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.     

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.

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.     

The risk for congenital heart defects in offspring of individuals with congenital heart defects

BACKGROUND: Congenital heart defects (CHDs) occur in approximately 1% of all live births. Although most CHDs are of unknown etiology, a family history of CHDs is a known risk factor, and offspring of individuals with CHDs are at a higher risk of having CHDs. The aim of this study was to investigate the relative risk for CHDs to offspring of individuals with CHDs. METHODS: The prevalence rates of CHDs in offspring of 203 individuals with CHDs and 282 individuals without CHDs were investigated. The study participants completed a questionnaire that included information on medical and reproductive history, lifestyle indicators, and family history of CHDs and other congenital malformations. The prevalence rates of CHDs in offspring were calculated. RESULTS: The prevalence of CHDs was 3.1% (18/575) in offspring of individuals with CHDs and 1.3% (8/589) in offspring of individuals without CHDs. The adjusted odds ratio for CHDs to offspring of parents with CHDs was 1.73 (95% confidence interval [95% CI] 0.89-2.44, p=0.02). The estimated relative risk for offspring to females with CHD was higher than for males [2.3 (95% CI 1.1-4.7, p=0.03) versus 1.31 (95% CI 0.48-4.30, p=0.66), respectively]. There was no suggestion of association between CHDs and maternal smoking, alcohol consumption, and use of medication during pregnancy. CONCLUSIONS: Offspring of parents with CHDs are at a higher risk for CHDs compared with the general population. Couples where one member is affected with CHD should receive pre-conceptional or pre-natal genetic counseling and should be informed about the magnitude of the potential risk of CHDs to the offspring.     

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.     

Differences in morbidity and mortality in Down syndrome are related to the type of congenital heart defect

Morbidity and mortality in Down syndrome (DS) are mainly related to congenital heart defects (CHDs). While CHDs with high prevalence in DS (typical CHDs), such as endocardial cushion defects, have been extensively described, little is known about the impact of less common CHDs (atypical CHDs), such as aortic coarctation and univentricular hearts. In our single‐center study, we analyzed, in observational, retrospective manner, data regarding cardiac features, surgical management, and outcomes of a cohort of DS patients. Literature review was performed to investigate previously reported studies on atypical CHDs in DS. Patients with CHDs were subclassified as having typical or atypical CHDs. Statistical analysis was performed for comparison between the groups. The study population encompassed 859 DS patients, 72.2% with CHDs, of which 4.7% were atypical. Statistical analysis showed a significant excess in multiple surgeries, all‐cause mortality and cardiac mortality in patients with atypical CHDs (p = .0067, p = .0038, p = .0001, respectively). According to the Kaplan–Meier method, survival at 10 and 40 years was significantly higher in typical CHDs (99 and 98% vs. 91 and 84%, log rank <0.05). Among atypical CHDs, it seems that particularly multiple complex defects in univentricular physiology associate with a worse outcome. This may be due to the surgical difficulty in managing univentricular hearts with multiple defects concurring to the clinical picture or to the severity of associated defects themselves. Further studies need to address this specific issue, also considering the higher pulmonary pressures, infective complications, and potential comorbidities in DS patients.     

Paternal risk factors for isolated membranous ventricular septal defects

A case-control study using data from the Baltimore-Washington Infant Study (BWIS) examined possible paternal risk factors in the etiology of isolated membranous ventricular septal defects (VSD). There were 641 total VSD case infants and 3,549 randomly selected control infants ascertained between 1981 and 1989. Isolated membranous VSDs were identified in 499 cases. Socio-demographic factors (such as parental age and race), social habits, and medical conditions were analyzed by multiple logistic regression in order to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI). Paternal age was not found to be a risk factor per se, but small positive associations were found for some social habits and maternal factors. Significant associations were found for paternal marijuana use (OR 1.36, 95% CI 1.05-1.76), African-American race of the infant (OR 1.34, 95% CI 1.09-1.65), and for cocaine use among older fathers (OR 3.92, 95% CI 1.30-11.86). These associations support a multifactorial etiologic hypothesis for isolated membranous VSDs and point to some interesting parental behavioral and medical considerations which may contribute to risk for this common birth defect. Am. J. Med. Genet. 71:42–46, 1997. © 1997 Wiley-Liss, Inc.     

