Editorial comment
Genomic characterization in dilated cardiomyopathy
Caracterização genómica na cardiomiopatia dilatada
Marina C. Costa
Instituto de Medicina Molecular João Lobo Antunes & Centro Cardiovascular Universidade de Lisboa (CCUL), Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
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"/21742049/0000003800000006/v1_201909140841/S2174204919301722/v1_201909140841/en/main.assets" ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Editorial comment</span>" "titulo" => "Genomic characterization in dilated cardiomyopathy" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "449" "paginaFinal" => "450" ] ] "autores" => array:1 [ 0 => array:3 [ "autoresLista" => "Marina C. Costa" "autores" => array:1 [ 0 => array:3 [ "nombre" => "Marina C." "apellidos" => "Costa" "email" => array:1 [ 0 => "marinacosta@medicina.ulisboa.pt" ] ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Instituto de Medicina Molecular João Lobo Antunes & Centro Cardiovascular Universidade de Lisboa (CCUL), Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal" "identificador" => "aff0005" ] ] ] ] "titulosAlternativos" => array:1 [ "pt" => array:1 [ "titulo" => "Caracterização genómica na cardiomiopatia dilatada" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Dilated cardiomyopathy (DCM), a leading cause of heart failure and sudden cardiac death, is characterized by ventricular dilatation and impaired systolic function in the absence of abnormal loading conditions or coronary artery disease.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">1</span></a> Its prevalence is approximately 1 in 2500 individuals, and 30-50% of cases are familial.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Familial DCM is a predominantly autosomal disease with dominant transmission, although autosomal recessive, X-linked and mitochondrial patterns of inheritance have also been described.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">2</span></a> In familial DCM, nearly 60% of cases display some form of mutation in one of more than 60 genes associated with DCM.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">3</span></a> Pathogenic variants in the gene coding for the titin protein (<span class="elsevierStyleItalic">TTN</span>) appear to be the main cause of familial DCM, being reported in 12-25% of cases.<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">3–5</span></a> The second most prevalent gene in familial DCM (<span class="elsevierStyleItalic">LMNA</span>) codes for lamin A/C, variants of which are found in around 10-15% of cases.<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">6,7</span></a> DCM patients with <span class="elsevierStyleItalic">LMNA</span> mutations are reported to have worse prognosis and more serious cardiovascular complications, including sudden cardiac death and a higher rate of heart transplantation (HT), compared to individuals with idiopathic DCM.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">8</span></a> Other genes, including those for beta-myosin heavy chain 7 (<span class="elsevierStyleItalic">MYH7</span>), cardiac troponin T type 2 (<span class="elsevierStyleItalic">TNNT2</span>), RNA-binding motif protein 20 (<span class="elsevierStyleItalic">RBM20</span>), Bcl2-associated athanogene 3 (<span class="elsevierStyleItalic">BAG3</span>), tropomyosin alpha-1 (<span class="elsevierStyleItalic">TPM1</span>), desmoplakin (<span class="elsevierStyleItalic">DSP</span>), calcium/sodium-handling proteins of sodium channel type V alpha subunit (<span class="elsevierStyleItalic">SCN5A</span>), cardiac muscle alpha actin 1 (<span class="elsevierStyleItalic">ACTC1</span>) and cardiac myosin-binding protein C (<span class="elsevierStyleItalic">MYBPC3</span>), appear to be involved in 5-10% cases of familial DCM.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">8</span></a> This genetic diversity in DCM has significant implications for molecular diagnosis and clinical genetic counseling.</p><p id="par0015" class="elsevierStylePara elsevierViewall">DCM can progress to a terminal stage due to various factors such as the aggressiveness of the disease, late initiation of pharmacotherapy, or, especially, the presence of an adverse genetic background and its relationship with environmental factors. These patients may eventually progress to HT, regardless of therapy. In this context, genetic characterization can be a useful tool to determine the mechanisms that result in failure to respond to heart failure therapies and progression to terminal disease.</p><p id="par0020" class="elsevierStylePara elsevierViewall">In the current issue of the <span class="elsevierStyleItalic">Journal</span>, Martins et al.