Title
Uncovering the Genetic Basis for Congenital Heart Disease
Speaker
Kim McBride, Center for Molecular and Human Genetics, Children's Research Institute
Abstract
Congenital heart defects (CHD) are common, occurring with a rate of 6–8 per 1000 live births. They contribute to 40% of the infant mortality due to birth defects, the leading cause of deaths for children under 1 year of age. CHD can be classified by their clinical presentation, or by the likely developmental mechanism that is disturbed. We have focused on a group of CHD that are caused by alteration of blood flow through the left side of the heart during development. These defects include bicuspid aortic valve, congenital aortic valve stenosis, coarctation of the aorta, and hypoplastic left heart syndrome, which are collectively known as left ventricular outflow tract (LVOT) malformations. Previous work has established a strong genetic component for LVOT malformations, including high heritability and recurrence risk, while formal segregation analysis suggests from 1–6 loci with the possibility of an autosomal dominant inheritance of a low penetrance allele in some families. We have collected and genotyped 400 microsatellite markers in 240 individuals from 34 families for a genome wide linkage analysis. Power calculations in the programs SIMULATE, FASTLINK and ELODHET suggested adequate power to obtain a LOD score of > 3.0. We analyzed the families using a variety of models, including autosomal dominant inheritance with various penetrance values under the assumption of locus heterogeneity, and by non-parametric linkage analysis. The highest HLOD and NPL LOD scores were obtained on chromosome 10, for a LOD of 2.57. Further analysis using a MODSCORE approach to simultaneously vary multiple parameters is underway using the GENHUNTER-MODSCORE program. We have also performed SNP genotyping in 200 candidate genes in a family based association study, using 220 affected case–parent trios. After correction for multiple testing by the False Detection Rate, several candidate genes in 4 developmental pathways were positively associated by the Transmission Disequilibrium Test with the LVOT malformations. We will present mutation screening data and the current status of the second stage association confirmation study of these results, and further data analysis by the SUMSTAT program.
Meet the speaker in Room 212 Cockins Hall at 4:30 p.m. Refreshments will be served.
