Ask the Mito Doc – November 2025 Q&A
All answers today are based on personal experience of the participants. As always, please consult your personal physician prior to taking any action.
Topic: Genetic Testing in Mitochondrial Disease – What Patients and Families Need to Know
Topic: Genetic Testing in Mitochondrial Disease: What Patients and Families Need to Know
Speakers:
- Erin McGinnis, MS, CGC, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL
- Rebecca McClellan, MGC, CGC, Kennedy Krieger Institute, Baltimore, MD
- Colleen Clarke Muraresku, MS, LCGC, Children’s Hospital of Philadelphia, Philadelphia, PA
- Andy McCarty, MS, CGC, (he/they), Clover Genetics, Pittsburgh, PA
- Liz Mizerik, MS, CGC, Baylor College of Medicine/Texas Children’s Hospital, Houston, TX
Q: What advise do you have for the undiagnosed patient still looking for answers? Does it help to seek multiple opinions?
A: Andy McCarty, MS, CGC: In terms of seeing genetics, I would say it can be of benefit to revisit with these providers if it has been a number of years as testing options can change. Likewise, a second opinion may provide insights that another provider may have missed or not considered. More broadly there are potentially research options e.g. UDN that can help pick up where clinical care hasn’t yet found a diagnosis.
A: Devin Shuman: No GT can rule out mito – even WGS with mtDNA as only 40-60% can find a genetic answer based on limitations to knowledge and technology (% varies depends on inclusion criteria for these studies). So genetic testing can rule mito in but cannot rule it out!
Q: What is the difference between a GeneDx testing and a WES genome testing? I had the Gene DX, but someone asked me if I had the other.
A: Rebecca McClellan, MGC, CGC: GeneDx is a genetic testing laboratory, not a specific test. WES stands for whole exome sequencing and genome likely refers to whole genome sequencing, a similar but more comprehensive genetic testing.
Q: Can you discuss what to test when, how to sort out and understand the range of testing options that are out there? The d ifferent labs, different kinds of tests, different ways of interpreting those tests, does there need to be mitochondrial specialization?
A: Colleen Clarke Muraresku, MS: With the broader-based testing like genome, this is going to solve a lot of these technology problems we’re having interchangeably. Cost is an issue, sample type’s a problem, how to do it. You know, if you find something and need a specialist, but you can get, like, your general geneticist or someone who’s savvy, like Divakar and work with a genetic counselor, it doesn’t have to be a mito specialist to help get you the testing that you may need.
A: Divakar S. Mithal, MD PhD: Colleen brought up sample as a problem; there’s different tests that are done in different places, which you kind of highlighted, but just to remind people, some places might do a cheek swab, some places might do a blood test. You’ve heard of muscle biopsies, I’m sure a lot of you guys have heard of those things, so there are different tissues that are tested.
A whole genome is going to go a long way to covering a lot of this stuff. It will also not solve the problem of mitochondrial testing being different. Mitochondrial genome being different in different tissues. So both of those things are still going to continue to be challenges. In terms of the labs that people send things to, and the sort of interpretation, there will be some differences in the technology at those different labs. I think they’re converging on better technology, so again, a lot of this comes down to reanalysis and sort of paying attention to the field.
Q: Is WGS alone enough to rule out mitochondrial disease, or is mtDNA or panel testing still needed?
A: Divakar S. Mithal, MD PhD: WGS alone is not sufficient – in most cases mtDNA testing is also indicated (and that is separate from whole genome).
Q: For WGS does saliva or blood sample make difference?
A: Erin McGinnis, MS, CGC: Right now, some labs may only accept blood for this test. In the future, most will accept saliva. For most genetic tests, blood is the preferred sample but saliva is good too. For mitochondrial disease, it may be important to test a variant identified on multiple sample types, like blood, saliva, and skin biopsy.
Q: If undiagnosed, does it matter where we get WGS done — should it be through a mito-specialized clinic?
A: Colleen Clarke Muraresku, MS, LCGC: Genome and even other broad-based testing can be done in non-specialized clinics. The important factors are they have good coverage/interpretation of mitochondrial DNA and a through symptom list for you. Then you can always see a specialist depending on the results.
