On January 10, 2014, her 38th wedding anniversary, Diane Wilkie and her husband Alan had just come in from a hotel pool in Florida when her genetic counselor called. Her test for a variant in the TTR gene, the cause of hereditary transthyretin amyloidosis, was positive. They sat on their small balcony and cried, and then Alan said something practical (Wilkie, Patient Worthy, 2025).
“I guess we'll be calling Mayo when we get home.”
Alan, Diane Wilkie's husband, as she recalled it in Patient Worthy, November 19, 2025
Diane was 56 and felt fine. At Mayo Clinic her blood tests and a fat sample were normal, but her heart wall was slightly thick and her ECG showed low voltage, a combination that did not add up. The team planned to repeat the tests in 3 months and consider a heart biopsy then. She asked why they would wait, and the biopsy was done the next morning. All 5 samples were positive for amyloid (Wilkie, 2025). That November, with no symptoms of any illness, she had a liver transplant, because the liver makes most of the body's transthyretin.
Her father never had that choice. In his late 40s he started tripping, losing feeling in his feet and having dizzy spells. Doctors at the University of Michigan diagnosed amyloidosis in 1967, told the family they had seen only a handful of cases, and said nothing could be done. He died on November 22, 1970, at 54, when Diane was 13 (Wilkie, 2025). Nobody then knew which protein was piling up in his nerves. Researchers in Portugal tied the deposits to a blood protein then called prealbumin, now transthyretin, in 1978, and the first disease-causing change in that protein was identified in Japanese and Portuguese families in 1983 and 1984 (Costa et al., 1978; Tawara et al., 1983; Saraiva et al., 1984).
What a TTR Gene Test Reads, and Why 1 Changed Building Block Breaks Transthyretin
The TTR gene sits on chromosome 18 and holds the recipe for transthyretin, a protein made mostly in the liver that carries thyroid hormone and vitamin A through the blood. The protein works in groups of 4, locked together into a unit called a tetramer. Most disease-causing variants swap a single building block of the protein, which weakens that unit until it comes apart, and the loose pieces misfold and pile up as amyloid in the heart, nerves and other organs (MedlinePlus Genetics).
The gene is small, just 4 exons covering 127 building blocks of the finished protein plus a short signal piece that is trimmed off (Sanguinetti et al., 2022). Every disease-causing variant found so far sits in exon 2, 3 or 4, and sequencing those stretches finds essentially all of them, which is how one test covers more than 130 known variants (GeneReviews; Adams et al., 2021).
Variant shares from Singh et al., Journal of Clinical Medicine, 2025; exon boundaries from Sanguinetti et al., Biomedicines, 2022; regional details from GeneReviews, Reilly et al., 1995, Wallace et al., 1986, Sattianayagam et al., 2012, Duran-Luciano et al., 2025 and Sideris et al., 2026.
The second name on each card trips people up. Older papers count positions after the 20-unit signal piece is trimmed off, while lab reports now count from the very start, so V122I, V142I and p.Val142Ile are the same variant, as are V30M and p.Val50Met (GeneReviews). If a relative's report and yours seem to name different variants, check the numbering before assuming the family carries 2.
Hereditary ATTR Amyloidosis Runs Down a Family Tree, 50% at a Time
Hereditary ATTR amyloidosis is autosomal dominant. A parent with 1 copy of a disease-causing TTR variant has a 50% chance of passing it to each child, son or daughter (GeneReviews). Inheriting the variant is not the same as getting sick, which is why a family like Diane's looks so uneven on paper.
The variant resurfaced in 2012. Diane's brother Doug, 59 and still playing basketball and biking, kept getting short of breath. His doctor ran tests, found nothing and suggested he slow down. Doug kept seeking other opinions until someone noticed amyloidosis in his family history, and a genetic test in 2013 came back positive (Wilkie, 2025). Until then the family had not known the disease could be inherited, or that it could go after the heart instead of the nerves.
