Penetrance

Penetrance in genetics is the proportion of individuals carrying a particular variant (or allele) of a gene (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 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 go on to develop the disease, showing its phenotype, whereas 5% will not.  

Penetrance only refers to whether an individual with a specific genotype exhibits any phenotypic signs or symptoms, and is not to be confused with variable expressivity which is to what extent or degree the symptoms for the disease are shown (the expression of the phenotypic trait). Meaning that, even if the same disease-causing mutation affects separate individuals, the expressivity will vary.

If 100% of individuals carrying a particular genotype express the associated trait, the genotype is said to show complete penetrance. Neurofibromatosis type 1 (NF1), is an autosomal dominant condition which shows complete penetrance, consequently everyone who inherits the disease-causing variant of this gene will develop some degree of symptoms for NF1.

The penetrance is said to be reduced if less than 100% of individuals carrying a particular genotype express associated traits, and is likely to be caused by a combination of genetic, environmental and lifestyle factors. BRCA1 is an example of a genotype with reduced penetrance. By age 70, the mutation is estimated to have a breast cancer penetrance of around 65% in women. Meaning that about 65% of women carrying the gene will develop breast cancer by the time they turn 70.

Many factors such as age, sex, environment, epigenetic modifiers, and modifier genes are linked to penetrance. These factors can help explain why certain individuals with a specific genotype exhibit symptoms or signs of disease, whilst others do not.

If clinical signs associated with a specific genotype appear more frequently with increasing age, the penetrance is said to be age dependent. Some diseases are non-penetrant up until a certain age and then the penetrance starts to increase drastically, whilst others exhibit low penetrance at an early age and continue to increase with time. For this reason, many diseases have a different estimated penetrance dependent on the age.

A specific hexanucleotide repeat expansion within the C9orf72 gene said to be a major cause for developing amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is an example of a genotype with age dependent penetrance. The genotype is said to be non-penetrant until the age of 35, 50% penetrant by the age of 60, and almost completely penetrant by age 80.

For some mutations, the phenotype is more frequently present in one sex and in rare cases mutations appear completely non-penetrant in a particular gender. This is called gender-related penetrance or sex-dependent penetrance and may be the result of allelic variation, disorders in which the expression of the disease is limited to organs only found in one sex such as testis or ovaries, or sex steroid-responsive genes. Breast cancer caused by the BRCA2 mutation is an example of a disease with gender-related penetrance. The penetrance is determined to be much higher in women than men. By age 70, around 86% of females in contrast to 6% of males with the same mutation is estimated to develop breast cancer.