These studies help to explain how sarcomere protein gene mutations cause the clinical features associated with FHC and to explain the variation in clinical features that is seen among affected individuals bearing the same mutation. FHC is characterized by unexplained myocardial hypertrophy. Clinical manifestations of the disorder can include syncope, arrhythmias, congestive heart failure, and sudden death. All of the mutations that have been identified to date are missense mutations or splicing mutations. Whether the FHC-causing mutations functionally inactivate the disease gene or encode poison polypeptides that act in a dominant fashion remains uncertain.
Some mutations cause severe disease, and others cause more benign forms of the disease.
This mutation has caused FHC in more than 20 members of a large family from eastern Canada. The disease is as or more severe in these individuals than in individuals with any other FHC-causing mutation. However, a few of these Arg403Gln-bearing individuals have somewhat milder cardiac hypertrophy than other affected individuals in the same family. The average life expectancy of individuals bearing this mutation is about 35 years. We have made mice bearing mutations in these two different genes.