The candidate gene approach to the diagnosis of monogenic disorders

The genetic basis of many human diseases has been elucidated by the candidate gene approach. Mouse models of human disease, whether naturally occurring or derived by transgenesis, have enabled a number of disease genes to be identified. Such approaches have formed the basis of the identification of candidate genes implicated in hypothalamo-pituitary development. Nevertheless, significant differences exist between murine and human models of disease. Chromosomal deletions, duplications and translocations that are visible microscopically are also informative and have allowed the discovery of disease genes such as SOX2 and SOX3. In addition, genome-wide mapping techniques using microsatellites have led to the identification of genes such as GPR54, mutations of which are associated with hypogonadotrophic hypogonadism. Newer techniques, such as array comparative genomic hybridization (CGH), have enabled the detection of submicroscopic chromosomal imbalances. These, in turn, can also lead to the identification of disease genes, as has been demonstrated by the discovery of mutations in CHD7 in some patients with the CHARGE syndrome. Most significant, however, is the recent optimization of high-density whole-genome single-nucleotide polymorphism arrays, which provides the potential to identify many disease genes and may revolutionize the field of human genetics.