Pathogenicity, penetrance, and de novo are scientific terms that come up often when reading about genetic mutations or variants. What do they mean?
Double-stranded DNA. Nucleotides on the DNA strand are shown as letters, such as G (guanine), C (cytosine), T (thymine), A (adenine). The circle around T indicates a genetic change.
Pathogenicity
To be pathogenic means to cause or be capable of causing disease. Genetic variants are often classified into five categories, which describe how likely they are to cause disease:
Pathogenic: Known to cause disease
Likely pathogenic: Likely to cause disease, but there isn't enough scientific evidence to be certain
Variant of uncertain significance (VUS): Can't be confirmed to play a role in disease development
Likely benign: Probably not responsible for disease, but there isn't enough scientific evidence to be certain
Benign: Not known to cause disease
Laboratories often use this five-point scale to assign pathogenicity, but not all laboratories follow these guidelines exactly, or use the same terminology when reporting results.
Penetrance
Penetrance measures the percentage of people who carry a particular mutation that ultimately become affected by the associated disorder. For example, Factor V Leiden is a blood clotting disorder caused by a mutation that has low penetrance. It is low penetrance because many carriers that have the mutation never develop the disease.
On the other hand, FAD genetic mutations are known to be highly penetrant, meaning nearly 100% of those who carry an FAD mutation end up developing Alzheimer’s disease if they live to their family’s age of onset.
De Novo
De novo is a Latin term that means “anew” or “from the beginning.” In genetics, it refers to something that has occurred for the first time.
A de novo mutation is a genetic variant that appears for the first time spontaneously in a person and has not been inherited from previous generations (so neither parent carries the variant). A de novo mutation can explain rare situations in which a person develops familial Alzheimer’s disease without having parents who developed FAD.
In many cases, there is not enough data available about a de novo mutation to know whether it causes disease.