Restless Legs Syndrome and Your Genes — What a 23andMe Polygenic Report Really Means

Restless Legs Syndrome and Your Genes — What a 23andMe Polygenic Report Really Means

This article is for educational purposes only. It is not a substitute for advice from a licensed physician, board-certified medical geneticist, or board-certified genetic counselor. For any decisions about testing, treatment, or care, consult a qualified clinician. In emergencies, call 911.

Bottom line: A “higher likelihood” band for restless legs syndrome on a 23andMe report is a population-level signal. It is not a diagnosis. Researchers have found more than 160 gene regions linked to the condition, but no blood or DNA test can diagnose it. A doctor diagnoses restless legs syndrome using a five-point symptom checklist instead. The one lab test that reliably helps is a ferritin and iron panel; ferritin is a blood marker of how much iron the body has in storage. Bring your report, and your symptoms, to a primary care doctor rather than acting on the band alone.

What you’ll learn

• Why there is no single “RLS gene,” and how researchers found the current set of risk regions
• How common restless legs syndrome actually is, in plain “about N out of 100 people” terms
• Which test matters clinically (it is not a DNA test), and why pregnancy and low iron connect to the genetics
• Which drugs are approved, by which regulator, and why dopamine agonists carry an “augmentation” warning

One Gene or Many? How the Restless Legs Syndrome Gene Hunt Grew

There is no single “restless legs syndrome gene.” Huntington’s disease works that way: one faulty gene, passed down in a clear pattern, causes it. Restless legs syndrome (RLS) does not.

RLS is polygenic. That means many common DNA spelling differences exist. Each one nudges risk up just a little. Together, they add up. No single variant is required, and no single variant is enough on its own.

The discovery story runs in clear, dated steps. In 2007, an Icelandic team led by deCODE Genetics found a common gene variant near a region called BTBD9. It raised the risk of RLS and a related sleep pattern called periodic limb movements. That same year, a separate German and Canadian team confirmed the BTBD9 finding on their own. They also found two more regions: one near a gene called MEIS1, and another near MAP2K5 and SKOR1.

Here is a plain-language pause. A carrier is simply someone who has one or more of these common variants in their DNA. Because the variants are common, most carriers never develop RLS symptoms bad enough to need treatment.

Each of those first-discovered variants raised relative risk by roughly 50 percent or more. Relative risk compares two groups to each other. It does not tell you how many people are actually affected. Absolute risk does that job: it says how many people out of 100 actually get the condition. This article uses “out of 100” language throughout for exactly that reason.

The gene count kept climbing after 2007. A 2017 study combined three large research datasets. It raised the confirmed locus total from 6 to 19 and pointed to genes involved in iron handling and nerve development. Then, in 2024, a much larger study looked at over 116,000 people with RLS and over 1.5 million people without it. Some participants came from 23andMe’s research program. This study raised the confirmed count to 164 regions: 161 on regular chromosomes and 3 on the X chromosome. It confirmed every earlier finding and added many new ones.

Year	Study	What it found
2007	Stefansson et al., deCODE Genetics (Iceland)	First common RLS risk variant, near BTBD9
2007	Winkelmann et al., Germany/Canada	Confirmed BTBD9, added MEIS1 and MAP2K5/SKOR1
2024	Schormair et al., international meta-analysis	164 confirmed regions, up from 19

Definition box — “polygenic”: many common DNA spelling differences, each adding a small nudge to risk, added together. No single gene switch controls the outcome.

The 164 regions point mainly toward two biological threads: how the body handles iron, and how two brain-signaling chemicals, dopamine and glutamate, do their work. The 2024 study also used a statistical method called Mendelian randomization. It uses genetic variants like a natural experiment. The result: RLS appears to be a real cause of higher type 2 diabetes risk, not just something that happens to occur alongside it. This finding has not changed any screening guideline yet. It is a preview of where research may be heading.

