322 Developmental genetics of the heart John Burn* and Judith Goodshipt 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 22ql 1 is second only to Down's syndrome as a cause of heart defects. Molecular dissection of the 22ql 1 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 disturbs the left--~right gradient in homozygotes, causing heart defects in many instances. Sadly, the original inserti0nal mutation has resulted in a complex deletion duplication which has slowed discovery of the coding sequence. Address Department of Human Genetics, University of Newcastle upon Tyne, 19/20 Claremont Place, Newcastle upon Tyne NE2 4AA, UK *e-mail: john burn@ncl.ac.uk ~e-mail: j a goodship@ncl.ac.uk Current Opinion in Genetics & Development 1996, 6:322-326 © Current Biology Ltd ISSN 0959-437X Abbreviations CATCH22 cardiac defects, abnormal facies, thymic hypoplasia, cleft palate and hypocalcaemia resulting from 22ql 1 deletions DGCR DiGeorge syndrome critical region inv inversion of embryo turning Introduction Where to begin? This question has deterred marly from even thinking of studying the genetic basis of human heart development and maldevelopment. The existence of major developmental genes liable to display Mendelian properties when defective was considered improbable until recently. As the importance of single gene defects became more obvious, the complexity of converting a tube of mesodermal cells into a complex four-chamber pump, while it is in constant use, provided a further deterrent to all but the farsighted or foolhardy. Now, at last, the power of both molecular genetics and experimental embryology have reached a point at which the genetic understanding of cardiac development is within reach. Cytogenetic clues From our clinical perspective, malformation is a driving force, both as a reason for study and as a source of experimental approach. The study of chromosome aneuploidy provided the first genetic advance in the demonstration that trisomy 21 causes 5% of heart defects in general and most cases of isolated atrioventricular septal defects. The major advance in recent months has resulted from a balanced 6;7 chromosome translocation associated with the supravalvar aortic stenosis, the characteristic heart defect of William's syndrome [1]. Demonstration of deletion of the elastin gene in syndromic cases and disruption of the gene in children with the isolated abnormality of the aorta [2] has provided a major insight into both the clinical disorder and the cellular mechanisms involved in aortic development. Olson eta/. [3] have recently found that a 30kb deletion within the elastin gene is associated with a severe form of supravalvar aortic stenosis and peripheral pulmonary artery stenoses. This demonstrates that loss of one allele of the elastin gene is sufficient to produce the cardiovascular phenotypc. Another genetic cause of heart malformation of an even greater significance, where the molecular genetics has not proved to be as simple as the elastin gene deletion, is the 22qli deletion. The recognition that submicroscopic deletions of chromosome 22ql 1 are responsible for the vast majority of cases of DiGeorge syndrome and a spectrum of overlapping phenotypes that can be summarised by the acronym CATCH22 (cardiac defects, abnormal facies, thymic hypoplasia, cleft palate and hypocalcacmia resulting from 22qll deletions) [41 had led us to assume that, in a short time, we would have identified a gent with a key role in cardiac development. The heart defects most commonly seen in CATCH22 arc interrupted aortic arch, truncus arteriosus, pulmonary atresia/ventricular septal defect and preliminary studies suggest that 30-50% of cases of interrupted aortic arch and trtmcus arteriosus are secondary to this chromosomal deletion. However, things have turned out to be far more complex than expected and--despite intensive work by a number of groups over the past 5 years--the genc or genes responsible for the cardiac phenotype have not been identified (or if they have been identified they have not been proven to bc such). In the majority of children with deletions, 2Mb of DNA is removed; the map illustrated as Figure 1 details the genes which have been cloned in this region [5-15]. The DiGeorgc syndrome critical region (DGCR), delineated from smaller deletions and which includes the only balanced translocation breakpoint, known as ADU [16], reported in DiGeorge syndrome, has also