Molecular genetic analysis of familial congenital heart disease

[摘要] Development of the human heart is a complex process controlled by multiple genes (in interacting pathways), many of which are still to be determined. Abnormal heart development results in a spectrum of congenital heart disease (CHD), occurring in isolation or part of a syndrome, and with or without a family history, implying a genetic basis in some individuals. In this project I investigated the molecular genetic basis of CHD, in 23 families with nonsyndromic CHD. Using autozygosity mapping, I initially investigated the molecular basis of CHD in a single large consanguineous family (CHD1), and identified a region of interest containing a candidate gene (GDF1). I proceeded to sequence GDF1 (and genes in the same developmental pathway - NODAL, CFC1, TDGF1, and FOXH1) in 9 kindreds, but did not identify any pathogenic mutations. I then utilised whole exome sequencing (WES) to identify candidate mutations in potential CHD genes (GMFG, WNT11 and DVL2), and investigated these further by conventional sequencing. A novel GMFG nonsense variant was validated in family CHD1 and was absent from ethnically matched controls. Bioinformatics analysis of WES data from 19 affected individuals from 9 kindreds did not identify a frequently mutated candidate gene (or further GMFG candidate mutations), though candidate variants in individual kindreds were identified. Further functional analysis using animal models is required to determine the pathophysiological effect of the GMFG truncating mutation in cardiac development.

[发布机构] University:University of Birmingham;Department:School of Clinical and Experimental Medicine, Department of Medical and Molecular Genetics

[关键词] Q Science;QH Natural history;QH426 Genetics