Karin Y van Spaendonck-Zwarts1, Anna Posafalvi2, Maarten P van den Berg3, Denise Hilfiker-Kleiner4, Ilse A E Bollen5, Karen Sliwa6, Mariëlle Alders7, Rowida Almomani2, Irene M van Langen2, Peter van der Meer3, Richard J Sinke2, Jolanda van der Velden5, Dirk J Van Veldhuisen3, J Peter van Tintelen8, Jan D H Jongbloed2. 1. 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. 2. Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. 3. Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. 4. Department of Cardiology and Angiology, Medical School Hannover, Hannover, Germany. 5. Department of Physiology, VU University Medical Center, Amsterdam, the Netherlands. 6. Hatter Institute for Cardiovascular Research in Africa, Department of Medicine and IIDMM, University of Cape Town, Cape Town, South Africa. 7. Department of Genetics, Academic Medical Center, University of Amsterdam, PO Box 22660, 1100 DD, Amsterdam, the Netherlands. 8. Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands Durrer Center for Cardiogenetic Research, Utrecht, the Netherlands.
Abstract
AIM: 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. METHODS AND 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. CONCLUSION: 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. Published on behalf of the European Society of Cardiology. All rights reserved.
AIM: 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. METHODS AND 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. CONCLUSION: 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. Published on behalf of the European Society of Cardiology. All rights reserved.
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