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Next generation sequencing for molecular confirmation of hereditary sudden cardiac death syndromes
Confirmación diagnóstica molecular mediante secuenciación masiva de nueva generación (“next generation sequencing”) en síndromes hereditarios de muerte súbita cardíaca
Manlio F. Márqueza,
Corresponding author
manlio.marquez@gmail.com

Corresponding author at: Instituto Nacional de Cardiología “Ignacio Chávez”, Juan Badiano 1, Sección XVI, Tlalpan, C.P. 14080 México, D.F., Mexico.
, David Cruz-Roblesb, Selene Ines-Realb, Gilberto Vargas-Alarcónb, Manuel Cárdenasa
a Departamento de Electrofisiología, Instituto Nacional de Cardiología Ignacio Chávez, México, D.F., Mexico
b Departamento de Biología Molecular, Instituto Nacional de Cardiología Ignacio Chávez, México, D.F., Mexico
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Hereditary sudden cardiac death &#40;SCD&#41; syndromes comprise a wide range of diseases resulting from alteration in cardiac ion channels&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">1</span></a> Genes involved in these syndromes represent diverse mutations that cause an altered encoding of the diverse proteins constituting these channels&#44; thus affecting directly the currents of the corresponding ions&#46; An increase or a diminution in the flow of these ions through the cell membrane&#44; markedly affects ventricular repolarization giving rise to severe &#40;potentially fatal&#41; ventricular arrhythmias &#40;ventricular tachycardia&#44; ventricular fibrillation or both&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">2&#8211;6</span></a> In the present article we will briefly review how to arrive to a clinical diagnosis and present the results of molecular genetic studies made in Mexican subjects attending the SCD Syndromes Clinic of the National Institute of Cardiology &#8220;Ignacio Chavez&#8221; Mexico City&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Clinical diagnosis of SCD syndromes</span><p id="par0010" class="elsevierStylePara elsevierViewall">Clinical diagnosis of hereditary SCD syndromes is established when there is a family history of SCD or a personal history of aborted SCD&#46; The 12-lead ECG usually has some of the characteristic signs&#44; specific to each of the different channel diseases including a long &#40;Long QT syndrome&#41; or a short QT interval &#40;Short QT syndrome&#41;&#44; an image of right bundle branch block with ST segment elevation &#40;Brugada syndrome&#41;&#44; <span class="elsevierStyleItalic">epsilon</span> waves &#40;Arrhythmogenic Right Ventricular Cardiomyopathy&#41; or large U waves &#40;Andersen&#8211;Tawil Syndrome&#41;&#44; etc&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">7</span></a> The clinical diagnosis should be confirmed whenever possible by a molecular study&#46; All family members should be screened to provide appropriate genetic counseling and help other possible affected members with the disease&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Even with the advance in genetic screening for cardiac ion channel diseases&#44; the diagnosis is still clinical&#46; Genealogy &#40;family history&#41; must be done by someone with enough expertise in order to obtain relevant information to SCD Syndromes&#46; It is important not only to ask the subject&#44; but also their relatives for obtaining a complete family history&#46; This is especially important in case of youngsters or people with low-educational background&#46; A detailed history using specific terms and their correspondent meanings must be explained to the patient&#46; Specific questions could be&#58; has someone in your family suddenly died&#63; Has someone in your family died before the age of 45&#63; Has someone in your family died because of a supposed heart attack&#63; Has someone in your family been diagnosed as epileptic&#63; Has someone in your family fainted&#63;</p><p id="par0020" class="elsevierStylePara elsevierViewall">In order to achieve a better clinical diagnosis when asking about the family history&#44; the question cannot rely only on the answers provided by the patient or their relatives&#46; It is very important to ask for official documents that could support the diagnosis&#46; These documents usually exist in the hospitals where the final attention to the deceased relatives occurred&#44; but many times nobody takes the trouble to collect and bring them to the physician to review the information&#46; Our duty is to ask for them as they may help to elaborate the clinical diagnosis&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">When asking the individual patient&#44; one must be aware of how the presentation of the different syndromes occurred&#46; Ask not only about the presence of syncope and pre-syncope&#44; but also about the specific circumstances in which they occurred&#58; the time of the day&#44; activity performed at that moment&#44; and the presence or absence of premonitory signs or symptoms&#46; Sometimes the relatives or the person that witnessed the episode may provide this information&#46; The