Think of one faulty gene like a single light switch. It is either on or off; cause and effect. Restless legs syndrome works more like a room with over 160 separate dimmer dials. Each dial is turned up or down slightly. The combined setting shapes how strong the risk signal is. The US government’s own neurological research agency describes RLS as running in families in many cases. It stresses that many gene regions are involved, not one gene. A primary care physician or sleep-medicine specialist is the right person to translate any of this into a plan for you.

Section recap: Restless legs syndrome has no single causal gene. Researchers have confirmed 164 risk regions as of 2024, pointing to iron-handling and dopamine/glutamate pathways.

How Common Is It, and How Much Does Family History Move the Odds?

Start with the baseline. Every multiplier is a multiplier of something. A 2024 global analysis modeled RLS prevalence in adults aged 20 to 79. The estimate: about 7 out of every 100 people, with a likely range of roughly 5 to 10 out of 100. Picture a row of 100 adults standing in line. Somewhere around 5 to 10 of them will have symptoms meeting the clinical definition at some point in life.

A separate 2023 review pooled 97 studies covering more than 480,000 people worldwide. It found a lower overall estimate, but a clear sex difference: about 4.7 out of 100 women, versus 2.8 out of 100 men. That works out to roughly 1.5 to 2 times more women affected than men. Two well-designed reviews can land on different overall numbers. This happens across the RLS research literature because studies use different case definitions. Both studies still agree on the same basic picture: RLS is common, and it affects women more than men.

Family history matters too, though the exact size of the effect is harder to pin down with a single clean number. One detailed patient study looked at people with an idiopathic form of RLS — meaning RLS with no other, outside medical cause. Among them, 42.3 percent had a family history strong enough to be called “definite” hereditary RLS. Among people whose RLS came from another medical cause, only 11.7 percent had that same family pattern. Twin studies in the broader literature estimate that genetics explains roughly 54 to 70 percent of the difference in who develops RLS. In plain terms: having a close relative with RLS puts you at meaningfully higher risk than the general population. It is not a guarantee, and it is not a precise fold-multiplier that any single study has nailed down.

A 23andMe polygenic likelihood report works differently from a family-history estimate. It places you somewhere in a reference population, based on the combined effect of dozens of common variants. Then it reports a band, such as “higher than typical”. Because RLS is common, and only moderately inherited, most people in a “higher likelihood” band will never develop symptoms bad enough to need treatment. Some people with an average or lower band already have symptoms. Those symptoms are usually driven by low iron, pregnancy, kidney disease, or a medication side effect, not by the polygenic score itself.

A “higher likelihood” band

What it means	What it does not mean
Your combined score sits toward the high end of a reference group	A diagnosis, or proof you will develop symptoms
One more piece of context for a doctor conversation	A fixed number; bands can shift when reference panels update
Useful alongside your own symptom history and iron levels	A reason to start or stop any treatment on your own

If nightly leg discomfort already disrupts your sleep, that lived pattern matters more than any band on a report. Describe it plainly to a primary care physician: when it happens, what relieves it, and how long it has been going on.

Section recap: RLS affects roughly 5 to 10 out of 100 adults worldwide, more often in women, and family history raises the odds meaningfully. Still, most people in a “higher likelihood” polygenic band never develop treatment-level symptoms.

Is There a Real Test for This, or Just the DNA Report?

Here is a common misconception worth correcting directly. There is no FDA-authorized diagnostic genetic test for restless legs syndrome. There is no insurance-covered clinical gene panel for it either. That is because no single gene causes it. Clinical genetic testing companies such as Invitae or Color do not offer an RLS-specific test. A 23andMe “Powered by 23andMe Research” polygenic report is a population-risk estimate, not a diagnostic tool.

The lab test that actually matters clinically is a serum ferritin and iron panel. Low iron stores in the brain and body are a well-documented, fixable contributor to RLS. A 2018 clinical guideline set a specific cutoff. It came from the International Restless Legs Syndrome Study Group. Oral iron is possibly helpful when serum ferritin is 75 micrograms per liter or lower. That number is roughly the same as 75 nanograms per milliliter, the way most US lab reports show it. The next section covers IV iron, which uses a different, higher cutoff. Do not confuse the two thresholds with each other.

