Chapter 59: Hypertrophic Cardiomyopathies
A 25-year-old woman seeks to establish care for hypertrophic cardiomyopathy (HCM). Her family history is notable for multiple affected family members. Which of the following is not true regarding the genetics of HCM?
A. She is most likely to have a mutation of a sarcomeric protein
B. 5% to 10% of cases are caused by metabolic or storage disorders
C. Missense single nucleotide variants of MYH7 are associated with a dominant negative effect
D. Nonsense mutations of MYBC3 are associated with haploinsufficiency
E. Unaffected family members cannot have the causal mutation
The answer is E. (Hurst’s The Heart, 14th Edition, Chap. 59) The majority of mutations that cause HCM involve sarcomeric proteins. Between 75% and 80% involve cardiac myosin heavy chain (MYH7) and cardiac myosin binding protein C (MYBPC3). Mutations in cardiac troponin T (TNNT2), troponin I (TNNI3), α-tropomyosin (TPM1), myosin light chains (MYL2, MYL3), and cardiac actin (ACTC1) account for 15% to 20% of mutation-positive individuals (option A).1 A further 5% to 10% of cases are caused by metabolic or storage disorders (eg, Anderson-Fabry disease, mitochondrial disorders, glycogen storage diseases), neuromuscular disorders, chromosome abnormalities, and genetic syndromes such as cardio-facial-cutaneous syndromes, including Noonan and LEOPARD syndromes (option B).2 Two pathogenic mechanisms are thought to account for disease associated with mutations in cardiac sarcomere proteins. Missense single nucleotide variants (a nucleotide change that results in an amino acid being substituted by another amino acid in the protein) predominantly lead to a dominant negative effect (described as a “poison peptide” mechanism) in which the mutated protein is not destroyed but rather integrates into the sarcomere, leading to the disease phenotype; this is thought to be characteristic of MYH7 variants (option C). Alternatively, nonsense single nucleotide variants or small frameshift insertion-deletions can introduce a premature stop codon and cause haploinsufficiency as a result of nonsense mRNA-mediated decay or proteolysis of a truncated (just partially translated) protein. This mechanism is believed to be typical of the majority of MYBPC3 disease-causing mutations (option D).3 HCM is characterized by variable intra- and interfamilial expression and incomplete and age-dependent clinical penetrance. Thus, unaffected family members can be carriers of the causal mutation (option E).4
You are asked to be an expert witness at a trial for an 18-year-old man who experienced sudden death while playing basketball. Which of the following autopsy findings are not consistent with a diagnosis of HCM?
A. Asymmetric septal hypertrophy with a small left ventricular cavity