KBTBD13 is a novel cardiomyopathy gene

Josine M. de Winter; Karlijn Bouman; Joshua Strom; Mei Methawasin; Jan D.H. Jongbloed; Wilma van der Roest; Jan van Wijngaarden; Janneke Timmermans; Robin Nijveldt; Frederik van den Heuvel; Erik Jan Kamsteeg; Baziel G. van Engelen; Ricardo Galli; Sylvia J.P. Bogaards; Reinier A. Boon; Robbert J. van der Pijl; Henk Granzier; Bobby Koeleman; Ahmad S. Amin; Jolanda van der Velden; J. Peter van Tintelen; Maarten P. van den Berg; Karin Y. van Spaendonck-Zwarts; Nicol C. Voermans; Coen A.C. Ottenheijm

doi:10.1002/humu.24499

KBTBD13 is a novel cardiomyopathy gene

Josine M. de Winter, Karlijn Bouman, Joshua Strom, Mei Methawasin, Jan D.H. Jongbloed, Wilma van der Roest, Jan van Wijngaarden, Janneke Timmermans, Robin Nijveldt, Frederik van den Heuvel, Erik Jan Kamsteeg, Baziel G. van Engelen, Ricardo Galli, Sylvia J.P. Bogaards, Reinier A. Boon, Robbert J. van der Pijl, Henk Granzier, Bobby Koeleman, Ahmad S. Amin, Jolanda van der VeldenJ. Peter van Tintelen, Maarten P. van den Berg, Karin Y. van Spaendonck-Zwarts, Nicol C. Voermans, Coen A.C. Ottenheijm

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

KBTBD13 variants cause nemaline myopathy type 6 (NEM6). The majority of NEM6 patients harbors the Dutch founder variant, c.1222C>T, p.Arg408Cys (KBTBD13 p.R408C). Although KBTBD13 is expressed in cardiac muscle, cardiac involvement in NEM6 is unknown. Here, we constructed pedigrees of three families with the KBTBD13 p.R408C variant. In 65 evaluated patients, 12% presented with left ventricle dilatation, 29% with left ventricular ejection fraction< 50%, 8% with atrial fibrillation, 9% with ventricular tachycardia, and 20% with repolarization abnormalities. Five patients received an implantable cardioverter defibrillator, three cases of sudden cardiac death were reported. Linkage analysis confirmed cosegregation of the KBTBD13 p.R408C variant with the cardiac phenotype. Mouse studies revealed that (1) mice harboring the Kbtbd13 p.R408C variant display mild diastolic dysfunction; (2) Kbtbd13-deficient mice have systolic dysfunction. Hence, (1) KBTBD13 is associated with cardiac dysfunction and cardiomyopathy; (2) KBTBD13 should be added to the cardiomyopathy gene panel; (3) NEM6 patients should be referred to the cardiologist.

Original language	English (US)
Pages (from-to)	1860-1865
Number of pages	6
Journal	Human Mutation
Volume	43
Issue number	12
DOIs	https://doi.org/10.1002/humu.24499
State	Published - Dec 2022

Keywords

KBTBD13
NEM6
cardiomyopathy
congenital myopathy

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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10.1002/humu.24499

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de Winter, J. M., Bouman, K., Strom, J., Methawasin, M., Jongbloed, J. D. H., van der Roest, W., Wijngaarden, J. V., Timmermans, J., Nijveldt, R., van den Heuvel, F., Kamsteeg, E. J., van Engelen, B. G., Galli, R., Bogaards, S. J. P., Boon, R. A., van der Pijl, R. J., Granzier, H., Koeleman, B., Amin, A. S., ... Ottenheijm, C. A. C. (2022). KBTBD13 is a novel cardiomyopathy gene. Human Mutation, 43(12), 1860-1865. https://doi.org/10.1002/humu.24499

de Winter, JM, Bouman, K, Strom, J, Methawasin, M, Jongbloed, JDH, van der Roest, W, Wijngaarden, JV, Timmermans, J, Nijveldt, R, van den Heuvel, F, Kamsteeg, EJ, van Engelen, BG, Galli, R, Bogaards, SJP, Boon, RA, van der Pijl, RJ, Granzier, H, Koeleman, B, Amin, AS, van der Velden, J, van Tintelen, JP, van den Berg, MP, van Spaendonck-Zwarts, KY, Voermans, NC & Ottenheijm, CAC 2022, 'KBTBD13 is a novel cardiomyopathy gene', Human Mutation, vol. 43, no. 12, pp. 1860-1865. https://doi.org/10.1002/humu.24499

@article{89ed4844f44f4ef6b35fe6ac94d24100,

title = "KBTBD13 is a novel cardiomyopathy gene",

abstract = "KBTBD13 variants cause nemaline myopathy type 6 (NEM6). The majority of NEM6 patients harbors the Dutch founder variant, c.1222C>T, p.Arg408Cys (KBTBD13 p.R408C). Although KBTBD13 is expressed in cardiac muscle, cardiac involvement in NEM6 is unknown. Here, we constructed pedigrees of three families with the KBTBD13 p.R408C variant. In 65 evaluated patients, 12% presented with left ventricle dilatation, 29% with left ventricular ejection fraction< 50%, 8% with atrial fibrillation, 9% with ventricular tachycardia, and 20% with repolarization abnormalities. Five patients received an implantable cardioverter defibrillator, three cases of sudden cardiac death were reported. Linkage analysis confirmed cosegregation of the KBTBD13 p.R408C variant with the cardiac phenotype. Mouse studies revealed that (1) mice harboring the Kbtbd13 p.R408C variant display mild diastolic dysfunction; (2) Kbtbd13-deficient mice have systolic dysfunction. Hence, (1) KBTBD13 is associated with cardiac dysfunction and cardiomyopathy; (2) KBTBD13 should be added to the cardiomyopathy gene panel; (3) NEM6 patients should be referred to the cardiologist.",

