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maximizing the number of bases sequenced in less time and at lower cost&#44; thereby generating large quantities of data that can be used to understand complex phenotypes and to assess individuals&#8217; predisposition to specific diseases&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Study of individuals&#8217; DNA can explain how variations in the genome play a role in health and disease&#44; helping to understand disease susceptibility and to assess the efficiency of pharmacological treatments as well as lifestyle alterations&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">There has recently been a proliferation of cardiovascular genetic clinics<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">1</span></a> using the expertise of specialists in genetics from different backgrounds &#40;cardiologists with special interest or training in cardiovascular genetics&#44; medical geneticists&#44; clinical laboratory geneticists and genetic counselors&#41;&#46; Working together&#44; these specialists are able to provide state-of-the-art genetic services to patients and families with cardiomyopathies&#44; a wide variety of inherited cardiac conditions that includes dilated cardiomyopathy &#40;DCM&#41;&#46; This is a rare cardiac disease characterized by left ventricular dilatation and systolic dysfunction that can lead to heart failure and sudden cardiac death&#46; Although various conditions have been reported as etiologies of the disease&#44; a large number of cases are still classified as idiopathic&#46; Recent studies have determined that nearly 60&#37; of cases are inherited and therefore have a genetic cause&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">2</span></a> Mutations in genes that encode cytoskeletal&#44; sarcomere&#44; and nuclear envelope proteins&#44; among others&#44; account for up to 35&#37; of cases&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">3</span></a> Technological advances in genetic analysis have identified over 60 genes associated with DCM&#44; the <span class="elsevierStyleItalic">TTN</span> gene being involved in 25&#37; of cases of familial DCM and severe disease requiring transplantation&#46;<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">2&#44;4&#44;5</span></a><span class="elsevierStyleItalic">TTN</span> truncations have been found in 13&#37; of unselected nonfamilial DCM cases&#44; but also in 2&#37; of the general population&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">6</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">In some patients with genetic DCM&#44; a particular gene defect may be suggested by cardiac conduction abnormalities &#40;e&#46;g&#46; <span class="elsevierStyleItalic">LMNA</span> or <span class="elsevierStyleItalic">SCN5A</span> mutations&#41; or elevated serum creatine kinase&#47;muscle weakness &#40;e&#46;g&#46; muscular dystrophy or <span class="elsevierStyleItalic">LMNA</span> mutations&#41;&#44; but most cases have no specific distinguishing phenotypic features&#46; Therefore&#44; the most important pointer to a genetic basis is the identification of other affected family members&#44; and all DCM patients should undergo a detailed family history covering at least three generations&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">4</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">In the current issue of the <span class="elsevierStyleItalic">Journal</span>&#44; Sousa et al&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">7</span></a> analyze 107 DCM patients&#44; of whom by the time of recruitment 57&#37; had had at least one previous cardiac-related hospitalization&#44; 27&#37; had received an implantable cardioverter-defibrillator&#44; 11&#37; cardiac resynchronization therapy&#44; 6&#37; a conventional pacemaker and 10&#37; had undergone heart transplantation&#46; In molecular analysis of all these patients&#44; 31 rare variants were identified in eight genes &#40;mainly <span class="elsevierStyleItalic">MYBPC3</span>&#44; <span class="elsevierStyleItalic">TNNT2</span> and <span class="elsevierStyleItalic">LMNA</span>&#41;&#44; most frequently sarcomeric genes&#46; Only four variants that the authors found in this population had been previously described in association with DCM&#44; 11 with hypertrophic cardiomyopathy&#44; and nine variants were novel&#46; Four variants were likely pathogenic and the remainder were of uncertain significance&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">This study reflects the complexity and diversity of DCM genetics and the importance of approaching the study and interpretation of the pathogenicity of variants by cascade screening&#46; One limitation of this study&#44; also pointed out by the authors&#44; is the small sizes of the families and the lack of informative data&#46; The latter points up the need to strengthen interdisciplinary collaboration&#44; including with primary health care providers&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">For some time&#44; conventional Sanger sequencing&#44; with its well-known limitations&#44; was the method used to study DCM&#46; In recent years&#44; enormous advances have been made with NGS techniques that have made it possible to investigate large numbers of disease genes simultaneously and accurately&#44; with decreased costs and turnaround times&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">8</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">These technological advances&#44; together with a better understanding of the DCM phenotype&#44; will contribute to improved diagnosis&#44; not only for the index case but also for family members at risk&#46; This will have effects on prevention and treatment of this complex disease&#46; The fact that pathogenic mutations are constantly being identified makes it important to use panels with more genes and to continue to reassess negative cases and those classified as having variants of unknown significance&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflicts of interest</span><p id="par0050" class="elsevierStylePara elsevierViewall">The author has no conflicts of interest to declare&#46;</p></span></span>"
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Molecular characterization of dilated cardiomyopathy
Caracterização molecular da miocardiopatia dilatada
Isabel Marques Carreira
Laboratório de Citogenética e Genómica, CNC.IBILI, CIMAGO, Faculdade de Medicina da Universidade de Coimbra, Coimbra, Portugal
