Congenital heart disease (CHD) is one of the most common major malformations occurring in 4-8/1000 live births. The etiology of CHD is thought to be multifactorial; both genetic and environmental factors have been implicated. However, few precise genetic or environmental causes have been defined. Data suggests that there is a genetic basis for the development of left sided obstructive cardiac lesions and that these defects may be familial more frequently than recognized. Left sided obstructive lesions include hypoplastic left heart syndrome, valvular aortic stenosis, coarctation of the aorta, bicuspid aortic valve and mitral valve abnormalities and comprise 13% of all types of CHD. This program is investigating the genetic etiology of left sided cardiac defects by performing clinical and eventually laboratory based projects. Approximately 25 families with at least one member with a left sided obstructive lesion are being evaluated to determine whether the disease is familial. To this end, a detailed family history for congenital heart disease or extracardiac congenital malformations is obtained. Further, the first degree relatives (parents and siblings) of patients with a left sided obstructive lesion are being examined by echocardiography for the presence of subclinical cardiac defects, such as a clinically silent bicuspid aortic valve. Samples of whole blood from the proband and from their parents, siblings and other relatives (where applicable) have been collected simultaneously thereby developing a clinical database and DNA bank for molecular studies. To some extent, the clinical observations made in this study will dictate the design of future laboratory based efforts. For example, if several large families with multiple affected individuals are identified, then a parametric linkage analysis to identify a disease locus will be conducted. If large families are not identified, then mutation analyses or non-parametric linkage analyses, such as transmission disequilibrium testing (TDT), of candidate loci will be performed. This project is initiating clinical and, in the future, molecular investigations on the genetic etiology of congenital left sided cardiac malformations. The results of the clinical study will also provide information critical for genetic counseling. The clinical database and DNA bank will be used to initiate molecular experiments.
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