Diane and her sister Deb were tested next, and both were positive. Doug's heart was already too damaged to rely on a new liver alone, so on September 30, 2015 he received a new heart and liver together. Deb showed no signs for years, until chest pain in 2018 led to an echocardiogram that found a thickening heart wall, and she joined a study of tafamidis (Wilkie, 2025).
- Grandpa. Died in his late 50s after years of what the family called heart trouble. Diane assumes he had hereditary ATTR; he was never tested.
- Aunt. Her children have hereditary ATTR amyloidosis, so she carried the variant.
- Aunt. Neither she nor her children ever had outward symptoms. All have died, so no one can know whether she carried it.
- Dad. Numbness and falls in his late 40s, diagnosed with amyloidosis at the University of Michigan in 1967, died November 22, 1970. No gene test existed.
- Cousins. Cousins on this side of the family have hereditary ATTR amyloidosis.
- Doug. Short of breath at 59 in 2012, positive in 2013, heart and liver transplant on September 30, 2015.
- Deb. Positive, then a thickened heart wall in 2018 and a tafamidis study.
- Diane. Positive on January 10, 2014 with no symptoms, amyloid in all 5 heart biopsy samples, liver transplant that November. Later Onpattro, then Amvuttra.
- Nieces and nephews. Half tested positive and are followed at Mayo Clinic; some already take tafamidis and some have carpal tunnel syndrome. Half tested negative.
- Her child. Diane's only child tested negative.
Only the youngest generation has been tested from end to end. The 2 generations above it are known mostly by inference, and the oldest only by family memory. Source: Diane Wilkie, Patient Worthy, November 19, 2025.
“My only child tested negative, so my line stops with me.”
Diane Wilkie, Patient Worthy, November 19, 2025
Half of her nieces and nephews tested positive and half negative, the split a 50% chance per child predicts. The ones who carry the variant are followed at Mayo, some already take tafamidis, and some have carpal tunnel syndrome, which the family now knows can come first (Wilkie, 2025).
Most families do not have a record this clear. In a no-charge US testing program that found a disease-causing TTR variant in 1,503 people from 2018 to 2022, only 32% of them reported a known family history, and Black patients were less likely to report one than other groups (Bhatt et al., 2024). Diane's own tree shows why. One aunt is known to have carried the variant only because her children have the disease, and her grandfather's "heart trouble" was never given a name.
Carpal Tunnel and Other ATTR Amyloidosis Red Flags That Come Years Before the Diagnosis
For Faye, the warning came as water. In 2018 she gained nearly 25 pounds of fluid in a month and spent 2 years going from doctor to doctor; an echocardiogram showed a thickened heart wall, and still no one considered ATTR (Faye, Patient Worthy, 2026). Her father had died of hereditary ATTR in 2010 after 13 biopsies and an initial misdiagnosis of AL amyloidosis, a different type driven by a blood cell disorder. It was her sister, who had tested positive years earlier, who finally told Faye her illness sounded just like their dad's.
The body often warns well before the heart gives out. The American College of Cardiology lists carpal tunnel syndrome, spinal stenosis, hip or knee replacement and prior shoulder surgery among the clues that should raise suspicion, and calls a spontaneous biceps tendon rupture and spinal stenosis findings unique to ATTR (ACC, 2023). Other clues include a thick heart wall without high blood pressure or a valve problem, dizziness from blood pressure that drops on standing, trouble tolerating ACE inhibitors or beta blockers, and high blood pressure that fades on its own over time (ACC, 2023; Maurer et al., 2019).
Carpal tunnel syndrome in both hands arrived first, on average 9.5 years before the diagnosis, and heart failure, the problem that usually brings someone to a cardiologist, arrived last. Source: Debonnaire et al., Acta Cardiologica, 2022.
