17 Aug, 2020

What is genetic risk?

Certified genetic counsellor Kira Dineen explains genetic risk and the role it plays in healthcare decisions.

Kira is a certified genetic counsellor in a private practice in the USA, specialising in high risk obstetrics. She is also a member of the National Society of Genetic Counselors’ Digital Ambassador program and is the creator and host of the podcast and radio show DNA Today: A Genetics Podcast.

“What is the chance this will happen?”; at some point most of us will have asked this question to a medical professional, as risk applies to nearly all areas of health, including cancer, prenatal, pediatrics, surgery and treatment.

What is genetic risk?

Let’s explore the types of risk within genetics. To do this we need to understand a few concepts in genetics. Starting with the basics, we inherit one set of genetic information from each biological parent, one from dad and one from mum. Since our parents have two copies of each gene, it’s random which of the two we inherit (this will be important to remember later). These genes are the instructions for our body to grow and function.

We inherit one set of genetic information from each biological parent.

The instructions are written in a genetic language using only four letters (A, T, G and C). In order for humans to not be identical, the instructions are written a little differently in every person. We call these differences variants. Most variants are harmless (benign) and account for the beautiful diversity that is the human race, however other variants are harmful (pathogenic) and can lead to disease. Harmful variants in the genetic instructions make it too hard for the body to understand how to work normally, so we can refer to genes with harmful variants as non-working.

Understanding inheritance patterns

It’s important to understand the two major types of genetic risk; the chance of inheriting a harmful variant and the chance of having a condition.

Applying this to a cancer situation, if a patient’s mother has a harmful variant in a gene that elevates her risk for cancer, what is the chance that the patient has inherited this harmful variant and is also at a higher risk for cancer? Breaking down this question can help us to understand the two major types of risk for this patient.

In this example, one copy of the mother’s gene is non-working (has a harmful variant) and one is working (has no harmful variants). The patient can inherit either of these copies, either the non-working copy or the working copy, so there are two potential outcomes. There is a 1 in 2 chance the patient will inherit the non-working gene. Other ways of framing this is to say there is a ½, 50:50 or 50% chance the patient will inherit the non-working gene. These can be difficult and abstract concepts to understand, so it can be helpful to think of risk in different ways.

Does inheriting a faulty gene mean inheriting a condition?

After establishing the inheritance risk of the harmful variant, the next step is to explore the chance the patient will develop cancer if they did inherit the non-working gene. This is going to vary widely depending on the specific gene and cancer type. Let’s pick BRCA1 as the gene with the harmful variant. Normally this gene helps us fight against breast cancer (and other types). Since the mother has a harmful variant of one copy of her BRCA1 gene, this means it isn’t working, her body is not fighting as hard against cancer compared to someone with two working copies of BRCA1. With her body fighting cancer less, she has a higher risk of cancer developing. Studies have found she has up to an 85% chance of developing breast cancer because of her non-working copy of the BRCA1 gene (Chen and Parmigiani 2007).

So far we have highlighted two different aspects of risk, the 50% chance the patient inherits their mother’s non-working copy of BRCA1 and, if they did inherit this non-working copy, the 85% risk of breast cancer development.

Infographic outlining different types of genetic inheritance

In our breast cancer example, a person is at an elevated risk if they inherit one non working copy of the BRCA1 gene. This is known as autosomal dominant inheritance. Another type of inheritance is called autosomal recessive inheritance, where a person has a condition if they inherit two non-working copies of a gene (one from each parent). If a person has just one non-working copy, they are considered a carrier. For most of these conditions you only need one working copy to be healthy, so people only know they are carriers if they participate in genetic screening called carrier screening. This is why carrier screening is offered to parents who are pregnant or planning on conceiving in the near future. If both parents are carriers for a condition, what is the chance that their child would have the condition?

The next generation

The risk for a child to inherit a non-working copy from one parent is the same as in our cancer scenario. If the mother has one working copy and one non-working copy, there is therefore a 1 in 2 chance the child inherits the non-working copy. What is the chance the child could inherit a non-working copy from the father? It’s the same situation as inheriting from the mother, so there is also a 1 in 2 chance. To put these risks together we multiply the ½ chance the child inherits from the mother multiplied by the ½ chance to inherit from the father, which equals a ¼ risk (1 in 4 or 25%).

Many factors, both genetic and environmental, play a role in the presence or development of a condition.

For complex diseases such as heart disease, diabetes, and obesity the inheritance is considered to be multifactorial. This means many factors, both genetic and environmental, play a role in the presence or development of a condition. For example, people who have a harmful variant in the APOE gene (specifically e4) have an increased risk of Alzheimer’s disease (Corder et. al. 1993). However, other risk factors for Alzheimer’s disease include head injuries, heart conditions, and most of all, age (Monique 2000). Often with multifactorial conditions there are multiple genes and environmental exposures that combine to lead to the condition. This makes it difficult to know the risk for people to develop these conditions as it’s not as straightforward as the autosomal dominant and autosomal recessive inheritance that we could calculate in our cancer and prenatal scenarios.

What is a genetic counsellor?

Genetic counsellors are medical professionals who help patients understand how their genetics affect their health, so that they can make informed healthcare decisions often involving genetic testing. A tool that can be used to help assess genetic risk is a family health history. In our cancer scenario, the patient already knew their mother had a harmful variant in her BRCA1 gene, which allows the healthcare provider (often a genetic counsellor) to provide a specific risk level to the patient. This concept applies to nearly all areas of genetic risk assessment, so prior to a genetics appointment it’s advantageous to ask your family about their health going back to your grandparents and including cancer diagnosis, birth defects, genetic conditions and genetic testing results.

Why is genetic risk important?

So far we’ve addressed how genetic risk can be assessed, but why is it important for people to understand their genetic risk? Let’s go back to our scenarios to find out how the patients can use this information. Our patient who had a 50% chance of inheriting the BRCA1 harmful variant now has the opportunity to learn about her options to reduce her risk of breast cancer, such as having her breasts surgically removed before any sign of cancer (prophylactic bilateral mastectomy) and increased surveillance with extra mammograms and MRI scans to spot early signs of cancer development. Our couple who are both carriers for the same genetic condition could see a fertility specialist and pursue preimplantation genetic testing (PGT) to only use embryos that don’t have the condition. Understanding genetic risk allows people to have options in their healthcare and genetic counsellors are there to help patients navigate the information and decisions along the way.

You can keep up with Kira via Twitter, @KiraDineen, or by tuning into the DNA Today podcast.

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