Hunting for the genetic cause in a case with familial Peripartum/Dilated cardiomyopathy using haplotype sharing analysis and exome sequencing

K.Y. Van Spaendonck-Zwarts, J.D.H. Jongbloed, P.A. Van Der Zwaag, A. Posafalvi, W. Koetsier, I.M. Van Langen, D.J. Van Veldhuisen, R.J. Sinke, M.P. Van Den Berg, J.P. Van Tintelen

OnderzoeksoutputAcademicpeer review


Background/purpose: Peripartum cardiomyopathy (PPCM) is a cause of pregnancyassociated heart failure. It typically develops during the last month of pregnancy and up to six months after delivery in women without known cardiovascular disease. Recently, we showed that some cases of PPCM are part of the spectrum of familial dilated cardiomyopathy (DCM), presenting in the peripartum period. Inherited DCM is genetically highly heterogeneous; more than 50 genes are known to be involved. We performed haplotype sharing analysis in combination with exome sequencing in a family with familial PPCM/DCM in order to identify the underlying genetic defect. Methods: Haplotype analysis (250K SNP genotypes) was used to identify shared haplotypes between affected individuals of a family with two individuals with PPCM and four individuals with DCM (index patient, two siblings, one niece, two nephews). In order to identify the causal gene, exome sequencing was performed using DNA of the index patient and one of her affected nephews. Results: Haplotype analysis revealed a shared haplotype of 71 cM on chromosome 15, containing approximately 600 genes. This region does not contain any knownDCMgene. Exome sequencing and subsequent data analysis revealed several potential pathogenic variants in this region that were shared by the index patient and her nephew. Carriership analysis in affected individuals, healthy relatives and controls is in progress. Conclusions: We identified potential pathogenic variants in a novel candidate region on chromosome 15 in a family with familial PPCM/DCM. Our results underscore the applicability of the combined approach of haplotype sharing analysis and exome sequencing for the identification of a genetic cause in familial cardiomyopathy.
Originele taal-2English
Pagina's (van-tot)216
Aantal pagina's1
TijdschriftEuropean Journal of Heart Failure, Supplement
StatusPublished - 1-mei-2011

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