Affiliation:
1. From the Inherited Cardiovascular Diseases Unit (J.P.K., J.E.D.), Institute of Child Health, University College London; Department of Medicine (P.S., W.J.M., P.M.E.), University College London; Great Ormond Street Hospital (J.P.K., M.T.T.E.); and The Heart Hospital (M.T.T.E., S.J., A.P., W.J.M., P.M.E.), University College London Hospitals, London, United Kingdom.
Abstract
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.
Methods and Results—
Seventy-nine 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
), the genes encoding desmin (
DES
), and the γ-2 subunit of AMP kinase (
PRKAG2
) were screened for mutations. A family history of HCM was present in 48 patients (60.8%). Forty-seven mutations (15 novel) were identified in 42 (53.2%) patients (5 patients had 2 mutations). The genes most commonly implicated were
MYH7
(48.9%) and
MYBPC3
(36.2%); mutations in
TNNT2
,
ACTC
,
MYL3
, and
TNNI3
accounted for <5% of cases each. A total of 16.7% patients with sarcomeric mutations were diagnosed before 1 year of age. There were no differences in clinical and echocardiographic features between those children with sarcomere protein gene mutations and those without or between patients with 2 mutations and those with 1 or no mutations.
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, the finding that one sixth of patients with sarcomeric disease were diagnosed in infancy suggests that current views on pathogenesis and natural history of familial HCM may have to be revised.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Genetics (clinical),Cardiology and Cardiovascular Medicine,Genetics
Cited by
166 articles.
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