Verkleij-Hagoort , A.C.

Phenotypic variability of atypical 22q11.2 deletions not including TBX1 (Article)

2012-10-01T00:00:00Z

Interstitial deletions of the chromosome 22q11.2 region are the most common microdeletions in humans. The TBX1 gene is considered to be the major candidate gene for the main features in 22q11.2 deletion syndrome, including congenital heart malformations, (para)thyroid hypoplasia, and craniofacial abnormalities. We report on eight patients with atypical deletions of chromosome 22q11.2. These deletions comprise the distal part of the common 22q11.2 deleted region but do not encompass the TBX1 gene. Ten similar patients with overlapping distal 22q11.2 deletions have been reported previously. The clinical features of these patients are described and compared to those found in the classic 22q11.2 deletion syndrome. We discuss the possible roles of a position effect or haploinsufficiency of distally located genes (e.g., CRKL) in the molecular pathogenesis of the 22q11.2 deletion syndrome.

High maternal vitamin E intake by diet or supplements is associated with congenital heart defects in the offspring (Article)

2009-02-01T00:00:00Z

Objective: To study associations between maternal dietary and supplement intake of antioxidants vitamin E, retinol and congenital heart defects (CHDs). Design: Case-control study. Setting: Erasmus MC, University Medical Center Rotterdam, the Netherlands. Population: Participants were 276 case mothers of a child with CHD and 324 control mothers with their children. Methods: Food frequency questionnaires covering the intake of the previous 4 weeks were filled out at 16 months after the index pregnancy. Data were compared between cases and controls using the Mann-Whitney U test. Risk estimates for the association between CHD and dietary intake of vitamin E and retinol were estimated in a multivariable logistic regression model. Main outcome measures: Medians (5-95th percentile) and odds ratios with 95% CI. Results: Dietary vitamin E intake was higher in case mothers than in controls, 13.3 (8.1-20.4) and 12.6 (8.5-19.8) mg/day (P = 0.05). CHD risk increased with rising dietary vitamin E intakes (P-trend = 0.01). Periconception use of vitamin E supplements in addition to a high dietary vitamin E intake above 14.9 mg/day up to nine-fold increased CHD risk. Retinol intakes were not significantly different between the groups and not associated with CHD risk. Conclusions: High maternal vitamin E by diet and supplements is associated with an increased risk of CHD offspring.

Maternal intake of fat, riboflavin and nicotinamide and the risk of having offspring with congenital heart defects (Article)

2008-10-01T00:00:00Z

Background: With the exception of studies on folic acid, little evidence is available concerning other nutrients in the pathogenesis of congenital heart defects (CHDs). Fatty acids play a central role in embryonic development, and the B-vitamins riboflavin and nicotinamide are co-enzymes in lipid metabolism. Aim of the study: To investigate associations between the maternal dietary intake of fats, riboflavin and nicotinamide, and CHD risk in the offspring. Methods: A case-control family study was conducted in 276 mothers of a child with a CHD comprising of 190 outflow tract defects (OTD) and 86 non-outflow tract defects (non-OTD) and 324 control mothers of a non-malformed child. Mothers filled out general and food frequency questionnaires at 16 months after the index-pregnancy, as a proxy of the habitual food intake in the preconception period. Nutrient intakes (medians) were compared between cases and controls by Mann-Whitney U test. Odds ratios (OR) for the association between CHDs and nutrient intakes were estimated in a logistic regression model. Results: Case mothers, in particular mothers of a child with OTD, had higher dietary intakes of saturated fat, 30.9 vs. 29.8 g/d; P < 0.05. Dietary intakes of riboflavin and nicotinamide were lower in mothers of a child with an OTD than in controls (1.32 vs. 1.41 mg/d; P < 0.05 and 14.6 vs. 15.1 mg/d; P < 0.05, respectively). Energy, unsaturated fat, cholesterol and folate intakes were comparable between the groups. Low dietary intakes of both riboflavin (<1.20 mg/d) and nicotinamide (<13.5 mg/d) increased more than two-fold the risk of a child with an OTD, especially in mothers who did not use vitamin supplements in the periconceptional period (OR 2.4, 95%CI 1.4-4.0). Increasing intakes of nicotinamide (OR 0.8, 95%CI 0.7-1.001, per unit standard deviation increase) decreased CHD risk independent of dietary folate intake. Conclusions: A maternal diet high in saturated fats and low in riboflavin and nicotinamide seems to contribute to CHD risk, in particular OTDs.

Two MTHFR polymorphisms, maternal B-vitamin intake, and CHDs (Article)

2008-06-01T00:00:00Z

BACKGROUND: The methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms are associated with complex congenital malformations. Whether these polymorphisms are associated with CHDs is not clear. We studied both MTHFR polymorphisms, folate and vitamin B2 by maternal food intake and supplements, and CHD risk. METHODS: A case-control family study was conducted in a European population in the Netherlands including 230 case and 251 control children with both parents. Approximately 17 months after the index pregnancy, mothers filled out standardized questionnaires on periconception use of folic acid supplements and a validated food frequency questionnaire on current dietary folate and vitamin B2 intake. All subjects were genotyped for the MTHFR C677T and A1298C polymorphisms. Data were analyzed by logistic regression analysis and ORs and 95% CIs were calculated. For the interaction analysis the dominant model was used. RESULTS: The risk estimates for the MTHFR 677 CT genotypes were 1.4 (0.9-2.0) in mothers, 1.1 (0.8-1.6) in fathers, and 1.2 (0.8-1.7) in children, and for the MTHFR 677 TT genotypes 0.9 (0.6-1.2), 1.4 (1.0-1.9), and 1.0 (0.7-1.3), respectively. The MTHFR 1298 CC genotype in fathers and the MTHFR 1298 AC genotype in children significantly reduced CHD risk, 0.6 (0.5-0.9) and 0.6 (0.4-0.9), respectively. Of interest is the significant interaction (p = .008) towards a nearly twofold increased risk in mothers carrying the MTHFR 1298 C allele and using a periconception folic acid supplement. CONCLUSIONS: The MTHFR C677T and A1298C polymorphisms are not strong risk factors for CHDs.

