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The French hypertrophic cardiomyopathy gene register: A systematic large gene screening for hypertrophic
Albert Hagège1, Tania Puscas2, Mohamed El Hachmi3
1AP-HP, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Department of Cardiology, Paris, France; AP-HP, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Centre de Référence des Cardiomyopathies et des Troubles du Rythme Cardiaque Héréditaires ou Rares, Paris, France; Université de Paris, INSERM U 970, Paris Cardiovascular Research Centre, Paris, France, Paris, France.
Insights
Systematic genetic screening for hypertrophic cardiomyopathy (HCM) is effective, identifying variants in nearly 40% of patients. Broader gene panels improve diagnostic yield, particularly for non-sarcomeric causes like Fabry disease and TTR amyloidosis.
Area of Science:
- Cardiovascular Genetics
- Medical Genetics
- Genomic Medicine
Background:
- Systematic genetic screening is recommended for hypertrophic cardiomyopathy (HCM), though optimal strategies remain debated.
- The GEREMY registry evaluated the performance of genetic screening in a French HCM cohort.
Purpose of the Study:
- To assess the diagnostic yield and performance of systematic genetic screening panels for hypertrophic cardiomyopathy (HCM).
- To identify the prevalence of genetic variants, including sarcomeric and non-sarcomeric causes, in an adult HCM cohort.
Main Methods:
- A prospective observational study of 748 adult HCM patients.
- Initial screening used a 12-gene panel, including GLA (Fabry disease) and TTR (transthyretin) genes.
- Larger gene panels (17-80 genes) were employed for patients with initially negative results or specific clinical profiles.
Main Results:
- Pathogenic variants were identified in 39.6% of patients, primarily in sarcomeric genes (MYBPC3, MYH7).
- Non-sarcomeric genes, including TTR and GLA, accounted for 8.8% and 3.0% of positive cases, respectively, often identified by larger panels.
- Screening performance was significantly higher in patients under 40 years and those with a family history of HCM.
Conclusions:
- Systematic genetic screening, even with limited panels, demonstrates good performance for HCM diagnosis.
- Larger gene panels increase diagnostic yield, identifying crucial non-sarcomeric conditions like Fabry disease and TTR amyloidosis.
- A significant proportion of patients benefit from expanded genetic testing, revealing variants missed by initial approaches.
Background:
Although the optimal approach is debated, systematic genetic screening for hypertrophic cardiomyopathy (HCM) is recommended.
Aims:
The performance of this approach was tested in GEREMY, a HCM prospective observational French register.
Methods:
Screening was based on a 12-gene panel, including the Fabry disease (GLA) and the transthyretin (TTR) genes. In case of a negative result and according to the clinical profile, 17-80 gene panels of were used.
Results:
A 748 adult cohort was examined: 68.9 % male, 54.6 ± 18.1 years, 27.5 % with a HCM family history, maximal wall thickness 19.1 ± 4.8 mm. Pathogenic or likely pathogenic variants were identified in 296 (39.6 %) patients, localized 1) in sarcomeric genes in 233, most frequently MYBPC3 (150) and MYH7 (42), with 24 identified only by large panels, with multiple variants in 8 patients and 2) in non-sarcomeric genes in 63, identified only with large panels in 26, predominantly TTR (26) and GLA(9), representing 8.8 % and 3.0 % of positive studies, respectively. Performance was 57.1 % before 40 years and 68.6 % in case of FH (vs otherwise 28.7 % and 26.1 % respectively, p < 0.001). In patients with a negative study, 148 had variants of unknown significance and 95 had senile or AL amyloidosis.
Conclusions:
Systematic genetic screening with a limited panel showed good performance, with diagnosis of Fabry disease (∼1 %) and hereditary TTR amyloidosis (∼3.5 %). Larger targeted panels were conclusive in 35.3 % of patients, of which 12 % had a negative initial approach.
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