Q: Does the lab doing the genetic testing impact the accuracy or interpretation, especially for mito-related variants?
A: Andy McCarty, MS, CGC: Yes, depending on the lab and the type of analysis there can be subtle and not so subtle differences in tests. For example, some tests like WGS include analysis of the mito genome while others do not. Each lab typically uses a standard interpretation framework (guidelines from ACMG) but there are differences from lab to lab that it is important to pay attention to and discuss with your provider.
Q: Can you talk about your experience with patients when there is no cure or treatment, but there is positive value in the diagnosis. That is, knowing the reason for symptoms, even if they can’t be treated. Thank you!
A: Erin McGinnis, MS, CGC: There is certainly a value for many families, even when there is no cure or treatment. Just knowing WHY can be incredibly helpful for patients and their providers. It can provide families and their providers with more information about prognosis or what to expect for the condition over time. It can open the door for clinical studies and research. It can also link families to condition-specific support groups and patient organizations. Finally, it can give families more information about this chance, which can happen again, and risks for other family members.
A: Liz Mizerik, MS, CGC: I agree with Erin – the why can sometimes help provide the finality of searching for a reason and can then focus on what that diagnosis may mean – or not mean. In the future, having a diagnosis may help us one day find helpful treatments or cures as well.
Q: Are AI tools already improving WGS interpretation? What changes in testing are expected in the next year?
A: Divakar S. Mithal, MD PhD: Yes, AI tools are helping. However, each organization/company is using AI differently, so it is hard to make concrete predictions about this. In the next year, I would say AI is going to be most helpful in decreasing the time it takes to report back results.
Q: Can secondary mitochondrial dysfunction, caused by another metabolic or genetic disorder, present as severely as primary mito disease? How do we test for or manage it in undiagnosed children?
A: Divakar S. Mithal, MD PhD: The short is answer is “yes”, secondary mitochondrial disorders can present very severely. Usually we will approach these disorders similarly to how we evaluate mitochondrial disease, with similar tools. However, they can be very challenging to diagnose.
Q: I have 11 brothers and sisters. (Why am) I the only one with a mitochondrial disease???
A: Erin McGinnis, MS, CGC: Genetic conditions, like mitochondrial disease, may not always show themselves in a family history. For example, we do not typically see a positive family history for autosomal recessive inheritance. With mitochondrial inheritance, relatives may carry the pathogenic variant at a low level of heteroplasmy, so they may not have symptoms. Still, they can have a child who may develop symptoms.
Q: My son was diagnosed in 2003. I am now in my 50’s and I’m wondering if I need to be tested. I have small issues popping up but thinking is it necessary for me to get tested. If I do where would I go. We are in FL ?? Thank you
A: Colleen Clarke Muraresku, MS, LCGC: It depends on the condition. If you are at risk it may be beneficial to explore for 2 reasons: we say for family members to guide your screening/management and there are new drug trials that you may be eligible. You can see a geneticist locally. We do virtual consults for FL telehealth at CHOP if you are interested.
Q: Do you know if CHOP does virtual consults in VA, MD or DC?
A: Colleen Clarke Muraresku, MS, LCGC: We can for VA has we physicians licensed in this state. We do not have MD and DC but do have DE depending on how easy to get into those states.
Q: What would you recommend regarding people seeking virtual consultations either due to travel restrictions or geographical access?
A: Rebecca McClellan, MGC, CGC: That’s a tough one, because it is very specific. Some genetic counselors will have licensure that is beyond their state’s. Licensure is done state-by-state for genetic counselors. Some counselors are only licensed in their own state, some have some licensure outside of their states. Many physicians, though, do not have licensure across state lines, and so it really depends on what type of evaluation you’re seeking and you need. Whether a genetic counselor can help you independent of an evaluation with a clinician. I don’t know, would anybody else add anything to that? It’s a little bit of a tricky question, given we don’t know how you might need.
A: Andy McCarty, MS, CGC: Yeah, I think I would just add that it depends on having that in-person physician can be really helpful. There are those telehealth, genetic counseling practices that can sometimes help facilitate working with.
