investigation of Genetic Risk Factors for Congenital Heart Defects in down Syndrome

Abstract

Down Syndrome (DS) is a complex condition, arising due to trisomy of chromosome 21. DS newlineindividuals have many congenital as well as acquired abnormalities with varying degree of newlineseverity. Congenital heart defects (CHD) is a common occurrence affecting nearly half of the DS newlineindividuals. One of the most severe structural anomalies is the atrioventricular septal defect newline(AVSD), a type of CHD with almost 60% penetrance in DS individuals who has CHD. Many newlinelines of evidence have indicated certain genetic and epidemiological factors apart from the newlinetrisomy 21 background whose interactions can cause such an effect. Through a robust newlinerecruitment effort in selection of study populations which included (1) families of DS newlineindividuals with CHD especially AVSD, (2) family of DS individuals with structurally normal newlineheart, (3) euploid individuals with AVSD and (4) euploid individual families with structurally newlinenormal heart, we have investigated the role of CRELD1 (a cell adhesion molecule), GATA4 (a newlinetranscription factor) and six folate pathway gene (MTHFR, MTR, MTRR, MTHFD1, SLC19A1 newlineAND CBS) polymorphisms in the pathogenesis of AVSD in our DS population. We have also newlineinvestigated the role of certain epidemiological parameters as risk factors for giving birth to DS newlinechild with AVSD. The results generated from the aforementioned comprehensive approach have newlineidentified certain polymorphic haplotypes of CRELD1 as a potential risk factors for causing newlineAVSD in DS. We have also shown significant association of GATA4 variants with AVSD in DS newlineindividuals. Investigation of folate pathway genes has also revealed gene-gene and geneenvironment newlineinteractions to be significantly associated in getting pregnant with DS child with newlineCHD. The experiments also showed that in addition to genetic perturbations, certain maternal newlinesociodemographic and lifestyle components are risk factors for giving birth to a DS child with newlineAVSD. newline