Genetic testing for neuropathy: who may benefit?

Genetic testing for neuropathy is not a routine test for everyone with numb or painful feet. It is most useful when the picture points to an inherited cause: high arches or curled toes, thin lower legs, symptoms that began young and change very slowly, or relatives with similar problems. A doctor, ideally together with genetic counselling, helps decide which test fits and what a result would mean.^{1, 2, 3}

I have neuropathy myself, and I know how tempting it is to hope that one blood test will finally explain everything. This page is about who is likely to benefit from genetic testing, what the tests look for, what the results can and cannot tell you, and how to prepare your family history. Charcot-Marie-Tooth disease and hereditary transthyretin amyloidosis each have their own pages on this site.

Who may benefit from genetic testing for neuropathy?

The American Academy of Neurology’s practice parameter on laboratory and genetic testing, first published in 2009 and reaffirmed in 2025, says genetic testing may be considered when a neuropathy has no known cause and looks like a hereditary neuropathy. For people whose neuropathy does not look hereditary, it found too little evidence to say whether routine genetic testing is useful.³

So the question is less “could my neuropathy be genetic?” and more “does my neuropathy look like the inherited kind?”. The CMAJ review describes thin calf muscles, hammer toes and high-arched feet (pes cavus) as signs of a long-standing neuropathy that are often seen in hereditary forms. It adds that someone whose reflexes are missing everywhere, without other problems on examination, may need a referral because the cause could be hereditary.¹

A review in Practical Neurology notes that many people with inherited neuropathy have few tingling or painful sensations, so they often come to a doctor only when weakness starts to get in the way of daily life. NINDS says Charcot-Marie-Tooth disease usually starts in the teens or early adulthood but can appear at any age, and GeneReviews describes the typical course as slowly progressive.^{5, 6, 2}

Other patterns that can point to a genetic cause

Some inherited neuropathies look quite different. Hereditary neuropathy with liability to pressure palsies (HNPP) typically causes repeated episodes of numbness and weakness in one nerve or several, often painless, at places where nerves are easily pressed, such as the elbow, wrist or the outside of the knee.⁷

Another example is a slowly worsening loss of feeling, often with poor balance, that starts in adulthood. GeneReviews describes a recessive condition caused by an expansion in the RFC1 gene, with onset after the age of 35 and a chronic cough that can come years before the nerve symptoms. In a study from neuropathy clinics in Italy and the UK, 43 of 125 people (34 percent) whose purely sensory neuropathy had been labelled “idiopathic” turned out to have this cause.^{8, 9}

Hereditary transthyretin amyloidosis can cause a slowly progressive neuropathy affecting feeling and strength and/or the autonomic nerves, and it can also affect the heart. GeneReviews lists treatments aimed specifically at this disease, which is one reason a genetic diagnosis can change what happens next.¹⁰

When it is usually not the first step

The CMAJ review says that in distal symmetric polyneuropathy, nearly 60 percent of people have an identified cause after the history and examination, and screening blood tests find a cause in another 10 percent. As I read the guidance, the ordinary work-up comes first, and genetic testing is added when the pattern suggests an inherited form.^{1, 3}

Doesn’t a family history settle it?

Not on its own, in either direction. GeneReviews explains that a person with Charcot-Marie-Tooth disease can have no known family history, because relatives may be only mildly affected, because the condition may be recessive, or because the change in the gene arose for the first time in that person. Practical Neurology says that examining family members can help, when that is possible.^{2, 5}

The opposite is also true. Neuropathy is common and has many causes that are not inherited, so one relative with neuropathy does not prove that yours is genetic, or that you share the same cause. That is my own reasoning, and it is exactly the kind of question a genetics specialist can help untangle.

Even when a condition is inherited, it does not pass on the same way in every family. GeneReviews describes dominant forms, where each child of an affected parent has a 50 percent chance of inheriting the change, recessive forms, where brothers and sisters of an affected person each have a 25 percent chance of being affected, and X-linked forms. For hereditary transthyretin amyloidosis, it notes that how often carriers become ill varies a lot between populations.^{2, 10}

NHGRI, the US genome research institute, points out that a positive result does not always mean you will develop a disease. The US patient organisation CMT Association adds that results cannot reliably predict how the disease will progress or how severe it will become, and that symptoms can vary widely even among people with the same genetic change.^{11, 12}

What does a genetic test for neuropathy look for?

For suspected Charcot-Marie-Tooth disease, GeneReviews recommends starting with a test for a duplication or deletion of the PMP22 gene, since the duplication alone accounts for up to half of all cases. If that is normal, the next step is a panel that looks at several genes at once, and whole exome or genome sequencing may be considered if the panel finds nothing.²

No single test covers everything. GeneReviews notes that the RFC1 repeat expansion cannot be found by sequence-based gene panels or exome sequencing, so it needs its own test. A review in Nature Reviews Neurology describes the growing challenge of interpreting the variants that broad sequencing returns, and how the clinical picture can be combined with genetic and other evidence to judge them.^{8, 13}

How often does testing find an answer?

