Genetic Testing Not Necessarily the Nail in the Coffin for HCM Diagnosis

For physicians who use genetic testing to confirm a diagnosis of hypertrophic cardiomyopathy (HCM) or to risk stratify family members of a patient diagnosed with the highly hereditary disease, a new study suggests that this method might not be as definitive as previously thought, particularly in certain patient populations.

Oftentimes, patients suspected to have the disease do not require genetic testing, since a diagnosis can be confirmed through “symptoms, physical exam, ECG, echocardiogram, and possibly cardiac MRI,” according to Michael A. Fifer, MD, director of the hypertrophic cardiomyopathy program at Massachusetts General Hospital in Boston, who commented on the study for TCTMD. However, over the past decade or so, genetic testing has been beneficial in confirming cases in which physicians weren’t sure, since HCM can often present similarly to conditions like hypertensive heart disease or athletic heart syndrome, he said.

But research appearing in the August 18, 2016, issue of the New England Journal of Medicine by Arjun Manrai, PhD (Harvard Medical School, Boston, MA), and colleagues has identified several benign genetic variants previously seen as pathogenic for HCM. Specifically, based on their analysis of publicly accessible exome data, only five of the 94 distinct variants linked with HCM in previous studies held up to the standards of being high-frequency variants for the disease.

The misclassification was due to the fact that previous studies mostly consisted of white patients, and none of them “involved persons of African ancestry explicitly,” according to the study authors. All five of the confirmed HCM genetic variants appeared more frequently among black Americans than white Americans in data from the NHLBI Exome Sequencing Project (P < 0.001).

Furthermore, Manrai and colleagues identified several patients who received misdiagnoses of HCM between 2005 and 2007, and all were of African or unspecified ancestry. They also showed that “even small studies of diverse populations are comparatively well-powered to avoid misclassification of the five high-frequency variants associated with hypertrophic cardiomyopathy.”

Quantitative Risk Estimates Needed

This study shows that a positive genetic test result for HCM is “is not a definitive diagnosis—it’s a probabilistic one,” Manrai told TCTMD. Because of this, “it’s critical to stay in contact, if possible, with families who have been referred to genetic testing because our knowledge about these variants is constantly evolving, possibly even years after positive genetic diagnosis,” he added. “Also, we have new resources today that help us evaluate a lot of the old assertions [as to] which are genetic mutations and which are not. It’s going to be critical especially for diverse populations to reevaluate those past assertions using new data types.”

Fifer agreed, particularly with regard to family members who receive genetic testing as a precautionary measure. Tests resulting in false positives cause “unnecessary concern for these other family members and unnecessary screening,” whereas false negatives could be potentially dangerous and erroneously “exonerate” family members from a lifetime of necessary screening, he said.

“Our study motivates a much larger systematic study across other ethnic groups both within HCM and outside of HCM to understand the full scope of this problem,” Manrai said.

Additionally, “we are desperately in need of quantitative risk estimates attached to these genetic variants” to help cardiologists interpret genetic test results, he continued. Today many clinicians “have a binary understanding” of genetic testing, often trusting positive results to “seal the case for HCM,” Manrai observed, “but at this time we’re not able to actually have a quantitative estimate.

“We need to have more caution in thinking about some of those studies that generated these associations as well as the conclusiveness of them,” he added. What that means for clinicians now is to “stay as up to date with the current annotations on these variants [by] having a good line of communication with the genetic counselor who was interpreting the variant and the testing lab, and trying to ensure if possible that those variant annotations are up to date for their patients,” Manrai suggested.

Fifer said he will do just that. “Now that I’m sensitized by this report, before I sent a specimen to a lab for genetic testing I would inquire if whether they had enough patients of similar ancestry to make it reasonable,” he said. “I would have to do some homework before committing the patient to the test. . . . There’s no point spending a few thousand dollars if you’re going to get useless information. It’s better to have no data than bad data.”


  • Manrai AK, Funke BH, Rehm HL, et al. Genetic misdiagnoses and the potential for health disparities. N Engl J Med. 2016;375:655-665.


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  • Manrai reports no relevant conflicts of interest.
  • Fifer reports receiving research grants from Gilead related to HCM and serving as a consultant to MyoKardia.