Role of the diphosphine chelate in emissive, charge-neutral iridium(III) complexes.

A class of neutral tris-bidentate Ir(III) metal complexes incorporating a diphosphine as a chelate is prepared and characterized here for the first time. Treatment of [Ir(dppb)(tht)Cl3] (1) with fppzH afforded the dichloride complexes, trans-(Cl,Cl)[Ir(dppb)(fppz)Cl2] (2) and cis-(Cl,Cl)[Ir(dppb)(fppz)Cl2] (3). The reaction of 3 with the dianionic chelate precursor bipzH2 or mepzH2, in DMF gave the complex [Ir(dppb)(fppz)(bipz)] (4) or [Ir(dppb)(fppz)(mepz)] (5), respectively. In contrast, a hydride complex [Ir(dppb)(fppz)(bipzH)H] (6) was isolated instead of 4 in protic solvent, namely: DGME. All complexes 2 - 6 are luminescent in powder forms and thin films where the dichlorides (2, 3) emit with maxima at 590-627 nm (orange) and quantum yields (Q.Y.s) up to 90% whereas the tris-bidentate (4, 5) and hydride (6) complexes emit at 455-458 nm (blue) with Q.Y.s up to 70%. Hybrid TD-DFT calculations showed considerable MLCT contribution to the orange-emitting 2 and 3 but substantial ligand-centered 3ππ* transition character in the blue-emitting 4 - 6. The dppb does not participate to these radiative transitions in 4 - 6, but it provides the rigidity and steric bulk needed to promote the luminescence by suppressing the self-quenching in the solid state. Fabrication of an OLED with dopant 5 gave a deep blue CIE chromaticity of (0.16, 0.15). Superior blue emitters, which are vital in OLED applications, may be found in other neutral Ir(III) complexes containing phosphine chelates

Microscopic images of post-mortem tissue.

<p>Pictures showed myofibrillar loss (A and C) and mild interstitial fibrosis (B and D). Nuclear pleomorphism and cellular atrophy is also observed (C). Hematoxylin-eosin labeling (A and C), and picro-Sirius Red labeling (B and D). Scale: A and B (200x) C and D (400x).</p

Echocardiographic findings in patients carrying the genetic variant associated with DCM.

<p>Gender: M, male; F, female. Symptoms: P, palpitations; T, transplanted; p-T, Pre-transplant stage; p-S, Presyncope; S, Syncope; SHF, sudden heart failure; (-) means no dyspnea. New York Heart Association Functional Classification is indicated by a rank between 1 and 4. LVEF indicates left ventricle ejection fraction; TDLVD, telediastolic left ventricle diameter; LAA1, left atrial volume; E/A ratio, relation between E-wave and A-wave in Doppler. Knock in myocardium is indicated by presence (1) or absence (0).</p

Genetic Analysis of Arrhythmogenic Diseases in the Era of NGS: The Complexity of Clinical Decision-Making in Brugada Syndrome

<div><p>Background</p><p>The use of next-generation sequencing enables a rapid analysis of many genes associated with sudden cardiac death in diseases like Brugada Syndrome. Genetic variation is identified and associated with 30–35% of cases of Brugada Syndrome, with nearly 20–25% attributable to variants in <i>SCN5A</i>, meaning many cases remain undiagnosed genetically. To evaluate the role of genetic variants in arrhythmogenic diseases and the utility of next-generation sequencing, we applied this technology to resequence 28 main genes associated with arrhythmogenic disorders.</p><p>Materials and Methods</p><p>A cohort of 45 clinically diagnosed Brugada Syndrome patients classified as <i>SCN5A</i>-negative was analyzed using next generation sequencing. Twenty-eight genes were resequenced: <i>AKAP9</i>, <i>ANK2</i>, <i>CACNA1C</i>, <i>CACNB2</i>, <i>CASQ2</i>, <i>CAV3</i>, <i>DSC2</i>, <i>DSG2</i>, <i>DSP</i>, <i>GPD1L</i>, <i>HCN4</i>, <i>JUP</i>, <i>KCNE1</i>, <i>KCNE2</i>, <i>KCNE3</i>, <i>KCNH2</i>, <i>KCNJ2</i>, <i>KCNJ5</i>, <i>KCNQ1</i>, <i>NOS1AP</i>, <i>PKP2</i>, <i>RYR2</i>, <i>SCN1B</i>, <i>SCN3B</i>, <i>SCN4B</i>, <i>SCN5A</i>, <i>SNTA1</i>, and <i>TMEM43</i>. A total of 85 clinically evaluated relatives were also genetically analyzed to ascertain familial segregation.</p><p>Results and Discussion</p><p>Twenty-two patients carried 30 rare genetic variants in 12 genes, only 4 of which were previously associated with Brugada Syndrome. Neither insertion/deletion nor copy number variation were detected. We identified genetic variants in novel candidate genes potentially associated to Brugada Syndrome. These include: 4 genetic variations in <i>AKAP9</i> including a <i>de novo</i> genetic variation in 3 positive cases; 5 genetic variations in <i>ANK2</i> detected in 4 cases; variations in <i>KCNJ2</i> together with <i>CASQ2</i> in 1 case; genetic variations in <i>RYR2</i>, including a <i>de novo</i> genetic variation and desmosomal proteins encoding genes including <i>DSG2</i>, <i>DSP</i> and <i>JUP</i>, detected in 3 of the cases. Larger gene panels or whole exome sequencing should be considered to identify novel genes associated to Brugada Syndrome. However, application of approaches such as whole exome sequencing would difficult the interpretation for clinical purposes due to the large amount of data generated. The identification of these genetic variants opens new perspectives on the implications of genetic background in the arrhythmogenic substrate for research purposes.</p><p>Conclusions</p><p>As a paradigm for other arrhythmogenic diseases and for unexplained sudden death, our data show that clinical genetic diagnosis is justified in a family perspective for confirmation of genetic causality. In the era of personalized medicine using high-throughput tools, clinical decision-making is increasingly complex.</p></div