physician should ask for true unconsciousness and how long it lasted&#46; The possibility of epileptic activity &#40;asking for proper signs and symptoms&#41; should be explored&#46; We must ask for agonic respiration&#46; If there were witnesses&#44; ask how they found the patient&#46; If medical or paramedical personnel attended the patient&#44; they might have reported how they found him or her&#46; Looking for their first ECG tracings if available could be relevant as well as asking about all the procedures applied by those personnel&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">The specific characteristics of each syndrome have been extensively reviewed by many groups and are not part of this review&#46;<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">8&#44;9</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Molecular diagnosis of SCD syndromes</span><p id="par0035" class="elsevierStylePara elsevierViewall">Together with the complete clinical history&#44; molecular genetic testing is an additional tool for the diagnosis of these syndromes&#46; It can help to establish or confirm a clinical or presumptive diagnosis&#44; and study relatives which is now called &#8220;cascade screening&#8221;&#46; It is also useful to stratify the risk associated with specific mutations and therefore&#44; to take therapeutic decisions such as the use of beta-blockers&#44; referral for sympathetic denervation or implantation of an implantable cardioverter-defibrillator &#40;ICD&#41;&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Detection of pathogenic mutation in family members should prompt regular cardiac evaluations with estimation of the risk of sudden cardiac death in each consultation&#46; The objective is to initiate early medical treatment to prevent SCD in relatives affected by the mutation&#46; This includes lifestyle advice &#40;generally restricted from competitive sports&#44; strenuous physical exercise or both&#41;&#44; drugs or ICD implantation&#46; For example&#44; in ARVD&#44; Hodgkinson et al&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">10</span></a> reported a subtype with a unique ECG finding &#40;poor progression of R wave&#41;&#44; high incidence of LV dilatation&#44; heart failure or both and early death&#44; particularly in males&#46; In this subtype of ARVD&#44; molecular pre-symptomatic diagnosis has the greatest clinical utility as adult males with the TMEM43 &#40;transmembrane protein 43&#41; p&#46;S358L gene mutation may benefit from early ICD therapy&#46; Bastarrika et al&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">11</span></a> reported a recent case of a male with some such characteristics although without genetic studies&#46; It will certainly be very useful to perform genetic screening in that type of families in order to identify these &#8220;high-risk&#8221; mutations&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">For subjects having this condition who wish to have children&#44; reproductive counseling &#40;&#8220;genetic counseling&#8221;&#41; about the risk of transmission of the mutation to their offspring may be provided&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">It is important to establish that in many diseases associated with SCD&#44; genetic tests are not indispensable in the diagnosis because they do not influence the disease management&#46; In consequence&#44; and to help physicians to incorporate the results of genetic testing into their practice&#44; the European Journal of Human Genetics has released a series of publications called &#8220;Clinical Utility Gene Cards&#8221;&#46; The one by Te Rijdt et al&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">9</span></a> on ARVD is highly recommended&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Next-generation sequencing for the molecular diagnosis in Mexican subjects with SCD syndromes</span><p id="par0055" class="elsevierStylePara elsevierViewall">Although hereditary SCD syndromes have clinical and electrocardiographic characteristics that generally allow their differentiation&#44; a molecular diagnosis of the underlying mutation is necessary for providing adequate genetic counseling for the rest of the family&#46; Through collaboration between the <span class="elsevierStyleItalic">Instituto Nacional de Cardiolog&#237;a &#8220;Ignacio Ch&#225;vez&#8221;</span> and a private enterprise &#40;<span class="elsevierStyleItalic">Sistemas Gen&#243;micos</span>&#44; Valencia&#44; Spain&#41;&#44; molecular analyses were performed in eight Mexican subjects with clinical diagnosis of a hereditary SCD syndrome&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> shows the complete list of genes screened and the results of genetic testing of the subjects studied&#44; who are either index cases &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>4&#41; or relatives of index cases &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>4&#41;&#46; The selection of genes to be analyzed by next generation sequencing &#40;NGS&#41; was based on the diagnosis or clinical