keywords = "KBTBD13, NEM6, cardiomyopathy, congenital myopathy",

author = "{de Winter}, {Josine M.} and Karlijn Bouman and Joshua Strom and Mei Methawasin and Jongbloed, {Jan D.H.} and {van der Roest}, Wilma and Wijngaarden, {Jan van} and Janneke Timmermans and Robin Nijveldt and {van den Heuvel}, Frederik and Kamsteeg, {Erik Jan} and {van Engelen}, {Baziel G.} and Ricardo Galli and Bogaards, {Sylvia J.P.} and Boon, {Reinier A.} and {van der Pijl}, {Robbert J.} and Henk Granzier and Bobby Koeleman and Amin, {Ahmad S.} and {van der Velden}, Jolanda and {van Tintelen}, {J. Peter} and {van den Berg}, {Maarten P.} and {van Spaendonck-Zwarts}, {Karin Y.} and Voermans, {Nicol C.} and Ottenheijm, {Coen A.C.}",

note = "Publisher Copyright: {\textcopyright} 2022 The Authors. Human Mutation published by Wiley Periodicals LLC.",

year = "2022",

month = dec,

doi = "10.1002/humu.24499",

language = "English (US)",

volume = "43",

pages = "1860--1865",

journal = "Human Mutation",

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T1 - KBTBD13 is a novel cardiomyopathy gene

AU - de Winter, Josine M.

AU - Bouman, Karlijn

AU - Strom, Joshua

AU - Methawasin, Mei

AU - Jongbloed, Jan D.H.

AU - van der Roest, Wilma

AU - Wijngaarden, Jan van

AU - Timmermans, Janneke

AU - Nijveldt, Robin

AU - van den Heuvel, Frederik

AU - Kamsteeg, Erik Jan

AU - van Engelen, Baziel G.

AU - Galli, Ricardo

AU - Bogaards, Sylvia J.P.

AU - Boon, Reinier A.

AU - van der Pijl, Robbert J.

AU - Granzier, Henk

AU - Koeleman, Bobby

AU - Amin, Ahmad S.

AU - van der Velden, Jolanda

AU - van Tintelen, J. Peter

AU - van den Berg, Maarten P.

AU - van Spaendonck-Zwarts, Karin Y.

AU - Voermans, Nicol C.

AU - Ottenheijm, Coen A.C.

PY - 2022/12

Y1 - 2022/12

N2 - KBTBD13 variants cause nemaline myopathy type 6 (NEM6). The majority of NEM6 patients harbors the Dutch founder variant, c.1222C>T, p.Arg408Cys (KBTBD13 p.R408C). Although KBTBD13 is expressed in cardiac muscle, cardiac involvement in NEM6 is unknown. Here, we constructed pedigrees of three families with the KBTBD13 p.R408C variant. In 65 evaluated patients, 12% presented with left ventricle dilatation, 29% with left ventricular ejection fraction< 50%, 8% with atrial fibrillation, 9% with ventricular tachycardia, and 20% with repolarization abnormalities. Five patients received an implantable cardioverter defibrillator, three cases of sudden cardiac death were reported. Linkage analysis confirmed cosegregation of the KBTBD13 p.R408C variant with the cardiac phenotype. Mouse studies revealed that (1) mice harboring the Kbtbd13 p.R408C variant display mild diastolic dysfunction; (2) Kbtbd13-deficient mice have systolic dysfunction. Hence, (1) KBTBD13 is associated with cardiac dysfunction and cardiomyopathy; (2) KBTBD13 should be added to the cardiomyopathy gene panel; (3) NEM6 patients should be referred to the cardiologist.

AB - KBTBD13 variants cause nemaline myopathy type 6 (NEM6). The majority of NEM6 patients harbors the Dutch founder variant, c.1222C>T, p.Arg408Cys (KBTBD13 p.R408C). Although KBTBD13 is expressed in cardiac muscle, cardiac involvement in NEM6 is unknown. Here, we constructed pedigrees of three families with the KBTBD13 p.R408C variant. In 65 evaluated patients, 12% presented with left ventricle dilatation, 29% with left ventricular ejection fraction< 50%, 8% with atrial fibrillation, 9% with ventricular tachycardia, and 20% with repolarization abnormalities. Five patients received an implantable cardioverter defibrillator, three cases of sudden cardiac death were reported. Linkage analysis confirmed cosegregation of the KBTBD13 p.R408C variant with the cardiac phenotype. Mouse studies revealed that (1) mice harboring the Kbtbd13 p.R408C variant display mild diastolic dysfunction; (2) Kbtbd13-deficient mice have systolic dysfunction. Hence, (1) KBTBD13 is associated with cardiac dysfunction and cardiomyopathy; (2) KBTBD13 should be added to the cardiomyopathy gene panel; (3) NEM6 patients should be referred to the cardiologist.

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KW - cardiomyopathy

KW - congenital myopathy

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ER -

KBTBD13 is a novel cardiomyopathy gene

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