Microarray expression profiling and heterozygote identification

Abstract

The classical definition of an autosomal recessive genetic disease is that only individuals who are homozygous for mutations are clinically affected, whereas heterozygous carriers show no obvious phenotype. However, careful study sometimes uncovers subtle differences, either beneficial or detrimental, between heterozygotes and non-carriers. Ataxia telangiectasia (AT) is a good example. AT is an uncommon recessive condition characterized by increased sensitivity to ionizing radiation, neurological problems, immune deficiency and cancer predisposition. Although heterozygous carriers do not show severe manifestations, cell-culture studies have shown an elevated sensitivity to ionizing radiation, in comparison to cells from non-carriers. Furthermore, epidemiological studies have suggested that AT heterozygotes have an increased risk of cancer, particularly breast cancer. Because these heterozygotes are common (∼1% of the population), it is important that the nature of the cancer risk is clarified. However, the gene concerned is very large and, therefore, difficult to screen by standard mutation detection methods. A recent paper [ 1. Watts J.A. et al. Gene expression phenotype in heterozygous carriers of ataxia telangiectasia. Am. J. Hum. Genet. 2002; 71: 791-800 Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar ] has demonstrated the potential of microarray analysis for classifying AT heterozygotes and non-carriers on the basis of differences in expression profiles.