A population-based study of craniosynostosis in metropolitan Atlanta, 1989-2003

Craniosynostosis is a birth defect characterized by premature fusion of one or more cranial sutures. We describe the birth prevalence of craniosynostosis and related risk factors among infants born to residents of metropolitan Atlanta during 1989-2003. Data from the Metropolitan Atlanta Congenital Defects Program (MACDP) were used to identify infants with craniosynostosis. Case records with a code for craniosynostosis were reviewed to substantiate the diagnosis of craniosynostosis and to classify infants as having isolated craniosynostosis (no other unrelated major defects), multiple defects (one or more additional major, unrelated defects), or a syndrome (recognized or strongly suspected single-gene condition or chromosome abnormality). Vital records data on births of Georgia residents were used to analyze craniosynostosis prevalence by year of birth, maternal race and age, parity, plurality, and infants' sex, birth weight, and gestational age. We identified 281 infants born with craniosynostosis in metropolitan Atlanta during 1989-2003: 84% with isolated craniosynostosis, 7% with multiple defects, and 9% with syndromes. The birth prevalence was 4.3 per 10,000 births, results consistent with findings from other population-based studies using similar case definitions. Apert syndrome was diagnosed in 40% of the syndromic cases, and sagittal synostosis was diagnosed in 39% of the cases of nonsyndromic craniosynostosis. Maternal age 35 years or older, multiple birth, male sex, and birth weight >4,000 g were risk factors for craniosynostosis.     

先天性心脏病的病因学研究进展

先天性心脏病（Congenital Heart Defects,CHD）是一类最常见的出生缺陷。其发病原因中遗传因素占有重要的位置。主要遗传因素有染色体畸变、单基因缺陷、多基因缺陷以及遗传代谢异常几类。本文按照心脏异常的不同种类分别就遗传因素的研究进展进行综述,并对研究前景进行展望。     

Functions of cilia in cardiac development and disease

Errors in embryonic cardiac development are a leading cause of congenital heart defects (CHDs), including morphological abnormalities of the heart that are often detected after birth. In the past few decades, an emerging role for cilia in the pathogenesis of CHD has been identified, but this topic still largely remains an unexplored area. Mouse forward genetic screens and whole exome sequencing analysis of CHD patients have identified enrichment for de novo mutations in ciliary genes or non-ciliary genes, which regulate cilia-related pathways, linking cilia function to aberrant cardiac development. Key events in cardiac morphogenesis, including left–right asymmetric development of the heart, are dependent upon cilia function. Cilia dysfunction during left–right axis formation contributes to CHD as evidenced by the substantial proportion of heterotaxy patients displaying complex CHD. Cilia-transduced signaling also regulates later events during heart development such as cardiac valve formation, outflow tract septation, ventricle development, and atrioventricular septa formation. In this review, we summarize the role of motile and non-motile (primary cilia) in cardiac asymmetry establishment and later events during heart development.     

Risk factors for primary congenital glaucoma in the National Birth Defects Prevention Study

Primary congenital glaucoma (PCG) is a rare but serious birth defect. Genetic mutations have been implicated in the development of PCG, but little is known about nongenetic risk factors. This study investigates potential risk factors for PCG in the National Birth Defects Prevention Study (NBDPS), a large population‐based case–control study of major birth defects in the United States. The analysis includes case infants with PCG (N = 107) and control infants without birth defects (N = 10,084) enrolled in NBDPS from birth years 2000–2011. Pregnancy/infant clinical characteristics, demographics, and parental health history were collected through maternal interview. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were computed to examine associations with all PCG cases and isolated PCG cases without other major malformations. Associations with all the cases included term low birth weight (<2,500 g; aOR = 2.80, CI 1.59–4.94), non‐Hispanic black maternal race/ethnicity (aOR = 2.42, CI 1.42–4.13), maternal history of seizure (aOR = 2.73, CI 1.25–5.97), maternal antihypertensive use (aOR = 3.60, CI 1.52–8.53), and maternal sexually transmitted infection (aOR = 2.75, CI 1.17–6.44). These factors were also associated with isolated PCG, as was maternal use of nonsteroidal anti‐inflammatory drugs (aOR = 2.70, CI 1.15–6.34). This study is among the first to examine a wide array of potential risk factors for PCG in a population‐based sample.     

A Three‐Way Interaction among Maternal and Fetal Variants Contributing to Congenital Heart Defects

Congenital heart defects (CHDs) develop through a complex interplay between genetic variants, epigenetic modifications, and maternal environmental exposures. Genetic studies of CHDs have commonly tested single genetic variants for association with CHDs. Less attention has been given to complex gene‐by‐gene and gene‐by‐environment interactions. In this study, we applied a recently developed likelihood‐ratio Mann‐Whitney (LRMW) method to detect joint actions among maternal variants, fetal variants, and maternal environmental exposures, allowing for high‐order statistical interactions. All subjects are participants from the National Birth Defect Prevention Study, including 623 mother‐offspring pairs with CHD‐affected pregnancies and 875 mother‐offspring pairs with unaffected pregnancies. Each individual has 872 single nucleotide polymorphisms encoding for critical enzymes in the homocysteine, folate, and trans‐sulfuration pathways. By using the LRMW method, three variants (fetal rs625879, maternal rs2169650, and maternal rs8177441) were identified with a joint association to CHD risk (nominal P‐value = 1.13e‐07). These three variants are located within genes BHMT2, GSTP1, and GPX3, respectively. Further examination indicated that maternal SNP rs2169650 may interact with both fetal SNP rs625879 and maternal SNP rs8177441. Our findings suggest that the risk of CHD may be influenced by both the intragenerational interaction within the maternal genome and the intergenerational interaction between maternal and fetal genomes.     