suspicion&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0065" class="elsevierStylePara elsevierViewall">Technical details of NGS are as follows&#58; Target regions were captured &#40;SureSelect&#44; Agilent&#41;&#44; and sequenced in an Illumina MiSeq platform&#46; Bioinformatic analysis consists of mapping and comparing reads against the reference sequence of the human genome&#44; aligning them&#44; identification of point variations and small indels&#44; as well as their functional annotation&#46; A series of filters were applied to the list of all annotated variants in order to catch the pathogenic mutation or obtain a few potentially pathogenic variants&#46; The candidate variants were then thoroughly researched in the scientific literature and databases&#46; For this&#44; a broad set of sources was consulted &#40;generic databases such as the HGMD Pro&#44; ClinVar and LOVD&#59; locus specific databases including the Sarcomere Protein Gene Mutation Database&#44; ARVD&#47;C mutation database&#44; etc&#46;&#44; as well as relevant bibliography via PubMed&#47;MEDLINE&#41;&#46; The Kaviar database&#44; which groups together 57 variation resources &#40;dbSNP135&#44; HapMap&#44; 1000Genomes&#44; 200Exomes&#44; etc&#46;&#41;&#44; was also used&#46; In silico algorithms were used in case of novel missense changes &#40;Align GVGD&#44; SIFT&#44; PolyPhen-2&#44; Condel&#44; MutationTaster&#44; MAPP and Mutpred&#41;&#44; or splice-site variants &#40;NNSPLICE&#44; Human Splicing Finder&#44; MaxEntScan&#44; GeneSplicer and SpliceSiteFinder-like&#41;&#46; All this information were taken into account for ranking and classifying variants into&#58; &#8216;pathogenic&#8217;&#44; &#8216;probably pathogenic&#8217;&#44; &#8216;variant of unknown significance &#40;GVUS&#44; genetic variant of unknown significance&#41;&#8217;&#44; &#8216;probably non-pathogenic&#8217;&#44; or &#8216;non-pathogenic&#8217; classes&#46; Those variants classified as &#8216;pathogenic&#8217;&#44; &#8216;possibly pathogenic&#8217;&#44; or &#8216;variant of unknown significance&#8217;&#44; undergo confirmation using Sanger sequencing&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">A molecular result was attained in seven out of eight patients&#46; Only in one girl with long QT syndrome it was not possible to obtain a result despite having analyzed 19 genes associated with SCD&#46; We detected four mutations with pathogenic significance and nine GVUS&#46; All mutations detected by NGS were confirmed through Sanger sequencing&#46; A Long QT Syndrome was confirmed in a woman in whom a pathogenic mutation was documented in <span class="elsevierStyleItalic">SCN5A</span> gene&#44; which codes for the sodium channel&#46; In all Andersen&#8211;Tawil syndrome cases a mutation of the potassium KCNJ2 channel was found&#46; This was previously reported by Plaster et al&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">12</span></a>&#46; We also found mutations classified as GVUS accompanying two cases of long QT syndrome and a case of Andersen&#8211;Tawil syndrome&#46; GVUS were also found in the patients with Brugada syndrome and with idiopathic ventricular fibrillation&#46; In all these patients&#44; GVUS were detected in genes that encode the potassium channel &#40;<span class="elsevierStyleItalic">KCNQ1</span>&#41;&#44; sodium channel &#40;<span class="elsevierStyleItalic">SCN5A</span>&#41;&#44; calcium channel &#40;<span class="elsevierStyleItalic">CACNA1C</span>&#41;&#44; ankyrin &#40;<span class="elsevierStyleItalic">ANK2</span>&#41;&#44; desmoplakin &#40;<span class="elsevierStyleItalic">DSP</span>&#41;&#44; and titin &#40;<span class="elsevierStyleItalic">TTN</span>&#41;&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">A comment about the limitations of genetic studies</span><p id="par0075" class="elsevierStylePara elsevierViewall">The need and usefulness of the genetic study has been emphasized in relatives of patients with any of these syndromes&#46; Concomitantly with the greater availability of the molecular analysis&#44; there is evidence that genetic studies also have certain limitations as those observed in our patients&#46; Schwartz et al&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">5</span></a> clearly presented these limitations by pointing out that&#58; only in 25 to 80&#37; of cases &#40;depending on the disease&#41; the mutation could be detected&#44; many of the variants detected might not be &#8220;pathogenic&#8221;&#46; That is&#44; not all can be considered as a cause of the disease&#44; as there are very few mutations in which functional studies have been performed to confirm their pathogenicity&#46; We want to emphasize the difficulties encountered in the interpretation of this new technique as a large number of GVUS would be identified by this method as observed in patient 8&#46; The increasing number of screened genes would increase the number of potential pathogenic mutations and false positive tests&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">We would like to point out that&#44; until now&#44; mainly the &#8220;exome&#8221; &#40;exons or coding sequences&#41; has