The complicated world of genetic testing for Parkinson’s disease

Genetic testing for Parkinson’s disease

People who have a family history of Parkinson’s disease (PD) want to know – is Parkinson’s hereditary? Will I get PD too? Research shows that about 10%-15% of people with PD carry an inherited genetic mutation known to increase PD risk. Therefore, many people with PD as well as those who have a family history of PD may be interested in genetic testing to determine whether they carry one of these inherited genetic mutations.

Who might consider genetic test for Parkinson’s?

There are two groups of people who might consider getting PD genetic testing and we will discuss each group separately.

1. People with PD, possibly with a family history of PD, may want to know if they can pass on a mutation to their children.
2. Children and siblings of people with PD who do not have PD but are concerned about whether they inherited a genetic risk of developing the disease.

Both groups are faced with two questions: Should I get genetic testing? And if so, what should I do with the results? Before we address these two questions, we need to learn more about the complexity of genetic testing in PD.

Why Is Parkinson’s Genetic Testing Complicated?

People with PD may assume that genetic testing for PD is a standard laboratory test. But this is not the case! There are multiple tests available which can be very different from each other. Therefore, understanding what test was performed and what the results mean is not straightforward and requires consultation with your neurologist and/or a genetic counselor.

Here are three ways to get genetic testing for Parkinson’s:

1. A doctor may order a Parkinson’s disease gene panel from a commercial lab.

Many commercial labs offer multi-gene panels for PD, which vary widely in what genes are tested. The number and types of genes tested therefore depends on which commercial lab your doctor uses. Another element of genetic testing that adds complexity to understanding the results, is that genetic testing may discover a variant of unknown significance (or VUS) in one of the tested genes. This means that a genetic anomaly in one of the known PD genes was identified, but this mutation has not been associated with disease. Your doctor will receive all these results and will be able to explain them to you or will refer you to a genetic counselor to help you understand the results.

2. Join the PD Generation study.

The PD Generation Study tests seven of the most well characterized genes associated with PD:

• GBA
• LRRK2
• PRKN
• SNCA
• PINK1
• PARK7
• VPS35

If you choose this option, you will have access to genetic counseling to help you understand your results.

3. You can take a direct-to-consumer genetic test for PD.

This typically does not require involvement of a physician, using a cheek swab sample that you mail in. Before you pursue this method of testing, however, you should consult with your neurologist and be aware of what PD genetic testing is being provided.

For example: the standard genetic testing of the direct-to consumer company 23andMe, consists of only two variants in the LRRK2 and GBA genes. Therefore, anyone who carries a mutation in another gene or who carries a less common disease-causing mutation in LRRK2 and GBA, will receive a report that they do not carry the tested mutations, and may misunderstand that they do not carry any mutation. If you do decide to pursue testing in this manner, please review the report with your neurologist to make sure that you understand it correctly.

It is important to realize that not all genes associated with PD contribute to disease in the same way:

• Autosomal dominant inheritance means that one abnormal copy of the gene is required to cause disease.
• Autosomal recessive inheritance means that two abnormal copies of the gene are required to cause disease.
• Risk factor modifiers are genes that when mutated, increase the risk of developing PD, presumably through interactions with other genetic or environmental causes.

In some situations, harboring one autosomal dominant or two autosomal recessive mutations is still not enough to cause disease. This phenomenon is referred to as reduced penetrance and means that a person may harbor the disease-causing mutation and not develop the disease. Additional genetic or environmental factors must also need to be in place for the disease-causing mutation to manifest itself.

To complicate the issue even more, some people with PD may have inherited genes that are not yet identified as contributing to PD risk. Some may have inherited genes that interact with specific environmental risk factors. These individuals may be more at risk of developing PD upon exposure to a particular environmental risk factor than others.

People with PD: Should I get tested, and what do I do with the results?

Despite all the complexities regarding PD genetic testing, there are an increasing number of reasons why knowing your genetic status might be beneficial to you. Here are a few examples:

Clinical trials for people with specific genetic mutations

As more information concerning genetics and PD is being discovered, treatments are being developed that target the effects of specific genetic mutations. Clinical trials of these potential medications typically look to enroll those who carry the relevant genetic mutation. This makes knowing your genetic status important to allow for participation in these trials.

GBA is a gene that increases the risk of developing PD. This gene encodes the GBA enzyme, a protein used by the body to break down cellular products. Having two abnormal GBA genes causes Gaucher’s disease, which is characterized by the buildup of these cellular products resulting in fatigue, bone pain, easy bleeding, and an enlarged spleen and liver. When a person inherits only one abnormal gene, he or she does not develop Gaucher’s disease, but does incur a small increased risk of PD. Most people with one mutated GBA gene do not develop PD.

Of note, enzyme replacement therapy in which the GBA protein is given intravenously is available as a treatment for Gaucher’s disease. This protein is too big to cross the blood-brain-barrier however, and so it does not enter the brain and does not treat any symptoms caused by the abnormal buildup of cellular components in the brain.

