||This article may be too technical for most readers to understand. (August 2013)|
Penetrance in genetics is the proportion of individuals carrying a particular variant of a gene (allele or genotype) that also expresses 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.
The proportion of individuals with a mutation causing a particular disorder who exhibit clinical symptoms of that disorder.
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%.
Some conditions are described as having reduced or incomplete penetrance. This means that clinical symptoms are not always present in individuals who have the disease-causing mutation. 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%. , 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.
- 1 Associated terminology
- 2 Determination
- 3 Why Do Phenotypes Show Differences in Penetrance and Expressivity?
- 4 See also
- 5 References
- 6 External Links
- 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.
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 neoplasia 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 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. Genome association studies may assess the influence of such variants on the penetrance of an allele.
- Epigenetic regulation. Example ... genomic imprinting by the paternal or maternal 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 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.
Determining the penetrance of the C282Y allele can be influenced when, in the course of a lifetime, 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. Thus a consensus definition of what constitutes the presence of a phenotype is essential for determining the penetrance of an allele.
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.
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.
Why Do Phenotypes Show Differences in Penetrance and Expressivity?
So, how does a scientist relate differences in penetrance and expressivity that are observed at the phenotypic level to changes at the molecular level? For example, how is it possible that one family member carrying a retinoblastoma mutation has the disease, while another carrying the same mutation does not? What accounts for such a difference in disease penetrance? In the case of neurofibromatosis, family members carrying the same mutated neurofibromin gene are unequally affected by the condition, with some family members showing more severe symptoms than others. Why does this disease show variable expressivity? Answering these questions is not an easy task. Nonetheless, research has shown that variable phenotypes can be caused by a number of factors, including the following:
♦ Modifier genes ♦ Environmental factors ♦ Allelic variation ♦ Complex genetic and environmental interactions
In most cases in which a particular genotype is inherited, it is not fully known why the same allele can cause subtly different or profoundly different phenotypes. In some cases, however, there is genetic evidence that modifier genes influence phenotypic variation.
Modifier genes can affect penetrance, dominance, and expressivity. A genetic modifier, when expressed, is able to alter the expression of another gene. Modifier genes can affect transcription and alter the immediate gene transcript expression, or they can affect phenotypes at other levels of organization by altering phenotypes at the cellular or organismal level (Nadeau, 2001). A five-column table shows a target modified gene, its modifier gene, the modifier effect, and the nature of the modified phenotype. The table’s fifth column indicates references for the information shown in column 1 through 4. The table shows 15 modified genes in mice and six modified genes in humans. View Full-Size ImageTable 1 Figure Detail
Some examples of modifier genes identified in mice and humans, along with their modifier effects and phenotypic consequences, are shown in Table 1. As you can see from the table, many more modifiers have been identified in mice than in humans because of the ability to perform gene targeting experiments on inbred mouse strains. For example, an unknown modifier associated with specific mouse genetic backgrounds can alter the penetrance of an allele (called disorganization), which causes birth defects. Likewise, another unknown modifier that is associated with specific mouse genetic backgrounds affects the expressivity of an allele (called brachyury), resulting in mice with different tail lengths. A third modifier gene, named dsu, suppresses the expression of a number of different coat color alleles in mice, including ashen, leaden, ruby-eye, and ruby-eye-2.
Role of Modifier
To better understand the role of modifier genes in humans, Saima Riazuddin and her colleagues studied 141 members of a family afflicted with isolated deafness (i.e., deafness was the only clinical finding in this family), which is caused by the DFNB26 gene. The researchers noticed that the disease was incompletely penetrant. While most individuals who were homozygous for the gene were deaf, seven homozygous family members had normal hearing. Through linkage studies, the scientists identified a dominant modifier, called DFNM1, which suppressed deafness in homozygous individuals (Riazuddin et al., 2000). It is not yet known how this modifier gene suppresses deafness. It may suppress the mutant gene's expression or prevent deafness through another mechanism. Three graphs show the frequency distribution of a trait in a population affected by penetrance (panel A), dominance modification (panel B), and expressivity and pleiotropy (panel C). The number of individuals associated with a particular trait distribution is shown on the Y-axis. Trait distribution is shown on the X-axis. The area below the curve in each graph is shaded orange, blue, or remains unshaded. In panel A, a modifier gene shifts the threshold for trait expression so that a greater proportion of homozygous recessive individuals display the trait. In panel B, a modifier gene shifts the threshold for trait expression so that the majority of homozygous recessive individuals and a small proportion of heterozygous individuals display the trait. In panel C, a modifier gene causes a more extreme phenotype for homozygous recessive individuals.
Model of Modification
A model of modification shows different ways that modifier genes can alter the phenotypes in an organism (Figure 2; Nadeau, 2001). As shown in Figure 2, a modifier gene can move the threshold for trait expression, which means that the modifier causes a smaller or greater proportion of individuals to express the disease. In this way, a modifier gene can change the level of penetrance.
The modifier gene DFNM1 moves the threshold for trait expression to the right, so that some individuals homozygous for the DFNB26 allele are not deaf, which results in incomplete penetrance. Meanwhile, other modifiers can increase the proportion of individuals affected by a disease-causing allele by decreasing the threshold for trait expression (Figures 2a and 2b). Modifiers may also shift the trait distribution, or the range of disease phenotypes, which causes more individuals carrying a disease-causing allele to express a more (or less) severe disease phenotype (Figure 2c). This process results in variable expressivity.
The patients with thalassemia, a disorder caused by defective beta-globin synthesis, have diverse clinical characteristics and variable expressivity. Patients with severe cases have profound anemia and require regular blood transfusions, while other individuals who carry the same allele have mild and undetectable symptoms. A number of factors underlie this phenotypic diversity, including the involvement of numerous modifier genes at other genetic loci that affect the production of globins (Weatherall, 2001).
As with thalassemia, other human diseases also vary according to genetic and environmental factors, which can lead to both incomplete penetrance and variable expressivity. In fact, for most diseases, variable expressivity of the disease phenotype is the norm among individuals who carry the same disease-causing allele or alleles (Nadeau, 2001), though the causes are not always clear. Thus, the identification of additional modifier genes will help scientists better understand the nature of a wide range of human diseases.
- Bessett JH et al. (Feb 1998). "Characterization of mutations in patients with multiple endocrine neoplasia type 1". American Journal of Human Genetics 62 (2): 232–44. doi:10.1086/301729. PMC 1376903. PMID 9463336.
- Hughes, David J. (2008-02-19). "Use of association studies to define genetic modifiers of breast cancer risk in BRCA1 and BRCA2 mutation carriers". Familial Cancer (Springer Netherlands) 7 (3): 233–244. doi:10.1007/s10689-008-9181-0. ISSN 1573-7292. PMID 18283561.
- Beutler, Ernest (2003-05-01). "Penetrance in hereditary hemochromatosis: The HFE Cys282Tyr mutation as a necessary but not sufﬁcient cause of clinical hereditary hemochromatosis". Blood 101 (9): 3347–3350. doi:10.1182/blood-2002-06-1747. PMID 12707220.
- KJ Allen, LC Gurrin, CC Constantine, et al. (2008-01-17). "Iron-Overload–Related Disease in HFE Hereditary Hemochromatosis". New England Journal of Medicine 358 (3): 221–230. doi:10.1056/NEJMoa073286. PMID 18199861.