Those years are the opening for a gene test, and they are routinely missed. In Medicare records of 7,770 people with ATTR heart disease, the median wait from a heart failure diagnosis to the ATTR diagnosis was 494 days. Women, and people who also had high blood pressure, diabetes, coronary disease, lung disease or a narrowed aortic valve, were more likely to wait longer than 6 months. Each of those conditions can also explain heart trouble and breathlessness, which the authors say calls for a higher index of suspicion (Spencer-Bonilla et al., 2026).
The nerve form has its own rule. Neurologists who wrote the 2021 expert recommendations advise TTR sequencing for anyone with a progressive nerve disease that has no explanation, or a CIDP diagnosis that behaves oddly, especially when it comes with at least 1 sign that the disease reaches beyond the nerves (Adams et al., 2021). Even carriers of the same variant can fare very differently. Among V30M carriers, about 80% in Portugal have the disease by 50, against 11% in Sweden (Adams et al., 2021).
V122I, the TTR Variant Carried by About 3% to 4% of Black Americans
Most hereditary ATTR in the US does not look like Diane's family. In Alnylam Act, 3,299 of the 4,297 people who tested positive from 2017 to 2023 carried a single variant, V122I (Singh et al., 2025). Large studies of Black Americans find it in roughly 1 of every 30 people, including 3.43% of 14,333 African Americans in a 2015 study, 3.5% of participants with African ancestry in the All of Us program and 3.2% in the Million Veteran Program (Jacobson et al., 2015; Grodin et al., 2025; Sideris et al., 2026). It is less common in Hispanic adults overall, though 2.6% of those of Dominican descent carry it (Duran-Luciano et al., 2025).
V122I mainly damages the heart and tends to show up late, and it does not always show up at all. Among 2,658 carriers in the Million Veteran Program, 54.9% had heart failure or cardiomyopathy by age 80, against 45.9% of matched non-carriers. Only 3.3% of the carriers had ever been diagnosed with amyloidosis, at a median age of 74, and the study's own authors noted that the genetic results had never been shared with their doctors (Sideris et al., 2026).
SCAN-MP also found ATTR heart disease in 17% of Black men over 75 with heart failure, and in more than half of the cases it found, the TTR gene was normal, the wild-type form (Ruberg et al., 2025). That second finding is why guidelines say to sequence the gene in every ATTR heart patient instead of guessing the type from age or ancestry.
Erin Poyant's family learned about V122I the hard way. Her father was diagnosed in 2014, already very sick, and died in 2020 (Poyant, Amyloidosis Research Consortium, 2026).
“He died without knowing he had passed this genetic risk on to me.”
Erin Poyant, Amyloidosis Research Consortium, March 31, 2026
In 2022 she developed numbness in her right hand and right foot that no doctor's office or emergency room could explain. Her father's amyloidosis team recommended a gene test, and she had to explain to her own primary care provider, step by step, why she needed it. She was positive. Her doctors now monitor her as a V122I carrier with symptoms but no confirmed diagnosis, and she has taken diflunisal since 2024 (Poyant, 2026). Diflunisal is an older anti-inflammatory pain reliever that also stabilizes transthyretin; a 2013 trial showed it slowed nerve damage in hereditary ATTR, and doctors use it off label (Berk et al., 2013).
Who Should Get TTR Genetic Testing, and Where It Fits in an ATTR Amyloidosis Diagnosis
The clearest rule covers people already diagnosed. The 2022 heart failure guideline from the American Heart Association, the American College of Cardiology and the Heart Failure Society of America gives its strongest recommendation, Class 1, to TTR gene sequencing for anyone found to have ATTR cardiac amyloidosis, to tell the hereditary form from the wild-type form (Heidenreich et al., 2022). European cardiologists recommend it regardless of age (Garcia-Pavia et al., 2021).