been analyzed&#46; To clear out the mystery of these false negative tests&#44; a lot of recent research has been focused on the introns &#40;non-coding sequences&#41; but we would like to mention that studies on epigenetic modifications&#44; which can somehow alter the genetic expression in general are also underway&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusion</span><p id="par0085" class="elsevierStylePara elsevierViewall">Genetic molecular analysis performed with this NGS approach allows the identification of DNA sequence changes in 87&#37; of cases&#44; including pathogenic mutations in 50&#37;&#46; The high percentage of GVUS obtained require co-segregation and functional studies to confirm their possible pathogenic significance&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Funding</span><p id="par0095" class="elsevierStylePara elsevierViewall">No endorsement of any kind received to conduct this study&#47;article&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Conflict of interest</span><p id="par0100" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interest&#46;</p></span></span>"
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          "identificador" => "xpalclavsec462820"
          "titulo" => "Keywords"
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          "identificador" => "sec0005"
          "titulo" => "Introduction"
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        5 => array:2 [
          "identificador" => "sec0010"
          "titulo" => "Clinical diagnosis of SCD syndromes"
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        6 => array:2 [
          "identificador" => "sec0015"
          "titulo" => "Molecular diagnosis of SCD syndromes"
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        7 => array:2 [
          "identificador" => "sec0020"
          "titulo" => "Next-generation sequencing for the molecular diagnosis in Mexican subjects with SCD syndromes"
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        8 => array:2 [
          "identificador" => "sec0025"
          "titulo" => "A comment about the limitations of genetic studies"
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          "titulo" => "Conclusion"
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          "titulo" => "Funding"
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          "identificador" => "sec0045"
          "titulo" => "Conflict of interest"
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          "identificador" => "xack131824"
          "titulo" => "Acknowledgments"
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        13 => array:1 [
          "titulo" => "References"
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    "pdfFichero" => "main.pdf"
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    "fechaRecibido" => "2014-03-26"
    "fechaAceptado" => "2014-12-08"
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          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec462820"
          "palabras" => array:4 [
            0 => "Arrhythmias"
            1 => "Hereditary sudden cardiac death syndromes"
            2 => "Right ventricle arrhythmogenic cardiomyopathy"
            3 => "Brugada syndrome"
          ]
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      ]
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        0 => array:4 [
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          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec462821"
          "palabras" => array:4 [
            0 => "Arritmias"
            1 => "S&#237;ndromes hereditarios de muerte s&#250;bita"
            2 => "Displasia Arritmog&#233;nica del ventriculo derecho"
            3 => "S&#237;ndrome de Brugada"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Hereditary sudden cardiac death syndromes comprise a wide range of diseases resulting from alteration in cardiac ion channels&#46; Genes involved in these syndromes represent diverse mutations that cause the altered encoding of the diverse proteins constituting these channels&#44; thus affecting directly the currents of the corresponding ions&#46; In the present article we will briefly review how to arrive to a clinical diagnosis and we will present the results of molecular genetic studies made in Mexican subjects attending the SCD Syndromes Clinic of the National Institute of Cardiology of Mexico City&#46;</p></span>"
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      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Los s&#237;ndromes hereditarios de muerte s&#250;bita card&#237;aca comprenden una amplia gama de enfermedades resultantes de la alteraci&#243;n en los canales i&#243;nicos card&#237;acos&#46; Los genes implicados en estos s&#237;ndromes presentan mutaciones que causan alteraciones de las diversas prote&#237;nas que constituyen estos canales y que&#44; por lo tanto&#44; afectan directamente a las diferentes corrientes i&#243;nicas&#46; En el presente art&#237;culo se revisa brevemente la forma de llegar a un diagn&#243;stico cl&#237;nico de dichos s&#237;ndromes y se presentan los resultados de los estudios gen&#233;ticos moleculares realizados en sujetos mexicanos que asisten a la Cl&#237;nica de S&#237;ndromes Hereditarios de Muerte S&#250;bita del Instituto Nacional de Cardiolog&#237;a Ignacio Ch&#225;vez&#46;</p></span>"