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

2008-05-01T00:00:00Z

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.

Complex congenital malformations and the impact of the plasminogen activator system and β-hCG in amniotic fluid (Article)

2007-11-01T00:00:00Z

Objective: The plasminogen activator system and β-hCG may affect neural crest cells and angiogenesis, and thereby embryogenesis. Therefore, we investigated these parameters in amniotic fluids of pregnancies with a complex congenital malformation. Study design: In a case-control study amniotic fluid samples were collected from 62 pregnancies with a complex congenital malformation and from 110 healthy control pregnancies at an obstetric department of a large university hospital in the Netherlands. We determined concentrations of tissue-type plasminogen activator (tPA), urokinase-type plasminogen activator (uPA), plasminogen activator inhibitors (PAI-1, PAI-2), tPA∼PAI-1 and uPA∼PAI-1 complexes, and β-hCG with enzyme-linked immunosorbent assays. Mann-Whitney U-tests and analysis of covariance, adjusting for gestational and maternal age, were performed for data comparisons. Results: Compared with controls, cases demonstrated significantly lower adjusted geometric mean levels of uPA (24%), tPA (≥19%) and tPA∼PAI-1 (35%). Cases showed significantly higher adjusted mean levels of β-hCG (≥48%) and PAI-2 (10 ng/mL) than controls. Mean PAI-1 and uPA∼PAI-1 levels were comparable between both groups. Conclusions: Disturbances in the plasminogen activator system and β-hCG levels are suggested to be involved in the pathogenesis of complex congenital malformations by affecting neural crest cell migration and angiogenesis.

Validation of the assessment of folate and vitamin B12 intake in women of reproductive age: The method of triads (Article)

2007-05-01T00:00:00Z

Objective: To validate the folate and vitamin B12intakes estimated by a food-frequency questionnaire (FFQ) designed to be used in a case-control study on the association between maternal dietary intake and the risk of having a child with a congenital heart defect. Design and subjects: The FFQ was filled out by 53 women of reproductive age. Immediately thereafter, blood samples were taken to determine serum folate, red blood cell (RBC) folate and serum vitamin B12concentrations. Subsequently, three dietary 24-h recalls (24HR) were completed during a period of three successive weeks and used as a reference method. The recalls comprised two weekdays and one weekend day. Using the method of triads, validity coefficients were calculated by comparing nutrient intakes derived from the FFQ and 24HR with the corresponding nutritional biomarkers in blood. The validity coefficient is the correlation between the dietary intake reported by the FFQ and the unknown 'true' dietary intake. Results: The comparison of B-vitaminin takes reported by the FFQ and the mean of the 24HR revealed deattenuated correlation coefficients of 0.98 for folate and 0.66 for vitamin B12. The correlation coefficients between the B-vitamin intakes estimated by the FFQ and concentrations of serum folate, RBC folate and serum vitamin B12were 0.20, 0.28 and 0.21, respectively. The validity coefficients for serum folate, RBC folate and serum vitamin B12were 0.94, 0.75 and 1.00, respectively. The estimated folate and vitamin B12intakes were comparable with the results of the most recent Dutch food consumption survey. Conclusions: The adapted FFQ is a reliable tool to estimate the dietary intake of energy, macronutrients, folate and vitamin B12in women of reproductive age. Therefore, this FFQ is suitable for the investigation of nutrient-disease associations in future.

Hyperhomocysteinemia and MTHFR polymorphisms in association with orofacial clefts and congenital heart defects: A meta-analysis (Article)

2007-05-01T00:00:00Z

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.

Homocysteine related Nutritional and Genetic Risk Factors for Human Congenital Heart Defects (Doctoral Thesis)

2007-04-25T00:00:00Z

Congenital heart defects (CHDs) belong to the most common group of major congenital malformations in newborns. Most CHDs are considered complex diseases with a multifactorial aetiology, which are thought to result from interactions between genetic and environmental factors. This thesis presents the results of the ongoing HAVEN study, in which human congenital heart anomalies and homocysteine related genetic and nutritional factors are investigated. We demonstrate that maternal hyperhomocysteinaemia more than three-fold increases the risk of CHD offspring. Moreover, a low maternal dietary vitamin B12 intake is associated with a nearly two-fold higher CHD risk. With regard to genetic factors, the 5,10-methylenetetrahydrofolate reductase (MHTFR) 1298 AA genotype in fathers and children showed a small but significantly increased CHD risk. Periconceptional folic acid supplementation is beneficial, particularly in children carrying the MTHFR 1298 AA genotype. Con! cerning vitamin B12 related polymorphisms, methionine synthase reductase 66 GG and transcobalamin 776 GG genotypes in mothers and children may contribute to CHD risk, especially combined with the maternal vitamin B12 status. These findings indicate that the maternal nutritional status and gene-nutrient interactions are involved in the pathogenesis of CHDs. Therefore, it might be favourable to advise women to use a diet rich in vitamin B12 and maybe a vitamin B12 supplement in addition to the daily folic acid supplement intake in the periconceptional period. These results can be directly implemented in the preconception care. Preconceptional screening is important for future risk assessment and counselling of parents to be and it may cause a reduced prevalence of CHDs.