VEGFA polymorphisms and cardiovascular anomalies in 22q11 microdeletion syndrome: a case-control and family-based study

Juan Francisco Calderón,M Luisa Guzmán,Patricia Sanz,Teresa Aravena,Gabriela M Repetto,Mariana Aracena,Marta Arriaza,Carmen Paz Astete,Alonso R Puga

doi:10.4067/s0716-97602009000400007

Abstract

Microdeletion 22q11 in humans causes velocardiofacial and DiGeorge syndromes. Most patients share a common 3Mb deletion, but the clinical manifestations are very heterogeneous. Congenital heart disease is present in 50-80% of patients and is a significant cause of morbidity and mortality. The phenotypic variability suggests the presence of modifiers. Polymorphisms in the VEGFA gene, coding for the vascular endothelial growth factor A, have been associated with non-syndromic congenital heart disease, as well as with the presence of cardiovascular anomalies in patients with microdeletion 22q11. We evaluated the association of VEGFA polymorphisms c.-2578C>A (rs699947), c.-1154G>A (rs1570360) and c.-634C>G (rs2010963) with congenital heart disease in Chilean patients with microdeletion 22q11. The study was performed using case-control and family-based association designs. We evaluated 122 patients with microdeletion 22q11 and known anatomy of the heart and great vessels, and their parents. Half the patients had congenital heart disease. We obtained no evidence of association by either method of analysis. Our results provide further evidence of the incomplete penetrance of the cardiovascular phenotype of microdeletion 22ql 1, but do not support association between VEGFA promoter polymorphisms and the presence of congenital heart disease in Chilean patients with this syndrome.

Highlights

Microdeletion 22q11 syndrome is the most frequent known microdeletion syndrome in humans with an estimated incidence of 1/4,000-1/10,000 live births
Given the relevance of validation of these studies in independent populations, and the benefits of using test for association that reduce potential population stratification bias (Ott 2004; Lewis 2002), we evaluated the association of these 3 polymorphisms in the VEGFA promoter with the presence of congenital heart disease (CHD) in Chilean patients with del22q11, using case-control and family-based designs
4.8 genotypic frequencies of VEGFA promoter polymorphisms in the parents were in Hardy-Weinberg equilibrium

Summary

Introduction

Microdeletion 22q11 syndrome (del22q11) is the most frequent known microdeletion syndrome in humans with an estimated incidence of 1/4,000-1/10,000 live births (reviewed in Kobrynski and Sullivan 2007). The microdeletion causes of approximately 80-90% of cases of DiGeorge syndrome and 95-100% of cases of velocardiofacial (VCFS) and conotruncal anomaly face syndromes. The clinical manifestations of del22q11 are highly variable, and over 180 clinical features have been described. The most frequent findings include congenital heart disease (CHD), seen in 50-80% of patients, palatal abnormalities in 70-100%, endocrine defects such as hypoparathyoidism, hypothyroidism and growth hormone deficiency in 15-50%, immune deficiencies in 10%, learning disabilities in 50-80% and psychiatric. * currently at McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

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