Penetrance in genetics is the proportion of individuals carrying a particular variant (or allele) of a gene (the genotype) that also expresses an associated trait (the phenotype). In medical genetics, the penetrance of a disease-causing mutation is the proportion of individuals with the mutation that 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: Highly penetrant alleles, and highly heritable symptoms, are easier to demonstrate, because if the allele is present, the phenotype is generally expressed. Mendelian genetic concepts such as recessiveness, dominance, and co-dominance are fairly simple additions to this principle. Alleles which are highly penetrant are more likely to be noticed by clinicians and geneticists, and alleles for symptoms which are highly heritable are more likely to be inferred to exist, and then are more easily tracked down.
Degrees
Complete and incomplete or reduced penetrance: An allele is said to have complete penetrance if all individuals who have the disease-causing mutation have clinical symptoms of the disease. In incomplete or reduced penetrance, some individuals will not express the trait even though they carry the allele. An example of an autosomal dominant condition showing incomplete penetrance is familial breast cancer due to mutations in the BRCA1 gene. Females with a mutation in this gene have an 80% lifetime risk of developing breast cancer. The penetrance of the condition is therefore 80%. High and low penetrance: If an allele is highly penetrant, then the trait it produces will almost always be apparent in an individual carrying the allele. An allele with low penetrance will only occasionally produce the trait with which it is associated. In cases of low penetrance, it can be difficult to distinguish environmental from genetic factors.
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: Age-related cumulative frequency: Penetrance is often expressed as a frequency of disease at different ages. For example, multiple endocrine neoplasia type 1, a hereditary disorder characterized by parathyroid hyperplasia and pancreatic islet-cell and pituitary adenomas, is caused by a mutation in the menin gene (MEN1) on human chromosome 11q13. In one study the age-related penetrance of MEN1 was 7% by age 10 but nearly 100% by age 60. Environmental modifiers: Penetrance may be affected by environmental factors. For example, several studies of BRCA1 and BRCA2 mutations, associated with an elevated risk of breast and ovarian cancer in women, have examined associations with environmental and behavioral modifiers such as pregnancies, history of breast feeding, smoking, diet, and so forth. Genetic modifiers: Penetrance at a given allele may be polygenic, modified by the presence or absence of polymorphic alleles at other gene loci. Genetic association studies may assess the influence of such variants on the penetrance of an allele. Epigenetic regulation: Epigenetics can affect the penetrance of genes through genomic imprinting by the paternal or maternal allele or epigenetic regulation resulting from environmental or other personal factors.