A sleep study, or a wrist-worn movement recording called actigraphy, is occasionally used. Its only job is to rule out a look-alike condition called periodic limb movement disorder. It does not diagnose restless legs syndrome itself.

Iron matters here for a specific reason: the brain uses it to help make dopamine, one of the signaling chemicals tied to the gene regions described above. Low iron availability in the brain is one of the most consistent biological threads in RLS research. A normal ferritin level from years ago is not the same as a current, useful reading. If that applies to you, it is worth mentioning to your doctor.

Test	Who orders it	What it tells you	Diagnoses RLS?
23andMe polygenic report	You do, direct-to-consumer	Where your combined risk score sits in a reference group	No
Clinical genetic panel (e.g., Invitae, Color)	A physician	Whether a specific single-gene condition is present	No RLS-specific panel exists
Ferritin and iron panel	A physician	Whether low iron stores may be driving symptoms	No, but guides treatment
Sleep study or actigraphy	A physician or sleep specialist	Whether a look-alike disorder is present instead	No, rules out mimics only

If your 23andMe report flagged a higher-likelihood band, here is the single most useful next step. Talk to a primary care physician about ordering a ferritin and iron panel, especially if you also have symptoms. A board-certified genetic counselor, searchable through NSGC.org, can help you understand what any DNA-based report can and cannot tell you.

Section recap: No genetic or blood test diagnoses restless legs syndrome. The one test that changes management is a ferritin and iron panel, using a serum ferritin cutoff of 75 or lower for oral iron.

Getting a Diagnosis: 5 Criteria, No Genetic Score Involved

Restless legs syndrome is diagnosed entirely by clinical history. Doctors use consensus criteria from the International Restless Legs Syndrome Study Group, last updated in 2014. A primary care physician or neurologist can typically make this diagnosis in a single visit. It uses five criteria, and none of them involve a DNA report.

1. An urge to move the legs, usually with an uncomfortable sensation
2. Symptoms that begin or worsen during rest, such as sitting or lying down
3. Symptoms that are partially or fully relieved by movement
4. Symptoms that are worse in the evening or at night than earlier in the day
5. The pattern is not solely explained by another condition, such as leg cramps or simple positional discomfort

Meeting all five points is usually enough. Describing when symptoms started, and how often they occur, gives a clinician what is needed. No lab confirmation is required beyond ruling out other causes, like low iron.

A note on “VUS”: for single-gene conditions, a genetic test can return a “variant of uncertain significance,” or VUS. That means a DNA change nobody yet knows how to classify. A polygenic likelihood band has no VUS equivalent. It is not scoring one variant; it is adding up many common ones. What can shift over time is the percentile itself, as reference panels get updated. That reflects the statistical model changing, not a change in your biology.

Bring a written symptom log to your next primary care visit. Cover when discomfort starts, what relieves it, and how it affects your sleep. That log, more than any DNA report, is what actually drives the diagnosis.

Section recap: Restless legs syndrome is diagnosed using five consensus clinical criteria, not a genetic score. There is no “variant of uncertain significance” category for a polygenic report.

Prevention and Vigilance: Iron, Triggers, Pregnancy, and Dialysis

The single intervention with the best evidence behind it, for people with low iron stores, is iron repletion. A placebo-controlled randomized trial gave 24 people with RLS two 500-milligram IV doses of ferric carboxymaltose, five days apart. Compared with 22 people who got a placebo, the treated group showed significantly greater symptom improvement over 28 days. That trial used a different iron dose than the threshold discussed above. A separate 2018 guideline recommends a 1000-milligram IV dose for more resistant cases. It applies specifically to people with ferritin under 300 micrograms per liter, a higher cutoff than the oral-iron threshold. Oral iron is usually tried first. Intravenous iron is reserved for people who do not respond to oral iron, or cannot tolerate it, always under a physician’s guidance.

