Advances in Clinical Genetic Testing for Parkinson Disease

In the United States, approximately 60,000 people are diagnosed with Parkinson disease (PD) each year, according to the Parkinson’s Foundation.1

At the American Neurological Association’s 145th Annual Meeting, Rachel Saunders-Pullman, MD, MPH; Tanya Simuni, MD; Tatiana Foroud, PhD; and Tara Hastings, MA, participated in a talk titled “Clinical Genetic Testing for Parkinson's Disease: What When and How.”2 After their talk, Neurology Learning Network caught up with them about the key advances in this area.

Dr Saunders-Pullman is a Bachmann-Strauss Professor of Neurology in the Icahn School of Medicine at Mount Sinai in New York City, and is on the Steering Committee of the National Institutes of Health Parkinson Disease Biomarker Program. Dr Simuni is the director of the Parkinson's Disease and Movement Disorders Center, chief of Movement Disorders in the Department of Neurology, and the Arthur C. Nielsen, Jr., Research Professor of Parkinson's Disease and Movement Disorders at Northwestern University’s Feinberg School of Medicine in Chicago, Illinois. Ms Hastings is the senior associate director of patient engagement at The Michael J. Fox Foundation for Parkinson’s Research.

Neurology Learning Network: Could you discuss recent research on common PD‑related genetic mutations?

Dr Saunders‑Pullman: Part of the challenge of developing treatments for PD has been the heterogeneity of PD. Genetics provides exciting avenues into parsing this heterogeneity and developing and applying therapeutics that are directed toward a specific etiology. We have learned that while mutations in the leucine-rich repeat kinase 2 (LRRK2) gene and the glucocerebrosidase (GBA) gene also occur in young-onset disease, they are major genetic determinants for typical late-onset PD. Thus, the prior axiom that only young-onset disease is genetic no longer holds.

In the case of the GBA gene, variants and mutations may be present in up to 10% of unselected cases with PD. For the LRRK2 gene, mutations may be present in approximately 1% of PD overall, in 4% of those with a family history, and up to 15% of people with PD who are of Ashkenazi Jewish heritage. Research has focused on understanding clinical features:  particularly, the frequency of these genes in different populations and the penetrance of these genes. It has also included delineating the phenotypes, with individual cases of LRRK2 and GBA mimicking idiopathic PD. However, LRRK2 mutation carriers as a group demonstrate less cognitive decline, and slightly slower motor progression, and GBA mutation carriers with PD demonstrating more non-motor features, with the type of the mutation mattering in determining progression.

Other major areas of research involve better understanding the mechanism of these genes, as well as biomarkers that help in understanding the pathophysiology and help to track progression and potential target engagement for evolving therapeutics. Work to date has already yielded pharmacologic targets. In particular, kinase inhibitors are being tested to decrease elevated LRRK2 kinase in LRRK2 mutation PD. For GBA mutations, which are believed to cause dysfunctional glucocerebrosidase enzyme (GCase), trials involving agents to improve GCase function in the lysosome, or decrease presumed deleterious upstream substrates are underway. Gene therapy trials are ongoing for GBA-related PD and planned for LRRK2 PD.

Ms Hastings: At The Michael J. Fox Foundation, we believe that the path to deepening our understanding of the disease requires collaboration and open sharing of data, processes, and results. To Dr Saunders-Pullman’s point about biomarkers, the Foundation is the sponsor of the Parkinson's Progression Markers Initiative (PPMI), which is our landmark observational clinical study to identify biomarkers of PD. Since launching in 2010, the study has enrolled a cohort of more than 600 people with genetic mutations that are being followed over time, and all of the data that are collected are available to the research community. To date, there have been 6.3 million downloads of that data by researchers across the globe.

It has been heartening to see how valuable this data has become to helping the scientific community advance PD research.

NLN: What mechanisms are currently used to genotype patients with PD?

Dr Simuni: For genetic forms of PD, we need to provide venues and mechanisms to test patients in the clinic and participants in research protocols. Currently, this field is in a very nascent stage for a number of reasons. Genetics of PD research, as Dr Saunders-Pullman indicated, has been exploding within the past 10 years. However, 10 years is still relatively recent, and this information was not taught in medical school to clinicians who are at least 10 years out of training.

Physicians are often not very comfortable bringing up the topic of genetic testing to people with PD for a number of reasons. In most cases, there is no insurance coverage for genetic testing. Genetic testing is an epically complex procedure that requires the involvement of a genetic counselor to explain the rationale for testing and then the results to the patient and to put this information into perspective. In addition, there is limited availability of genetic counselors nationally. With all of these factors in mind, there is really no established paradigm from the clinical standpoint. However, as Tara has indicated, the Foundation and a number of other foundations here have been keenly involved in making genetic testing possible for people with PD.

Over a year ago, the Parkinson's Foundation launched a study called PD GENEration, which offers free genetic testing focused on 7 PD genetic mutations that have the strongest data linkage to PD risk. The study is currently conducted at Parkinson's Foundation Centers of Excellence and is being expanded nationwide. They have an ambitious goal to test about 10,000 to 15,000 participants through that mechanism. The Michael J. Fox Foundation has a number of programs enabling genetic testing, also through the research mechanisms. The PPMI study mentioned earlier is currently seeking patients with PD with a certain family history or racial/ethnic background that increases their risk of PD, as well as unaffected family members.

We also need to enable the platforms for genetic testing, and to educate clinicians on the role of genetics in PD. This is where educational programs like the American Neurological Association’s PD program play an important role.

