Evaluating Clinicians’ Differential Diagnosis Using Genotypic and Phenotypic Similarities and Differences in Patients with ATTR or Other Inherited CVDs

Hereditary or variant transthyretin amyloidosis (ATTRv) is a progressive and fatal disease caused by the misfolding of mutant transthyretin (TTR) proteins that causes the deposition of amyloid fibrils throughout the body, including the heart. The etiology of subsequent cardiomyopathy manifestations and symptoms is often attributed to other cardiovascular diseases (CVDs). Keller and colleagues evaluated a genetic testing program’s ability to successfully enhance clinicians’ differential diagnosis in patients with TTR mutations compared with other CVDs associated with other mutations that may be inherited. In turn, the goal of their study was to weigh the similarities and differences among patients with ATTR or other inherited CVDs from both genotypic and phenotypic levels.

The investigators reviewed real-world data from patients registered in the ATTRv Compass program, which is a program in the United States (including Puerto Rico) and Canada that provides confidential genetic testing to patients who either have a family history of ATTRv or who are simply at risk for ATTRv with polyneuropathy. Next-generation sequencing was performed using a 92-gene panel associated with inherited CVD called CardioNEXT.

Testing with the CardioNEXT panel was used for a total of 4265 patients who had been referred for the study; of these patients, 8% (N = 321) were positive for TTR mutations and 11% (N = 448) tested positive for other non-TTR CVD pathogenic mutations. More than three-quarters of patients (82% of non-TTR and 81% of TTR) were referred to the program by a cardiology specialist.

The majority (91%) of TTR mutation patients had p.V142I/V122I, which typically presents as a cardiomyopathy phenotype.

Notably, in this study, most (82%) patients who tested positive for a TTR mutation had no known ATTRv familial history. Patients with non-TTR mutations were younger than those with TTR mutations, as reflected in the mean age of 53 years compared with 68 years.

Of those patients who responded to questions about their prediagnosis experience, the majority of patients saw ≥2 physicians before they received genetic testing. Among patients who responded to questions about ethnicity, the most common ethnicity among patients with a TTR mutation was African American (85%) and the most common ethnicity among patients with non-TTR mutations was Caucasian (63%).

The proportion of heart disease was similar in both groups, with 94% in the TTR cohort compared with 96% in the other CVD cohort. In patients with non-TTR compared with TTR mutations, some key indicators of ATTRv were more prevalent; for example, autonomic symptoms were seen in 27% of non-TTR patients compared with 21% of TTR patients and gastrointestinal dysfunction was present in 20% compared with 9%, respectively. However, in patients with TTR mutations, there were differences in the prevalence of certain red-flag findings such as sensory dysfunction (20% compared with 27%) and bilateral carpal tunnel syndrome (3% compared with 20%).

The authors concluded that ATTRv remains frequently undiagnosed and can progress rapidly despite diagnostic advances. It often presents similarly to other cardiovascular disorders, which can make it difficult to render an accurate and definitive diagnosis. Whereas the majority of patients with the non-TTR mutation were Caucasian, patients with the p.V142I mutation were predominantly African American. Given the prevalence of p.V142I in the African American population, clinicians should suspect ATTRv in patients with red-flag symptoms to establish an appropriate disease-modifying treatment regimen. To accurately diagnose and treat ATTRv, clinicians need to be aware of red-flag symptoms (eg, bilateral carpal tunnel symptoms) and recognize the critical value of genetic testing, which can improve accurate and timely diagnosis. Guidelines and position statements support the use of appropriate genetic testing in these cases.

Source: Keller A, Shah K, Delgado D, et al. Genotypic and phenotypic differences, and similarities among patients with transthyretin amyloidosis or other inherited cardiovascular diseases: insights from a genetic testing program. Presented at: ACC.21, American College of Cardiology 70th Annual Scientific Session & Expo, May 15-17, 2021.

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