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Published on: August 8, 2022
Familial and sporadic hypertrophic myopathy: differences and similarities in a genotyped population. A long follow-up
Dulce Brito1, Pascale Richard, Michel Komajda
1Clínica Universitária de Cardiologia, Faculdade de Medicina de Lisboa, Portugal. dulcebrito@spc.pt
Insights
Familial and sporadic hypertrophic cardiomyopathy (HCM) show similar disease progression and clinical outcomes, suggesting they are the same condition. Differences in genetic findings and age at diagnosis point to potential de novo mutations in sporadic HCM.
Area of Science:
- Cardiology
- Genetics
- Molecular Biology
Background:
- Hypertrophic cardiomyopathy (HCM) is a genetic heart condition caused by mutations in sarcomere protein genes.
- While mutations are found in two-thirds of HCM cases, particularly familial forms, the origin of sporadic HCM remains unclear.
Purpose of the Study:
- To compare the long-term phenotypic expression of familial and sporadic hypertrophic cardiomyopathy (HCM) in a genotyped population.
- To investigate potential differences in disease course and genetic underpinnings between familial and sporadic HCM.
Main Methods:
- Seventy-nine HCM patients were divided into familial (G1) and sporadic (G2) groups and followed for over 12 years.
- Clinical, ECG, and echocardiographic features were assessed at diagnosis and during follow-up.
- Five key sarcomere genes (MYH7, MYBPC3, TNNT2, MYL2, TNNI3) were screened for mutations.
Main Results:
- Thirteen mutations were found in familial HCM, versus only one in sporadic HCM.
- Sporadic HCM patients were diagnosed later in life and had less family history of sudden cardiac death.
- Both groups exhibited similar clinical progression, ECG changes (including trends toward atrial fibrillation), and echocardiographic findings (ventricular hypertrophy, atrial dilatation).
Conclusions:
- The similar long-term clinical course of familial and sporadic HCM suggests they are manifestations of the same disease.
- Differences in genetic findings and age at diagnosis imply that sporadic HCM may arise from de novo mutations in other sarcomeric genes with reduced penetrance.
Background:
Hypertrophic cardiomyopathy (HCM) is a genetic disease associated with mutations in genes encoding cardiac sarcomere proteins. A mutation is identified in two-thirds of cases, and more frequently in familial forms. Doubts remain concerning the true identity of the sporadic form.
Objective:
To compare, in a genotyped population, the phenotypic expression of the disease over time in patients with familial and sporadic HCM.
Methods:
79 patients with HCM, aged 39 +/- 17.8 years at diagnosis, were followed for 12 +/- 9.5 (1-30) years and divided into two groups: G1 (familial)--68 patients (24 unrelated index patients, 44 relatives), follow-up time (FUP) 12 +/- 9.8 (1-30) years; G2 (sporadic)1 index patients (no phenotypic disease in first-degree relatives), FUP 10.8 +/- 8 (2-24) years. Fabry disease was excluded in G2. The two groups were compared regarding clinical, ECG and echocardiographic (echo) features at diagnosis and after FUP. Five sarcomere genes (MYH7, MYBPC3, TNNT2, MYL2 and TNNI3) were screened for mutations by direct sequencing, after PCR amplification with intronic sets of oligonucleotide primers designed according to the published genomic sequence of the genes.
Results:
A) Thirteen different mutations (in 3 genes) were identified in 14 index patients in G1; only in one patient in G2 was a mutation found. B) The two groups differed clinically in age at diagnosis (G1: 37.18 (4-79) years; G2: 51 +/- 14 (19-67) years; p = 0.02), and family history of sudden cardiac death (G1: 12/24 families; G2: 1/11 families; p = 0.04). Age, gender, FUP, symptoms, need for medical treatment, cardiovascular (CV) hospitalization and mortality (CV or any cause) were similar. C) ECG patterns did not differ, although significant (but similar) changes occurred in 45% (G1) and 36% (G2) of patients (p = 0.75). These changes were in the same direction, with a trend in both groups toward the development of atrial fibrillation and/or advanced conduction disease. D) Echo features (only considered in adults) were similar despite significant changes during FUP (in 68% of G1, and 82% of G2; p = 0.48). These changes also followed the same tendency: progression to a more diffuse pattern of ventricular hypertrophy (G1: 52%; G2: 73%; p = 0.33) and development of left atrial dilatation (G1: 37%; G2: 45%; p = 0.52).
Conclusions:
The similar phenotypic expression and behavior over time in familial and sporadic forms of HCM strongly indicate that the disease is one and the same. Differences in genetic findings, age at diagnosis and family history of sudden death suggest that sporadic forms may be caused by low penetrance de novo mutations in sarcomeric genes other than those associated with familial disease.
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