Detailed list and characteristics of putative mutations.

<p>Detailed list and characteristics of putative mutations.</p

Pedigree and qPCR results from family A and U.

<p>qPCR showed a ~50% reduction of exon 4 <i>PKP2</i> DNA in affected individuals A.1, A.2 and A3 compared to the healthy father A.4 (used as a control). <i>PKP2</i> DNA quantification was normal in exon 3 and 5 for all individuals. In family U, qPCR showed a 50% reduction of <i>PKP2</i> DNA in exon 4 and 13 in affected individuals U.1 and U.2 and their mother U.3 whereas it was comparable to controls in father U.4. Individuals U.1 and U.2 also carried the p.Gly712Arg (G712R) rare <i>PKP2</i> variant that falsely appeared in the Sanger chromatogram as homozygous (HmZ) instead of hemizygous because of the absence of the other <i>PKP2</i> allele. This variant was inherited from the father, in absence of familial history of consanguinity, in whom it appeared heterozygous(Htz).</p

Clinical data of probands and relatives carrying a large <i>PKP2</i> heterozygous deletion.

<p>Clinical data of probands and relatives carrying a large <i>PKP2</i> heterozygous deletion.</p

Schematic view of <i>PKP2</i> deletions.

<p>Schematic view of <i>PKP2</i> deletions.</p

Representative immunolocalization of intercalated disc proteins in ARVD/C patient right ventricles.

<p>Representative pictures of plakophilin-2, β-catenin, plakoglobin, desmoglein-2 and desmocollin-2 labeling are shown (in green). Cardiac myosin-binding protein C (cMyBP-C) and α-actinin-2 (both red labeling) were used as cardiomyocyte specific markers. The figure shows heart tissue from two patients with ARVD/C compared to a representative (non ARVD/C) control.</p

Quantitative immunoblotting of selected intercalated disk proteins; plakophilin-2, plakoglobin and β-catenin.

<p>Representative immunoblots obtained for (a) plakoglobin (left Ventricle), (b) β-catenin (septum) and (c) plakophilin-2 (septum). Bar graphs indicate the mean ± SEM following quantification of protein signals from all blots from the seven patient tissue samples and all compartments after normalization to the cardiac protein α-actinin-2 (ACTN2) or cardiac myosin-binding protein C (cMyBP-C) and to the control with the strongest signal level. NS for <i>p</i>>0.05, Mann Whitney test.</p

Quantitative RT-PCR analysis of <i>DSG2</i> and <i>DSC2</i> relative to <i>ACTN2</i> mRNA transcripts.

<p>Relative quantification was performed using RNA isolated from the septum or right ventricle of heart samples. Bar graphs show the mean ± SEM of six samples (2^-ΔΔCT method). <i>p</i>>0.05, Mann Whitney Test.</p

Electron microscopy of heart samples from ARVD/C 6.

<p>The electronic microscopy study of heart tissue from the p.Arg46Trp mutation-carrier (ARVD/C6) showed the presence of small desmosomes (white arrows) associated with abnormal inter-membrane vacuoles (black stars) in both ventricles (LV; left ventricle, RV; right ventricles).</p

Gene-level association analysis of genes identified in the SNP-level analysis

<p>Gene-level association analysis of genes identified in the SNP-level analysis</p

DCM gene set association analysis

<p>DCM gene set association analysis</p