Several everyday substances and medication classes are known to worsen restless legs syndrome. It helps to bring an accurate list of everything you take to a doctor visit, rather than guessing which one might be involved.

Trigger-avoidance checklist

• Caffeine, especially in the afternoon and evening
• Alcohol, particularly close to bedtime
• Nicotine
• Many antihistamines, including common over-the-counter sleep aids
• Antidepressants, particularly SSRIs and SNRIs
• Antiemetics (anti-nausea medications) in some cases

Two populations deserve extra vigilance. The first is pregnancy. A 2020 systematic review of ten studies, covering over 2,400 pregnant people, found that about 23 out of 100 experience RLS in the third trimester. Symptoms are linked to falling iron and folate stores during pregnancy, and they typically fade within weeks of delivery. That matches a common pattern many people describe: symptoms fading and later returning across a person’s reproductive years.

The second is dialysis-dependent chronic kidney disease. A 2024 review of 97 studies, covering over 23,000 hemodialysis patients worldwide, found that about 27 out of 100 people on hemodialysis experience RLS. That is several times the general adult estimate of roughly 7 out of 100.

Callout: two special-vigilance groups

Group	Why it matters
Pregnancy	About 23 out of 100 pregnant people have RLS in the third trimester, tied to iron/folate shifts; usually resolves after delivery
Dialysis-dependent kidney disease	About 27 out of 100 hemodialysis patients have RLS, several times the general adult estimate

If symptoms appeared during a pregnancy, faded, and have since returned, mention that full history to a primary care physician. It is a recognized clinical pattern, not an unusual coincidence. It is worth an iron check regardless of what any DNA report says.

Section recap: Iron repletion has outperformed placebo in a randomized trial, using specific ferritin cutoffs to guide oral versus IV dosing. Pregnancy and dialysis are two well-documented high-prevalence contexts.

Treatment in 2026: Iron and Non-Dopamine Drugs First, With an Augmentation Warning

Headlines about restless legs syndrome medication rarely mention who approved what, or why first-line advice changed. Here is the dated map, for both US and Canadian regulators.

Drug or class	What it does	Regulator and date	Augmentation risk
Iron repletion (oral or IV)	Corrects low iron stores linked to symptoms	Supported by a 2011 placebo-controlled RCT	No
Gabapentin enacarbil (Horizant)	Alpha-2-delta calcium channel ligand	FDA approved 2011-04-06 for moderate-to-severe primary RLS. This brand did not turn up in the Health Canada drug records checked for this article. Its Canadian status is therefore unconfirmed, not known to be unapproved. A Canadian pharmacist or physician can check it directly	No
Pregabalin	Alpha-2-delta calcium channel ligand	Shown at least as effective as pramipexole in a 2014 randomized trial	Lower than dopamine agonists
Dopamine agonists (pramipexole, ropinirole, rotigotine)	Effective short-term symptom control	Long-established under the FDA. Health Canada’s current pramipexole (MIRAPEX) monograph also lists RLS as an approved indication	Yes, well-documented

A quick note on that Health Canada line. The MIRAPEX monograph lists an “Initial Authorization” date of January 29, 1998. That date is when the drug itself was first authorized in Canada. It was most likely authorized for Parkinson’s disease, its original use. The monograph does not state a separate date for when the RLS indication specifically was added. So here is what the monograph confirms: the RLS indication is listed today, in an active Health Canada document. Here is what it does not state: the exact date that indication was added.

The 2016 American Academy of Neurology practice guideline marked a real shift. It moved dopamine agonists away from being an automatic first choice. The reason: a documented risk called augmentation. Augmentation means something specific. Symptoms start earlier in the day. They spread to the arms or trunk. They get worse over months to years, while a person stays on dopamine-agonist therapy.

