Shared genetic causes of cardiac hypertrophy in children and adults

Hiroyuki Morita, Heidi L. Rehm, Andres Menesses, Barbara McDonough, Amy E. Roberts, Raju Kucherlapati, Jeffrey Towbin, J. G. Seidman, Christine E. Seidman

Research output: Contribution to journalArticle

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Abstract

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 earlyonset 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 mutationpositive 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.

Original languageEnglish (US)
Pages (from-to)1899-1908
Number of pages10
JournalNew England Journal of Medicine
Volume358
Issue number18
DOIs
StatePublished - May 1 2008

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Cardiomegaly
Cardiomyopathies
Mutation
Hypertrophy
Medical History Taking
Genes
Sarcomeres
Implantable Defibrillators
Missense Mutation
Heart Transplantation
Sudden Death
Proteins

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Morita, H., Rehm, H. L., Menesses, A., McDonough, B., Roberts, A. E., Kucherlapati, R., ... Seidman, C. E. (2008). Shared genetic causes of cardiac hypertrophy in children and adults. New England Journal of Medicine, 358(18), 1899-1908. https://doi.org/10.1056/NEJMoa075463

Shared genetic causes of cardiac hypertrophy in children and adults. / Morita, Hiroyuki; Rehm, Heidi L.; Menesses, Andres; McDonough, Barbara; Roberts, Amy E.; Kucherlapati, Raju; Towbin, Jeffrey; Seidman, J. G.; Seidman, Christine E.

In: New England Journal of Medicine, Vol. 358, No. 18, 01.05.2008, p. 1899-1908.

Research output: Contribution to journalArticle

Morita, H, Rehm, HL, Menesses, A, McDonough, B, Roberts, AE, Kucherlapati, R, Towbin, J, Seidman, JG & Seidman, CE 2008, 'Shared genetic causes of cardiac hypertrophy in children and adults', New England Journal of Medicine, vol. 358, no. 18, pp. 1899-1908. https://doi.org/10.1056/NEJMoa075463
Morita H, Rehm HL, Menesses A, McDonough B, Roberts AE, Kucherlapati R et al. Shared genetic causes of cardiac hypertrophy in children and adults. New England Journal of Medicine. 2008 May 1;358(18):1899-1908. https://doi.org/10.1056/NEJMoa075463
Morita, Hiroyuki ; Rehm, Heidi L. ; Menesses, Andres ; McDonough, Barbara ; Roberts, Amy E. ; Kucherlapati, Raju ; Towbin, Jeffrey ; Seidman, J. G. ; Seidman, Christine E. / Shared genetic causes of cardiac hypertrophy in children and adults. In: New England Journal of Medicine. 2008 ; Vol. 358, No. 18. pp. 1899-1908.
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abstract = "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 earlyonset 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 mutationpositive 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.",
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AU - Morita, Hiroyuki

AU - Rehm, Heidi L.

AU - Menesses, Andres

AU - McDonough, Barbara

AU - Roberts, Amy E.

AU - Kucherlapati, Raju

AU - Towbin, Jeffrey

AU - Seidman, J. G.

AU - Seidman, Christine E.

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N2 - 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 earlyonset 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 mutationpositive 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.

AB - 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 earlyonset 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 mutationpositive 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.

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