Key result
LGE is linked to ~3.5-fold higher odds of positive genetic retesting in HCM.
Why the study?
Modern genetic testing in HCM now includes newly described HCM-associated genes and full intronic regions of classic sarcomeric genes, motivating evaluation of the yield and predictors of genetic retesting in patients with a prior negative test.
Does genetic retesting using an updated NGS-based panel identify HCM-related variants in patients with hypertrophic cardiomyopathy and a prior negative genetic test?
Observational (n=508)
Yes
Does genetic retesting using an updated NGS-based panel identify HCM-related variants in patients with hypertrophic cardiomyopathy and a prior negative genetic test?
Genetic retesting with updated panels identifies disease-related variants in 9% of previously gene-negative HCM patients, with yield enriched up to 50-80% when prioritizing patients with late gadolinium enhancement and high Mayo or Toronto clinical scores.
Answers are grounded in this paper and cite their sources.
Supports targeted retesting in HCM patients with late gadolinium enhancement; hypothesis-generating before changing practice or guidelines.
BACKGROUND AND AIMS: Modern genetic testing in hypertrophic cardiomyopathy (HCM) includes newly described HCM-associated genes and full intronic regions of certain classic sarcomeric genes. This study evaluated genetic retesting in HCM patients with a prior negative test and identified predictors of a positive result to guide retesting. METHODS: This multicentre study included patients with HCM who previously had negative next-generation sequencing (NGS)-based genetic testing at four centres. Subjects were retested using an updated NGS-based HCM panel. RESULTS: Of 508 retested HCM patients (median age 70 years; 66.9% male; median maximal left ventricular wall thickness 18 mm; median interval from initial genetic test 6.6 years), 46 (9%) had 48 HCM-related variants: 14 in new HCM-associated genes, 3 in deep intronic MYBPC3 regions, 18 intermediate-effect variants, and 13 (8 reclassified) in classic HCM-associated genes. In multivariable analysis, the presence of late gadolinium enhancement (LGE) [odds ratio (OR) 3.52; 95% confidence interval (CI) 1.38-10.25], the Mayo HCM score (OR 1.46 per 1 point increase; 95% CI 1.08-2.01), and the Toronto HCM score (OR 1.18 per 1 point increase; 95% CI 1.08-1.30) were independent predictors of detecting HCM-related variants at retesting. The diagnostic yields in patients with LGE and a high Toronto score (≥13 points), and with LGE and a high Mayo score (≥4 points), were 80% and 50%, respectively. CONCLUSIONS: In patients with HCM and prior negative genetic testing, retesting identified HCM-related variants in 9% of individuals, allowing counselling and risk stratification. Late gadolinium enhancement, combined with the Mayo and Toronto scores, may be used to guide which patients should be prioritized for genetic retesting.
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Castro et al. (2026) conducted an observational in Hypertrophic cardiomyopathy (n=508). Genetic retesting using an updated NGS-based HCM panel was evaluated on Detection of HCM-related genetic variants at retesting (OR 3.52, 95% CI 1.38-10.25). Genetic retesting in HCM patients with prior negative tests identified HCM-related variants in 9%, independently predicted by LGE (OR 3.52; 95% CI 1.38-10.25), Mayo, and Toronto scores.
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