ABSTRACT
Molecular genetics advances have accelerated the discovery of the genetic etiology of many syndromes and diseases, and progress has been made in sorting out the causes of more complex traits such as diabetes and mental illness. Genotype-phenotype correlation study is a powerful method used to link the DNA code (genotype) with observable, measurable characteristics (the phenotype). The traditional method of gene discovery has proceeded from the phenotype to the genotype, but new techniques of gene manipulation have allowed experiments in the opposite direction-from genotype to phenotype. This reverse genetics includes knocking out a candidate gene in an animal and measuring the effects on the organism and its development. In experimental animals, the gene can be knocked out in different strains, which also allows study of gene expression clues regarding modifying genes. In humans, genotype to phenotype study is possible when a rare chromosome anomaly such as a translocation or inversion disrupts a single gene, providing a candidate gene for the phenotype. Unlike animal studies, however, humans with particular genetic mutations or deletions do not have the same genetic background or environment, potentially clouding the interpretation of the phenotype. Many of these chromosomal syndromes include common complex conditions such as mental retardation as part of the phenotype. Discovery of a gene accounting or predisposing for mental retardation in a particular syndrome likely identifies one of the quantitative trait loci in the general population. Further, such an advance may lead to the discovery of a family of genes or a biologic pathway that contributes to normal neurodevelopment. However, the individual gene would probably account for only a small percentage of the variability of the trait in the general population with nonsyndromic mental retardation.