A 2014 randomized trial, published in the New England Journal of Medicine, compared pregabalin with pramipexole over 52 weeks. Pregabalin worked at least as well. It caused significantly less augmentation. That trial directly informed the 2016 guideline shift.

That caution has held up over time. A newer clinical practice guideline came from the American Academy of Sleep Medicine. It was published in 2024, and appeared formally in print in 2025. It is the first full update since 2012. It continues to flag dopamine-agonist augmentation as a central treatment concern, built on new trial evidence gathered since 2016.

Something else is on the horizon, but not in clinics yet. The 2024 genetics study flagged glutamate receptor genes, including GRIA1 and GRIA4, as promising drug targets. No glutamate-targeted RLS medication is approved anywhere as of this writing. If a medication you have read about online is not in the table above, ask your physician directly. Do not order it independently.

For a Canadian reader specifically: general treatment practice follows the same iron-first, non-dopaminergic-first pattern described above. It draws on the same international trial evidence. Health Canada’s own drug approvals confirm at least one dopamine agonist, pramipexole, is currently authorized there for RLS. Country-specific prescribing details should still be confirmed with a Canadian physician, rather than assumed identical to US practice.

Section recap: Gabapentin enacarbil received FDA approval on 2011-04-06. Health Canada’s current pramipexole monograph lists RLS as an approved indication. Both the 2016 AAN guideline and the newer 2024/2025 AASM guideline favor non-dopaminergic options and iron repletion first, because dopamine agonists carry a well-documented augmentation risk.

What It Means for Your Children and Siblings

There is no 50-percent rule to quote here, the way there might be for a single-gene condition. Each child inherits a random half of each parent’s collection of risk variants. Full siblings, including two daughters of the same parents, can land in meaningfully different polygenic likelihood bands. This happens even though they share the same family tree.

Cascade testing is the practice of systematically testing blood relatives, one by one, after a genetic finding. It applies to single-gene conditions, where one confirmed variant tells you exactly what to look for in relatives. There is no equivalent pathway for restless legs syndrome. There is no single causal variant to trace through a family.

That does not make family history useless. The opposite is true. A strong family history remains clinically informative on its own, independent of any DNA report. It costs nothing to ask relatives directly about their symptoms.

A four-question family-history checklist

1. Which blood relatives have had nightly leg discomfort or an urge to move their legs?
2. At what age did symptoms start for each of them?
3. Did symptoms appear or worsen during anyone’s pregnancy?
4. Does anyone in the family have chronic kidney disease or dialysis-dependent kidney failure?

Bring the answers to a primary care visit, alongside your own symptom pattern. A written family history is free. It carries real clinical weight, even without a DNA test attached to it.

Percentiles on a polygenic report can shift slightly over time. This happens as the reference panel behind the score gets updated. It is a statistical adjustment, not a change in anyone’s DNA. If your band, or a relative’s band, looks different on a repeat check, that is the most likely explanation. It is worth asking a genetic counselor about, rather than assuming the earlier result was wrong.

Section recap: There is no fixed inheritance fraction for a polygenic trait like RLS. Siblings can land in very different likelihood bands, and cascade testing has no equivalent here. A plain family-history conversation still carries real weight.

The Hidden Toll: Sleep Loss, Relationships, and What GINA Actually Covers

Restless legs syndrome is not a trivial nuisance. It is a chronic sleep disruptor. Ongoing sleep loss affects both the person with RLS and their bed partner. A 2024 global prevalence analysis also reports a positive association between restless legs syndrome and depression. That burden deserves to be named plainly, not minimized.

Fear of a genetic report being used against someone is common. In the United States, the law that covers this is the Genetic Information Nondiscrimination Act of 2008, usually shortened to GINA. The legal picture differs meaningfully between the United States and Canada.

