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ACMG Recommendations Aim to Spark Physician, Patient Discussion on Genetic Testing

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NEW YORK (GenomeWeb) – The American College of Medical Genetics and Genomics last week issued five recommendations on when not to perform genetic testing that the group hopes will be a springboard for discussions between physicians and patients.

The recommendations — which the ACMG emphasized are not official guidelines from the college but suggestions — were issued as part of the American Board of Internal Medicine's Choosing Wisely campaign and are intended to facilitate conversations about genetic testing. In general, Choosing Wisely recommendations aim to encourage a dialogue between healthcare providers and patients about avoiding unneeded and wasteful medical interventions.

ABIM invited ACMG to participate in the campaign, which more than 100 local and national societies, healthcare collaboratives, and consumer groups have joined "This particular campaign is targeting overutilization of procedures, tests, and prescribing medication," Maren Scheuner, ACMG VP of clinical genetics and coauthor of the Choosing Wisely recommendations, told GenomeWeb.

A number of ACMG committees and its board came up with the recommendations, whittling 18 items under consideration down to five that they agreed would improve the quality of care and reduce costs. It was challenging for ACMG experts to come up with the suggestions for curtailing overutilization in genetic testing, said Scheuner, "because more often than not there is underutilization of genetic services."

Among the recommendations, ACMG provides two general points of advice. First, providers and patients should avoid duplicative genetic testing for inherited conditions unless there is reason to doubt the validity of the first result. The college also advises against exome or genome sequencing without obtaining patients' informed consent, and recommends educating them that they may learn things about their health they didn't anticipate. 

Repeat genetic testing is a common problem when patients change providers and results don't travel with the patient, according to Joy Larsen Haidle, president of the National Society of Genetic Counselors. Another time it happens is when patients are having a hard time accepting that they have a particular marker. But if testing has been done according to standards by a certified lab, chances are very low that the results are wrong, and "there wouldn't be a benefit to repeating the test," Haidle told GenomeWeb.

Sometimes testing the same genes again might be appropriate when new scientific knowledge comes to light. For example, in the case of BRCA mutation testing, early tests sequenced the BRCA1 and BRCA2 genes, but didn't detect certain large rearrangements that researchers later found also to be associated with increased risk for breast and ovarian cancer. Guidelines now recommend that all women who qualify for BRCA testing be assessed for large rearrangements.

So, conceivably, if a woman has been tested for BRCA mutations but not for large rearrangements, they could get broader analysis. "You're looking at the genes again, but you're looking at it in a different way," Haidle said. "You're not repeating the exact same test."

ACMG's Choosing Wisely advice on exome and genome testing reflects its current policy that qualified healthcare professionals obtain written consent from patients for clinical exome or genome sequencing, explain the uncertainty and privacy issues associated with such testing, and discuss the potential impact results could have on family members. Additionally, the group recommends analysis and reporting of variants in 56 "highly medically actionable" genes associated with 24 inherited conditions, but patients can opt out of this analysis.

"This puts responsibility on the provider but also on the public, so they're fully informed and part of the conversation, and they can say what they want and what they don't want," Haidle said.

When not to test

The college also provided specific recommendations on three types of tests: APOE, MTHFR, and HFE. According to ACMG, APOE genetic testing shouldn't be ordered as a predictive test for Alzheimer's; MTHFR testing shouldn't be used for assessing risk of hereditary thrombophilia; and HFE testing shouldn't be ordered for patients who don't have iron overload or a family history of HFE-related hereditary hemochromatosis.

"APOE is probably one of the more misunderstood tests as far as how useful it is and how much information you get from it," Haidle said. "There's an association there [with Alzheimer's risk], but it's not diagnostic and it's misunderstood in the general population."

Even though APOE4 remains the most important genetic marker discovered in association with late-onset Alzheimer's disease, a carrier of one or two copies of the variation isn't destined to get the disease. Family history is a key factor, and researchers have made additional genetic discoveries related to mitochondrial insufficiency that in concert with APOE variations suggest a far more complex biological mechanism underlying Alzheimer's and cognitive decline. 

APOE is probably one of the more misunderstood tests as far as how useful it is and how much information you get from it.

Mutations in MTHFR genes are associated with increased homocysteine levels and may heighten a person's risk of thrombosis. But studies have shown that hemocysteine can also be increased by other factors and people with MTHFR mutations may never get a clot. "MTHFR, for a long time, was such an important gene," Haidle said. "As we've gotten more data over time, we have learned that the risk with that gene isn't as high as we had thought based on original studies."

