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The Definition of Sarcomeric and Non-Sarcomeric Gene Mutations in Hypertrophic Cardiomyopathy Patients: A Multicenter
Veysel Oktay1, Omaç Tüfekçioğlu2, Dilek Çicek Yılmaz3
1Department of Cardiology, İstanbul University-Cerrahpaşa, Institute of Cardiology, İstanbul, Türkiye.
Insights
Genetic testing in 392 hypertrophic cardiomyopathy patients revealed mutations in 12 genes. While sarcomeric gene mutations were slightly less common than in other populations, the study confirmed molecular diagnoses in over half of positive cases.
Area of Science:
- Cardiovascular Genetics
- Molecular Diagnostics
- Genetic Epidemiology
Background:
- Hypertrophic cardiomyopathy (HCM) is a prevalent genetic heart disease, with 40%-60% of cases linked to sarcomere protein gene mutations.
- Accurate genetic diagnosis is crucial for understanding HCM's etiology and patient management.
Purpose of the Study:
- To identify pathogenic or likely pathogenic sarcomeric and non-sarcomeric gene mutations in patients diagnosed with hypertrophic cardiomyopathy.
- To establish a definitive molecular diagnosis for HCM patients through comprehensive genetic analysis.
Main Methods:
- A nationwide multicenter study involving 392 patients with hypertrophic cardiomyopathy across 23 centers in Türkiye.
- Next-generation sequencing (NGS) was employed using a 17-gene panel covering key sarcomeric and non-sarcomeric genes associated with HCM.
Main Results:
- NGS identified positive genetic variants in 12 genes for 121 out of 392 patients (30.9%).
- Confirmed molecular diagnoses were achieved in 69 of 121 positive samples (57.0%), with sarcomeric gene mutations found in 30.4% of all samples.
- The study also detected variants related to Fabry disease (0.5%) and TTR amyloidosis (0.025%).
Conclusions:
- The genetic mutation profile, including Fabry disease and TTR amyloidosis prevalence, in the Turkish HCM population aligns with global data.
- A slightly lower percentage of sarcomeric gene mutations was observed compared to other populations.
- Genetic testing provides a significant diagnostic yield for hypertrophic cardiomyopathy and related conditions.
Background:
Hypertrophic cardiomyopathy is a common genetic heart disease and up to 40%-60% of patients have mutations in cardiac sarcomere protein genes. This genetic diagnosis study aimed to detect pathogenic or likely pathogenic sarcomeric and non-sarcomeric gene mutations and to confirm a final molecular diagnosis in patients diagnosed with hypertrophic cardiomyopathy.
Methods:
A total of 392 patients with hypertrophic cardiomyopathy were included in this nationwide multicenter study conducted at 23 centers across Türkiye. All samples were analyzed with a 17-gene hypertrophic cardiomyopathy panel using next-generation sequencing technology. The gene panel includes ACTC1, DES, FLNC, GLA, LAMP2, MYBPC3, MYH7, MYL2, MYL3, PLN, PRKAG2, PTPN11, TNNC1, TNNI3, TNNT2, TPM1, and TTR genes.
Results:
The next-generation sequencing panel identified positive genetic variants (variants of unknown significance, likely pathogenic or pathogenic) in 12 genes for 121 of 392 samples, including sarcomeric gene mutations in 30.4% (119/392) of samples tested, galactosidase alpha variants in 0.5% (2/392) of samples and TTR variant in 0.025% (1/392). The likely pathogenic or pathogenic variants identified in 69 (57.0%) of 121 positive samples yielded a confirmed molecular diagnosis. The diagnostic yield was 17.1% (15.8% for hypertrophic cardiomyopathy variants) for hypertrophic cardiomyopathy and hypertrophic cardiomyopathy phenocopies and 0.5% for Fabry disease.
Conclusions:
Our study showed that the distribution of genetic mutations, the prevalence of Fabry disease, and TTR amyloidosis in the Turkish population diagnosed with hypertrophic cardiomyopathy were similar to the other populations, but the percentage of sarcomeric gene mutations was slightly lower.
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