16 research outputs found
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
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
Case-Family 1.
<p>Segregation of the <i>ANK2</i> c.8843C>G (p.(Ala2948Gly)) (rs138438183) and lack of segregation on <i>PKP2</i> c.1577C>T (p.(Thr526Met)) (rs146882581_CM113820[<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0133037#pone.0133037.ref011" target="_blank">11</a>]), rare variant also detected in case 3. Case 1 (II.1), 47-year-old woman. Individuals (II.2 and II.3) were also diagnosed with BrS both with previous syncope and one of them (II.2) showed a positive ajmaline test.</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
Case-Family 5.
<p>Positive segregation of <i>JUP</i> c.475G>T (p.(Val159Leu)) with the pathology in the family. This variant was previously considered as a pathogenic variant (CM1010258). Case II.1 is a 30-year-old man with a positive basal BrS ECG, syncope, and positive EPS. His brother (II.2), a 26-year-old man diagnosed with a positive ECG after flecainide test, and a positive EPS was also a carrier of the detected variation. Both relatives carry an ICD. Family history includes BrS diagnosed in their father (I.1).</p
Specific Ensemble isoforms and RefSeq codes included in the target resequencing custom panel.
<p>The design interrogates 191.12 Kb of enriched genomic regions.</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
Case-Family 4.
<p>Positive segregation of <i>HCN4</i> c.3577G>C (p.(Glu1193Gln)) (rs200507617) with the pathology in the family. Individual II.1 is a symptomatic 70-year-old man (II.1) who showed a pathologic BrS ECG pattern and positive EPS, and had an ICD implanted. The genetic variant, predicted as deleterious, was absent in his healthy brother (II.2), with a non-pathological ECG.</p
Large Genomic Imbalances in Brugada Syndrome (Part 2)
The last thirty-one pair of files of a sixty-three cohort of non-related patients of European descent with a definite BrS phenotype and negative genetic results (for Single Nucleotide Variants -SNVs- and small insertions/deletions -indels-
Characteristics of the Spanish BrS patients carrying rare genetic variations.
<p>The table shows the clinical characteristics of the probands who carried rare genetic variations in <i>SCN5A</i>, <i>SCN2B</i>, or <i>RANGRF</i>. All of them are potentially pathogenic except that found in <i>RANGRF</i>, which is of unknown significance (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0132888#sec014" target="_blank">discussion</a>). All the potentially pathogenic variations (PPVs) that had been previously reported, except p.P1725L and p.R1898C, had been identified in BrS patients. p.P1725L had been associated with Long QT Syndrome and p.R1898C was found in Exome Variant Server with a MAF of 0.0079%. No rare variations were identified in the control population. Patient’s age is expressed in years. Bold identifies the patients carrying variations that had not been described previously. M, male; F, female; S, syncope; ICD, intracardiac cardioverter defibrillator; UK, unknown; EPS, electrophysiological studies (+, positive response;-, negative response; N/P, not performed). The two patients who carried two PPVs each are identified by <sup>a</sup> and <sup>b</sup>, respectively.</p