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 percent 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.
Subject(s)
Adolescent , Adult , Child , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Male , Young Adult , DiGeorge Syndrome/genetics , Heart Defects, Congenital/genetics , Polymorphism, Genetic/genetics , Vascular Endothelial Growth Factor A/genetics , DiGeorge Syndrome/complications , Family , Gene Frequency , Haplotypes , Heart Defects, Congenital/etiology , Young AdultABSTRACT
Cystic fibrosis (CF) is caused by mutations in the CFTR gene. More than 1600 mutations have been described, with frequencies that differ worldwide according to the ethnic origin of patients. A small group of mutations are recurrent on several populations. It has been shown that they each tend occur on specific chromosome 7 haplotypes, supporting the notion of a single origin for them. Less than 50 percent of mutations in Chilean patients have been identified to date. To indirectly assess the possible presence of a predominant founder mutation in the remaining unknown al¡eles, we evaluated 2 polymorphic markers, XV-2c and KM.19, tightly linked to the CFTR locus. The study was done in Chilean CF patients with unknown or delt F508 ( F508) CFTR mutations and their haplotypes were compared to affected family-based controls. F508 showed marked linkage disequilibrium with XV-2c/KM.19 haplotype B, with 90 percent of al¡eles on that haplotype. There was no difference in haplotype distribution between unknown mutations and normal controls. These results support a European origin for F508 al¡eles in Chilean patients, and make unlikely the presence of a predominant founder mutation in the so-far unknown alíeles.