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Novel Genetic Variants in BAG3 and TNNT2 in a Swedish Family with a History of Dilated Cardiomyopathy and Sudden Cardiac Death
Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus. Lund University, Sweden.
Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.ORCID iD: 0000-0002-3756-207X
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2017 (English)In: Pediatric Cardiology, ISSN 0172-0643, E-ISSN 1432-1971, Vol. 38, no 6, p. 1262-1268Article in journal (Refereed) Published
Abstract [en]

Familial dilated cardiomyopathy is a rare cause of dilated cardiomyopathy (DCM), especially in childhood. Our aim was to describe the clinical course and the genetic variants in a family where the proband was a four-month-old infant presenting with respiratory problems due to DCM. In the family, there was a strong family history of DCM and sudden cardiac death in four generations. DNA was analyzed initially from the deceased girl using next-generation sequencing including 50 genes involved in cardiomyopathy. A cascade family screening was performed in the family after identification of the TNNT2 and the BAG3 variants in the proband. The first-degree relatives underwent clinical examination including biochemistry panel, cardiac ultrasound, Holter ECG, exercise stress test, and targeted genetic testing. The index patient presented with advanced DCM. After a severe clinical course, the baby had external left ventricular assist as a bridge to heart transplantation. 1.5 months after transplantation, the baby suffered sudden cardiac death (SCD) despite maximal treatment in the pediatric intensive care unit. The patient was shown to carry two heterozygous genetic variants in the TNNT2 gene [TNNT2 c.518G amp;gt; A(p.Arg173Gln)] and BAG3 [BAG3 c.785C amp;gt; T(p.Ala262Val)]. Two of the screened individuals (two females) appeared to carry both the familial variants. All the individuals carrying the TNNT2 variant presented with DCM, the two adult patients had mild or moderate symptoms of heart failure and reported palpitations but no syncope or presyncopal attacks prior to the genetic diagnosis. The female carriers of TNNT2 and BAG3 variants had more advanced DCM. In the family history, there were three additional cases of SCD due to DCM, diagnosed by autopsy, but no genetic analysis was possible in these cases. Our findings suggest that the variants in TNNT2 and BAG3 are associated with a high propensity to life-threatening cardiomyopathy presenting from childhood and young adulthood.

Place, publisher, year, edition, pages
SPRINGER , 2017. Vol. 38, no 6, p. 1262-1268
Keywords [en]
Familial DCM; DCM; SCD; BAG3; TNNT2
National Category
Pediatrics
Identifiers
URN: urn:nbn:se:liu:diva-139519DOI: 10.1007/s00246-017-1655-0ISI: 000405798800025PubMedID: 28669108OAI: oai:DiVA.org:liu-139519DiVA, id: diva2:1130195
Note

Funding Agencies|Region Ostergotland (ALF); FORSS (Medical Research Council of Southeast Sweden); Samariten Foundation, Stockholm

Available from: 2017-08-08 Created: 2017-08-08 Last updated: 2018-05-03

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Fernlund, Eva

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Fernlund, EvaWålinder Österberg, AnnaKuchinskaya, EkaterinaGustafsson, MikaelJansson, KjellGunnarsson, Cecilia
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Division of Children's and Women's healthFaculty of Medicine and Health SciencesH.K.H. Kronprinsessan Victorias barn- och ungdomssjukhusDivision of Cell BiologyDivision of Cardiovascular MedicineDepartment of Cardiology in LinköpingClinical geneticsCenter for Business support and Development
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