{"id":117910,"date":"2018-03-11T10:47:38","date_gmt":"2018-03-11T10:47:38","guid":{"rendered":"https:\/\/www.deberes.net\/tesis\/sin-categoria\/estudio-genetico-de-muerte-subita-en-la-region-de-murcia\/"},"modified":"2018-03-11T10:47:38","modified_gmt":"2018-03-11T10:47:38","slug":"estudio-genetico-de-muerte-subita-en-la-region-de-murcia","status":"publish","type":"post","link":"https:\/\/www.deberes.net\/tesis\/cardiologia\/estudio-genetico-de-muerte-subita-en-la-region-de-murcia\/","title":{"rendered":"Estudio gen\u00e9tico de muerte s\u00fabita en la regi\u00f3n de murcia"},"content":{"rendered":"<h2>Tesis doctoral de <strong> Caricia Perez Ruescas <\/strong><\/h2>\n<p>Resumen  objetivos 1)\testudiar las causas de ms no isqu\u00e9mica en la regi\u00f3n de murcia. 2)\tdescribir desde el punto de vista histopatol\u00f3gico los casos de ms con sospecha o evidencia de miocardiopat\u00eda. 3)\tevaluar el funcionamiento de un protocolo de estudio patol\u00f3gico, gen\u00e9tico y familiar de los casos de ms no isqu\u00e9mica. 4)\tidentificar las alteraciones gen\u00e9ticas asociadas a las causas de ms con sospecha de cardiopat\u00eda hereditaria. 5)\testudiar mediante el uso de herramientas bioinform\u00e1ticas la causalidad de las variantes encontradas y estimar su patogenicidad, mediante la relaci\u00f3n entre el tipo de variante y las manifestaciones cl\u00ednicas (correlaci\u00f3n genotipo-fenotipo). 6)\testudiar la segregaci\u00f3n de la enfermedad con el genotipo y su penetrancia a partir del estudio de familiares de primer grado de los afectados. metodolog\u00eda 1.\tAutopsia se realiz\u00f3 un estudio necr\u00f3psico completo con disecci\u00f3n reglada del coraz\u00f3n por especialistas del imlrm. \tse procedi\u00f3 a la recogida, conservaci\u00f3n y almacenamiento de muestras sangu\u00edneas (2 tubos edta, 4 ml), para la realizaci\u00f3n del estudio molecular, dichas muestras de sangre fueron tratadas, siguiendo procedimiento habitual para purificaci\u00f3n y amplificaci\u00f3n del dna.  2.\tEstudio familiar se trazaron \u00e1rboles familiares de forma detallada. Se realiz\u00f3 un estudio cl\u00ednico completo, en funci\u00f3n de cada caso. se interrog\u00f3 acerca de la edad y las causas de los fallecimientos y se recogi\u00f3 la historia m\u00e9dica, en los casos en que esta informaci\u00f3n estaba disponible. 3.\tAn\u00e1lisis estad\u00edstico \tse cre\u00f3 una base de datos espec\u00edfica para el estudio. Se emple\u00f3 el programa estad\u00edstico spps (versi\u00f3n 15.0) para el an\u00e1lisis de resultados.     4.\tEstudio molecular miocardiopat\u00edas\tgenes estudiados mch \tmybpc3, myh7 hivi\tmybpc3, myh7 mavd\tpkp2, dsp, dsg2 mcd\tlmna dilatada\/espongiforme\tmybpc3, myh7, lmna, cypher\/zasp canalopat\u00edas\t genes estudiados sqtl\tscn5a, kcnq1, kcnh2 sb\tscn5a sqtc\tkcnq1, kcnh2 tabla 1. Resumen de los genes estudiados por secuenciaci\u00f3n directa.   a)\textracci\u00f3n del adn gen\u00f3mico b)\tamplificaci\u00f3n y purificaci\u00f3n del adn gen\u00f3mico c)\tsecuenciaci\u00f3n autom\u00e1tica directa d)\tnext generation secuencing  e)\tan\u00e1lisis bioinform\u00e1tico de las variantes encontradas f)\tan\u00e1lisis bioinform\u00e1tico de las nuevas variantes identificadas: estudios in silico  conclusiones 1)\tla incidencia media de casos de ms relacionados con cardiopat\u00edas hereditarias, estimada en la regi\u00f3n de murcia, fue de 14 personas\/a\u00f1o con una media de edad al diagn\u00f3stico de 36,0\u00c2\u00b119,6 a\u00f1os.  2)\texiste un claro predominio del sexo var\u00f3n en todos los casos de ms de nuestra poblaci\u00f3n, destacando la asociaci\u00f3n significativa en el grupo de las mcp. 3)\tel estudio histol\u00f3gico o la evaluaci\u00f3n cardiol\u00f3gica exhaustiva, permitieron obtener un rendimiento diagn\u00f3stico en el 60,9% de los casos, siendo la mch la causa de ms m\u00e1s com\u00fan en nuestro medio.  4)\tmediante el estudio molecular dirigido de en los 50 casos de ms, con sospecha o evidencia de cardiopat\u00eda hereditaria, se ha conseguido un rendimiento global del diagn\u00f3stico gen\u00e9tico positivo del 10,0%.  5)\ttras el an\u00e1lisis con herramientas in silico, la consulta en la literatura cient\u00edfica y el estudio de la relaci\u00f3n genotipo-fenotipo, se ha considerado que el 30,0% de los casos portaba al menos una variante de significado cl\u00ednico incierto, se han identificado entre ellas, variantes missense de mayor probabilidad pat\u00f3gena. 6)\tcomo estrategia diagn\u00f3stica, el an\u00e1lisis molecular contribuy\u00f3 a aumentar el rendimiento diagn\u00f3stico positivo; de los familiares estudiados cl\u00ednica y gen\u00e9ticamente, el 27,5% era portador de al menos una de las mutaciones identificadas como causantes o probablemente causante de la enfermedad, el 16,0% estaba afectado cl\u00ednicamente y el 10,3% no lo estaba.  7)\tla creaci\u00f3n de un grupo multidisciplinar que integra pat\u00f3logos, cardi\u00f3logos y bi\u00f3logos moleculares, ha permitido profundizar en las causas de ms en la regi\u00f3n de murcia    abstract objectives 1)\tto study the causes of nonischemic sudden death in murcia. 