Familial hypertrophic cardiomyopathy

Familial hypertrophic cardiomyopathy, also known as FHC or HCM, is a rare condition best known publicly for it's association with sudden death among young athletes. It is estimated that about 1 in 500 people have HCM and the associated thickening of the heart muscle (hypertrophy). An irregular heartbeat (arrhythmia) may lead to collapse and death during or after an athletic competition. There are usually no symptoms of a heart condition before the sudden collapse, which is also called 'sudden cardiac death' or SCD. Fortunately, SCD occurs to a very small fraction of those carrying HCM mutations.

Ordinary screening does not pick up this condition. A family history of sudden death before age 50 may be the only clue that a child or teenager needs a closer medical check before starting a sport. Most HCM appears to be inherited in a dominant fashion. Family members who carry the same genes may not have cardiac hypertrophy; those who do have hypertrophy can be treated clinically, and they will probably be advised not to participate in aerobic sports. Some cardiologists recommend that donors be tested for cardiovascular diseases such as HCM before their sperm is used for in vitro fertilization. [PMID 19843903]

Although some HCM gene panels include 50 or more genes, eleven genes comprise the vast majority of mutations seen more than once, and of those 11, nine (bolded below) have corresponding ClinGen Actionability summaries [1],[PMID 25611685]:

• MYH7 mutations are associated with 30% to 40% of FHC cases
  • rs3218713
  • rs3218714
• MYBPC3, 20-40% of FHC cases
  • rs375882485, p.Arg502Trp, up to 5% of FHC cases
  • rs397515963, p.Trp792fs, up to 3% of cases
• TNNT2, 3-5% of FHC cases
• TNNI3, fewer than 5% of FHC cases
• TPM1, 2-5% of FHC cases
  • rs28934269
  • rs28934270
• MYL3, fewer than 1% of FHC cases
• MYL2
  • rs28933099
  • rs28932774
• PRKAG2
  • rs28938173
• ACTC1
• TTN
  • rs28933405

The occurrence of different major mutations for HCM between one genetically isolated population and another leads to population-specific "most frequent" sets of HCM mutations. Among such sets are the following:

• Finland: the following 4 mutations comprise ~30% of all HCM patients [PMID 30775854]
  • rs397516005: MYBPC3‐Gln1061Ter, c.3181C>T
  • rs587782962: MYH7‐Arg1053Gln, c.3158G>A
  • rs104894503:TPM1‐Asp175Asn, c.523G>A
  • rs121913627: MYH7‐Val606Met, c.1816G>A

• Iceland: one mutation accounts for >50% of all HCM patients [PMID 25078086]
  • rs397516082: MYBPC3, c.927-2A>G

• Netherlands: one mutation accounts for 25% of all HCM patients
  • rs397515963: MYBPC3, c.2372_2373insG