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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">The remarkable advances over the last decade in molecular technologies&#44; particularly next-generation sequencing &#40;NGS&#41; and genome analysis&#44; have led to significant improvement in our knowledge of the human genome and its role in health and disease&#46; Thousands of genomes of various ethnic origins have been sequenced in recent years&#44; and genome analysis provides opportunities for research and new approaches to therapeutic development&#44; health care and public health management&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Although our knowledge of the human genome is still far from complete&#44; current advances in genomics research show us how powerful this tool can be when used in combination with clinical medicine&#46; The introduction of NGS has made it possible to investigate large numbers of disease genes simultaneously&#44; maximizing the number of bases sequenced in less time and at lower cost&#44; thereby generating large quantities of data that can be used to understand complex phenotypes and to assess individuals&#8217; predisposition to specific diseases&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Study of individuals&#8217; DNA can explain how variations in the genome play a role in health and disease&#44; helping to understand disease susceptibility and to assess the efficiency of pharmacological treatments as well as lifestyle alterations&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">There has recently been a proliferation of cardiovascular genetic clinics<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">1</span></a> using the expertise of specialists in genetics from different backgrounds &#40;cardiologists with special interest or training in cardiovascular genetics&#44; medical geneticists&#44; clinical laboratory geneticists and genetic counselors&#41;&#46; Working together&#44; these specialists are able to provide state-of-the-art genetic services to patients and families with cardiomyopathies&#44; a wide variety of inherited cardiac conditions that includes dilated cardiomyopathy &#40;DCM&#41;&#46; This is a rare cardiac disease characterized by left ventricular dilatation and systolic dysfunction that can lead to heart failure and sudden cardiac death&#46; Although various conditions have been reported as etiologies of the disease&#44; a large number of cases are still classified as idiopathic&#46; Recent studies have determined that nearly 60&#37; of cases are inherited and therefore have a genetic cause&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">2</span></a> Mutations in genes that encode cytoskeletal&#44; sarcomere&#44; and nuclear envelope proteins&#44; among others&#44; account for up to 35&#37; of cases&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">3</span></a> Technological advances in genetic analysis have identified over 60 genes associated with DCM&#44; the <span class="elsevierStyleItalic">TTN</span> gene being involved in 25&#37; of cases of familial DCM and severe disease requiring transplantation&#46;<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">2&#44;4&#44;5</span></a><span class="elsevierStyleItalic">TTN</span> truncations have been found in 13&#37; of unselected nonfamilial DCM cases&#44; but also in 2&#37; of the general population&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">6</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">In some patients with genetic DCM&#44; a particular gene defect may be suggested by cardiac conduction abnormalities &#40;e&#46;g&#46; <span class="elsevierStyleItalic">LMNA</span> or <span class="elsevierStyleItalic">SCN5A</span> mutations&#41; or elevated serum creatine kinase&#47;muscle weakness &#40;e&#46;g&#46; muscular dystrophy or <span class="elsevierStyleItalic">LMNA</span> mutations&#41;&#44; but most cases have no specific distinguishing phenotypic features&#46; Therefore&#44; the most important pointer to a genetic basis is the identification of other affected family members&#44; and all DCM patients should undergo a detailed family history covering at least three generations&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">4</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">In the current issue of the <span class="elsevierStyleItalic">Journal</span>&#44; Sousa et al&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">7</span></a> analyze 107 DCM patients&#44; of whom by the time of recruitment 57&#37; had had at least one previous cardiac-related hospitalization&#44; 27&#37; had received an implantable cardioverter-defibrillator&#44; 11&#37; cardiac resynchronization therapy&#44; 6&#37; a conventional pacemaker and 10&#37; had undergone heart transplantation&#46; In molecular analysis of all these patients&#44; 31 rare variants were identified in eight genes &#40;mainly <span class="elsevierStyleItalic">MYBPC3</span>&#44; <span class="elsevierStyleItalic">TNNT2</span> and <span class="elsevierStyleItalic">LMNA</span>&#41;&#44; most frequently sarcomeric genes&#46; Only four variants that the authors found in this population had been previously described in association with DCM&#44; 11 with hypertrophic cardiomyopathy&#44; and nine variants were novel&#46; Four variants were likely pathogenic and the remainder were of uncertain significance&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">This study reflects the complexity and diversity of DCM genetics and the importance of approaching the study and interpretation of the pathogenicity of variants by cascade screening&#46; One limitation of this study&#44; also pointed out by the authors&#44; is the small sizes of the families and the lack of informative data&#46; The latter points up the need to strengthen interdisciplinary collaboration&#44; including with primary health care providers&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">For some time&#44; conventional Sanger sequencing&#44; with its well-known limitations&#44; was the method used to study DCM&#46; In recent years&#44; enormous advances have been made with NGS techniques that have made it possible to investigate large numbers of disease genes simultaneously and accurately&#44; with decreased costs and turnaround times&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">8</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">These technological advances&#44; together with a better understanding of the DCM phenotype&#44; will contribute to improved diagnosis&#44; not only for the index case but also for family members at risk&#46; This will have effects on prevention and treatment of this complex disease&#46; The fact that pathogenic mutations are constantly being identified makes it important to use panels with more genes and to continue to reassess negative cases and those classified as having variants of unknown significance&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflicts of interest</span><p id="par0050" class="elsevierStylePara elsevierViewall">The author has no conflicts of interest to declare&#46;</p></span></span>"
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Article information
ISSN: 21742049
Original language: English
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