In that setting the gene test usually comes last. Doctors first rule out AL amyloidosis with a serum free light chain test and immunofixation of blood and urine, because the 2 diseases are treated very differently. If those are normal, a nuclear bone scan with a tracer such as PYP, DPD or HMDP that lights up the heart at grade 2 or 3 confirms ATTR heart disease without a biopsy. A biopsy is still needed when the light chain tests are abnormal, when the heart uptake is only grade 1, or when suspicion stays high after a negative scan, since a few variants do not show up on it (ACC, 2023; Garcia-Pavia et al., 2021). Sequencing then sorts hereditary from wild-type.
For relatives without symptoms, the guidance favors genetic counseling before and after the test and testing adults only; testing children who have no symptoms is discouraged (Obici et al., 2016; Garcia-Pavia et al., 2021). Family history raises the odds a great deal. Of 89,760 people tested through Alnylam Act, 4.8% had a disease-causing TTR variant, but among those with a confirmed family history the figure was 32.2% (Singh et al., 2025).
Free TTR Gene Testing Through Alnylam Act and NavigATTR
| Alnylam Act | NavigATTR | |
|---|---|---|
| Sponsor | Alnylam | AstraZeneca |
| Lab | PreventionGenetics | PreventionGenetics |
| Cost | None; no patient, doctor or insurer is billed | None |
| Who orders it | A clinician, who confirms eligibility | A cardiology, genetics or neurology clinician |
| Who qualifies | A family history of hereditary ATTR, a positive heart scan or amyloid biopsy, or at least 2 suspicious signs; US and Canada | US residents 18 and older with a family history of hereditary ATTR, a positive PYP scan or an amyloid biopsy; 2 or more red flags may qualify |
| Sample | Blood, saliva or cheek swab | Blood, saliva or cheek swab |
| Results | About 2 to 4 weeks | 2 to 3 weeks |
| Genetic counseling | Free through Genome Medical, before or after the test | Included at no charge |
Both sponsors sell ATTR drugs. Alnylam makes the silencers Onpattro and Amvuttra, and AstraZeneca sells the silencer Wainua. Through Alnylam Act's counseling service, the patient gets a summary report by email and can share it with any of their doctors. Alnylam also suggests asking relatives about the family's medical history before the counseling appointment, including who was diagnosed with what and at what age.
What a Positive, Negative or VUS TTR Gene Test Result Means
- Pathogenic or likely pathogenic variantWhat it meansYou carry a variant that can cause hereditary ATTR amyloidosis, and each of your children has a 50% chance of inheriting it. On its own it is not a diagnosis; doctors look for amyloid with heart and nerve tests, and many carriers stay well for years.On the reportA named variant such as p.Val142Ile, the same as V122I. Doctors act on likely pathogenic results much as they do on pathogenic ones.
- Variant of uncertain significanceWhat it meansThe lab found a change it cannot yet classify. It does not confirm or rule out the disease, it should not drive medical decisions, and it can be reclassified later as evidence builds.On the reportVUS, or variant of uncertain significance, next to the change.
- No disease-causing variantWhat it meansIf your relative's variant is known and you do not carry it, you cannot pass it on. If you already have ATTR heart disease, a negative test points to the wild-type form, which is not caused by an inherited variant.On the reportNo pathogenic variant detected. A harmless change such as p.Gly26Ser, also called Gly6Ser, can appear and means nothing.
Sources: Adams et al., Journal of Neurology, 2021; Richards et al., Genetics in Medicine, 2015; GeneReviews.
A positive result with no symptoms starts a schedule. European cardiologists recommend beginning checks 10 years before the age at which affected relatives got sick, with a yearly ECG, blood tests for heart strain such as NT-proBNP and troponin, an echocardiogram and nerve and eye exams, plus a Holter monitor every 2 years and a bone scan and cardiac MRI every 3 years or sooner if anything changes (Garcia-Pavia et al., 2021). Experts in the UK and Ireland give the same 10-year lead (Gillmore et al., 2022).