Ms Hastings: The Michael J. Fox Foundation also has an online clinical study called Fox Insight. In this study, we aim to accelerate breakthroughs by capturing the experience of people both with or without PD. Through a collaboration with 23andMe, which is a consumer genetics company, people who join Fox Insight and have PD can access 23andMe health and ancestry services at no cost. They can then add that genetic information to their study profile and receive genetic counseling to understand their results. This can be done through the mail and with phone counseling making it another avenue where patients can access genetic testing if they are interested.

Dr Saunders‑Pullman: It is important to note that, although we have identified PD genes and a variety of mutations that increase disease risk, not all assays can test for the entire range of mutations. It is key for neurologists to be aware of the type of testing that is performed and what is included in that testing, because some earlier methods of testing may miss some mutations, particularly some of the mutations that are associated with more rapidly progressive disease.

NLN: What is the role of genetic counseling in PD, and could you discuss any ethical issues surrounding genetic testing in PD?

Dr Saunders‑Pullman: From an ethical standpoint, major concerns related to genetic testing are patient autonomy, or informed consent, and the principle of beneficence—whether something may benefit the patient. Through genetic counseling, patients obtain the information that helps them make informed decisions and weigh the advantages and disadvantages of testing based on their own values and situation. I also believe that testing improves diagnosis and prognostication of a patient’s PD. There could also be implications for treatment, and it may eliminate some of the uncertainty and work‑up. 

A further tangible benefit of genetic testing is that knowing one’s genetic status affects eligibility for clinical trials. Some of the current, evolving landmark studies are related to genetic forms of PD. In addition, genetic testing helps clarify the risk of PD to relatives and improves carrier testing if family members wish to undergo testing. There is power in knowledge and hope for research, which I believe is a benefit of testing.

Potential downsides of testing are that we cannot necessarily prognosticate on an individual level, and that our studies are really group‑based. At this point, genetic testing may not have any bearing in terms of treatment and prevention of PD. Another concern is that undergoing genetic testing can sometimes increase a patient’s feelings of guilt in terms of passing on a condition. There may be a burden on their families. The cost of testing may be high, and the yields may be low. Another key point is that a negative test does not necessarily mean that a patient’s PD is not genetic.

These are all points that are discussed with a genetic counselor, and this is why it is important to have a genetic counselor onboard to work with patients with PD and determine whether those patients want to know their genetic results or not.

Ms Hastings: Anecdotally, we have heard from patients who say that participating in research can make them feel hopeful and empowered in their journey with PD. That said, it may not be the right thing for everyone, and it does not preclude a patient from pursuing other research opportunities.

Patients are the experts on their own disease. They should be front and center in the research process and ultimately informed to make appropriate decisions for themselves and for their families about how they want to proceed. The field of PD genetics has transformed in recent years, but it is still critical to have more participation from the community to maintain momentum. At the Foundation, we are focused on creating opportunities for patients and families to decide whether they wish to pursue genetic testing. We are glad to have a role to support patients, families, communities, and clinicians in this area.

NLN: What key clinical takeaways about this topic do you hope to leave with neurologists and neurology providers?

Dr Simuni: We are in the era of personalized medicine across a number of medical subspecialties. In PD research, we are stepping into the field of personalization of therapeutics so that we do not approach the disease as a one‑size‑fits‑all matter, but instead based on the biology that drives the disease in each individual person. Genetic status is an important part of reaching this goal of personalization. As Dr Saunders‑Pullman and Ms Hastings have mentioned, it is important to understand the biology of the disease for more accurate counseling on disease progression, and there are clinical trials in the clinic today that are recruiting participants with specific genetic mutations, such as LRRK2 mutation and GBA mutations.

There are multiple reasons why this is important as this field moves forward. First, genetic testing must be performed responsibly. Second, clinicians need to be informed of the role of genetics in PD. Third, we need to establish the platforms for genetic testing. And finally, we need to offer genetic counseling to be responsible in providing the results to the participants. All of this will require collaboration between a number of research organizations, patient advocacy organizations, as well as health care providers and insurance companies. It is very rewarding to see this process move forward.

Dr Saunders‑Pullman: I would like to reiterate that the field of genetics is a key factor in personalized medicine for PD. I believe this field is leading us in new directions, and without the knowledge of genetics, we would not be as informed when it comes to guiding patients who are interested to clinical trials. In my clinical experience, I have found that it can make a huge difference for patients to have this information.

At the same time, we definitely need to temper it and ensure that genetic counseling is in place. It can be quite overwhelming for neurologists to figure out the right resources in terms of referrals for testing. Some key resources that are currently available, which Dr Simuni and Ms Hastings mentioned, are the PD GENEration study; the Fox Insight 23andMe initiative with The Michael J. Fox Foundation, and Rostock International Parkinson's Disease Study. In addition, The National Society for Genetic Counselors can help with finding a genetic counselor if none are available on site.

Ms Hastings: This is an exciting (and busy) time for PD research. Research opportunities across the entire spectrum exist, and there are many resources available for both clinicians and patients to take part. Specifically, the Foundation has an online tool called the Fox Trial Finder, which clinicians can share with their patients. They can search for trials quickly and easily based on their geographical location and disease stage. Opportunities like this continue to grow, and we want to ensure that patients who are interested in participating in research have the opportunity to do so and to be partners in their care with their physicians.

—Christina Vogt


  1. Parkinson’s Foundation. Statistics. Accessed November 2, 2020.
  2. Simuni T, Saunders-Pullman R, Foroud T. Clinical genetic testing for Parkinson’s disease: what, when and how. Talk presented at: American Neurological Association 145th Annual Meeting; October 9, 2020; Virtual.