methylation, histone acetylation) contributes to rare disorders such as the Prader-Willi syndrome and Angelman syndrome (Adams, 2008), but it may be even more important as a contributory factor in modulating gene expression and, therefore, disease predisposition and severity. These epigenetic modifications are likely acquired as the result of an array of exposures (e.g., prenatal exposure to tobacco smoke) and experiences (e.g., stress). Investigators are now using microarray and sequencing to analyze methylation patterns as biomarkers that can have clinical value.
Whole genome sequencing provides a complete analysis of the entire complement of an individual’s DNA. It can now be used to identify genetic variants associated with rare diseases in individual patients or families (Lupski et al., 2010; Roach et al., 2010). The cost for sequencing has fallen dramatically, but it remains resource intensive and challenging because each exome contains a large number of polymorphisms (variants), only one of which is typically the primary gene alteration (Lifton, 2010; Wade, 2010).
Microarray methods, which are used to comprehensively assess which genes are transcribed and which are not active in making proteins, are not diagnostic for genetic diseases. They can, however, be helpful in working out pathways that are dysfunctional in both genetic and acquired rare disorders (Wong and Wang, 2008). Experimental methods to interrupt gene expression in cell culture systems and animal models include the introduction of target-specific microRNAs, a tool that has been used to confirm the role of genes and pathways in the pathogenesis and modulation of disease.
Exome sequencing is a promising new approach to the search for disorder-causing genes for rare diseases (Kuehn, 2010; Tabor and Bamshad, 2010). The method focuses on the less than 5 percent of the genome that actually codes for protein. With this method, identification of genes associated with disorders of previously unknown etiology is possible using DNA from as few as two to four patients (Ng et al., 2009; Johnston et al., 2010). This approach provides a particular advantage to rare diseases, given that biological specimens are often scarce. It is expected to accelerate the rate of identification of gene defects for rare diseases.
Researchers have made significant progress in the cataloging of genetic variation and its correlation with disease predisposition, initiation, and progression. Parallel initiatives for protein variation are also important.