CRELD1 mutations contribute to the occurrence of cardiac atrioventricular septal defects in Down Syndrome

Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, Maryland, United States
American Journal of Medical Genetics Part A (Impact Factor: 2.05). 11/2006; 140(22):2501-5. DOI: 10.1002/ajmg.a.31494
Source: PubMed
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    ABSTRACT: Cardiac affection is a common issue in the Down syndrome (DS) population, in the form of both congenital and acquired heart disorders. There are different types of congenital heart disease (CHD) in children with Down syndrome (DS). Echocardiography plays an important role in the detection of both structural and functional abnormalities in this group of patients. Fetal echocardiography can help in the early recognition of Down syndrome by detecting soft markers of DS, but its main role is to define the exact nature of the suspected cardiac problem in the fetus. Postnatal echocardiography is mandatory in the first month of life for all neonates with DS. It is also indicated before any cardiac surgery and for serial follow-up after cardiac surgery. In this Lecture, we discuss the types and mechanism of cardiac abnormalities in DS children and the role of both fetal and postnatal echocardiography in the detection of these abnormalities.
    First International Pediatric Conference, International Hospital of Bahrain, Kingdom of Bahrain, Mabama, Regency InterContinental Hotel, Bahrain; 10/2013
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    ABSTRACT: Atrioventricular septal defects (AVSD) are highly heritable, clinically significant congenital heart malformations. Genetic and environmental modifiers of risk are thought to work in unknown combinations to cause AVSD. Approximately 5-10% of simplex AVSD cases carry a missense mutation in CRELD1. However, CRELD1 mutations are not fully penetrant and require interactions with other risk factors to result in AVSD. Vascular endothelial growth factor-A (VEGFA) is a well-characterized modulator of heart valve development. A functional VEGFA polymorphism, VEGFA c.-634C, which causes constitutively increased VEGFA expression, has been associated with cardiac septal defects suggesting it may be a genetic risk factor. To determine if there is an allelic association with AVSD we genotyped the VEGFA c.-634 SNP in a simplex AVSD study cohort. Over-representation of the c.-634C allele in the AVSD group suggested that this genotype may increase risk. Correlation of CRELD1 and VEGFA genotypes revealed that potentially pathogenic missense mutations in CRELD1 were always accompanied by the VEGFA c.-634C allele in individuals with AVSD suggesting a potentially pathogenic allelic interaction. We used a Creld1 knockout mouse model to determine the effect of deficiency of Creld1 combined with increased VEGFA on atrioventricular canal development. Morphogenic response to VEGFA was abnormal in Creld1-deficient embryonic hearts, indicating that interaction between CRELD1 and VEGFA has the potential to alter atrioventricular canal morphogenesis. This supports our hypothesis that an additive effect between missense mutations in CRELD1 and a functional SNP in VEGFA contributes to the pathogenesis of AVSD.
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    ABSTRACT: Study of monogenic congenital heart disease (CHD) has provided entry points to gain new understanding of heart development and the molecular pathogenesis of CHD. In this review, we discuss monogenic CHD caused by mutations of the cardiac transcription factor genes NKX2-5 and GATA4. Detailed investigation of these genes in mice and humans has expanded our understanding of heart development, shedding light on the complex genetic and environmental factors that influence expression and penetrance of CHD gene mutations.
    Cold Spring Harbor Perspectives in Medicine 10/2014; 4(10). DOI:10.1101/cshperspect.a013946 · 7.56 Impact Factor