Abstract
Despite an obvious role for consanguinity in congenital heart disease (CHD), most studies fail to document a monogenic model of inheritance except for few cases. We hereby describe a first-degree cousins consanguineous Lebanese family with 7 conceived children: 2 died in utero of unknown causes, 3 have CHD, and 4 have polydactyly. The aim of the study is to unveil the genetic variant(s) causing these phenotypes using next generation sequencing (NGS) technology. Targeted exome sequencing identified a heterozygous duplication in CSRP1 which leads to a potential frameshift mutation at position 154 of the protein. This mutation is inherited from the father, and segregates only with the CHD phenotype. The in vitro characterization demonstrates that the mutation dramatically abrogates its transcriptional activity over cardiac promoters like NPPA. In addition, it differentially inhibits the physical association of CSRP1 with SRF, GATA4, and with the newly described partner herein TBX5. Whole exome sequencing failed to show any potential variant linked to polydactyly, but revealed a novel missense mutation in TRPS1. This mutation is inherited from the healthy mother, and segregating only with the cardiac phenotype. Both TRPS1 and CSRP1 physically interact, and the mutations in each abrogate their partnership. Our findings add fundamental knowledge into the molecular basis of CHD, and propose the di-genic model of inheritance as responsible for such malformations.
Highlights
Congenital heart defects arise during pregnancy, and are subsequently the most prevalent birth defects worldwide (Hoffman and Kaplan, 2002)
A congenital heart disease (CHD) consanguineous multiplex family with CHD and polydactyly was recruited as part of the Congenital Heart Disease Genetics Program at the American University of Beirut (Figure 1)
Our results show that only GATA4 and GATA6 readily interact with CSRP1 while GATA5 does not (Figure 4)
Summary
Congenital heart defects arise during pregnancy, and are subsequently the most prevalent birth defects worldwide (Hoffman and Kaplan, 2002). They affect chamber and valve formation and function leading to different phenotypes referred to as Congenital Heart Disease (CHD), the major cause of neonatal morbidity and mortality in humans. CSRP1 and Congenital Heart Disease of all main congenital defects with variable prevalence crosswise countries. In Lebanon, the incidence of infants born with CHD between 1980 and 1995 was 11.5 per 1,000 live births (Bitar et al, 1999), and twenty per cent of those patients were found to be from first degree cousin mating (Nabulsi et al, 2003). At least 50 human disease genes have been associated with CHD, a small set of developmental genes [for example, NKX2-5 (MIM# 600584), GATA4 (MIM# 600576) and NOTCH1] harbor the majority of these CHD-associated mutations (Fahed et al, 2013)
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