Thus, predictive or presymptomatic testing for late-onset neurological disorders, such as Huntington’s disease or cerebellar ataxia in younger relatives of patients, is well established. Moreover, kits for the diagnosis of several human disorders (via mutation detection) including cystic fibrosis, β-thalassemia, and Tay-Sachs disease, among others, are commercially

available. The problem of genetic heterogeneity Even from these single-gene disorders, we have indications Inhibitors,research,lifescience,medical that the situation is not that simple. Geneticists are familiar with terms such as “epigenetics,” ie, genetic phenomena that cannot be explained by traditional Inhibitors,research,lifescience,medical genetics. One example of this is disease transmission and severity being affected by the sex of the transmitting parent and “modifying factors” (probably other genes that affect, disease severity); this is the case for cystic fibrosis13 and hemochromatosis.14 We increasingly observe that, even if the gene buy NVP-BKM120 causing the disorder is known, the phenotype-genotype relationship is not

clear. This genetic heterogeneity poses a real problem for diagnostic testing. The connection between a patient’s symptoms, diagnosis, and the underlying Inhibitors,research,lifescience,medical mechanism of disease is often obscure. For example, patients with mutations in different, genes may present as clinically identical, while patients with the same mutation may present, clinically disparate. Alzheimer’s disease (AD) is an oft-quoted Inhibitors,research,lifescience,medical example of a disorder with different forms of inheritance and illustrates the problem that genetic heterogeneity creates for diagnostic testing. Early-onset AD is strongly familial, whereas late-onset AD is considered a complex disease with strong environmental influences. Mutations in the y4PP,presenilin 1 (PS1), and presenilin 2 (PS2) genes can cause clinically indistinguishable forms of early AD.15-17 On the other Inhibitors,research,lifescience,medical hand, different

mutations in the same gene, eg, APP, can lead to two distinct diseases, early-onset AD and recurrent, intracerebral hemorrhage.18 The more disease genes that are discovered, the more apparent this phenomenon becomes. Another example is mutations Fossariinae in the androgen receptor gene (AR) in which the expansion of the trinucleotide triplet repeat CAG in the first exon of the gene leads to adult-onset motor neuron disease19 (spinal and bulbar muscular atrophy [SB MA] or Kennedy disease), whereas different types of mutations in the other exons of the same gene lead to androgen insensitivity20; these are two completely different, pathologies. Thus, it is not hard to imagine that the situation is even more complex for polygenic disorders, which are caused by many different, genes and have an environmental component.