Penetrance
Encyclopedia
Penetrance in genetics
is the proportion of individuals carrying a particular variant 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
.
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 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.
. 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.
Genetics
Genetics , a discipline of biology, is the science of genes, heredity, and variation in living organisms....
is the proportion of individuals carrying a particular variant of a gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
(allele
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
or genotype
Genotype
The genotype is the genetic makeup of a cell, an organism, or an individual usually with reference to a specific character under consideration...
) that also express an associated trait (phenotype
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
). In medical genetics
Medical genetics
Medical genetics is the specialty of medicine that involves the diagnosis and management of hereditary disorders. Medical genetics differs from Human genetics in that human genetics is a field of scientific research that may or may not apply to medicine, but medical genetics refers to the...
, the penetrance of a disease-causing mutation is the proportion of individuals with the mutation who exhibit clinical symptoms. For example, if a mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
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:
- 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.
Penetrance only considers whether individuals express the trait or not. For variation in the degree of expression of a given trait, see expressivity
Expressivity
Expressivity is a term used in genetics to refer to variations in a phenotype among individuals carrying a particular genotype. The term can be used to characterize qualitatively or quantitatively the extent of phenotypic variation given a particular genotype. The term is analogous to the...
.
Associated terminology
- complete penetrance. The allele is said to have complete penetrance if all individuals who have the disease-causing mutation have clinical symptoms of the disease.
- highly penetrant. If an allele is highly penetrant, then the trait it produces will almost always be apparent in an individual carrying the allele.
- incomplete penetrance or reduced penetrance. Penetrance is said to be reduced or incomplete when some individuals fail to express the trait, even though they carry the allele.
- low penetrance. An allele with low penetrance will only sometimes produce the symptom or trait with which it has been associated at a detectable level. In cases of low penetrance, it is 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 codeterminants 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, determined cumulatively, at different ages. For example, multiple endocrine neoplasiaMultiple endocrine neoplasiaThe term multiple endocrine neoplasia encompasses several distinct syndromes featuring tumors of endocrine glands, each with its own characteristic pattern. In some cases, the tumors are malignant, in others, benign...
1 (MEN 1), a hereditary disorder characterized by parathyroid hyperplasia and pancreatic islet-cell and pituitary adenomas, is caused by a mutation in the menin gene on human chromosome 11q13. In one study the age-related penetrance of MEN1 was 7% by age 10 but increased to nearly 100% by age 60. - Environmental modifiers. Penetrance may be expressed as a frequency at a given age, or determined cumulatively at different ages, depending on environmental modifiers. For example, several studies of BRCA1BRCA1BRCA1 is a human caretaker gene that produces a protein called breast cancer type 1 susceptibility protein, responsible for repairing DNA. The first evidence for the existence of the gene was provided by the King laboratory at UC Berkeley in 1990...
and BRCA2BRCA2BRCA2 is a protein that in humans is encoded by the BRCA2 gene.BRCA2 orthologs have been identified in most mammals for which complete genome data are available....
mutations, associated with an elevated risk of breastBreast cancerBreast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
and ovarian cancerOvarian cancerOvarian cancer is a cancerous growth arising from the ovary. Symptoms are frequently very subtle early on and may include: bloating, pelvic pain, difficulty eating and frequent urination, and are easily confused with other illnesses....
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. Genome association studiesGenetic associationGenetic association is the occurrence, more often than can be readily explained by chance, of two or more traits in a population of individuals, of which at least one trait is known to be genetic....
may assess the influence of such variants on the penetrance of an allele. - Epigenetic regulation. Example ... genomic imprinting by the paternal or maternal allele.
Ascertainment bias
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 C282YA allele of the HFE geneHFE gene
Human hemochromatosis protein also known as the HFE protein is a protein which in humans is encoded by the HFE gene.The HFE gene is located on short arm of chromosome 6 at location...
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 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
Cirrhosis
Cirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis, scar tissue and regenerative nodules , leading to loss of liver function...
. Thus a consensus definition of what constitutes the presence of a phenotype is essential for determining the penetrance of an allele.
Attributable risk
For alleles with incomplete penetrance, the penetrance of the allele is not the same as the attributable riskAttributable risk
In epidemiology, attributable risk is the difference in rate of a condition between an exposed population and an unexposed population.. Attributable risk is mostly calculated in cohort studies, where individuals are assembled on exposure status and followed over a period of time. Investigators...
. 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.