[Molecular-genetic approach to congenital malformation syndromes]

The causes of congenital malformation syndromes had long remained obscure, because their biochemical bases were unknown. However, with recently developed reverse-genetic and/or Human Genome Project-derived technology, we have been able to approach such disorders. These new methods include positional cloning techniques, candidate gene approach and positional candidate strategies. Among them, positional cloning has become most reliable nowadays, and three ways are mainly available to obtain position information of disease genes, i.e., data from linkage analysis of disease families; comparative maps between different species; breakpoints of disease-related de novo chromosomal translocations. I present here some examples for each strategy: a large kindred with mesomelic dysplasia Kantaputra type for linkage data, and its seemingly allelic bone dysplasia associated with t (2; 8) for positional cloning that starts from a chromosomal translocation; Waardenburg syndrome for candidate gene approach; and the p57KIP2 gene for positional candidate approach to Wiedemann-Beckwith syndrome. I finally emphasize that a human link composed of general physicians, molecular geneticists and clinical researchers is essential to reach a goal of reverse genetics. Without such a goal, we can neither understand the genesis of diseases nor develop their therapy.