2)\tto describe from a histopathological point of view, cases of sudden death with evidence or suspected of cardiomyopathy. 3)\tto evaluate the performance of  an organized pathological, genetic and family study of cases of nonischemic sudden death 4)\tto identify genetic alterations associated with the causes of sudden death with suspected hereditary disease. 5)\tto study the causality of the variants found, by bioinformatics tools and estimate its pathogenicity by the relationship between type of variation and clinical manifestations (genotype-phenotype correlation). 6)\tto study the segregation of the disease with genotype and its penetrance from of first-degree relatives of those affected. methods 1.\tAutopsy a full necropsy with formal dissection of the heart was performed by specialists of the institute of legal medicine of the region of murcia (imlrm). to realize molecular studies, we proceeded to the collection, preservation and storage of blood samples (2 edta tubes, 4 ml), these blood samples were treated, following routine purification and dna amplification procedure. 2.  Family study family pedigrees were outlined in detail from the questioning of patients and families. A complete clinical study was made, depending on each case. families were questioned about the age and cause of death and medical history was collected, in cases where this information was available. 3. Statistical analysis specific data base was created for the study. Spps statistical software (version 15.0) was used for the analysis of results.  4.\tMolecular study cardiomyopathy\tstudied genes mch \tmybpc3, myh7 hivi\tmybpc3, myh7 mavd\tpkp2, dsp, dsg2 mcd\tlmna dilatada\/espongiforme\tmybpc3, myh7, lmna, cypher\/zasp channelopathies\tstudied genes sqtl\tscn5a, kcnq1, kcnh2 sb\tscn5a sqtc\tkcnq1, kcnh2 table 1. Summary of the studied genes by direct sequencing for each cardiomyopathies and \/ or channelopathies.  a) extraction of genomic dna. b) amplification and purification of genomic dna. c) automatic direct sequencing. d) next generation secuencing. e) bioinformatic analysis of the variants found. f)  bioinformatic analysis of the new genetic variants identified: in silico studies.  conclusions 1)\tit was estimated that the average incidence of sudden death related hereditary disease, estimated in murcia, was 14 people\/ year with a mean age at diagnosis of 36.0 \u00c2\u00b1 19.6 years. 2)\ta clearly predominance of male sex in all cases of sudden death in our population was shown, highlighting the significant association in the group of cardiomyopathies. 3)  \thistological examination or comprehensive cardiac evaluation (in case of a resurrected cardiac arrest), showed a yield of 60.9%, being  mch  the most common cause of sudden death in our clinical area.   4) \tusing molecular studies on 50 cases of sudden death, with evidence or suspected of hereditary disease, it has achieved an overall yield of positive genetic diagnosis of 10.0%. 5)  \tafter analysis with in silico tools, scientific literature consultation and the study of genotype-phenotype relationship, it is considered that the 30.0% of cases carrying at least one variant of uncertain clinical significance. Have been identified, missense variants of pathogenic greater probability. 6)          as a diagnostic strategy, molecular analysis helped to increase the positive diagnostic yield; relatives clinically and genetically studied, 27.5% were carrying at least one of the mutations identified as causing or likely to cause the disease, 16.0% were clinically affected and 10.3% was not. 7) \tthe multidisciplinary group created, which it is integrated by pathologists, cardiologists and molecular biologists, has allowed deepened in sudden death causes in murcia.<\/p>\n<p>&nbsp;<\/p>\n<h3>Datos acad\u00e9micos de la tesis doctoral \u00ab<strong>Estudio gen\u00e9tico de muerte s\u00fabita en la regi\u00f3n de murcia<\/strong>\u00ab<\/h3>\n<ul>\n<li><strong>T\u00edtulo de la tesis:<\/strong>\u00a0 Estudio gen\u00e9tico de muerte s\u00fabita en la regi\u00f3n de murcia <\/li>\n<li><strong>Autor:<\/strong>\u00a0 Caricia Perez Ruescas <\/li>\n<li><strong>Universidad:<\/strong>\u00a0 Murcia<\/li>\n<li><strong>Fecha de lectura de la tesis:<\/strong>\u00a0 17\/07\/2015<\/li>\n<\/ul>\n<p>&nbsp;<\/p>\n<h3>Direcci\u00f3n y tribunal<\/h3>\n<ul>\n<li><strong>Director de la tesis<\/strong>\n<ul>\n<li>Juan  Ramon Gimeno Blanes<\/li>\n<\/ul>\n<\/li>\n<li><strong>Tribunal<\/strong>\n<ul>\n<li>Presidente del tribunal: isabel Tovar zapata <\/li>\n<li>Jos\u00e9 Antonio Noguera velasco (vocal)<\/li>\n<li>  (vocal)<\/li>\n<li>  (vocal)<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<p>&nbsp;<\/p>\n","protected":false},"excerpt":{"rendered":"<p>Tesis doctoral de Caricia Perez Ruescas Resumen objetivos 1) estudiar las causas de ms no isqu\u00e9mica en la regi\u00f3n de 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