Genomic Screening Identifies Individuals at High Risk for Hereditary Transthyretin Amyloidosis

Abstract

The TTR V142I variant associated with hereditary transthyretin amyloidosis (hATTR) is present in up to 4% of African American (AA) and 1% of Hispanic/Latinx (HL) individuals and increases risk for heart failure. Delayed and missed diagnoses could potentiate health disparities in these populations. We evaluated whether population-based genomic screening could effectively identify individuals at risk for hATTR and prompt initiation of risk management. We identified participants of the BioMe Biobank in New York City who received TTR V142I results through a pilot genomic screening program. We performed a retrospective medical record review to evaluate for the presence hATTR-related systemic features, uptake of recommended follow-up, and short-term outcomes. Thirty-two AA (N = 17) and HL (N = 15) individuals received a TTR V142I result (median age 57, 81% female). None had a previous diagnosis of hATTR. Eighteen (56%) had hATTR-related systemic features, including 4 (13%) with heart failure, 10 (31%) with carpal tunnel syndrome, and 10 (31%) with spinal stenosis. Eighteen (56%) pursued follow-up with a cardiologist within 8 months. One person received a diagnosis of hATTR. Thus, we found that the majority of V142I-positive individuals had hATTR-related systemic features at the time of result disclosure, including well-described red flags. Genomic screening can help identify hATTR risk and guide management early on, avoiding potential delays in diagnosis and treatment.

Real-world utilization of guideline-directed genetic testing in inherited cardiovascular diseases

“…Other approaches have also been proposed. In 2021, Birnbaum et al ( 20 ) and Ingoe et al ( 23 ) demonstrated increased diagnosis of FH and utilization of genetic testing after system-wide scanning of the EHR to identify patients at high risk; and Soper et al ( 59 ) described a genomic screening program that identified individuals with variants in TTR , none of whom had a previous diagnosis of hereditary transthyretin amyloidosis. Adopting implementation science frameworks and practices may also facilitate the uptake of guideline-directed genetic testing.…”

From the patient to the population: Use of genomics for population screening

“…This was not a systematic review, nor was a formal quality appraisal of studies conducted. Moreover, this review was limited to Tier 1 conditions-future research and evidence synthesis will be needed to address other actionable gene-condition pairs (e.g., other genes for hereditary breast and ovarian cancer including PALB2, RAD51C, RAD51D, and BRIP1 ( Manchanda et al, 2018 ); TTR for hereditary transthyretin amyloidosis ( Soper et al, 2021 ); endocrine tumour genes ( Savatt et al, 2022 ); arrhythmia syndrome genes ( Walsh et al, 2022 )) and their suitability for population genomic screening.…”

Genomic Screening for Pathogenic Transthyretin Variants Finds Evidence of Underdiagnosed Amyloid Cardiomyopathy From Health Records

“…The advent of more widespread genetic testing facilitated by next-generation DNA sequencing technologies presents new opportunities to potentially redefine our understanding and approach to hATTR diagnosis and treatment. Identifying individuals at risk through systematic screening for genomic variants in TTR , rather than symptom-based clinical ascertainment, could both clarify the true scope of the disease at a population scale and enable earlier intervention to potentially mitigate disease progression and thereby improve outcomes ( 5 ). Because hATTR cardiomyopathy is generally only clinically recognized once profound ventricular remodeling and dysfunction are present these opportunities for improving outcomes may be substantial, particularly in light of newly approved treatments ( 1 , 6 ).…”