Comparison of two genetic strategies for diagnostic work-up of hypertrophic cardiomyopathy: impact on the diagnosis of Fabry disease or transthyretin amyloidosis

TL;DR

This study compares two genetic testing approaches for diagnosing heart conditions in patients with hypertrophic cardiomyopathy, finding that targeted testing based on clinical signs is faster, cheaper, and more effective.

Contribution

Demonstrates that targeted genetic testing outperforms broad panel testing in diagnosing specific inherited heart diseases in hypertrophic cardiomyopathy patients.

Findings

Targeted testing identified 28.6% of pathogenic variants in TTR/GLA genes, compared to 1.0% with multigene panels.

Targeted testing was 7.5 times faster and significantly cheaper than multigene panel analysis.

Clinical analysis guided by red flags improves diagnostic efficiency and reduces delays in treatment.

Abstract

Diagnostic work-up of patients with hypertrophic cardiomyopathy is crucial for appropriate management. However, the optimal genetic strategy remains debatable. We compared two strategies: targeted testing based on careful examination of clinical red flags versus large multigene panel analysis without gene prioritization. We applied the strategy to the diagnosis of Fabry disease or Hereditary Transthyretin Amyloidosis (GLA or TTR genes respectively).

We studied 341 hypertrophic cardiomyopathy index patients. Patients of subgroup 1 (n = 42) had careful clinical analysis and high suspicion of Hereditary Transthyretin Amyloidosis or Fabry disease. They underwent targeted Sanger sequencing. Patients in subgroup 2 (n = 299) did not have clinical selection, and underwent next-generation sequencing analysis of 107 cardiac genes.

The yield of genetic testing for pathogenic/likely pathogenic variants in GLA and/or TTR was 28.6% in subgroup 1 (12/42: 5 TTR and 7 GLA) versus 1.0% in subgroup 2 (3/299: 1 TTR and 2 GLA), p < 0.01. Genetic results were obtained after a median of 26.0 days [IQR = 18–59.8] in subgroup 1 versus 193.5 days [IQR = 174–218] in subgroup 2, p < 0.01. Finally, genetic testing cost was 615.60€ or 769.50€ for TTR or GLA targeted analysis respectively, versus 1503.90€ for multigene panel analysis.

Both molecular strategies in hypertrophic cardiomyopathy patients are useful for the identification of pathogenic/likely pathogenic variants in TTR/GLA genes. However, targeted genetic testing based on clinical red flags identified causal mutations more efficiently, faster and at a lower cost. Careful clinical analysis is therefore important in guiding molecular strategy and may reduce diagnostic wandering and accelerate delivery of appropriate therapy.

The online version contains supplementary material available at 10.1186/s13023-025-03815-z.

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