Evaluation of heterogeneity in the association between congenital heart defects and variants of folate metabolism genes: Conotruncal and left-sided cardiac defects

AbstractSitus ambiguous comprises of 3% of congenital heart defects and is present in at least 1 in 10,000 live births. Most cases diagnosed prenatally are associated with complex cardiac defects which can be detected by ultrasonography. This is a case report of a fetus presenting with hydrops, which was detected to have situs ambiguous, a complex cardiac defect and multiple laterality defects on autopsy.

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Congenital Cardiac Defects and Critical Congenital Heart Defects

Fast Facts for The Neonatal Nurse ◽

10.1891/9780826184917.0019 ◽

2020 ◽

Keyword(s):

Congenital Heart Defects ◽

Congenital Heart ◽

Heart Defects ◽

Cardiac Defects ◽

Congenital Cardiac Defects

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Blood flow patterns underlie developmental heart defects

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00641.2016 ◽

2017 ◽

Vol 312 (3) ◽

pp. H632-H642 ◽

Cited By ~ 29

Author(s):

Madeline Midgett ◽

Kent Thornburg ◽

Sandra Rugonyi

Keyword(s):

Blood Flow ◽

Congenital Heart Defects ◽

Dose Response ◽

Congenital Heart ◽

Heart Defects ◽

Flow Patterns ◽

Early Embryo ◽

Response Type ◽

Cardiac Defects ◽

Blood Flow Patterns

Although cardiac malformations at birth are typically associated with genetic anomalies, blood flow dynamics also play a crucial role in heart formation. However, the relationship between blood flow patterns in the early embryo and later cardiovascular malformation has not been determined. We used the chicken embryo model to quantify the extent to which anomalous blood flow patterns predict cardiac defects that resemble those in humans and found that restricting either the inflow to the heart or the outflow led to reproducible abnormalities with a dose-response type relationship between blood flow stimuli and the expression of cardiac phenotypes. Constricting the outflow tract by 10–35% led predominantly to ventricular septal defects, whereas constricting by 35–60% most often led to double outlet right ventricle. Ligation of the vitelline vein caused mostly pharyngeal arch artery malformations. We show that both cardiac inflow reduction and graded outflow constriction strongly influence the development of specific and persistent abnormal cardiac structure and function. Moreover, the hemodynamic-associated cardiac defects recapitulate those caused by genetic disorders. Thus our data demonstrate the importance of investigating embryonic blood flow conditions to understand the root causes of congenital heart disease as a prerequisite to future prevention and treatment. NEW & NOTEWORTHY Congenital heart defects result from genetic anomalies, teratogen exposure, and altered blood flow during embryonic development. We show here a novel “dose-response” type relationship between the level of blood flow alteration and manifestation of specific cardiac phenotypes. We speculate that abnormal blood flow may frequently underlie congenital heart defects.

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The genetics of folate metabolism and maternal risk of birth of a child with Down syndrome and associated congenital heart defects

Frontiers in Genetics ◽

10.3389/fgene.2015.00223 ◽

2015 ◽

Vol 6 ◽

Cited By ~ 28

Author(s):

Fabio Coppedè

Keyword(s):

Down Syndrome ◽

Congenital Heart Defects ◽

Congenital Heart ◽

Heart Defects ◽

Folate Metabolism ◽

Maternal Risk

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Risk of congenital heart defects is influenced by genetic variation in folate metabolism

Cardiology in the Young ◽

10.1017/s1047951112000431 ◽

2012 ◽

Vol 23 (1) ◽

pp. 89-98 ◽

Cited By ~ 13

Author(s):

Karen E. Christensen ◽

Yassamin Feroz Zada ◽

Charles V. Rohlicek ◽

Gregor U. Andelfinger ◽

Jacques L. Michaud ◽

...

