Vast Underdiagnosis of Monogenic CV Disease Seen in Cath Referrals

August 10, 2020

Monogenic disorders with heart and vascular effects are each pretty rare in clinical practice but collectively can make up a fair proportion of the patients cardiologists see. Still, the diagnosis is missed more often than not, even when the clinical signs are there, suggests an observational study, said to support broader genetic testing in cardiovascular patients.

In a cohort of more than 8000 patients referred for cardiac catheterization, diagnosis of such a monogenic cardiovascular disease (MCVD) was made in only 35% of those with one related gene variant and signs of phenotypic expression in the electronic health record (EHR).

The findings are novel for measuring the field's "burden of missed diagnoses" in patients with MCVD, which "represent a missed opportunity that could be addressed by genetic screening," contends the study report, published in the August 18 issue of the Journal of the American College of Cardiology.

"The under-recognition of these diseases underscores the importance of including monogenic diseases in the treating physician's differential diagnosis," say the authors, led by Jawan W. Abdulrahim, MD, Duke University School of Medicine, Durham, North Carolina.

Diagnosis of MCVDs can be important, the group writes, because many, including familial transthyretin amyloidosis (TTR) and other disorders that pose an increased risk for sudden death, "have evidence-based treatment modalities available or are clinically actionable." Identification of patients with MCVD variants is also "important for cascade screening of family members who are at risk of inheriting the pathogenic mutations."

"We tend to ignore these monogenic diseases because they are so rare individually but, in aggregate, monogenic diseases are actually quite common," senior author Svati H. Shah, MD, MHS, Duke University School of Medicine, told | Medscape Cardiology.

The results "support that the cardiology community over time adopt a genotype-forward approach," one in which every patient presenting to a cardiovascular clinic is genotyped, she said.

One implication of such an approach, Shah agreed, is that "we would be able to pick these people up earlier in their disease, especially in the context of therapies that could improve certainly their progression, but even their survival."

For now, she said, the study suggests that "these disorders are more frequent than perhaps all cardiologists are aware of, and we just need to keep our eyes open and know when to refer patients to a cardiovascular genetics clinic, which maybe has more time and can deal with all the nuances that go along with genetic testing."

In the total cohort, 4.5% were found to carry a gene variant known or believed to cause such diseases. The most frequently represented conditions were familial TTR, hereditary hemochromatosis, heterozygous familial hypercholesterolemia, and various cardiomyopathies.

Of those patients, 52 received a clinical diagnosis of the monogenic disorder after an EHR review. Of the 290 without such a diagnosis, two-thirds didn't show evidence in their EHR of the variant's phenotypic signs. But the records of the other third featured at least some signs that the disease had manifested clinically.

"These data serve as a reminder that monogenic Mendelian disease, including heart and vascular disease, varies in penetrance from individual to individual and may not always present with clinically detectable phenotypes," notes an editorial accompanying the report.

They also "provide a compelling basis for expanding the role of targeted genetic testing in patients with more traditional forms of heart and vascular disease," agree Scott M. Damrauer, MD, University of Pennsylvania, Philadelphia, and William S. Weintraub, MD, Medstar Washington Hospital Center and Georgetown University, Washington, DC.

"Based on the current report, the number needed to screen in a complex cardiovascular patient population to detect 1 case of undiagnosed monogenic cardiovascular disease is 85," they write.

"This places targeted genetic testing well within what is considered to be efficacious for most screening programs and in the range of that of other common cardiovascular diseases and cancers."

Among the 342 patients with a variant predicting a single MCVD —in addition to the 52 who received a diagnosis — 193 had records with no indication of phenotypic expression and so did not receive a diagnosis.

But the 97 patients without a diagnosis who nevertheless had documented signs of some phenotypic expression were deemed, on the basis of extent of expression, to represent a possibly, probably, or definitely missed diagnosis.

Familial TTR made up about 45% of such potentially missed diagnoses, the report notes.

Broader screening of patients with cardiovascular disease, Shah speculated, "might actually be not only a clinically useful endeavor, but — when we think about the aggregate burden of these monogenic disorders- — potentially even cost-effective."

As the price of genetic sequencing drops, she said, "I think we'll start to see even more health systems wanting to incorporate the genotype-forward approach."

Shah reports serving as primary investigator for research sponsored by Verily Life Sciences and AstraZeneca. Abdulrahim reports no relevant relationships. Disclosures for the other authors are in the report. Damrauer discloses receiving research support from RenalytixAI and consulting fees from Calico Labs. Weintraub had no relevant disclosures.

J Am Coll Cardiol. 2020;76:797-808, 809-811. Abstract, Editorial

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