Developmental genetics of the heart

Studies of children with heart defects and chromosomal anomalies have led to the discovery that loss of an elastin gene can cause supravalvar aortic stenosis and that a 2 Mb deletion from 22q11 is second only to Down's syndrome as a cause of heart defects. Molecular dissection of the 22q11 region to find the genes which produce the outflow-tract defects and other disorders of neural crest migration has proven more difficult, as there are a large number of genes in the deleted region. Classic mapping studies have located a gene which can cause total anomalous venous drainage near the centromere of chromosome 4. Knockout mouse studies have demonstrated an important role in cardiac development for, amongst others, endothelin-1 and neuregulin. Functional redundancy and maternal rescue are two reasons why knockouts do not always live up to our expectations. Serendipitous findings in the mouse are equally important. Work continues to isolate the inversion of embryo turning (inv) gene which invariably disturb the left-->right gradient in homozygotes, causing heart defects in many instances. Sadly, the original insertional mutation has resulted in a complex deletion duplication which has slowed discovery of the coding sequence.