Keyword(s):

Aortic Valve ◽

Ventricular Septal Defect ◽

Aortic Valve Stenosis ◽

Congenital Heart Defects ◽

Odds Ratio ◽

Multiple Testing ◽

Congenital Heart ◽

Septal Defect ◽

Heart Defects ◽

Folate Metabolism

AbstractGenetic disturbances in folate metabolism may increase risk for congenital heart defects. We examined the association of heart defects with four polymorphisms in folate-related genes (methylenetetrahydrofolate reductase (MTHFR) c.677C > T, MTHFR c.1298A > C, methionine synthase reductase (MTRR) c.66A > G, and reduced folate carrier (SLC19A1) c.80A > G) in a case–control study of children (156 patients, 69 controls) and mothers of children with heart defects (181 patients, 65 controls), born before folic acid fortification. MTRR c.66A > G in children modified odds ratios for overall heart defects, specifically ventricular septal defect and aortic valve stenosis (p-value below 0.05). The 66GG and AG genotypes were associated with decreased odds ratios for heart defects (0.42, 95% confidence interval (0.18–0.97) and 0.39 (0.18–0.84), respectively). This overall association was driven by decreased risk for ventricular septal defect for 66GG and AG (odds ratio 0.32 (0.11–0.91) and 0.25 (0.09–0.65)) and decreased odds ratio for aortic valve stenosis for 66AG (0.27 (0.09–0.79)). The association of ventricular septal defect and 66AG remained significant after correction for multiple testing (p = 0.0044, multiple testing threshold p = 0.0125). Maternal MTHFR 1298AC genotype was associated with increased odds ratio for aortic valve stenosis (2.90 (1.22–6.86), p = 0.0157), but this association did not meet the higher multiple testing threshold. No association between MTHFR c.677C > T or SLC19A1 c.80A > G and heart defect risk was found. The influence of folate-related polymorphisms may be specific to certain types of heart defects; larger cohorts of mothers and children with distinct sub-classes are required to adequately address risk.

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Unexpected death in children with severe congenital heart defects in Norway 2004–2016

Archives of Disease in Childhood ◽

10.1136/archdischild-2020-319936 ◽

2021 ◽

pp. archdischild-2020-319936

Author(s):

Gunnar Wik ◽

Jarle Jortveit ◽

Vasileios Sitras ◽

Gaute Døhlen ◽

Arild E Rønnestad ◽

...

Keyword(s):

Oxygen Saturation ◽

Congenital Heart Defects ◽

Congenital Heart ◽

Heart Defects ◽

Low Oxygen ◽

Clinical Registry ◽

Cardiac Intervention ◽

Cardiac Defects ◽

Staged Surgery

AimsUpdated knowledge on the rates and causes of death among children with severe congenital heart defects (CHDs) is needed to further improve treatment and survival. This study investigated nationwide mortality rates in children with severe CHDs with an emphasis on unexpected mortality unrelated to cardiac intervention.Methods and resultsData on all pregnancies and live-born children in Norway from 2004 to 2016 were obtained from national registries, the Oslo University Hospital’s Clinical Registry for CHDs and medical records. Among 2359 live-born children with severe CHDs, 234 (10%) died before 2 years of age. Of these, 109 (46%) died in palliative care, 58 (25%) died of causes related to a cardiac intervention and 67 (29%) died unexpectedly and unrelated to a cardiac intervention, either before (n=26) or following (n=41) discharge after a cardiac intervention. Comorbidity (38/67, 57%), persistent low oxygen saturation (SaO2; <95%; 41/67, 61%), staged surgery (21/41, 51%), residual cardiac defects (22/41, 54%) and infection (36/67, 54%) were frequent in children who died unexpectedly unrelated to an intervention. Two or more of these factors were present in 62 children (93%). The medical reports at hospital discharge lacked information on follow-up in many patients who died unexpectedly.ConclusionsThe numbers of unexpected deaths unrelated to cardiac intervention in children <2 years of age without comorbidity were low in Norway. However, close follow-up is recommended for infants with comorbidities, persistent low oxygen saturation, staged surgery or residual cardiac defects, particularly when an infection occurs.

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