​Penetrance​

Penetrance helps in understanding the basics of genetics including the relationship between the genetic mutations and the expression of the associated traits. It explains how the traits are shaped by the genes and the numerous factors that contribute to the variations in gene expression. Identifying the genetic mutation can help in predicting the expression of a trait and if it is expressed as a disease, preventive measures can be followed.

What is Penetrance?

Penetrance in genetics is the percentage of individuals carrying a particular gene and expressing the trait associated with it. The likelihood of a genetic variation to express its traits in an individual is characterized by penetrance. The traits can be completely or incompletely expressed. Penetrance plays a significant role in studying the link between phenotype and genotype. This can help in predicting the occurrence of a disease or certain trait in individuals with a particular gene.

What Are the Types of Penetrance?

Based on the percentage of expression of a particular trait, penetrance can be divided into two types.

• Complete Penetrance: Complete penetrance indicates that every individual with a certain genotype shows the expected phenotype. Genes for a trait when expressed in all the individuals having it are said to show complete penetrance.
• Incomplete Penetrance: Reduced or incomplete penetrance indicates the expression of a gene in only a particular percentage of individuals. The presence of a certain gene may not be expressed at all times and hence it is incomplete.

How Is the Penetrance Calculated?

The number of individuals expressing the trait associated with the genetic variation is identified and given an alphabet X.

• The total number of individuals with a particular genetic variant is identified as Y
• Based on the identified data, penetrance (%) can be calculated as the following.

Penetrance(%) = [Number of individuals expressing the trait associated with the genetic variation (X)]/ [Total number of individuals with a particular genetic variant (Y)] x 100

What Is the Association Between Penetrance and Expressivity?

Penetrance and expressivity are closely related with minor differences. Expressivity helps in understanding the penetrance in a better way. While penetrance indicates the individuals showing the trait associated with the genes, expressivity describes the extent to which the trait is expressed in an individual.

• High Penetrance and Variable Expressivity: In certain cases with high penetrance, every individual expresses the associated trait, but the degree or severity of the trait being expressed varies between them.
• Low Penetrance and Variable Expressivity: In cases where all the individuals do not express the trait or with reduced penetrance, expressivity also can vary. The individuals expressing the trait show variations in the severity.

Causes of Penetrance

The exact causes of penetrance are not known but a combination of genetic, environmental and lifestyle factors many of which are unknown may be thought as the probable causes.

1. Genetic factors : Repeat expansion disorders are caused by genomic expansions of short tandem repeat (STR) sequences that either affect the gene expression or protein sequence. For genetically heterogeneous monogenic diseases, the penetrance may vary between different genes or variants, with the same phenotype caused by numerous different variants across multiple genes.
2. Environmental factors : The environment can affect disease penetrance in both negative and positive manner which includes diet, drugs, in utero exposures, education, alcohol intake, physical activity, ultraviolet light, socio-economic status and many other factors. Epigenetic factors can provide a link between the environment and gene expression and studies of the human microbiome can also explain some extreme variability in genotype–phenotype presentation.
3. Stochastic factors : Stochastic variation within normal cellular and developmental processes can potentially be amplified by disease causing variants thus playing a role in incomplete penetrance.
4. Epigenetic modification : Epigenetic modifications are molecularly heritable changes that change the expression of genes without altering the DNA sequence itself. It includes DNA methylation, histone modifications, and microRNA (miRNA) expression. Differential epigenetic modifications between individuals carrying the same pathogenic genotype can lead to incomplete penetrance.
5. Incomplete penetrance in some genetic disorders : Incomplete penetrance can be observed in both dominant and recessive conditions.

Diseases Associated with Penetrance

The diseases associated with Penetrance are as follows:

