Hypertrophic cardiomyopathy (HCM) is a highly heterogeneous disease displaying considerable interfamilial and intrafamilial phenotypic variation, including disease severity, age of onset, and disease progression. This poorly understood variance raises the possibility of genetic modifier effects, particularly in MYBPC3-associated HCM. In a large consanguineous Chinese HCM family, we identified 8 members harboring the MYBPC3 c.3624delC (p.Lys1209Serfs) disease-causing mutation, but with very disparate phenotypes. Genotyping ruled out the modifying effect of previously described variants in renin-angiotensin-aldosterone system. Afterwards, we screened for modifying variants in all known causing genes and closely related genes for cardiomyopathy and channelopathy by performing targeted next-generation sequencing. For first time, we showed that a c.1598C>T (p.Ser533Leu) mutation in voltage-dependent l-type calcium channel subunit beta-2 (CACNB2) was present in all severely affected HCM patients, but not in those moderately affected or genotype-positive phenotype-negative patients. This CACNB2 p.Ser533Leu mutation is extremely conserved in evolution, and was not found in 550 healthy controls. Our results suggest that CACNB2 is a possible candidate genetic modifier of MYBPC3-associated familial HCM, but more genetic evidence and functional experiments are needed to confirm.
机构:
Harvard Univ, Sch Med, Dept Genet, Boston, MA USA
Brigham & Womens Hosp, Cardiovasc Div, Boston, MA 02115 USA
Howard Hughes Med Inst, Boston, MA 02115 USALandspitali, IS-101 Reykjavik, Iceland
机构:
Univ Sao Paulo, Lab Genet & Mol Cardiol, Heart Inst InCor, Sao Paulo, BrazilUniv Sao Paulo, Lab Genet & Mol Cardiol, Heart Inst InCor, Sao Paulo, Brazil
Carneiro Marsiglia, Julia Daher
;
Credidio, Flavia Laghi
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Univ Sao Paulo, Lab Genet & Mol Cardiol, Heart Inst InCor, Sao Paulo, BrazilUniv Sao Paulo, Lab Genet & Mol Cardiol, Heart Inst InCor, Sao Paulo, Brazil
Credidio, Flavia Laghi
;
Mimary de Oliveira, Theo Gremen
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Univ Sao Paulo, Lab Genet & Mol Cardiol, Heart Inst InCor, Sao Paulo, BrazilUniv Sao Paulo, Lab Genet & Mol Cardiol, Heart Inst InCor, Sao Paulo, Brazil
Mimary de Oliveira, Theo Gremen
;
Reis, Rafael Ferreira
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Univ Sao Paulo, Lab Genet & Mol Cardiol, Heart Inst InCor, Sao Paulo, BrazilUniv Sao Paulo, Lab Genet & Mol Cardiol, Heart Inst InCor, Sao Paulo, Brazil
Reis, Rafael Ferreira
;
Antunes, Murillo de Oliveira
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Univ Sao Paulo, Clin Unit Cardiomyopathies, Heart Inst InCor, Sao Paulo, BrazilUniv Sao Paulo, Lab Genet & Mol Cardiol, Heart Inst InCor, Sao Paulo, Brazil
Antunes, Murillo de Oliveira
;
de Araujo, Aloir Queiroz
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Federal Univ Espirito Santo, Vitoria, ES, BrazilUniv Sao Paulo, Lab Genet & Mol Cardiol, Heart Inst InCor, Sao Paulo, Brazil
de Araujo, Aloir Queiroz
;
Pedrosa, Rodrigo Pinto
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Pronto Socorro Cardiol Pernambuco PROCAPE, Sleep & Heart Lab, Recife, PE, BrazilUniv Sao Paulo, Lab Genet & Mol Cardiol, Heart Inst InCor, Sao Paulo, Brazil
Pedrosa, Rodrigo Pinto
;
Bemfica Barbosa-Ferreira, Joao Marcos
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Federal Univ Amazonas, Manaus, Amazonas, BrazilUniv Sao Paulo, Lab Genet & Mol Cardiol, Heart Inst InCor, Sao Paulo, Brazil
Bemfica Barbosa-Ferreira, Joao Marcos
;
Mady, Charles
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Univ Sao Paulo, Clin Unit Cardiomyopathies, Heart Inst InCor, Sao Paulo, BrazilUniv Sao Paulo, Lab Genet & Mol Cardiol, Heart Inst InCor, Sao Paulo, Brazil
