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Sudden cardiac death in familial hypertrophic cardiomyopathy: are "benign" mutations really benign?
1Department of Molecular and Clinical Genetics, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.
Insights
Familial hypertrophic cardiomyopathy (FHC) mutations are classified as benign or malignant. However, a "benign" mutation caused early sudden cardiac death in one family, challenging current classifications.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Genetic Medicine
Background:
- Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant condition linked to left ventricular hypertrophy and sudden cardiac death.
- Mutations in the cardiac beta-myosin heavy chain gene are implicated in FHC, with some classified as 'benign' or 'malignant'.
- Genotype-phenotype correlations are crucial for understanding FHC's clinical variability.
Observation:
- A specific family (family L) presented with early sudden cardiac death, contrary to the expected 'benign' nature of their identified mutation.
- Clinical, electrocardiographic, and echocardiographic assessments were performed on family members.
- DNA analysis identified the Val606Met missense mutation in the cardiac beta-myosin heavy chain gene.
Findings:
- The Val606Met mutation, previously considered 'benign' with low penetrance and normal lifespan, exhibited a more malignant phenotype in family L.
- One affected individual in family L died suddenly at age 14 during exercise.
- This case highlights significant variability in clinical presentation despite a shared genetic mutation.
Implications:
- The classification of FHC mutations as strictly 'benign' or 'malignant' may be an oversimplification.
- Caution is advised when interpreting genotype-phenotype correlations due to limited family data.
- Further research is needed to refine the understanding of FHC mutation behavior and clinical risk stratification.
Abstract:
Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant disorder characterised predominantly by left ventricular hypertrophy and sudden cardiac death. Mutations in the cardiac beta-myosin heavy chain gene have been identified in several families and designated as "benign" or "malignant". We describe a family (family L) with a "benign" mutation in which early sudden cardiac death has occurred. The family was studied by clinical, electrocardiographic and echocardiographic assessment. DNA analysis involved screening for the six most common cardiac beta-myosin heavy chain gene mutations using allele specific oligonucleotide probes and restriction enzyme analysis. The Val606Met missense mutation was found. This mutation has been described in four families as being "benign" since it was associated with low penetrance and a near normal life span. Sudden cardiac death was an infrequent finding. In contrast, family L has a more malignant clinical picture with one sudden death in three affected individuals. The proband died suddenly at age 14 years during exercise. Designating gene mutations in FHC as benign or malignant has major clinical implications. As these mutations have only been described in a limited number of families, caution needs to be taken when interpreting genotype-phenotype correlations in this disorder.