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          "leyenda" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">ATS<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>Andersen&#8211;Tawil Syndrome&#44; GVUS<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>genetic variant of unknown significance&#44; ICD<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>implantable automatic defibrillator&#44; VF<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>ventricular fibrillation&#44; LQTS<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>long QT syndrome&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Pt&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Sex&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Age&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Diagnosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">ICD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Index case or relative&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Genes screened&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Affected genes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Aminoacid&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Effect&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Genotype&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">36&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">LQTS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Relative&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AKAP9&#44; ANK2&#44; CACNA1C&#44; CAV3&#44; KCNE1&#44; KCNE2&#44; KCNH2&#44; KCNJ2&#44; KCNJ5&#44; KCNQ1&#44; SCN4B&#44; SCN5A&#44; SNTA1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SCN5AAKAP9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">p&#46;Arg1644Hisp&#46;Lys1762Glu&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PathogenicGVUS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">c&#46;4931G&#62;Ac&#46;5284A&#62;G&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">LQTS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Relative&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AKAP9&#44; ANK2&#44; CACNA1C&#44; CACNB2&#44; CAV3&#44; GPD1L&#44; HCN4&#44; KCNE1&#44; KCNE2&#44; KCNE3&#44; KCNH2&#44; KCNJ2&#44; KCNJ5&#44; KCNQ1&#44; SCN1B&#44; SCN3B&#44; SCN4B&#44; SCN5A&#44; SNTA1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">None&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ATS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Index Case&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">KCNJ2&#44; CACNA1C&#44; KCNQ1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">KCNJ2 CACNA1C&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">p&#46;Arg218Trpp&#46;&#61;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PathogenicGVUS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">c&#46;652C&#62;Tc&#46;5235C&#62;T&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">4<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ATS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Relative<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">KCNJ2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">KCNJ2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">p&#46;Asp71Val&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pathogenic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">c&#46;212A&#62;T&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">5<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ATS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Relative<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">KCNJ2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">KCNJ2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">p&#46;Asp71Val&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pathogenic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">c&#46;212A&#62;T&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">34&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Brugada Sx&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Index Case&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AKAP9&#44; ANK2&#44; CACNA1C&#44; CACNB2&#44; CAV3&#44; GPD1L&#44; HCN4&#44; KCNE1&#44; KCNE2&#44; KCNE3&#44; KCNH2&#44; KCNJ2&#44; KCNJ5&#44; KCNQ1&#44; SCN1B&#44; SCN3B&#44; SCN4B&#44; SCN5A&#44; SNTA1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">DSPTTN&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">p&#46;Arg1458Glyp&#46;Arg16487Gln&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">GVUSGVUS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">c&#46;4372C&#62;Gc&#46;49460G&#62;A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">49&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Idiopathic VF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Index