Authors:
J.P. Kaski¹, P. Syrris¹, M.T. Tome Esteban², S. Jenkins², A. Pantazis², J.E. Deanfield¹, W.J. Mckenna², P.M. Elliott², ¹University College London - London - United Kingdom, ²The Heart Hospital - London - United Kingdom,

Background: Hypertrophic cardiomyopathy (HCM) in infants and children is thought to be commonly associated with metabolic disorders and malformation syndromes. Familial disease caused by mutations in cardiac sarcomere protein genes, which accounts for most cases in adolescents and adults, is believed to be a very rare cause of HCM in young children, but this hypothesis has not been systematically tested.

Methods: Eighty consecutive patients diagnosed with HCM aged 13 years or younger underwent detailed clinical and genetic evaluation. The protein-coding sequences of 9 sarcomere protein genes (MYH7, MYBPC3, TNNI3, TNNT2, TPM1, MYL2, MYL3, ACTC, and TNNC1) and the genes encoding desmin (DES) and the gamma-2 subunit of adenosine monophosphate kinase (PRKAG2) were screened for mutations.

Results: A family history of HCM was present in 48 patients (60%). Forty-eight mutations were identified in 43 (53.8%) patients (5 patients had two mutations), including 15 novel mutations. The genes most commonly implicated were MYH7 (47.9%) and MYBPC3 (37.5%); mutations in TNNT2, ACTC, MYL3 and TNNI3 accounted for less than 5% of cases each. 19% of patients with sarcomere protein gene mutations were first diagnosed with HCM below the age of 1.

Conclusions: This study shows that familial disease is common among infants and children with HCM and that, in most cases, disease is caused by mutations in cardiac sarcomere protein genes. The major implication is that all first-degree relatives of any child diagnosed with HCM should be offered screening. Furthermore, these results suggest that current views on the pathogenesis of childhood HCM may need to be revised, and current family screening guidelines should be updated to include even very young infants and children.