title: Titin gene mutations are common in families with both peripartum cardiomyopathy and dilated cardiomyopathy.
abstract: OBJECTIVE
  Peripartum cardiomyopathy (PPCM) can be an initial manifestation of familial dilated cardiomyopathy (DCM). We aimed to identify mutations in families that could underlie their PPCM and DCM.
  
  
  RESULTS
  We collected 18 families with PPCM and DCM cases from various countries. We studied the clinical characteristics of the PPCM patients and affected relatives, and applied a targeted next-generation sequencing (NGS) approach to detect mutations in 48 genes known to be involved in inherited cardiomyopathies. We identified 4 pathogenic mutations in 4 of 18 families (22%): 3 in TTN and 1 in BAG3. In addition, we identified 6 variants of unknown clinical significance that may be pathogenic in 6 other families (33%): 4 in TTN, 1 in TNNC1, and 1 in MYH7. Measurements of passive force in single cardiomyocytes and titin isoform composition potentially support an upgrade of one of the variants of unknown clinical significance in TTN to a pathogenic mutation. Only 2 of 20 PPCM cases in these families showed the recovery of left ventricular function.
  
  
  CONCLUSIONS
  Targeted NGS shows that potentially causal mutations in cardiomyopathy-related genes are common in families with both PPCM and DCM. This supports the earlier finding that PPCM can be part of familial DCM. Our cohort is particularly characterized by a high proportion of TTN mutations and a low recovery rate in PPCM cases.
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands Department of Genetics, Academic Medical Center, University of Amsterdam, PO Box 22660, 1100 DD, Amsterdam, the Netherlands k.y.vanspaendonck@amc.nl.
authors.forename: Karin Y
authors.initials: KY
authors.lastname: van Spaendonck-Zwarts
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Anna
authors.initials: A
authors.lastname: Posafalvi
authors.affiliation: Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Maarten P
authors.initials: MP
authors.lastname: van den Berg
authors.affiliation: Department of Cardiology and Angiology, Medical School Hannover, Hannover, Germany.
authors.forename: Denise
authors.initials: D
authors.lastname: Hilfiker-Kleiner
authors.affiliation: Department of Physiology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Ilse A E
authors.initials: IA
authors.lastname: Bollen
authors.affiliation: Hatter Institute for Cardiovascular Research in Africa, Department of Medicine and IIDMM, University of Cape Town, Cape Town, South Africa.
authors.forename: Karen
authors.initials: K
authors.lastname: Sliwa
authors.affiliation: Department of Genetics, Academic Medical Center, University of Amsterdam, PO Box 22660, 1100 DD, Amsterdam, the Netherlands.
authors.forename: Mariëlle
authors.initials: M
authors.lastname: Alders
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Rowida
authors.initials: R
authors.lastname: Almomani
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Irene M
authors.initials: IM
authors.lastname: van Langen
authors.affiliation: Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: van der Meer
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Sinke
authors.affiliation: Department of Physiology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Jolanda
authors.initials: J
authors.lastname: van der Velden
authors.affiliation: Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: Van Veldhuisen
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands Durrer Center for Cardiogenetic Research, Utrecht, the Netherlands.
authors.forename: J Peter
authors.initials: JP
authors.lastname: van Tintelen
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Jan D H
authors.initials: JD
authors.lastname: Jongbloed
mesh_terms: D000328:Adult; D009202:Cardiomyopathies / Q000235:genetics*; D002311:Cardiomyopathy, Dilated / Q000235:genetics; D015331:Cohort Studies; D064211:Connectin / Q000235:genetics*; D005260:Female; D006801:Humans; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D011644:Puerperal Disorders / Q000235:genetics*; D050796:STAT3 Transcription Factor / Q000235:genetics; D055815:Young Adult
chemical_list: D064211:Connectin; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human
keywords: Cardiomyopathy; Genetics; Peripartum cardiomyopathy; Pregnancy; Titin