How Genetics, Race, and Inequality Play Into Misdiagnoses

I, like many medical professionals, chose this career to make a difference, to prevent disease, and hopefully to save lives. As an African-American genetic counselor and scientist, I have hopes that my work will help close the gap in racial and ethnic health disparities. But the fact is that we still have far to go, something that hit home for me less than a year ago when I lost my father to heart disease, a condition that disproportionately impacts African Americans. We know that heart disease impacts African Americans at higher rates partially because of social determinants of health, but genetics also play a role. My father’s death reinforces for me that we are still missing the mark not just in care but also in genomic health equity. Because African Americans and other non-Europeans groups are not well represented in most genetic studies, we currently know less about the genetic contribution to disease risks in these groups compared to Europeans. And as health care professionals, we need to be better at understanding health issues that are unique to each of these groups — information that is already available to us — so we can offer appropriate care.

Recently, an accomplished neurologist shared with me the case of a young African-American man who presented to his local ER with shortness of breath. It wasn’t his first visit. It was his fourth, and each time he came in with the same exact symptom — dyspnea. The first three times doctors reluctantly prescribed pain medication but seemed perplexed by his labored breathing. Shortly after walking into the ER for the fourth time, the young man collapsed and went into cardiac arrest. It wasn’t until a battery of tests were performed that the medical team was able to diagnose the patient with an often under recognized and underdiagnosed genetic condition called TTR-related hereditary cardiac amyloidosis (ATTR-CM).

ATTR-CM is a fatal condition that disproportionately affects African Americans, and has been identified as a common cause of heart failure in Afro-Caribbeans. ATTR-CM can be associated with mutant forms of the transthyretin (TTR) protein. One of the best-studied mutations in the TTR gene that is linked to ATTR-CM results from a valine-to-isoleucine amino acid substitution at position 122 in the protein. This mutation, called V122I, is estimated to be found in three to four percent of African Americans and individuals of West African descent. That amounts to an estimated 1.5 to 2 million TTR V122I carriers in the United States alone. And yet, few medical professionals are aware of this condition. There is an added concern that the similarities in symptoms between ATTR-CM and other forms of heart disease may contribute to the prevalence of misdiagnosed and undiagnosed ATTR-CM cases. As a result, hypertension and other symptoms confound accurate and timely diagnosis and treatment for many individuals with ATTR-CM. These are missed opportunities to provide an already medically underserved population with an appropriate diagnosis and care. These are opportunities to make meaningful differences. First, to raise awareness about ATTR-CM within the medical community; second, to identify TTR V122I carriers; third, to appropriately diagnose ATTR-CM; and fourth, to possibly prevent the onset of ATTR-CM or identify the condition at earlier stages in order to optimize treatment options and delay the progression of ATTR-CM.

ATTR-CM is a form of the broader condition, TTR-related hereditary amyloidosis (hATTR), which results from misfolded transthyretin clumping together to form amyloid fibrils. The amyloid fibrils can build up in the heart, nerves, and other parts of the body. Symptoms are dependent upon multiple factors such as the specific TTR variant one carries and the location of amyloid fibril accumulation. Even among individuals or family members with the same TTR variant, symptoms and onset of the condition can vary widely from person to person. Because of this wide variation, a family history of the condition can easily go unnoticed. In some patients, complications present as autonomic or peripheral neuropathy; others may experience cardiomyopathy; some patients experience both.

Another layer of disparity in ATTR-CM is that FDA approval of tafamidis in the U.S. was obtained as recently as May 2019. Prior to approval of tafamidis, there was a limited time when approved treatment options were only available for the form of hATTR that is more commonly diagnosed in people of European and Japanese descent. This means that there were no therapeutic options available for a fatal form of TTR that disproportionately impacts African Americans, an already medically marginalized and underserved population. This kind of gap in care is unacceptable as no population should be left behind as we develop new standards of care, diagnosis, and treatment. Now that the FDA has approved tafamidis in the U.S. as the only form of therapy available to treat ATTR-CM and a number of other companies are in pursuit of FDA approval for alternative treatments, it will be even more critical that health care professionals are better at identifying individuals at increased risk of developing ATTR-CM and are also making accurate diagnoses. This will be paramount in the ability of this potentially life-saving therapy to be appropriately prescribed as soon as symptoms begin and to decrease the severity of the symptoms/disease. Early diagnosis and prompt treatment would contribute to improvements in prognosis and cardiovascular-related health outcomes.

What Next?

ATTR-CM is a condition that is not often considered or diagnosed, and our understanding of the clinical presentation and natural history of the condition in TTR V122I carriers and homozygotes is limited. In order to maximize equitable utility of tafamidis and the treatment of ATTR-CM, we must increase awareness of the high TTR V122I variant frequency in people of African descent and the increased risk of ATTR-CM associated with this variant. This may help us more accurately determine the overall prevalence of ATTR-CM and determine if there are disparities or differences in care and health outcomes. Let’s start by bringing this underdiagnosed and underrecognized condition to the attention of more clinicians, policy-makers, pharmaceutical companies, governmental officials, and researchers. We must make identifying, diagnosing, and treating this disease a priority. And we could ask ourselves some hard questions about our own knowledge, our current clinical practice, and our own ability to identify people affected by this condition.

Finally, we must increase awareness of ATTR-CM more broadly, not just among health care professionals, but among those most impacted. We could advocate for better clinical guidelines that outline a population health screening approach and develop diagnostic testing protocols that are standard of care. Together, we may be able to increase awareness and ensure appropriate treatment for all patients with TTR-CM regardless of ethnicity, class, gender, and genetic status.  

Altovise Ewing, PhD, LCGC, is a medical science liaison-genetic counselor at 23andMe. She is also trained as a health disparities researcher and dedicates her professional career to ensuring that emerging genetic and genomic services and resources do not further exacerbate health disparities.

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