjects (P<0.05). Logistic analysis showed that the subjects with haplotypes A-G and G-G had lower risk of PAH-CHD compared with the ones with haplotype A-A (OR=0.47, 95% CI=0.24-0.92). In the subjects of PAH-CHD and control, plasma P-selectin concentration was higher in subjects with -825TT genotype than the ones with haplotypes T-C and C-C (P<0.05). Conclusion: P-selectin probably involves in the development of PAH-CHD. The polymorphism of -825T/C is associated with the risk of PAH-CHD, and may be one of its risk factors.     

The MTHFD1 p.Arg653Gln variant alters enzyme function and increases risk for congenital heart defects

Methylenetetrahydrofolate dehydrogenase)methenyltetrahydrofolate cyclohydrolase)formyltetrahydrofolate synthetase (MTHFD1) is a trifunctional enzyme that interconverts tetrahydrofolate (THF) derivatives for nucleotide synthesis. A common variant in MTHFD1, p.Arg653Gln (c.1958G>A), may increase the risk for neural tube defects (NTD). To examine the biological impact of this variant on MTHFD1 function, we measured enzyme activity and stability in vitro and assessed substrate flux in transfected mammalian cells. The purified Arg653Gln enzyme has normal substrate affinity but a 36% reduction in half)life at 42 degrees C. Thermolability is reduced by magnesium adenosine triphosphate and eliminated by the substrate analog folate pentaglutamate, suggesting that folate status may modulate impact of the variant. The mutation reduces the metabolic activity of MTHFD1 within cells: formate incorporation into DNA in murine Mthfd1 knockout cells transfected with Arg653Gln is reduced by 26%+/-7.7% (P<0.05), compared to cells transfected with wild)type protein, indicating a disruption of de novo purine synthesis. We assessed the impact of the variant on risk for congenital heart defects (CHD) in a cohort of Quebec children (158 cases, 110 controls) and mothers of children with heart defects (199 cases, 105 controls). The 653QQ genotype in children is associated with increased risk for heart defects (odds ratio [OR], 2.11; 95% confidence interval [CI], 1.01-4.42), particularly Tetralogy of Fallot (OR, 3.60; 95% CI, 1.38-9.42) and aortic stenosis (OR, 3.13; 95% CI, 1.13-8.66). There was no effect of maternal genotype. Our results indicate that the Arg653Gln polymorphism decreases enzyme stability and increases risk for CHD. Further evaluation of this polymorphism in folate)related disorders and its potential interaction with folate status is warranted.     

血管内皮生长因子基因多态性与先天性心脏病相关性的Meta分析

目的 评价血管内皮生长因子（VEGF）等位基因、基因型、基因单倍型多态性与先天性心脏病（CHD）的相关性.方法 检索Cochrane图书馆、Medline、PubMed、EMBASE、中国期刊全文数据库、万方数据库及中国生物医学文献数据库,检索起止时间均为建库至2011年12月,并且对重要文献的参考文献采取手工回溯检索.获取VEGF与CHD相关性的病例对照研究和传递不平衡检验文献.对文献进行质量评价.采用RevMan 5.1.1软件进行异质性检验,根据检验结果选择适当的效应模型进行Meta分析.结果 6篇文献共10项独立研究纳入分析,漏斗图检验存在发表偏倚.Meta分析结果显示：① VEGF C-2578A和G-1154A位点等位基因变异显著增加DiGeorge综合征患者的CHD易感性,OR分别为1.40（95%CI：1.04～1.16）和1.87（95%CI：1.27～2.75）;G-634C位点的等位基因变异显著增加普通病例的CHD易感性,OR=1.29,95%CI：1.02～1.62.② G-1154A位点（AA＋AG）为DiGeorge综合征患者合并CHD的危险因素,OR=2.10,95%CI：1.32～3.34.③单倍型AAG在DiGeorge综合征患者中显著增加CHD易感性,OR=1.82,95%CI：1.31～2.54;单倍型CGC显著降低普通病例CHD风险的保护作用,OR=0.79,95%CI：0.63～0.99.结论 VEGF等位基因、基因型、基因单倍型多态性与CHD易感性存在一定的相关性,且在DiGeorge综合征患者与普通患者间存在差异;在不伴DiGeorge综合征的人群中,特定单倍型（CGC）则有显著降低CHD风险的保护作用,其作用机制尚需进一步明确.     

Congenital heart defects in Kabuki syndrome

Kabuki makeup (Niikawa-Kuroki) syndrome (KS) is characterized by distinct facial anomalies, mental retardation, congenital heart defect (CHD), and skeletal malformations. In the present study we analyze cardiac characteristics and differences in sex prevalence of specific CHDs in our series of patients with KS and review published reports from the literature. Between January 1992 and February 2000, 60 patients (37 males and 23 females) with KS underwent phenotypic and cardiac evaluations at our hospital. CHD was diagnosed in 35 (58%) of our patients. Aortic coarctation (COA) (23%), atrial septal defect (ASD) (20%), and ventricular septal defect (VSD) (17%) were the most frequent CHDs in our series and in previous reports from the literature. Male preponderance was noted in patients with COA. In conclusion, CHD is a cardinal feature of KS. There is an overlap between cardiac malformations of KS and those of Turner syndrome. Male preponderance in patients with KS and COA supports the hypothesis that genes located on the X chromosome may be involved in determining KS in some patients. The high prevalence of CHD prompts accurate re-examination of patients evaluated by pediatric cardiologists in order to identify mild and still unrecognized cases of KS.     

Prenatal Diagnosis of Congenital Heart Diseases and Associations with Serum Biomarkers of Aneuploidy: A Multicenter Prospective Cohort Study

PurposeWe assessed prenatal detection rates of congenital heart disease (CHD) and associations between maternal serum biomarkers and non-chromosomal CHD in singleton pregnancies.Materials and MethodsThis study was conducted as a secondary analysis of data obtained during a multicenter prospective cohort study that investigated the cost-effectiveness of prenatal testing for fetal aneuploidy. We analyzed the prenatal detection rate and accuracy for CHD screening via ultrasound during the second trimester, as well as associations between serum biomarkers and CHDs, in singleton newborns without chromosomal abnormalities.ResultsAmong 6715 women, 142 (2.1%) newborns were born with CHDs, of which 67 (1.0%) newborns had major CHDs. The prenatal detection rate for all CHDs and major CHDs were 34.5% and 58.2%, respectively. After excluding isolated ventricular septal defects, the detection rate for critical CHDs was 85.9%. Women with low pregnancy-associated plasma protein A (PAPP-A) (<0.4 multiples of the median, MOM) face increased risks of non-chromosomal CHDs [adjusted odds ratio (aOR) 2.76; 95% confidence interval (CI) 1.36–5.13] and major CHDs (aOR 7.30; 95% CI 3.18–15.59), compared to those without CHDs. A higher inhibin A level (≥2.5 MOM; aOR 4.84; 95% CI 1.42–12.46) was associated with non-chromosomal major CHDs.ConclusionUltrasonography performed during the second trimester by obstetricians detected over 85% of critical CHDs. Low maternal serum PAPP-A or high inhibin-A was associated with non-chromosomal CHDs. These results may contribute to an improvement in prenatal diagnosis of CHDs.