There are several clinical trials that focus on improving abnormal GBA cellular function.

Below, a link is provided to each trial’s National Clinical Trial (NCT) number on clinicaltrials.gov, a database of clinical trials.

• Ambroxol, approved in Europe for respiratory illnesses, improves the function of GBA in neurons – NCT05287503 . A second trial, NCT02914366, is investigating ambroxol for Parkinson’s disease dementia in those with or without a GBA mutation

• BIA 28-6156 is a small molecule that activates the GBA enzyme – NCT05819359
• A gene therapy trial of PR001A introduces the normal GBA gene into the brain – NCT04127578

LRRK2 is a gene that causes autosomal dominant PD (only one abnormal gene is needed to cause PD), but with a reduced penetrance of 30% (only 30% of people who have one abnormal gene will develop PD). The gene encodes the LRRK2 enzyme which adds phosphate groups onto other proteins. Mutations in LRRK2 that cause PD, increase the activity of LRRK2.

These clinical trials focus on LRRK2 biology:

• BIIB122 is a small molecule that inhibits LRRK2 kinase activity NCT06602193
• NEU-411 is another small molecule that inhibits LRRK2 kinase activity. NCT06680830

Treatment decisions for those with specific genetic mutations

In addition to informing whether a person can participate in certain clinical trials, new research suggests that genetic testing may be helpful in informing a person with PD’s treatment options. Currently, results of genetic testing are not considered in clinical decision making, and there are no treatment guidelines that differentiate people with PD based on their genetic status. This, however, may be changing. A recent paper suggests that outcomes of deep brain stimulation (DBS) may differ based on mutation status, with certain mutations predicting a better outcome than others. If additional research continues to support this, then genetic testing may become part of the pre-surgical planning as part of the decision about whether to proceed with surgery. As more research is done, there may be other treatment options that vary with genetic status further encouraging the field to make genetic testing a standard part of the PD workup.

Genetic testing as part of rubric for PD staging

A disease staging system is a framework used to describe the progression or severity of a particular medical condition. Up until now, the standard staging of PD was the Hoehn and Yahr system, based on a neurologist’s observation of the motor symptoms of the disease.  The scientific community is now evaluating whether a biological staging system for PD is feasible. 

Two systems have been suggested. One, called Syn-Neur-Ge, takes into account genetic testing (‘Ge’), along with pathological alpha-synuclein in tissues such as skin or CSF (‘Syn’), and evidence of underlying neurodegeneration defined by neuroimaging (’Neur’). To be implemented, the Syn-Neur-Ge system will require more widespread adoption of genetic testing for people with PD.

Family members without symptoms: Should I get tested and what do I do with the results?

As discussed above, reasons to obtain genetic testing for people with PD are mounting. For those with a family history of PD but no symptoms, however, there is more hesitation. As mentioned above, some mutations that cause PD have decreased penetrance and a large percentage of even those who carry the mutation will not develop the disease. For example, LRRK2 is only 30% penetrant, which means that only 30% of the people who have the mutation will develop the disease. This makes testing of asymptomatic people more complicated because even with the mutation, there is a 70% chance of never having to worry about the disease at all. The decision to get genetic testing must therefore be made after fully understanding of all the available information and with the advice of a genetic counselor.

Different people in this position will make different decisions about whether they want to be tested. There are those who want to understand as much about their health as possible and despite the uncertainty surrounding the testing, will want to have this information. There are others who will not want to pursue genetic testing.

APDA-sponsored research

More research is necessary to further our understanding of how genetic mutations increase PD risk. APDA is proud to fund research that pushes the boundaries of our understanding of the genetic contribution to PD.

• Francesca Magrinelli, MD, PhD, identified PSMF1 as a new gene associated with early-onset PD and parkinsonism in multiple families and is working to understand its role in PD.
• Ronald Emeson, PhD worked to design a short piece of RNA bearing the same mutation as the most common PD-associated variant of the LRRK2 gene, to act as a repair agent. His studies aimed to repair mutant LRRK2 transcripts expressed in human stem cells isolated from a PD patient carrying the mutation.

Tips and Takeaways

• 10-15% of people with PD carry one of the known, inherited genes that contributed to their risk of developing PD. Others may have inherited genes that are not yet identified as increased the risk of PD.
• The issues surrounding genetic testing are complex and are different whether testing is being pursued by someone who has PD or someone who has a family history of PD, without symptoms of the disease.
• Genetic testing for several genes that contribute to PD is available. However, there is much that is not yet known and most people with PD, even with a family history, will not carry one of these abnormal genes.
• Before you pursue genetic testing for Parkinson’s, it is vital to meet with your neurologist and/or a genetic counselor who can explain what the testing will and will not be able to tell you.
• As the field of PD management evolves, genetic testing may become more commonplace as treatment decisions begin to be informed by genetic information, specific medications are developed to combat genetic mutations, and PD staging takes genetic information into account.

If you’d like to support important PD research and help provide hope and optimism to the PD community, please consider donating today.