TY - JOUR
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.
N1 - Funding Information:
This work was supported by the Dutch Foundation for Scientific Research (ZonMW‐VICI 91819613 to CACO); the Princess Beatrix Muscle Foundation (W.OR17‐08 to CACO, NV, and BvE); Amsterdam Cardiovascular Sciences (post‐doc grant to JMdW); Dutch Heart Foundation (Crazy Idea Grant to JMdW); Dutch Foundation for Scientific Research (ZonMW‐VENI 09150161910168 to JMdW); the Netherlands Cardiovascular Research Initiative, an initiative supported by the Dutch Heart Foundation (CardioVasculair Onderzoek Nederland (CVON); PREDICT2 2018‐30, eDETECT 2015‐12 and Double‐Dose 2020B005 to JPvT).
Publisher Copyright:
© 2022 The Authors. Human Mutation published by Wiley Periodicals LLC.
PY - 2022/12/1
Y1 - 2022/12/1
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.
KW - KBTBD13
KW - NEM6
KW - cardiomyopathy
KW - congenital myopathy
UR - https://www.scopus.com/pages/publications/85142334342
U2 - 10.1002/humu.24499
DO - 10.1002/humu.24499
M3 - Article
C2 - 36335629
SN - 1059-7794
VL - 43
SP - 1860
EP - 1865
JO - Human mutation
JF - Human mutation
IS - 12
ER -
SDG 3 Good Health and Well-being