ACMG's Scheuner, who is also chief of medical genetics at the Veterans Affairs Greater Los Angeles Healthcare System, recently consulted a patient whose brother was hit by a car and died at 41. He had a history of deep vein thrombosis and had a MTHFR mutation. "She was completely anxiety ridden by that and was desperate to have genetic testing," Scheuner recalled. But she also pointed out that because MTHFR mutations are fairly common among Hispanics, learning that she didn't have a mutation wouldn't have discounted her familial risk for clotting.

"There are all these other factors that are going to influence whether you're ever going to get a clot," Scheuner said. "It's just how proximal you want to be and what makes sense clinically in terms of evaluating someone and being able to manage that risk."

Hereditary hemochromatosis is an autosomal recessive disorder resulting in iron overload that gone undiagnosed can cause liver disease and other complications. The disease is usually caused by C282Y or H63D mutations in the HFE gene. According to the US Centers for Disease Control and Prevention, some experts have advocated for population screening of HFE mutations, but recent studies have suggested that a very small subset of people who have these mutations develop clinical symptoms.

"Doing the genetic testing before there are any concerns of early symptoms is not the best strategy," Scheuner said. A physician may be concerned that a patient has iron overload if they have symptoms such as decreased libido, arthritis, abdominal pain, diabetes, brown skin, and cardiomyopathy. But hemochromatosis may be only one among a dozen possible explanations for why a patient may have these non-specific symptoms. So, "the most important is to look for iron overload and if there is evidence of that, then I would hope the doctor does the genetic testing to confirm if iron overload is due to a genetic cause or not," Scheuner said.

Struggle for balance

ACMG's Choosing Wisely recommendations come at a time when experts in the field are at loggerheads about how freely consumers should have access to genetic tests, especially when they don't provide much information about a person's risk for disease and could end up causing unnecessary worry. Among consumers, however, a growing subset wants access to genetic testing without physician involvement.

In an email to GenomeWeb, Stephen Cobb, whose wife has hemochromatosis, wrote he was "shocked" by ACMG's advice against ordering HFE testing for patients without iron overload or a family history of the disease. Many people don't know their parents had HFE-related hereditary hemochromatosis, he noted, because it's hard to diagnose.

"I have no family history of HFE-related hereditary hemochromatosis but I sure as heck had the test when I saw how iron overload crippled my wife and ruined her life," said Cobb. "Personally, I will continue to recommend HFE testing to anyone who is curious, and proactively urge testing for all women approaching menopause. Thankfully, you can get the results for $99 without seeing a doctor."

Until 2013, consumers could learn whether they carried HFE mutations and their genetic predisposition for a host of other conditions from 23andMe for $99, but the firm had to stop selling health-related test reports due to regulatory challenges. After recently garnering US Food and Drug Administration clearance for carrier testing for Bloom syndrome, the firm is working on relaunching a broader offering of similar reports that consumers can order directly. Meanwhile, the genealogy website Ancestry.com is also inching toward the healthcare space. 

It's always good when recommendations are put in place, but it's also important that patients' perspectives are part of the creation of those recommendations.

Since 2008, the ACMG's position has been that a genetics expert should be involved in ordering and interpreting tests, and consumers should be informed about the testing limitations. ACMG plans to update its statement on DTC genetic testing next year. "What is the alternative? That we should be testing regardless of patients' clinical indications for testing?" Scheuner posited. "If that is the alternative, then what are the unintended consequences of testing without any clinical indications or known family history? If we don't think of the unintended consequences, then we're being very short sighted and potentially causing harm."

Proponents of DTC genetic testing will point to studies showing that this information doesn't cause undue stress, but these investigations largely involve people who have high genetic literacy, who volunteered to get tested, or who purchased testing. Critics have maintained that we still don't have a full appreciation for the potential consequences of broad genetic screening, and have cautioned that testing without knowing the utility of having that information is a waste of resources.

Advocacy organization Genetic Alliance doesn't have a position on the Choosing Wisely recommendations at this point. "It's always good when recommendations are put in place, but it's also important that patients' perspectives are part of the creation of those recommendations," Natasha Bonhomme, VP of strategic development at Genetic Alliance, told GenomeWeb.

Family history is not always apparent or known, she said, echoing Cobb's concerns. "We're still trying to do an education campaign to tell people it's important to talk about what runs in your family and get a sense of actual diagnoses," Bonhomme said. "I understand how relying on family history can make sense on paper, from a [recommendation] standpoint, and the theory of how healthcare should work, but for the actual patient … it can feel really limiting."

Scheuner hopes that the Choosing Wisely recommendations will further discussions on consumer access to genetic testing and their limitations. Her group will soon publish a piece for consumers that provides detailed explanations on the five points. In issuing the advice as part of Choosing Wisely "we were limited in the length of each recommendation and how much text we could include," Scheuner explained.

Ultimately, Bonhomme expects these recommendations will have the impact ACMG is hoping for and spark discussion among patients and healthcare providers in coming months.

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