Q: Our daughter currently cannot travel due to exercise/flare‑triggered illness. Do you offer virtual or telemedicine initial consultations with your mitochondrial/metabolic genetics team? If so, can every part of the first visit be done remotely (history, review of labs, genetic counselling), and at what point would an in‑person visit be required? Does in state or out of state matter?
A: Andy McCarty, MS, CGC: I can’t speak to every program but we have worked with families in a telehealth manner (history, review of systems, coordination of testing using saliva) and AFTER genetic testing was done did we refer to an in-person mitochondrial center though there are pros and cons to this approach given an in person exam by a knowledgeable physician team. The labs (beyond genetic testing) that can be performed at a hospital center may vary from what can be done from home as easily. There are implications with states as most though not all states have licensure issues so where you are present during an appointment can impact who you may see.
Q: Can you use a tooth or hair for testing? Diagnosis made with a blood sample at age 27, but would more information be able to help?
A: Rebecca McClellan, MGC, CGC: There is generally not enough DNA available from a hair sample or tooth for clinical genetic testing like exome or genome sequencing.
Q: I’m 44 years old and was diagnosed this year. In hindsight I have had symptoms for 7 years. How did my mitochondria work for 37 years and then suddenly stop working right?
A: Erin McGinnis, MS, CGC: This is a great question that many people ask. Because mitochondrial disease is an energy problem, symptoms of mitochondrial disease begin to set in when the body is under “stress” and lacking sufficient energy. You may be perfectly healthy, and then symptoms may hit after an illness or event that stresses the body. Symptoms can also come and go depending on the energy needs of the body. Our bodies mitochondria can also functionally decline with age. Therefore, someone’s body may no longer be able to produce as much energy as they once did with age.
Q: Hello, our son has been diagnosed with tk2d, and has had been experiencing nausea/vomiting for years every day until approximately 3pm. Is this a symptom of tk2d? And if so, does the medication help at all with nausea/vomiting? Thank you.
A: Colleen Clarke Muraresku, MS, LCGC: I am sorry to hear about your son’s diagnosis and his ongoing nausea vomiting. It is not a specific symptom in Tk2d but lactic acidosis can be and this can cause nausea if not well controlled. Something to talk to your doctors about. There are also other medicines that can help when nausea sets in to help reduce or eliminate the progression to vomiting that you can talk with a GI doctor. Wishing your son some relief soon.
Q: Mito Swab- positive. Muscle biopsy-positive. Submitted to Simply Genetics and no variants considered sufficient to cause disease identified. What now? I’m in St. Louis, MO and don’t have a mito doctor here just my neurologist. How do I go forward with testing or helping myself? Is one just in limbo at that point?
A: Colleen Clarke Muraresku, MS, LCGC: I am sorry to hear about your long diagnostic journey. There can be ‘limbo’ periods but you can explore to get more clinical information understanding the symptoms. Genome is evolving a newer technology will be more readily available, called long read whole genome clinically. You can see a geneticist and even see about an undiagnosed disease program.
Q: I had the muscle biopsy 7 years ago, before my specialist, Dr. Brass in Buffalo NY, had the “software” to read my report and determine WHICH gene of mine is defective. He since has passed and I became complacent and didn’t approach Dr. Ambrus to become one of his patients. Where can I and other former Dr. Brass patients that are in the same position, go to get counseling in the Buffalo area?
A: Rebecca McClellan, MGC, CGC: You can look up genetic counselors by region and often specialty. For counselors with expertise in mitochondrial disease you would seek someone in a Metabolic clinic or general pediatric genetic clinic. https://findageneticcounselor.nsgc.org/?reload=timezone
Q: What do you do when you get to the end of testing and still do not have an answer. Where do you go from here?
A: Rebecca McClellan, MGC, CGC: I would say that if you feel comfortable with your team and feel like they have carefully worked through the evaluation with you, I think if you feel like you have lingering thoughts that things haven’t been addressed or well answered, then by all means, seek a second opinion. But if you feel confident in the evaluation that you’ve had and the team that you’ve worked with, then sometimes it’s a matter for waiting for the technology to catch up. I know that that is less than a satisfying answer, and a very hard thing to ask a family or a patient who’s struggling to do, but sometimes, we just have to let the field get smarter and the technology get better.