Types of inheritance, terms, and genetic testing
Monogenic inheritance means that a disease is caused by a pathogenic genetic variant in a single gene. These variants, as well as the diseases or syndromes they cause, are rare in the general population. There are various kinds of monogenic inheritance, including autosomal dominant and autosomal recessive, which we’ll describe here.
Autosomal dominant inheritance
In the case of autosomal dominant inheritance, only one copy of the varied gene (from either your mother or your father) is needed for the individual to develop the disease. The parent from which the varied gene is inherited typically has the disease. First-degree relatives (parents, siblings, or children) of someone with a pathogenic variant have a 50% probability of also carrying the genetic variant, and thereby developing the disorder.
For some dominantly inherited disorders, such as Huntington’s disease, all carriers of a pathogenic variant will develop the disease. The proportion of carriers who develop the disease is referred to as penetrance. In the case of Huntington’s disease, the penetrance is 100%. When a pathogenic variant is dominantly inherited but not all carriers develop disease, the variant’s penetrance is described as reduced. Most genetic variants that cause hereditary cancer have reduced penetrance. Reduced penetrance is likely the result of risk-reducing genetic factors, and even environmental factors, that to varying degrees compensate for the genetic variant that increases risk. This explains why some hereditary diseases appear to skip generations, even though they genetically do not. For this reason, reviewing the family cancer history is not always sufficient when assessing hereditary cancer.
Another aspect that complicates identification of a dominantly inherited disease is that the same genetic variant can manifest itself in different ways in different individuals. Neurofibromatosis 1 (NF1), for example, can cause vastly different symptoms in different members of the same family. One such symptom is breast cancer.
Even hereditary cancer can manifest itself in various ways. For example, some women with a pathogenic variant in the BRCA1 gene only develop breast cancer, others develop only ovarian cancer, and some develop both. Biological sex impacts manifestation as well. Men with a pathogenic variant in the BRCA1 gene have a slightly increased risk for prostate cancer, while women with the same variant have a significantly increased risk for breast and ovarian cancers.
Autosomal recessive inheritance
In the case of autosomal recessive inheritance, two pathogenically varied copies of the gene must be inherited – one from the mother and one from the father – for the individual to develop the disease. The parents in this case are typically free from the disease, or healthy carriers. The two variants do not need to be identical but must occur in the same gene. If an individual develops a recessive disease, then both parents are healthy carriers. Each child of two healthy carriers has a 25% probability of inheriting two varied copies and developing the disease.
Within hereditary cancer, there exists one recessively inherited colorectal cancer syndrome called MUTYH-associated polyposis. Another recessive disease that you may have heard of is cystic fibrosis.
Most diseases and conditions are not monogenically inherited but are caused by several genetic variants in various genes. These genetic variants are commonly occurring and are called polymorphisms. Because they are so common, there are many carriers that will never develop the associated disease. On its own, one polymorphism has minimal effect on disease risk. Together, however, a combination of many polymorphisms can lead to increased risk.
Through studying hundreds of thousands of genetic variants found in thousands of individuals, it’s been observed that certain variants are more common in those with a specific disease as compared to healthy individuals. Similarly, there exist genetic variants that protect against disease.
Even common variants impact cancer risk. There are many families, for example, with several generations of breast cancer without any monogenically inherited pathogenic variant to explain the disease penetrance. These families likely carry a very large quantity of risk polymorphisms, indicating an increased breast cancer risk for those with close family members with breast cancer. It is harder to estimate increased risk due to polymorphisms than a monogenetic cause with a genetic test. Genetic testing of common variants is therefore not utilized in clinical practice today. Family cancer history is instead used as a surrogate to estimate a health individual’s cancer risk. Genetic testing of common variants will likely come into standard practice in the not-so-distant future.