The Potential Clinical and Public Health Implications of Presymptomatic Genetic Testing for Transthyretin Amyloidosis in American/Black Adults in the United States

Inderjeet Bharaj¹Simar J Singh²Juzer Munaim¹Harneet Grewal¹Sonia Sabrowsky³Andrew Boshara⁴Marc A Silver⁵Katherine H Brendish⁶Paul Underwood⁷Sandesh Dev⁶Mayowa Osundiji^3*

• ¹Abrazo Health Care, Phoenix, United States
• ²The University of Arizona College of Medicine Phoenix, Phoenix, United States
• ³Mayo Clinic Arizona, Scottsdale, United States
• ⁴CommonSpirit Dignity Health, Phoenix, United States
• ⁵The University of Arizona Health Sciences Phoenix Campus, Phoenix, United States
• ⁶Arizona State University, Tempe, United States
• ⁷CardioMedSci, Phoenix, United States

Opinion Introduction ATTR Cardiomyopathy (ATTR-CM) is increasingly being recognized as a significant cause for heart failure in African American/Black adults (1-3). Approximately 3.43% of African Americans harbor at least one copy of the. The TTR V122I allele, which is known to be associated with an increased risk of ATTR Cardiomyopathy (ATTR-CM), has a prevalence of approximately 3.43% in the African American population (4). It has been estimated that Black Americans will lose nearly 1 million life years due to ATTR (5). Genetic testing is currently recommended to patients with a suspected clinical diagnosis of ATTR-CM (6). With the increasing development and potential availability of drugs targeting transthyretin (7, 8), debates on the possibilities of targeted presymptomatic genetic screening of vulnerable populations [including African American adults] for ATTR is emerging (9, 10) and topical considering the growing need to promote health equity (11). In this article, we report the arguments raised for and against genetic screening for ATTR in asymptomatic Black adults at a debate that was held at Arizona State University on November 20, 2023. The debate was attended by a board-certified Cardiologist, Genetic Counselors, and a Medical Geneticist, who are routinely involved in the clinical care of individuals with ATTR. Opinion The Debate: Pros and Cons Points raised in support include: the increased risk of ATTR-CM in Black Americans, the high frequency of the pathogenic TTR variants [especially Val122Ile (or pV142I)], and the potential benefits of presymptomatic diagnosis in facilitating preventative and therapeutic options. The challenges highlighted include: the incomplete and age-dependent penetrance of TTR variants, uncertainties regarding acceptability of genetic screening, the risk of genetic discrimination, the uncertain impact for presymptomatic diagnosis, the costs of screening and limitations associated with variants of uncertain significance (VUS). Pros: Team A argued that presymptomatic screening of African Americans, can pave the way for potentially preventative approaches, awareness of symptoms, and improved surveillance for ATTR (12). Additionally, presymptomatic screening is likely to lead to timely initiation of treatment (13). With the United States Food and Drug Administration's (FDA) approval of Tafamidis (7, 14) and the growing possibilities (15) for other preventative as well as therapeutic approaches that may alter the disease course [such as RNA-targeted therapies [like Patisiran, Eplontersen, and Inotersen (16)] CRISPR-Cas9 gene editing [e.g. nexiguran, and ziclumeran (17)], team A argued that presymptomatic screening will result in early interventions including therapeutic and supportive management. Moreover, cascade testing of asymptomatic family members will be a potential secondary benefit of presymptomatic screening (13). Team A maintained that direct-to-consumer genetic tests are already reporting the common TTR variants (10). Team A cited an example of a 45-year-old African American male who self-Opinion referred to genetics clinic in Arizona after a nonclinical, direct-to-consumer, genetic test revealed that he had a heterozygous TTR p.V122I variant, in the absence of personal or family history of symptoms related to ATTR. This case highlighted the potential for presymptomatic diagnosis in more African American patients, if opportunities for screening for common TTR variants are created. Cons: Team B argued that the penetrance of ATTR appears to be incomplete as well as being subject to age-dependent penetrance (18). In a study, involving 3856 subjects from the Atherosclerosis Risk in Communities (ARIC) cohort, Selvaraj and colleagues reported significant increases in heart failure and mortality risk became apparent from around age 65 years in individuals harboring TTR p.V142I (19). Approximately 150 variants in TTR have been identified in individuals with ATTR amyloidosis (20). Team B maintained that a comprehensive screening program for Black adults may be difficult to achieve based on the current clinical scientific knowledge of TTR variants due to challenges associated with variants of uncertain significance [VUS] (21, 22). The psychological, ethical, and economic consequences of VUS cannot be overemphasized (23-27). Team B explained that presymptomatic screening for ATTR may need to focus on established pathogenic and likely pathogenic TTR variants, potentially limiting the capacity of such screening program for individuals with non-founder mutations. Team B contended that the uptake of ethnicity centered presymptomatic genetic screening might be low in Black communities for historic reasons (28) without appropriate pre-test counseling and a well-defined post-test counseling and clinical management pathway (29). Team Opinion B cited that the current limitations of Genetic Information Nondiscrimination Act (GINA) may also complicate presymptomatic pre-test counselling for an already vulnerable population (30). The potential costs associated with widespread presymptomatic genetic screening for Black adults were also underscored by team B. The cost effectiveness of genomic population health screening programs is a subject of ongoing investigations that is topical considering the resource constrains faced by many healthcare systems. A recent review of eight modeling studies of cost effectiveness of genomic population screening in adults for three countries [United States, United Kingdom and Australia] using quality-adjusted life year (QALYs) and incremental cost-effectiveness ratio (ICER) as well as willingness to pay (WTP) threshold suggests that genomic population health screening is likely to be cost-effective (31). Discussion and Conclusion This debate highlights the complexities that are potentially associated with implementing routine genetic screening for ATTR in the Black population despite the growing need for the public health screening program. The panel recognized that the increased risk of ATTR cardiac amyloidosis in African American adults (2, 4, 18) together with the challenges of racial disparities in access to care results in increased vulnerability (2). Screening approaches will need to be guided by allele frequency, penetrance, predictive value, and preventative as well as therapeutic implications. Opinion The development of programs that can create an improved public awareness of the increased vulnerability of African Americans to ATTR-CM is increasingly becoming necessary. The results of this debate and new evidence suggest that early detection of ATTR-CM via widespread ATTR variant genetic testing in asymptomatic Black adults may potentially improve patient outcomes (6-9), however to facilitate increased uptake of genetic testing, we believe that additional evidence generation on the risks and benefits of genetic screening of at-risk communities is required (31). A recent study estimated that Black Americans will lose nearly 1 million life years due to ATTR (5). The ongoing and future clinical trials may shed further light on novel approaches to delay the development of ATTR CM and/or polyneuropathy in asymptomatic patients (32). The panel concluded that clinical genetic tests for the common TTR variants should be increasingly offered to Black adults, following appropriate risk and culturally tailored pretest counseling, considering the preventative and therapeutic benefits. The panel posits that approaches to increase the awareness of ATTR-CM in Black people will be beneficial. Pilot programs, and cost-effectiveness clinical trials, as well as culturally tailored pre and post-test counseling are therefore warranted. Opinion