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PenetrancePenetrance in genetics is the proportion of individuals carrying a particular variation of a gene (allele or genotype) that also express an associated trait (phenotype). In medical genetics, the penetrance of a disease-causing mutation is the proportion of individuals with the mutation who exhibit clinical symptoms. For example, if a mutation in the gene responsible for a particular autosomal dominant disorder has 95% penetrance, then 95% of those with the mutation will develop the disease, while 5% will not. Common examples used to show degrees of penetrance are often highly penetrant. There are several reasons for this:
Penetrance only considers whether individuals express the trait or not. For variation in the degree of expression of a given trait, see expressivity.
[edit] Associated terminology
[edit] Determination of penetrancePenetrance can be difficult to determine reliably, even for genetic diseases that are caused by a single polymorphic allele. For many hereditary diseases, the onset of symptoms is age related, and is affected by environmental codeterminants such as nutrition and smoking, as well as genetic cofactors and epigenetic regulation of expression:
[edit] Ascertainment biasFor hereditary hemochromatosis, a disease caused by excess intestinal iron absorption, the degree of penetrance has been a subject of controversy for many years and illustrates the challenges facing investigators seeking a quantitative measure of penetrance. Individuals who are homozygotes for the C282YA allele of the HFE gene are at risk for developing lethal concentrations of iron, particularly in the liver. Typically patients develop clinical disease in late-middle age.[3] Determining the penetrance of the C282Y allele can be influenced by when, in the course of a lifetime, homozygotes are evaluated by the medical community. Many of those afflicted do not seek treatment until symptoms are advanced, and with age-related conditions, some individuals die first of other causes. This dilemma is known as an ascertainment bias. There can be a bias favoring only the ascertainment of the most severely affected, or there can be a bias in the other direction, deeming that a homozygote is affected with the disease if they simply have elevated blood iron levels, but no physiological evidence of organ disease such as cirrhosis. Thus a consensus definition of what constitutes the presence of a phenotype is essential for determining the penetrance of an allele.[4] [edit] Attributable riskFor alleles with incomplete penetrance, the penetrance of the allele is not the same as the attributable risk. For example, many alleles have been shown, through association studies, to cause some form of cancer, often with low penetrance. But cases of the cancer would arise even without the presence of the allele. Attributable risk is that proportion of total risk which can be attributed to the presence of the allele. [edit] Polygenic traitsMost biological traits (such as height or intelligence in humans) are multifactorial, influenced by many genes as well as environmental conditions and epigenetic expression. Only a statistical measure of association is possible with such polygenic traits. [edit] See also[edit] References
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