	United States	Canada
Health insurance	Protected under GINA	Protected
Employment	Protected at employers with 15 or more staff	Protected under a broader ban
Life, disability, long-term care insurance	Not protected by GINA, a documented gap	Protected, because Canada’s ban covers any contract or service
Legal backing	Federal law (2008), enforced by the EEOC and federal health agencies	Federal law (2017), upheld by the Supreme Court of Canada in 2020

The US Genetic Information Nondiscrimination Act of 2008 bars most health insurers, and employers with 15 or more employees, from using genetic information. That includes a 23andMe polygenic report. It applies to coverage and hiring decisions. But the law stops short of life, disability, and long-term-care insurance. State laws vary further on top of that.

Canada’s federal Genetic Non-Discrimination Act, passed in 2017, is broader in scope. It is not limited to health insurance or employment. Its constitutionality was upheld by the Supreme Court of Canada in a 2020 ruling.

Before you disclose a result to family or an insurer, consider

• Who in the family might be affected by what you share
• Whether the finding is a DTC polygenic report or an actual clinical diagnosis, since the two are treated differently
• Whether a short conversation with a primary care physician would help you frame it first

An unshared direct-to-consumer report generally sits outside a formal medical record. It is treated differently from a clinical diagnosis. Sharing your symptoms with your own doctor is one decision; it puts them in your chart alongside a real treatment plan. Sharing a DNA report with an employer or insurer is a separate decision entirely.

Section recap: Chronic sleep disruption from restless legs syndrome carries a real burden, and prevalence research reports an association with depression. GINA protects US health insurance and most jobs, but not life, disability, or long-term-care insurance, while Canada’s 2017 law is broader.

Frequently Asked Questions

Will I get the disease?

A “higher likelihood” band is not a diagnosis. It means your combined score for dozens of common variants sits toward the high end of a reference group. Globally, roughly 5 to 10 out of 100 adults are affected overall. Most people with a higher-likelihood band never develop symptoms severe enough to need treatment.

Will my children inherit it?

Not as a fixed percentage. Each child gets a random half of your risk variants. Siblings can land in very different likelihood bands, even with the same parents. Family history still matters, though: it is worth asking relatives directly about their own symptoms.

Will this affect my health or life insurance?

In the United States, health insurance is protected under GINA. Life, disability, and long-term-care insurance are not. In Canada, the 2017 Genetic Non-Discrimination Act is broader. It covers any contract or service, including insurance.

Can my employer find out?

US employers with 15 or more staff cannot request or use your genetic information for hiring, firing, or promotion decisions under GINA. Smaller employers are exempt. Canada’s federal ban is broader and applies more widely.

Should I get a second opinion?

Bringing a 23andMe report to a primary care physician is not really a second opinion. It functions more like the first real medical opinion on the finding. A board-certified genetic counselor, found through NSGC.org, can help you understand exactly what a polygenic report can and cannot tell you before that visit.

Summary

Restless legs syndrome is polygenic, not single-gene. The confirmed risk-region count grew from 3 in 2007, when the BTBD9, MEIS1, and MAP2K5/SKOR1 regions were first identified, to 164 in a 2024 meta-analysis. That same study also linked the condition causally to type 2 diabetes risk. Roughly 5 to 10 out of every 100 adults worldwide are affected, more often in women, and family history raises the odds meaningfully. Still, a “higher likelihood” band on a 23andMe report is a population signal, not a personal forecast.

There is no genetic or blood test that diagnoses restless legs syndrome. Diagnosis rests on five clinical criteria from the International Restless Legs Syndrome Study Group. The one lab test that reliably guides treatment is a ferritin and iron panel, with a cutoff of 75 or lower for oral iron. On treatment, gabapentin enacarbil received FDA approval on 2011-04-06, and Health Canada’s current pramipexole monograph lists RLS as an approved indication. Both the 2016 AAN guideline and the newer 2024/2025 AASM guideline favor non-dopaminergic options and iron repletion first, because dopamine agonists carry a well-documented augmentation risk.