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">9</span></a> analyze thirteen HT recipients with end-stage DCM. In this group, they screened for mutations in 15 genes – <span class="elsevierStyleItalic">LMNA</span>/C, <span class="elsevierStyleItalic">MYH7</span>, <span class="elsevierStyleItalic">MYBPC3</span>, <span class="elsevierStyleItalic">TNNT2</span>, <span class="elsevierStyleItalic">ACTA1</span>, <span class="elsevierStyleItalic">TPM1</span>, <span class="elsevierStyleItalic">CSRP3</span>, <span class="elsevierStyleItalic">TCAP</span>, <span class="elsevierStyleItalic">SGCD</span>, <span class="elsevierStyleItalic">PLN</span>, <span class="elsevierStyleItalic">MYL2</span>, <span class="elsevierStyleItalic">MYL3</span>, <span class="elsevierStyleItalic">TNNI3</span>, <span class="elsevierStyleItalic">TAZ</span> and <span class="elsevierStyleItalic">LDB3</span>. The genetic characterization was carried out using next-generation sequencing (NGS), which identified nine variants in six (46%) patients: five in <span class="elsevierStyleItalic">LMNA</span>, two in <span class="elsevierStyleItalic">LBD3</span>, one in <span class="elsevierStyleItalic">TNNT2</span> and one in <span class="elsevierStyleItalic">TCAP.</span> Most of these variations were considered non-pathogenic or of uncertain significance, except for one variant in <span class="elsevierStyleItalic">LMNA</span> that was classified as likely pathogenic (c.1003C>T; p.Arg335Trp).</p><p id="par0025" class="elsevierStylePara elsevierViewall">The study by Martins et al. presents some limitations that are clearly stated by the authors, including the small numbers of patients and of genes studied, which limit the study's conclusions. Nevertheless, the paper accurately depicts the genetic variation of DCM-related genes in a Portuguese patient cohort and highlights the importance of genetic characterization in HT recipients due to end-stage DCM, stressing the need for further studies.</p><p id="par0030" class="elsevierStylePara elsevierViewall">Previously, clinical genetic testing was mainly based on conventional molecular techniques like Sanger sequencing, but recent advances in DNA and RNA sequencing technology mean that larger numbers of genes can now be studied simultaneously.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">10</span></a> The high-throughput sequencing methods of NGS are able to rapidly analyze a large number of genetic loci and samples. The data thus generated provide researchers and clinicians with an assortment of tools to study genomes in greater depth and can lead to a better understanding of genomic variation, phenotype and disease. Consequently, whole-exome and genome sequencing for clinical screening are currently entering clinical practice in various medical specialties, particularly in cardiology.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">10</span></a> The application of NGS technology in genetic analysis, together with a better knowledge of the DCM phenotype, will help to improve diagnosis, prognosis and risk stratification. It may contribute to our knowledge of the genetic mechanisms of cardiomyopathies that do not respond to medical therapy, which includes DCM patients undergoing HT.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflicts of interest</span><p id="par0035" class="elsevierStylePara elsevierViewall">The author has no conflicts of interest to declare.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Conflicts of interest" ] 1 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:10 [ 0 => array:3 [ "identificador" => "bib0055" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:1 [ "autores" => array:1 [ 0 => array:3 [ "colaboracion" => "Classification of the cardiomyopathies: a position statement from the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases" "etal" => true "autores" => array:3 [ 0 => "P. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 8 | 8 | 16 |
| 2024 October | 31 | 22 | 53 |
| 2024 September | 35 | 18 | 53 |
| 2024 August | 34 | 29 | 63 |
| 2024 July | 22 | 23 | 45 |
| 2024 June | 32 | 29 | 61 |
| 2024 May | 27 | 22 | 49 |
| 2024 April | 28 | 25 | 53 |
| 2024 March | 28 | 24 | 52 |
| 2024 February | 24 | 18 | 42 |
| 2024 January | 26 | 23 | 49 |
| 2023 December | 20 | 26 | 46 |
| 2023 November | 27 | 38 | 65 |
| 2023 October | 13 | 13 | 26 |
| 2023 September | 19 | 27 | 46 |
| 2023 August | 13 | 18 | 31 |
| 2023 July | 30 | 16 | 46 |
| 2023 June | 22 | 12 | 34 |
| 2023 May | 41 | 26 | 67 |
| 2023 April | 30 | 2 | 32 |
| 2023 March | 31 | 20 | 51 |
| 2023 February | 34 | 18 | 52 |
| 2023 January | 18 | 15 | 33 |
| 2022 December | 31 | 15 | 46 |
| 2022 November | 26 | 32 | 58 |
| 2022 October | 21 | 19 | 40 |
| 2022 September | 29 | 36 | 65 |
| 2022 August | 24 | 31 | 55 |
| 2022 July | 24 | 41 | 65 |
| 2022 June | 16 | 25 | 41 |
| 2022 May | 18 | 26 | 44 |
| 2022 April | 26 | 29 | 55 |
| 2022 March | 21 | 35 | 56 |
| 2022 February | 17 | 24 | 41 |
| 2022 January | 14 | 25 | 39 |
| 2021 December | 20 | 21 | 41 |
| 2021 November | 19 | 35 | 54 |
| 2021 October | 28 | 44 | 72 |
| 2021 September | 23 | 27 | 50 |
| 2021 August | 19 | 34 | 53 |
| 2021 July | 17 | 26 | 43 |
| 2021 June | 20 | 16 | 36 |
| 2021 May | 26 | 35 | 61 |
| 2021 April | 42 | 52 | 94 |
| 2021 March | 28 | 18 | 46 |
| 2021 February | 21 | 13 | 34 |
| 2021 January | 22 | 18 | 40 |
| 2020 December | 22 | 18 | 40 |
| 2020 November | 12 | 17 | 29 |
| 2020 October | 16 | 15 | 31 |
| 2020 September | 11 | 5 | 16 |
| 2020 August | 11 | 8 | 19 |
| 2020 July | 25 | 9 | 34 |
| 2020 June | 9 | 20 | 29 |
| 2020 May | 31 | 3 | 34 |
| 2020 April | 33 | 3 | 36 |
| 2020 March | 27 | 12 | 39 |
| 2020 February | 74 | 53 | 127 |
| 2020 January | 51 | 6 | 57 |
| 2019 December | 36 | 5 | 41 |
| 2019 November | 23 | 3 | 26 |
| 2019 October | 22 | 4 | 26 |
| 2019 September | 16 | 11 | 27 |
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