1. Hereditary ovarian and breast cancer: BRCA1 and BRCA2 gene mutations in individuals have a higher risk of developing cancer of the breast and ovary. Not all individuals with the mutations develop cancer. As the penetrance is incomplete, factors such as gender and age also influence the development of hereditary ovary and breast cancer.
2. Neurofibromatosis type 1: Mutations in the NF1 gene can lead to the development of tumors. Penetrance is generally high in individuals with the gene NF1. This means that most individuals develop symptoms but the severity of the symptoms can differ.
3. Huntington’s disease: This is a disease associated with high penetrance where individuals with HTT gene mutations are sure to develop the disease which is characterized by a decline in cognition skills, motor dysfunction, and psychiatric symptoms.
4. Familial Adenomatous polyposis: Development of polyps in the rectum and colon which may progress into colorectal cancer is seen in familial adenomatous polyposis which occurs due to APC gene mutations. Development of polyps is seen in almost every individual as the penetrance is high. Preventive measures can help in reducing the occurrence and severity of the symptoms.
5. Retinoblastoma: Eye cancer developing in children with RB1 gene mutations is retinoblastoma. Penetrance is incomplete and they may or may not develop cancer. Certain environmental and genetic factors also influence the development of retinoblastoma.

Determination of Penetrance

Penetrance analysis is figuring out what percentage of people who carry a certain genetic mutation really display the phenotype or attribute that goes along with it.

• Only large-scale demographic studies are able to determine penetration.
• The more people with a mutation who can be examined for presence or absence of the associated phenotype, the more accurate the penetrance estimate will be.
• A web-based tool named ‘CalPen’ is used for calculation of penetrance and its credible intervals. It is used by entering the number of mutations identified in controls and patients, and the number of patients and controls studied.
• For validation purposes, it is shown that CalPen-derived penetrance values are in good agreement with the published values.

Importance of Penetrance in Clinical Settings

Penetrance is important not only for research purposes but also in the clinical settings in the following ways.

• Genetic counselors understand penetrance to convey the most accurate information to individuals with a family history of unwanted genetic mutations. This helps the individual regarding decision-making and further preventive measures.
• The information regarding penetrance can help physicians to assess the likelihood of a gene developing a particular condition. This helps them follow preventive measures and monitor throughout.
• Treatment strategies can also be selected according to the penetrance. In conditions with high penetrance, aggressive interventions are recommended.
• In certain cases, genetic information can influence the treatment and hence understanding penetrance is important. Few genetic variations can impact the response to medications and hence understanding penetrance is essential to guide the treatment plan.
• It also plays an important role in the research side. Penetrance stands as a guide to selecting the participants in a clinical trial which improves the effectiveness of the research.
• Understanding penetrance can enhance the quality of treatment and also navigate the loopholes in the genetic information.

Difference between Penetrance and Expressivity

The difference between Penetrance and Expressivity are as follows:

Penetrance	Expressivity
Describes the expression level of a particular phenotype, which corresponds to a dominant genotype.	Describes the extent of a given genotype expressed at the phenotypic level.
Describes the expression of a single gene.	Explains about the expression of a group of characters or syndrome.
If the penetrance is incomplete then its genetic analysis becomes more difficult.	If the expressivity is variable then more difficulty is faced during its genetic analysis.
Example: Expression of BRCA1 and BRCA2 genes develop cancer in some individuals but not in others.	Example: Polydactyly or occurrence of extra toes in cats

Conclusion – Penetrance

Penetrance is fundamental in genetics and provides insights into gene expression. The complexity arises with the involvement of lifestyle, genetic, and environmental factors that contribute to the manifestation of the associated traits. It is a key element in understanding the relationship between the genotype and phenotype along with their expressions. All together it helps in predicting the occurrence of a disease and also in the treatment of the same.

FAQs – Penetrance

What is the Difference between Penetrance and Expressivity?

Penetrance is the percentage of individuals that expresses the traits associated with the underlying genes and expressivity defines the degree of the expressed traits.

What are the Examples for Incomplete Penetrance?

Human polydactyly is a condition with extra toes and fingers. The gene GL13 for polydactyly shows incomplete penetrance and hence not all individuals with the gene show polydactyly.

What are the Diseases Associated with Penetrance?

Diseases associated with penetrance include familial Adenomatous polyposis, retinoblastoma, hereditary ovarian and breast cancer, neurofibromatosis type 1 and Huntington’s disease.

How does Penetrance help in Treatment Planning?

Understanding penetrance can help in assessing the severity of the disease and accordingly the treatment can be planned.

What is the Law of Penetrance?

Complete penetrance refers to expression of the gene in all the population who have the gene, whereas incomplete refers to the expression of a gene in only some percentage of the population containing the gene.

What Causes Penetrance?

The exact causes of penetrance are not known. But a combination of genetic, environmental and lifestyle factors many of which are unknown may be thought as the probable causes.