Family risk does not follow a simple percentage. GINA protects US health insurance and most jobs, but leaves life and disability insurance uncovered, a gap Canada’s broader 2017 law closes. The next step is straightforward.

• Write down when symptoms happen, what relieves them, and how long this has been going on
• Ask a primary care physician for a ferritin and iron panel
• Take the report and your symptom history to that visit, rather than acting on the band alone

This article is for educational purposes only. It is not a substitute for advice from a licensed physician, board-certified medical geneticist, or board-certified genetic counselor. For any decisions about testing, treatment, or care, consult a qualified clinician. In emergencies, call 911.

References

1. Schormair B, Zhao C, Bell S, et al. Genome-wide meta-analyses of restless legs syndrome yield insights into genetic architecture, disease biology and risk prediction. Nat Genet. 2024;56(6). PMID 38839884. https://pubmed.ncbi.nlm.nih.gov/38839884/
2. Stefansson H, Rye DB, Hicks A, et al. A genetic risk factor for periodic limb movements in sleep. N Engl J Med. 2007;357(7):639-647. PMID 17634447. https://pubmed.ncbi.nlm.nih.gov/17634447/
3. Winkelmann J, Schormair B, Lichtner P, et al. Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions. Nat Genet. 2007;39(8):1000-1006. PMID 17637780. https://pubmed.ncbi.nlm.nih.gov/17637780/
4. Schormair B, Zhao C, Bell S, et al. Identification of novel risk loci for restless legs syndrome in genome-wide association studies in individuals of European ancestry: a meta-analysis. Lancet Neurol. 2017;16(11):898-907. PMID 29029846. https://pubmed.ncbi.nlm.nih.gov/29029846/
5. Allen RP, Picchietti DL, Garcia-Borreguero D, et al. Restless legs syndrome/Willis-Ekbom disease diagnostic criteria: updated International Restless Legs Syndrome Study Group (IRLSSG) consensus criteria — history, rationale, description, and significance. Sleep Med. 2014;15(8):860-873. PMID 25023924. https://pubmed.ncbi.nlm.nih.gov/25023924/
6. Winkelman JW, Armstrong MJ, Allen RP, et al. Practice guideline summary: Treatment of restless legs syndrome in adults: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2016;87(24):2585-2593. PMID 27856776. https://pubmed.ncbi.nlm.nih.gov/27856776/
7. Winkelman JW, Berkowski JA, DelRosso LM, et al. Treatment of restless legs syndrome and periodic limb movement disorder: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2025;21(1):137-152 (published online 2024-09-26). PMID 39324694. https://pubmed.ncbi.nlm.nih.gov/39324694/
8. Manconi M, Garcia-Borreguero D, Schormair B, Videnovic A, Berger K, Ferri R, Dauvilliers Y. Restless legs syndrome. Nat Rev Dis Primers. 2021. PMID 34732752. https://pubmed.ncbi.nlm.nih.gov/34732752/
9. Allen RP, Adler CH, Du W, Butcher A, Bregman DB, Earley CJ. Clinical efficacy and safety of IV ferric carboxymaltose (FCM) treatment of RLS: a multi-centered, placebo-controlled preliminary clinical trial. Sleep Med. 2011;12(9):906-913. PMID 21978726. https://pubmed.ncbi.nlm.nih.gov/21978726/
10. Allen RP, Chen C, Garcia-Borreguero D, Polo O, DuBrava S, Miceli J, Knapp L, Winkelman JW. Comparison of pregabalin with pramipexole for restless legs syndrome. N Engl J Med. 2014;370(7):621-631. PMID 24521108. https://pubmed.ncbi.nlm.nih.gov/24521108/
11. US Food and Drug Administration, Drugs@FDA. Approval of gabapentin enacarbil extended-release tablets (Horizant) for moderate-to-severe primary restless legs syndrome; original approval 2011-04-06. https://www.accessdata.fda.gov/scripts/cder/daf/