Stop-Gain Mutations in PKP2 Are Associated with a Later Age of Onset of Arrhythmogenic Right Ventricular Cardiomyopathy

<div><p>Background</p><p>Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a cardiac disease characterized by the presence of fibrofatty replacement of the right ventricular myocardium, which may cause ventricular arrhythmias and sudden cardiac death. Pathogenic mutations in several genes encoding mainly desmosomal proteins have been reported. Our aim is to perform genotype-phenotype correlations to establish the diagnostic value of genetics and to assess the role of mutation type in age-related penetrance in ARVC.</p><p>Methods and Results</p><p>Thirty unrelated Spanish patients underwent a complete clinical evaluation. They all were screened for <i>PKP2, DSG2, DSC2, DSP, JUP</i> and <i>TMEM43</i> genes. A total of 70 relatives of four families were also studied. The 30 patients fulfilled definite disease diagnostic criteria. Genetic analysis revealed a pathogenic mutation in 19 patients (13 in <i>PKP2</i>, 3 in <i>DSG2</i>, 2 in <i>DSP</i>, and 1 in <i>DSC2)</i>. Nine of these mutations created a truncated protein due to the generation of a stop codon. Familial assessment revealed 28 genetic carriers among family members. Stop-gain mutations were associated to a later age of onset of ARVC, without differences in the severity of the pathology.</p><p>Conclusions</p><p>Familial genetic analysis helps to identify the cause responsible for the pathology. In discrepancy with previous studies, the presence of a truncating protein does not confer a worse severity. This information could suggest that truncating proteins may be compensated by the normal allele and that missense mutations may act as poison peptides.</p></div

Representation of genetic results.

<p><b>A</b>- Prevalence of mutations in desmosomal genes. <b>B-</b> Prevalence of truncating protein mutations (black) and missense mutations (grey).</p

Report of rare variants detected.

<p>NA: DNA not available from relatives. IP: Incomplete penetrance. CM: Human gene variation database code. MAF: Minor allele frequency in the NHLBI Exome Sequencing Project (ESP). LOVD ID: Submission ID on Leiden Open Variation Database. EA: European American population. AA: African American population. Last revised January 2015. Predictors: C: Condel; MT: Mutation Taster; PPH2: Polyphen; Prov: Provean. N:N eutral; D: Deleterious; P: Polymorphism; DC: Disease causing; B: Benign; PD: Possibly_Damaging pathogenicity score based in Campuzano et al. score [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0133037#pone.0133037.ref009" target="_blank">9</a>] and applied to BrS. VUS: Variant of uncertain significance.</p

ECG of family members.

<p>(A) Twelve-lead ECG of index case. The ECG shows QTc of 500 ms. (B) Twelve-lead ECG of mother’s index case. The ECG shows a normal QTc, and (C) a LQT during tachycardia registered by Holter. (D) Twelve-lead ECG of brother’s index case. The ECG shows QTc of 485 ms.</p

Relationship of genes in which rare variation was detected.

<p>Segregation study outcomes are shown. BrS: Brugada syndrome, LQTS: Long QT syndrome, ATS: Anderson-Tawil syndrome. CPVT: catecholaminergic polymorphic right ventricular tachycardia. SSS: Sick Sinus syndrome. *Cerrone <i>et al</i>. recently defined the co-existence of clinical BrS and genetic variations in <i>PKP2</i> [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0133037#pone.0133037.ref010" target="_blank">10</a>].</p

Pedigree of the family with variants that did not show segregation (ID#18–19).

<p>Pedigree of the family with variants that did not show segregation (ID#18–19).</p