Case&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ABCC9&#44; AKAP9&#44; ANK2&#44; CACNA1C&#44; CACNB2&#44; CASQ2&#44; CAV3&#44; DES&#44; DPP6&#44; DSC2&#44; DSG2&#44; DSP&#44; GJA1&#44; GJAS&#44; GPD1L&#44; HCN4&#44; JUP&#44; KCNQ1&#44; NPPA&#44; PKP2&#44; PRKA2&#44; RPSA&#44; RYR2&#44; SCN1B&#44; SCN3B&#44; SCN4B&#44; SCN5A&#44; SNTA1&#44; TGFB3&#44; TMEM43&#44; TRPM4&#44; TTN&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">DSP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">p&#46;Asp2070Asn&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">GVUS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">c&#46;6208G&#62;A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">LQTS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Index Case&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ABCC9&#44; AKAP9&#44; ANK2&#44; CACNA1C&#44; CACNB2&#44; CASQ2&#44; CAV3&#44; DES&#44; DPP6&#44; DSC2&#44; DSG2&#44; DSP&#44; GJA1&#44; GJAS&#44; GPD1L&#44; HCN4&#44; JUP&#44; KCNQ1&#44; NPPA&#44; PKP2&#44; PRKA2&#44; RPSA&#44; RYR2&#44; SCN1B&#44; SCN3B&#44; SCN4B&#44; SCN5A&#44; SNTA1&#44; TGFB3&#44; TMEM43&#44; TRPM4&#44; TTN&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">KCNQ1SCN5AANK2CACNA1C&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">p&#46;Asp446Glup&#46;Val1951Leup&#46;Gly2221Glup&#46;Arg1889Cys&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">GVUSGVUSGVUSGVUS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">c&#46;1338C&#62;Gc&#46;5851G&#62;Tc&#46;6662G&#62;Ac&#46;5665C&#62;T&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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              "identificador" => "tblfn0005"
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">These are two siblings from a mother with ATS and a known pathogenic mutation in KCNJ2&#46;</p>"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Clinical characteristics of the subjects studied by next generation sequencing&#44; including genes studied and affected&#46; Exact mutations and its effect &#40;pathogenic or not&#41; are described&#46;</p>"
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                            0 => "N&#46;M&#46; Plaster"
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        "titulo" => "Acknowledgments"
        "texto" => "<p id="par0105" class="elsevierStylePara elsevierViewall">We would like to express our gratitude to Sistemas Gen&#243;micos &#40;Valencia&#44; Spain&#41; by sponsoring the next-generation sequencing in these Mexican Patients&#46;</p>"
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Article information
ISSN: 14059940
Original language: English
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2023 December 14 20 34
2023 November 18 9 27
2023 October 14 11 25
2023 September 8 5 13
2023 August 24 8 32
2023 July 11 2 13
2023 June 21 1 22
2023 May 44 9 53
2023 April 45 0 45
2023 March 39 1 40
2023 February 25 4 29
2023 January 15 6 21
2022 December 16 6 22
2022 November 33 6 39
2022 October 16 15 31
2022 September 23 13 36
2022 August 28 7 35
2022 July 17 9 26
2022 June 17 11 28
2022 May 22 12 34
2022 April 17 10 27
2022 March 21 12 33
2022 February 13 6 19
2022 January 46 11 57
2021 December 22 13 35
2021 November 14 10 24
2021 October 18 21 39
2021 September 22 12 34
2021 August 15 7 22
2021 July 16 7 23
2021 June 16 10 26
2021 May 14 9 23
2021 April 16 33 49
2021 March 27 8 35
2021 February 28 12 40
2021 January 19 11 30
2020 December 19 11 30
2020 November 18 9 27
2020 October 21 7 28
2020 September 22 14 36
2020 August 24 11 35
2020 July 16 11 27
2020 June 11 12 23
2020 May 17 8 25
2020 April 14 8 22
2020 March 15 7 22
2020 February 19 7 26
2020 January 18 9 27
2019 December 32 10 42
2019 November 22 5 27
2019 October 22 3 25
2019 September 21 9 30
2019 August 21 3 24
2019 July 39 8 47
2019 June 26 23 49
2019 May 103 35 138
2019 April 34 22 56
2019 March 11 6 17
2019 February 7 7 14
2019 January 6 6 12
2018 December 25 4 29
2018 November 15 3 18
2018 October 10 7 17
2018 September 25 8 33
2018 August 4 3 7
2018 July 10 6 16
2018 June 6 6 12
2018 May 9 3 12
2018 April 11 1 12
2018 March 13 1 14
2018 February 7 1 8
2018 January 9 2 11
2017 December 13 1 14
2017 November 22 3 25
2017 October 11 3 14
2017 September 9 4 13
2017 August 12 2 14
2017 July 9 2 11
2017 June 18 7 25
2017 May 23 1 24
2017 April 29 10 39
2017 March 12 53 65
2017 February 21 5 26
2017 January 15 3 18
2016 December 37 7 44
2016 November 43 5 48
2016 October 51 8 59
2016 September 44 10 54
2016 August 42 2 44
2016 July 23 5 28
2016 June 37 7 44
2016 May 45 32 77
2016 April 34 8 42
2016 March 23 9 32
2016 February 30 19 49
2016 January 31 22 53
2015 December 33 13 46
2015 November 23 8 31
2015 October 28 8 36
2015 September 31 7 38
2015 August 23 21 44
2015 July 12 16 28
2015 June 17 22 39
2015 May 94 60 154
2015 April 43 40 83
2015 March 49 33 82
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es en pt

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

Are you a health professional able to prescribe or dispense drugs?

Você é um profissional de saúde habilitado a prescrever ou dispensar medicamentos