The bone scan earns its place. In a European study of 159 relatives at risk, 25% already had ATTR heart disease at their first screening, and in 13% of those the ECG, echocardiogram and blood tests looked normal, so only the scan found it. Repeating the evaluation about 3 years later found new cases in 9.4% (Muller et al., 2024).
Testing relatives also changes how early the disease is caught. When an Italian network screened 1,243 relatives of 398 patients, 569 carried the family's variant and 108 of them already had the disease. Of the 461 who were still well, 16.7% were diagnosed over a median 5.3 years, and some were diagnosed more than 10 years earlier than their family's predicted age. Relatives who turned out to have the disease at screening had less than half the risk of death of the family members who had been diagnosed first (Cappelli et al., 2026). How fast carriers became ill depended heavily on the variant, from 42.2% for Glu89Gln to 5.1% for V122I.
GINA, Life Insurance and the TTR Test Kit That Sat on Faye's Kitchen Table
Before he died, Faye's father asked both his daughters to get tested. Her sister did and was positive. Faye did not; she has written that fear convinced her not knowing would protect her, and that she worried what a genetic diagnosis would mean for insurance, her future and her children (Faye, 2026). When she finally ordered the test, it did not move quickly.
“The test kit sat on my kitchen table for two weeks.”
Faye, Patient Worthy, March 27, 2026
She tested positive in March 2020. The federal law that answers part of her worry is the Genetic Information Nondiscrimination Act of 2008, or GINA. Health insurers cannot use genetic information, which includes family medical history, to decide eligibility, coverage or premiums, and employers cannot use it to hire, fire, promote or set pay. The health insurance protections reach private plans, Medicare, Medicaid, federal employee plans and Veterans Health Administration care (NHGRI).
GINA has real gaps. It does not cover life, disability or long-term care insurance, it does not apply to employers with fewer than 15 employees, and the military can use genetic information in employment decisions (NHGRI). It also does not protect against discrimination once the disease itself has appeared, though the Affordable Care Act separately bars health insurers from refusing coverage or charging more for a pre-existing condition (HHS).
A few states go further. Florida bars health, life and long-term care insurers from using genetic test results to cancel, limit or deny coverage or set rates for someone without a related diagnosis, although they can still consider a diagnosis already in the medical record (Florida Statutes, s. 627.4301). Louisiana restricts genetic information in life and long-term care insurance under Act 224 of 2024. California's AB 1798, signed September 30, 2026, will bar life and disability insurers from using certain genetic test results of people without symptoms starting January 1, 2027 (California Department of Insurance, 2026).
ACT-EARLY and the First Trial to Treat TTR Carriers Before They Get Sick
Every FDA-approved ATTR drug is for people who already have the disease. "Current approved therapies for ATTR amyloidosis are only approved to treat diagnosed disease," Dr. Ahmad Masri of Oregon Health & Science University said when BridgeBio dosed the first patient in a trial built to change that (BridgeBio, 2025). Our ATTR treatment comparison covers those approved drugs, and the treatment page shows them side by side.
That trial, ACT-EARLY (NCT06563895), gives acoramidis, sold as Attruby, or a placebo twice a day to about 600 carriers aged 18 to 75 whose age is within 10 years of the age their family's disease is predicted to start. It counts how long it takes for ATTR heart or nerve disease to appear, over up to about 7 years. People who already show signs of either form, have taken a TTR drug, or cannot have a cardiac MRI are excluded. It is recruiting at 104 sites in 24 countries, including the US, and its estimated primary completion date is October 2031 (ClinicalTrials.gov; BridgeBio, 2025).
For V122I carriers aged 30 to 80 with no heart failure, UT Southwestern is recruiting an observational study (NCT05489549) that uses heart imaging to look for amyloid before it causes symptoms, with sites at UT Southwestern, Columbia and Cleveland Clinic. You can also search ATTR trials near you, check which trials you might qualify for or find help paying for ATTR drugs.
