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Induced pluripotent stem cells (iPSC) represent an appealing cell source to develop disease-modeling assays, drug testing assays and cell-based replacement therapies especially for cardiac disorders.The development of efficient protocols to generate pure populations of cardiac myocytes is a prerequisite to provide reproducible, robust and valid assays. Different techniques have been recently proposed that allow production of high-yield high-quality cardiomyocytes. In addition, the newly developed genome-editing techniques offer multiple opportunities to manipulate the genome of patient-specific iPSC thus generating syngeneic iPSC lines. Genome-editing techniques will also allow engineering of iPSC to make them suitable for replacement therapies.Since their discovery, iPSCs have shown promise to revolutionize the way human diseases are studied. During the last years, different protocols have been developed to achieve reproducible and efficient differentiation of iPSCs including in cardiac and vascular cells. The recent introduction of the genome-editing techniques now allow targeted manipulation of the genome of patient-specific and control iPSCs lines. This approach would help to address a couple of current limitations, including the generation of isogenic lines for disease modeling and of clinical-grade lines for replacement therapy.

Aims Dilated cardiomyopathy (DCM) is an important cause of heart failure with a strong familial component. We performed an exome-wide array-based association study (EWAS) to assess the contribution of missense variants to sporadic DCM. Methods and results Overall, 116,855 single nucleotide variants (SNVs) were analyzed in 2796 DCM patients and 6877 control subjects from 6 populations of European ancestry. We confirmed two previously identified associations with SNVs in BAG3 and ZBTB17 and discovered six novel DCM-associated loci (Q-value Conclusion We identified eight loci independently associated with sporadic DCM. Overlap between susceptibility gene and familial DCM causing gene suggests a continuum of effect size, or penetrance, in DCM associated molecular variants. The functions of the best candidate genes at these loci also suggest that proteostasis regulation might play a role in DCM pathophysiology.

Background Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is an inherited heart muscle disease mainly caused by desmosomal gene mutations. PKP2 is the major ARVC causing-gene and presents frequent truncating mutations leading to haploinsufficiency. Large deletions of PKP2 , which are not detected with standard Sanger sequencing, have been reported in few ARVC patients. This study aimed to compare different screening methods for detection of large PKP2 deletions and to determine their prevalence in the ARVC population. Methods We included 19 patients and 1 family of 4 members with a diagnosis of familial ARVC, which were screened negative by Sanger sequencing. A whole exome capture was performed with the Agilent SureSelect ® all Exon V5 50Mb kit and sequenced with a HiSeq2000 ® . The depth of coverage distribution of each PKP2 exon was analysed and compared to the mean coverage distribution of the cohort. Heterozygous PKP2 deletion was suspected in presence of coverage ® was performed in 50 supplementary unrelated ARVC probands and in our cohort to compare the accuracy of this method with exome sequencing. Results The analysis of coverage depth identified one patient with a heterozygous deletion of the whole PKP2 gene and in the family, a heterozygous deletion of PKP2 exon 4 which cosegregrated(Figure). qPCR and MLPA ® analysis confirmed this result. The prevalence of large deletions of PKP2 in gene negative familial ARVC was 10,5%. MLPA ® identified large PKP2 deletions in two additional unrelated probands. Conclusion Our study shows that large PKP2 deletions are not infrequent in ARVC and should therefore be screened in patients with unidentified mutations. This study demonstrates that whole exome sequencing is an accurate technique to detect such mutations. However, MLPA ® appears as an efficient and costless technique in this purpose. Download full-size image Figure: Heterozygous PKP2 exon 4 deletion in the family