Associations between chromosomal anomalies and congenital heart defects: A database search

Recent technical advances in molecular biology and cytogenetics, as well as a more developmental approach to congenital heart disorders (CHDs), have led to considerable progress in our understanding of their pathogenesis, especially of the important causative role of genetic factors. The complex embryology of the heart suggests the involvement of numerous genes, and hence, numerous chromosomal loci, such as the recently identified 22q11, in normal cardiomorphogenesis. In order to identify other loci, the Human Cytogenetics DataBase was searched for all chromosome anomalies associated with CHD. Through the application of several (arbitrary) criteria we have selected associations occurring so frequently that they may not be forfuituous, suggesting assignment of a gene or genes responsible for specific CHDs to certain chromosome regions. The results of this study may be a first step in the detection of specific chromosome defects responsible for CHD, which will be useful in daily patient care and may provide clues for further cytogenetic and molecular studies. Am. J. Med. Genet. 84:158–166, 1999. © 1999 Wiley-Liss, Inc.     

Congenital heart defects and copy number variants associated with neurodevelopmental impairment

A genetic etiology is identifiable in 20%–30% of patients with congenital heart defects (CHD). Chromosomal microarray analysis (CMA) can detect copy number variants (CNV) associated with CHD. In previous studies, the diagnostic yield of postnatal CMA testing ranged from 4% to 28% in CHD patients. However, incidental pathogenic CNV and variants of unknown significance are often discovered without any known association with CHD. The study objective was to describe the rate of pathogenic CNV associated with neurodevelopmental impairment (NDI) and compare clinical findings in CHD neonates with genetic results. A single-center retrospective review was performed on all consecutive newborns with CHD admitted to a tertiary neonatal intensive care unit from January 2013 to March 2019 (n = 525). CHD phenotypes were classified as per the National Birth Defect Prevention Study. CMA detected pathogenic CNV in 21.3% (61/287) of neonates, and karyotype or fluorescence in situ hybridization detected aneuploidies in an additional 11% of the overall cohort (58/525). Atrioventricular septal defects and conotruncal defects showed the highest diagnostic yield by CMA (28.6% and 27.2%, respectively). Among neonates with pathogenic CNV on CMA, 78.7% (48/61) were associated with NDI. Neonates with pathogenic CNV were smaller in length at birth compared to those with benign CNV or variants of unknown significance (p = 0.005) and were more likely to be discharged with an enteral feeding tube (p = 0.027). CMA can discover genetic variants associated with NDI and are common in neonates with CHD. Genetic testing in the neonatal period can heighten awareness of genetic risk for NDI.     

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.     

Possible association between complex congenital heart defects and 11p15 hypomethylation in three patients with severe Silver–Russell syndrome

Silver–Russell syndrome (SRS) is characterized by pre‐ and post‐natal growth restriction that spares head growth, feeding difficulties, and variable dysmorphic facial features without major malformations. Hypomethylation of the paternal 11p15 imprinting control region 1 (ICR1) and maternal uniparental disomy of chromosome 7 are found in 50–60% and in 5–10% of SRS patients, respectively. We report on the pre‐ and post‐natal features of three unrelated SRS patients with unusual congenital heart defects (CHDs). Two patients born prematurely had total anomalous pulmonary venous return and died shortly after birth, and a third patient, now 4 years old, had cor triatriatum sinistrum, which was surgically corrected. In all three patients, the underlying molecular defect was 11p15 ICR1 hypomethylation. Based on a large cohort with molecularly proven SRS, the prevalence of CHD in SRS is estimated at 5.5%. We suggest that the occurrence of CHD in SRS with 11p15 ICR1 hypomethylation is not coincidental, but specific to this genotype. © 2013 Wiley Periodicals, Inc.     

Recent progress in the molecular genetics of congenital heart defects

Congenital heart defects (CHD) constitute the single most common anatomic class of birth defects and are a major cause of infant mortality. Correlation of normal and pathological embryology/anatomy has led to the formulation of mechanistic models, but there is limited understanding of the genetic basis for the inferred embryological processes. Most evidence points to extensive etiologic heterogeneity and a re-evaluation of simple multifactorial models is required. The recent identification of several genes responsible for congenital heart defects in the context of more complex clinical disorders provides significant entry points for the genetic analysis of human heart development. The association of aneusomies (particularly microdeletion syndromes) with specific cardiac lesions provides further strong support for mechanistic classification. Studies in the mouse are laying the groundwork for a comprehensive genetic model of cardiac organogenesis. Nevertheless, the basis for the large majority of CHD, especially isolated defects, remains obscure. Dissection of the genetic components of CHD is one of the greatest challenges in medical genetics for the coming decades.