Penetrance

Penetrance in genetics is the proportion of individuals carrying a particular variant (or allele) of a gene (the genotype) that also express an associated trait (the phenotype). In medical genetics, the penetrance of a disease-causing mutation is the proportion of individuals with the mutation who exhibit clinical symptoms among all individuals with such mutation. 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.
A condition, most commonly inherited in an autosomal dominant manner, is said to show complete penetrance if clinical symptoms are present in all individuals who have the disease-causing mutation. A condition which shows complete penetrance is neurofibromatosis type 1 – every person who has a mutation in the gene will show symptoms of the condition. The penetrance is 100%.
Common examples used to show degrees of penetrance are often highly penetrant. There are several reasons for this:
Determination.
Penetrance 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 factors such as nutrition and smoking, as well as genetic cofactors and epigenetic regulation of expression:
Ascertainment bias.
A consensus definition of what constitutes the presence of a phenotype is essential for determining the penetrance of an allele. For 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 C282Y 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.
Determining the penetrance of the C282Y allele can be influenced when the medical community evaluates homozygotes. 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.
Attributable risk.
For 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 that can be attributed to the presence of the allele.
Polygenic traits.
Most 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.