Detection of Prevalent Genetic Alterations Predisposing to Hemochromatosis and Other Common Human Diseases (Editorial‪)‬

The explosion of recent knowledge in basic genetics has spawned numerous clinical follow-up studies that have confirmed an unequivocal association between the presence of specific prevalent genetic alterations and susceptibility to some very common human diseases. In addition, the imminent completion of the Human Genome Project's sequencing efforts will contribute yet more candidate disease genes that will require both research-based genetic association studies (to confirm suspected disease links) and, if positive, the translation of these disease-genotype associations to routine diagnostic clinical practice. Given this expanding repertoire of confirmed and reputed disease genes (many for common diseases), the demand for rapid, sensitive, specific, inexpensive assays for their clinical- and/or research-based detection is growing quickly. As a consequence, clinical genetic testing laboratories, once accustomed to manual, low-volume, high-labor tests on patients with rare, untreatable classic "genetic" diseases, will soon need to develop more high-throughput, semiautomated methods. In the fast-approaching molecular medicine era, these new genotyping methods will be utilized not only for diagnosing symptomatic patients, but perhaps more importantly, for presymptomatically identifying individuals at risk for common, treatable diseases for whom effective preventative interventions may be available. A prototypical example of the forthcoming primary public health role of molecular diagnostics is the identification of individuals affected by or at-risk for the iron overload disorder hereditary hemochromatosis. More than 90% of the cases of this most common of all single-gene disorders (present in 0.5% of whites) are caused by the presence of a homozygous well-conserved single nucleotide substitution (nucleotide G845A; amino acid C282Y) in the transferrin receptor binding protein FIFE (1). This loss-of-function mutation abolishes HFE's usual cell surface expression, thus preventing its ability to down-regulate the affinity of transferrin receptor for transferrin-bound iron. The result is a dysregulation of normal cellular iron metabolism and a resulting constitutive intestinal iron absorption. This excess toxic iron deposits in numerous organs and, if not removed, causes progressive chronic damage to the liver, heart, endocrine glands, joints, and skin. Because hemochromatosis is a common, underdiagnosed (but easily diagnosable), progressive chronic disease with late-onset symptomatology for which an effective, safe (preventative) therapy is widely available (phlebotomy), it is perhaps the ideal disease for the implementation of a population-based screening program. Universal population-based hemochromatosis screening (by transferrin saturation) has been recommended by the College of American Pathologists (2), and a more conservative phenotypic screening of "symptomatic" individuals has been recommended by an expert consensus panel of the CDC and NIH (3). More universal recommendations for widespread population screens may result from the recently initiated NIH study (HEIRS) of 100 000 apparently healthy Americans that will evaluate the benefits and risks of iron overload screening by both genotypic and phenotypic determinations.