Mady, Charles
;
Krieger, Jose Eduardo
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Univ Sao Paulo, Lab Genet & Mol Cardiol, Heart Inst InCor, Sao Paulo, BrazilUniv Sao Paulo, Lab Genet & Mol Cardiol, Heart Inst InCor, Sao Paulo, Brazil
Krieger, Jose Eduardo
;
Arteaga-Fernandez, Edmundo
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Univ Sao Paulo, Clin Unit Cardiomyopathies, Heart Inst InCor, Sao Paulo, BrazilUniv Sao Paulo, Lab Genet & Mol Cardiol, Heart Inst InCor, Sao Paulo, Brazil
Arteaga-Fernandez, Edmundo
;
Pereira, Alexandre da Costa
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Univ Sao Paulo, Lab Genet & Mol Cardiol, Heart Inst InCor, Sao Paulo, BrazilUniv Sao Paulo, Lab Genet & Mol Cardiol, Heart Inst InCor, Sao Paulo, Brazil
机构:
Harvard Univ, Sch Med, Dept Genet, Boston, MA USA
Brigham & Womens Hosp, Cardiovasc Div, Boston, MA 02115 USA
Howard Hughes Med Inst, Boston, MA 02115 USALandspitali, IS-101 Reykjavik, Iceland
机构:
Univ Sao Paulo, Lab Genet & Mol Cardiol, Heart Inst InCor, Sao Paulo, BrazilUniv Sao Paulo, Lab Genet & Mol Cardiol, Heart Inst InCor, Sao Paulo, Brazil
Carneiro Marsiglia, Julia Daher
;
Credidio, Flavia Laghi
论文数: 0引用数: 0
h-index: 0
机构:
Univ Sao Paulo, Lab Genet & Mol Cardiol, Heart Inst InCor, Sao Paulo, BrazilUniv Sao Paulo, Lab Genet & Mol Cardiol, Heart Inst InCor, Sao Paulo, Brazil
Credidio, Flavia Laghi
;
Mimary de Oliveira, Theo Gremen
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h-index: 0
机构:
Univ Sao Paulo, Lab Genet & Mol Cardiol, Heart Inst InCor, Sao Paulo, BrazilUniv Sao Paulo, Lab Genet & Mol Cardiol, Heart Inst InCor, Sao Paulo, Brazil
Mimary de Oliveira, Theo Gremen
;
Reis, Rafael Ferreira
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h-index: 0
机构:
Univ Sao Paulo, Lab Genet & Mol Cardiol, Heart Inst InCor, Sao Paulo, BrazilUniv Sao Paulo, Lab Genet & Mol Cardiol, Heart Inst InCor, Sao Paulo, Brazil
Reis, Rafael Ferreira
;
Antunes, Murillo de Oliveira
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h-index: 0
机构:
Univ Sao Paulo, Clin Unit Cardiomyopathies, Heart Inst InCor, Sao Paulo, BrazilUniv Sao Paulo, Lab Genet & Mol Cardiol, Heart Inst InCor, Sao Paulo, Brazil
Antunes, Murillo de Oliveira
;
de Araujo, Aloir Queiroz
论文数: 0引用数: 0
h-index: 0
机构:
Federal Univ Espirito Santo, Vitoria, ES, BrazilUniv Sao Paulo, Lab Genet & Mol Cardiol, Heart Inst InCor, Sao Paulo, Brazil
de Araujo, Aloir Queiroz
;
Pedrosa, Rodrigo Pinto
论文数: 0引用数: 0
h-index: 0
机构:
Pronto Socorro Cardiol Pernambuco PROCAPE, Sleep & Heart Lab, Recife, PE, BrazilUniv Sao Paulo, Lab Genet & Mol Cardiol, Heart Inst InCor, Sao Paulo, Brazil
Pedrosa, Rodrigo Pinto
;
Bemfica Barbosa-Ferreira, Joao Marcos
论文数: 0引用数: 0
h-index: 0
机构:
Federal Univ Amazonas, Manaus, Amazonas, BrazilUniv Sao Paulo, Lab Genet & Mol Cardiol, Heart Inst InCor, Sao Paulo, Brazil
Bemfica Barbosa-Ferreira, Joao Marcos
;
Mady, Charles
论文数: 0引用数: 0
h-index: 0
机构:
Univ Sao Paulo, Clin Unit Cardiomyopathies, Heart Inst InCor, Sao Paulo, BrazilUniv Sao Paulo, Lab Genet & Mol Cardiol, Heart Inst InCor, Sao Paulo, Brazil
Mady, Charles
;
Krieger, Jose Eduardo
论文数: 0引用数: 0
h-index: 0
机构:
Univ Sao Paulo, Lab Genet & Mol Cardiol, Heart Inst InCor, Sao Paulo, BrazilUniv Sao Paulo, Lab Genet & Mol Cardiol, Heart Inst InCor, Sao Paulo, Brazil
Krieger, Jose Eduardo
;
Arteaga-Fernandez, Edmundo
论文数: 0引用数: 0
h-index: 0
机构:
Univ Sao Paulo, Clin Unit Cardiomyopathies, Heart Inst InCor, Sao Paulo, BrazilUniv Sao Paulo, Lab Genet & Mol Cardiol, Heart Inst InCor, Sao Paulo, Brazil
Arteaga-Fernandez, Edmundo
;
Pereira, Alexandre da Costa
论文数: 0引用数: 0
h-index: 0
机构:
Univ Sao Paulo, Lab Genet & Mol Cardiol, Heart Inst InCor, Sao Paulo, BrazilUniv Sao Paulo, Lab Genet & Mol Cardiol, Heart Inst InCor, Sao Paulo, Brazil