Penetrance

Penetrance is a term used in genetics describing the proportion of individuals carrying a particular variation of a gene (an allele or genotype) that also express a particular trait (the phenotype). For example, known mutations in the gene responsible for Huntington disease have 95% penetrance, whereby 5% of those with the dominant allele for Huntington disease don't develop the disease and 95% do. In other words, penetrance is the percentage of individuals with a specific genotype that possess an associated phenotype. For example, if 50% of the individuals carrying the "blue" allele are blue, the "blue" allele has 50% penetrance. Penetrance only considers whether individuals express the trait or not — for variation in the degree of expression of a given trait, see expressivity.

If an allele is "highly penetrant", the trait it produces will always or almost always be apparent in an individual carrying the allele. Penetrance is said to be "reduced" or "incomplete" when some individuals fail to express the trait, even though they carry the allele. An allele with "low penetrance" will only sometimes produce the symptom or trait with which it has been associated at a detectable level. In the case of low penetrance it is difficult to distinguish environmental from genetic factors.

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 – if the allele is present, the phenotype is expressed (recessivity, dominance, and co-dominance are fairly simple additions to this principle);
#Alleles which are highly penetrant are more easily noticed by geneticists, and alleles for symptoms which are highly heritable are more easily inferred to exist, and then more easily tracked down.

Penetrance can be difficult to determine reliably. For one disease, hemochromatosis, a heritable disease of excess intestinal iron absorption, the degree of penetrance has been a subject of controversy for many years and illustrates the challenges facing investigators quantitating penetrance. Those persons 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. Thus, determining the penetrance of the C282Y allele can be influenced by when, in the course of their lives, the homozygotes are evaluated by the medical community (if ever). This dilemma is known as a bias of ascertainment. 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 a homozygote 'affected' with the disease if they simply have elevated blood iron levels, but no evidence of organ disease such as cirrhosis. And deciding on what is disease and what is simply an indicator of excess iron influences the determination of penetrance. Thus a consensus definition of what constitutes the presence of a phenotype is essential for determining penetrance of an allele.

A good example of age-related penetrance is multiple endocrine neoplasia 1 (MEN 1), a disorder characterized by parathyroid hyperplasia and pancreatic islet-cell and pituitary adenomas. It is owing to a mutation in the menin gene on human chromosome 11q13. In one study the age-related penetrance of MEN1 was 7 percent by age 10 years but nearly 100 percent by age 60 years.

Relatively few alleles show high penetrance. Most traits such as height or intelligence are influenced by many genes as well as environmental factors. The phenotypic range of polygenic traits is often normally distributed, meaning it falls along a bell curve.

ee also

*Expressivity
*Phenotype
*Genotype
*Mendelian inheritance

References

*Bessett JH et al. "Characterization of mutations in patients with multiple endocrine neoplasia type 1." Am J Hum Genet 1998 Feb;62(2):232-44.