|
|
Background The childhood onset of idiopathic cardiac hypertrophy that occurs without a family history of cardiomyopathy can portend a poor prognosis. Despite morphologic similarities to genetic cardiomyopathies of adulthood, the contribution of genetics to childhood-onset hypertrophy is unknown.
Methods We assessed the family and medical histories of 84 children (63 boys and 21 girls) with idiopathic cardiac hypertrophy diagnosed before 15 years of age (mean [±SD] age, 6.99±6.12 years). We sequenced eight genes: MYH7, MYBPC3, TNNT2, TNNI3, TPM1, MYL3, MYL2, and ACTC. These genes encode sarcomere proteins that, when mutated, cause adult-onset cardiomyopathies. We also sequenced PRKAG2 and LAMP2, which encode metabolic proteins; mutations in these genes can cause early-onset ventricular hypertrophy.
Results We identified mutations in 25 of 51 affected children without family histories of cardiomyopathy and in 21 of 33 affected children with familial cardiomyopathy. Among 11 of the 25 children with presumed sporadic disease, 4 carried new mutations and 7 inherited the mutations. Mutations occurred predominantly (in >75% of the children) in MYH7 and MYBPC3; significantly more MYBPC3 missense mutations were detected than occur in adult-onset cardiomyopathy (P<0.005). Neither hypertrophic severity nor contractile function correlated with familial or genetic status. Cardiac transplantation and sudden death were more prevalent among mutation-positive than among mutation-negative children; implantable cardioverter–defibrillators were more frequent (P=0.007) in children with family histories that were positive for the mutation.
Conclusions Genetic causes account for about half of presumed sporadic cases and nearly two thirds of familial cases of childhood-onset hypertrophy. Childhood-onset hypertrophy should prompt genetic analyses and family evaluations.
Source Information
From the Department of Genetics, Harvard Medical School (H.M., B.M., R.K., J.G.S., C.E.S.); the Harvard Medical School–Partners HealthCare Center for Genetics and Genomics (H.L.R., A.E.R., R.K., J.G.S.); the Howard Hughes Medical Institute and Brigham and Women's Hospital (B.M., C.E.S.); and the Department of Cardiology, Children's Hospital (A.E.R.) — all in Boston; and the Department of Pediatrics, Baylor College of Medicine, Houston (A.M., J.A.T.).
Drs. J.G. Seidman and C.E. Seidman contributed equally to this article.
This article (10.1056/NEJMoa075463) was published at www.nejm.org on April 9, 2008.
Address reprint requests to Dr. Christine Seidman at the Department of Genetics, Harvard Medical School, Rm. 256 NRB, 77 Ave. Louis Pasteur, Boston, MA 02115, or at cseidman{at}genetics.med.harvard.edu.
This article has been cited by other articles:
HOME | SUBSCRIBE | SEARCH | CURRENT ISSUE | PAST ISSUES | COLLECTIONS | PRIVACY | HELP | beta.nejm.org Comments and questions? Please contact us. The New England Journal of Medicine is owned, published, and copyrighted © 2008 Massachusetts Medical Society. All rights reserved. |
Previous
