Identification of a Complex Congenital Heart Defect Susceptibility Locus by Using DNA Pooling and Shared Segment Analysis

• Published in: Human molecular genetics Vol. 6; no. 1; pp. 117 - 121
• Main Authors: Sheffield, Val C., Pierpont, Mary Ella, Nishimura, Darryl, Beck, John S., Burns, Trudy L., Berg, Mary Anne, Stone, Edwin M., Patil, Shivanand R., Lauer, Ronald M.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.01.1997
• Subjects: Biological and medical sciences; Cardiology. Vascular system; Chromosome Mapping; Congenital heart diseases. Malformations of the aorta, pulmonary vessels and vena cava; DNA; Endocardial Cushion Defects - genetics; Female; Genetic Predisposition to Disease; Heart; Humans; Male; Medical sciences; Pedigree; Genetic mapping; Human; Complex defect; Genetic inheritance; Linkage; Congenital; Family study; Chromosome A1; Cardiovascular disease; Congenital disease; Gene; Heart disease; Risk factor; Predisposition; Genetics
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/6.1.117

The identification of genetic loci involved in most forms of congenital heart disease has been hampered by the complex inheritance patterns of these disorders. Atrioventricular canal defects (AVCDs) are most commonly associated with Down syndrome, although non-syndromic cases also occur. Non-syndromic AVCDs have been attributed to multifactorial inheritance. However, the occurrence of a few kindreds with multiple affected individuals has suggested that a major genetic locus can account for the disorder in some families. We have used a combination of DNA pooling and shared segment analysis to perform a high density screen of the entire autosomal human genome in an extended kindred. In so doing, we have identified a genetic locus on chromosome 1 shared by all affected individuals. Our data demonstrate the existence of a congenital heart defect susceptibility gene, inherited as an autosomal dominant with incomplete penetrance, involved in AVCD. Furthermore, our data demonstrate the power of using key isolated kindreds in combination with high density genomic screens to identify loci involved in complex disorders such as congenital heart defects.