It depends a great deal on the type of neuropathy and on who is tested. At one specialist inherited-neuropathy centre in the UK, 1,515 people with a clinical diagnosis of Charcot-Marie-Tooth disease or a related disorder were assessed between 2009 and 2023, and 76.9 percent received a genetic diagnosis. The rate was 96.8 percent in the demyelinating type (CMT1) but less than 50 percent in the axonal type (CMT2), in purely motor forms and in complex neuropathies.¹⁴

In a study of 220 consecutive people tested with gene panels at two specialist centres in London and Iowa, 30 percent got a definite diagnosis. Another 33 percent had a variant of uncertain significance, a change whose meaning was not clear. The yield was 73 percent in demyelinating neuropathy, where the common PMP22 change had already been ruled out, and 22 percent in the axonal or intermediate types.¹⁵

These are expert centres with carefully selected people, so the figures don’t tell you your own chances. What they do show is that a genetic test can give a clear answer, a partial answer or no answer at all.

What can a result mean: positive, negative or uncertain?

Laboratories usually describe a genetic finding with one of five terms from the American College of Medical Genetics and Genomics: pathogenic, likely pathogenic, uncertain significance, likely benign or benign. The same guidance says laboratories suggest that doctors check back with them from time to time, because what is known about a variant of uncertain significance can change.¹⁶

MedlinePlus explains that a negative result means the laboratory did not find a change known to affect health, but that a test can miss a disease-causing change because many tests cannot detect every kind of genetic change. The CMT Association says that when testing does not find the genetic cause, this does not rule out Charcot-Marie-Tooth disease; the responsible gene may not have been included in the test, or may not have been discovered yet.^{17, 12}

A clear answer can still help. According to the CMT Association, a result can confirm a clinical diagnosis, identify the subtype, which may matter for research or clinical trials, give insight into medical management and support informed family planning. For HNPP, GeneReviews advises avoiding long periods of pressure on nerves, such as sitting with the legs crossed, and notes that the cancer medicine vincristine has been reported to make HNPP worse.^{12, 7}

Why genetic counselling matters

GeneReviews describes genetic counselling as giving people and families information about the nature, inheritance and implications of genetic disorders, so they can make informed medical and personal decisions. The National Society of Genetic Counselors lists what a counsellor can help with: your genetic risk based on your family history, whether testing might be right for you, what a result may mean for you and your family, and support while you decide.^{2, 18}

MedlinePlus stresses that genetic testing is voluntary, and that deciding whether to be tested is personal and complex. NHGRI notes that a result can have implications for blood relatives, and GeneReviews describes how, once a family’s genetic change is known, relatives at risk can be offered their own testing. The NHS suggests that people who have, or whose partner has, a family history of Charcot-Marie-Tooth disease and are thinking about having a baby see their GP, who can refer them for genetic counselling.^{19, 11, 10, 20}

Rules on how genetic information may be used, for example by insurers or employers, differ from country to country. MedlinePlus describes the US law as one example, and notes that it does not cover life, disability or long-term care insurance. Ask your genetics team what applies where you live before you test.²¹

What about home DNA tests?

I would not use a consumer DNA kit to answer the neuropathy question. MedlinePlus says further testing through a healthcare provider is usually needed before results from such tests can be used to diagnose a condition or make healthcare decisions. The US Food and Drug Administration says they are not a substitute for a traditional health care evaluation and that not all genetic tests look for all the variants that can contribute to disease.^{22, 23}

The American College of Medical Genetics and Genomics recommends that results be interpreted and delivered by a board-certified genetics professional and warns about misinterpretation. In one US laboratory study of 49 samples sent for confirmation, mostly for cancer-risk genes, 40 percent of the variants reported in consumer raw data were false positives.^{24, 25}

Family history to prepare before your appointment

MedlinePlus suggests gathering health information across three generations, noting when problems started, talking to relatives and using records where you can. Here is how I would adapt that for neuropathy. It is fine to write “don’t know” in places; relatives decide for themselves what they want to share.²⁶

What to write down	Why it can matter
Who: parents, brothers and sisters, children, grandparents, aunts, uncles, cousins, nieces and nephews	Three generations make an inheritance pattern easier to see
Anyone with high arches, curled toes, thin lower legs, weak ankles or trouble walking	Foot shape and wasting are classic clues to long-standing, often inherited neuropathy
Anyone with repeated numbness or weakness after pressure, such as leaning on an elbow	This pattern can point to HNPP
Anyone with balance problems starting in adulthood together with a long-lasting cough	A combination described in the RFC1 condition
Neuropathy together with heart problems, and which country or region the family comes from	Relevant to hereditary transthyretin amyloidosis, where risk differs between populations
The age when symptoms began, and how fast they changed	Early onset and very slow change fit inherited forms better
Diagnoses, nerve tests or genetic results relatives already have	A known family variant makes testing more targeted
Other possible causes in relatives, such as diabetes, heavy drinking or chemotherapy	Helps your doctor judge whether a relative’s neuropathy is likely to be inherited

Questions you could ask

• Does my neuropathy look like an inherited form, and why or why not?
• Which test would you start with, and what would it not be able to find?
• How would the result change my care, or the care of my relatives?
• Can I see a genetic counsellor before and after the test?
• What happens if the result is negative or uncertain? Will an uncertain variant be reviewed again later?
• What rules apply to genetic information and insurance where I live?

I’m not a doctor. I’ve written this from published research and guidance, and to help you prepare questions for your own care.

Sources

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