12. National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health. Restless Legs Syndrome (fact sheet). https://www.ninds.nih.gov/health-information/disorders/restless-legs-syndrome
13. Genetic Information Nondiscrimination Act of 2008 (Pub. L. 110-233), as summarized by the National Human Genome Research Institute and the US Equal Employment Opportunity Commission. https://www.genome.gov/about-genomics/policy-issues/Genetic-Discrimination
14. Genetic Non-Discrimination Act, S.C. 2017, c. 3 (Government of Canada); Reference re Genetic Non-Discrimination Act, 2020 SCC 17 (Supreme Court of Canada). https://laws-lois.justice.gc.ca/eng/acts/G-2.5/
15. Health Canada Drug Product Database; Boehringer Ingelheim (Canada) Ltd. Product Monograph: MIRAPEX (pramipexole dihydrochloride monohydrate) tablets. Date of Initial Authorization: 1998-01-29; Date of Revision: 2024-03-20. https://health-products.canada.ca/dpd-bdpp/info?lang=eng&code=80082
16. Allen RP, Picchietti DL, Auerbach M, et al. Evidence-based and consensus clinical practice guidelines for the iron treatment of restless legs syndrome/Willis-Ekbom disease in adults and children: an IRLSSG task force report. Sleep Med. 2018;41:27-44. PMID 29425576. https://pubmed.ncbi.nlm.nih.gov/29425576/
17. Song P, Wu J, Cao J, et al. The global and regional prevalence of restless legs syndrome among adults: a systematic review and modelling analysis. J Glob Health. 2024. PMID 38843039. https://pubmed.ncbi.nlm.nih.gov/38843039/
18. Broström A, Alimoradi Z, Lind J, Ulander M, Lundin F, Pakpour A. Worldwide estimation of restless legs syndrome: a systematic review and meta-analysis of prevalence in the general adult population. J Sleep Res. 2023. PMID 36600470. https://pubmed.ncbi.nlm.nih.gov/36600470/
19. Winkelmann J, Wetter TC, Collado-Seidel V, Gasser T, Dichgans M, Yassouridis A, Trenkwalder C. Clinical characteristics and frequency of the hereditary restless legs syndrome in a population of 300 patients. Sleep. 2000;23(5):597-602. PMID 10947027. https://pubmed.ncbi.nlm.nih.gov/10947027/
20. Darvishi N, Daneshkhah A, Khaledi-Paveh B, et al. The prevalence of Restless Legs Syndrome/Willis-Ekbom disease (RLS/WED) in the third trimester of pregnancy: a systematic review. BMC Neurol. 2020;20:132. PMID 32284042. https://pubmed.ncbi.nlm.nih.gov/32284042/
21. Zhou XH, Liu Y, Zhang XR, Wang C, Liu SS, Jiang Y. Global prevalence of restless legs syndrome among hemodialysis patients: a systematic review and meta-analysis. Brain Behav. 2024;14:e3378. PMID 38376019. https://pubmed.ncbi.nlm.nih.gov/38376019/

---

Last updated: 2026-09-12

Author: Yu Mizuno (Editor-in-Chief, non-physician), GeneLumen editorial team. This article aggregates 21 sources from peer-reviewed medical literature and public health agencies (tier 1=13 / tier 2=8), including the NIH National Institute of Neurological Disorders and Stroke, the FDA, Health Canada, the US Equal Employment Opportunity Commission, the Government of Canada, Nature Genetics, the Lancet, and PubMed-indexed publications. Editorial lead: Yu Mizuno, non-physician research editor.

This article is for educational purposes only and is not a substitute for medical advice from a licensed physician, board-certified medical geneticist, or board-certified genetic counselor. In emergencies, call 911 (US/Canada) or 119 (Japan).

Related: Neurogenetic Diseases category

🇯🇵 For readers in Japan — a separate Japanese edition written for Japan’s healthcare system (not a translation): むずむず脚症候群の遺伝的リスクとは｜164のGWAS座位と2型糖尿病リスク、治療の最新動向まで