Diane went back to Mayo every November after her transplant. Since 2020 she has had slowly spreading numbness in her left foot, confirmed as amyloid, and a pacemaker since 2022. She took Onpattro infusions every 3 weeks before switching to Amvuttra shots every 3 months in 2023, and the numbness does not seem to be getting worse (Wilkie, 2025). Her old liver, healthy except for the protein it made, went to a critically ill man the night of her surgery in what is called a domino transplant. She visits him every year when she goes back for her checkups.
One email when ATTR Amyloidosis trials change or an FDA decision lands. No newsletter, no spam.
Frequently Asked Questions About TTR Gene Testing
What is TTR gene sequencing?
It is a genetic test that reads the TTR gene, which makes the protein transthyretin, to look for variants that cause hereditary ATTR amyloidosis. Every disease-causing variant found so far sits in exons 2, 3 or 4 of this small gene, and sequencing finds essentially all of them. The sample can be blood, saliva or a cheek swab.
Who should get tested for hereditary ATTR amyloidosis?
US heart failure guidelines recommend TTR gene sequencing for everyone diagnosed with ATTR cardiac amyloidosis, to tell the hereditary form from the wild-type form. Neurologists recommend it for unexplained progressive nerve disease. Adult relatives of someone with a known TTR variant can be tested after genetic counseling.
Is there free genetic testing for hATTR amyloidosis?
Yes. Alnylam Act, sponsored by Alnylam, and NavigATTR, sponsored by AstraZeneca, offer TTR testing at no charge through PreventionGenetics, with counseling included. A family history of hereditary ATTR qualifies on its own. A clinician orders the test, and NavigATTR requires a cardiology, genetics or neurology clinician.
How long do TTR genetic test results take?
PreventionGenetics lists 2 to 3 weeks for both sponsored programs, and Alnylam says results arrive in 3 to 4 weeks on average.
Does a positive TTR gene test mean I have amyloidosis?
No. A TTR variant alone cannot confirm the disease, and many carriers stay well for years or never develop it. Doctors look for amyloid with heart and nerve tests, and carriers usually start regular checks about 10 years before the age their affected relatives got sick.
Is V122I the same as V142I?
Yes. V122I counts positions after the protein's 20-unit signal piece is trimmed off, and V142I, also written p.Val142Ile, counts from the start. Lab reports now use the newer name. The same shift turns V30M into p.Val50Met and T60A into p.Thr80Ala.
How common is the V122I variant in Black Americans?
About 3% to 4%. Studies found it in 3.43% of 14,333 African Americans, 3.5% of All of Us participants with African ancestry and 3.2% in the Million Veteran Program. Many carriers never develop the disease; in the Million Veteran Program only 3.3% of carriers had been diagnosed with amyloidosis.
Should children be tested for the TTR gene?
Expert guidance discourages testing children who have no symptoms and recommends genetic counseling and testing for adults. Monitoring for carriers usually begins about 10 years before the age at which relatives became ill.
Can life insurance companies use my genetic test results?
The federal law, GINA, covers health insurance and most employers but not life, disability or long-term care insurance. Some states add protection: Florida bars health, life and long-term care insurers from using genetic test results when there is no diagnosis, Louisiana covers life and long-term care, and California's AB 1798 covers life and disability insurers from January 1, 2027.
What can a TTR carrier do before symptoms?
Regular monitoring at an amyloidosis center, usually an ECG, blood tests, an echocardiogram and nerve exams each year, with a bone scan and cardiac MRI every 3 years. No drug is approved for carriers without disease, but the ACT-EARLY trial (NCT06563895) is testing acoramidis in carriers aged 18 to 75 who are within 10 years of their family's predicted onset age.
Is wild-type ATTR amyloidosis inherited?
No. Wild-type ATTR happens with a normal TTR gene, when the protein becomes unstable with age, and it mostly affects older men. That is why a TTR gene test matters after an ATTR heart diagnosis: a negative result points to wild-type, while a positive one means relatives may carry the variant.