Determinación de variantes genéticas en una muestra de población colombiana con miocardiopatías hereditarias: Un estudio piloto

iustraciones, fotografías, graficas, tablas

Autores:
Rucinski Calderón, Cynthia
Tipo de recurso:
Fecha de publicación:
2020
Institución:
Universidad Nacional de Colombia
Repositorio:
Universidad Nacional de Colombia
Idioma:
spa
OAI Identifier:
oai:repositorio.unal.edu.co:unal/79466
Acceso en línea:
https://repositorio.unal.edu.co/handle/unal/79466
https://repositorio.unal.edu.co/
Palabra clave:
610 - Medicina y salud::612 - Fisiología humana
570 - Biología::576 - Genética y evolución
610 - Medicina y salud
Miocardiopatía
Canalopatía
Miocardiopatía hipertrófica
Miocardiopatía arritmogénica
Síndrome de QT largo
Síndrome de Brugada
Colombia
Genética
Cardiomyopathy
Channelopathy
Hypertrophic cardiomyopathy
Arrhythmogenic cardiomyopathy
Long QT syndrome
Brugada syndrome
Genetics
Genética humana
Ciencias médicas
Rights
openAccess
License
Atribución-NoComercial-SinDerivadas 4.0 Internacional
id UNACIONAL2_12897640168ae88e44324c247c5ac1bf
oai_identifier_str oai:repositorio.unal.edu.co:unal/79466
network_acronym_str UNACIONAL2
network_name_str Universidad Nacional de Colombia
repository_id_str
dc.title.spa.fl_str_mv Determinación de variantes genéticas en una muestra de población colombiana con miocardiopatías hereditarias: Un estudio piloto
dc.title.translated.eng.fl_str_mv Determination of genetic variants in a Colombian population sample with hereditary cardiomyopathies: A pilot study
title Determinación de variantes genéticas en una muestra de población colombiana con miocardiopatías hereditarias: Un estudio piloto
spellingShingle Determinación de variantes genéticas en una muestra de población colombiana con miocardiopatías hereditarias: Un estudio piloto
610 - Medicina y salud::612 - Fisiología humana
570 - Biología::576 - Genética y evolución
610 - Medicina y salud
Miocardiopatía
Canalopatía
Miocardiopatía hipertrófica
Miocardiopatía arritmogénica
Síndrome de QT largo
Síndrome de Brugada
Colombia
Genética
Cardiomyopathy
Channelopathy
Hypertrophic cardiomyopathy
Arrhythmogenic cardiomyopathy
Long QT syndrome
Brugada syndrome
Genetics
Genética humana
Ciencias médicas
title_short Determinación de variantes genéticas en una muestra de población colombiana con miocardiopatías hereditarias: Un estudio piloto
title_full Determinación de variantes genéticas en una muestra de población colombiana con miocardiopatías hereditarias: Un estudio piloto
title_fullStr Determinación de variantes genéticas en una muestra de población colombiana con miocardiopatías hereditarias: Un estudio piloto
title_full_unstemmed Determinación de variantes genéticas en una muestra de población colombiana con miocardiopatías hereditarias: Un estudio piloto
title_sort Determinación de variantes genéticas en una muestra de población colombiana con miocardiopatías hereditarias: Un estudio piloto
dc.creator.fl_str_mv Rucinski Calderón, Cynthia
dc.contributor.advisor.none.fl_str_mv Yunis Londoño, Juan José
dc.contributor.author.none.fl_str_mv Rucinski Calderón, Cynthia
dc.contributor.researchgroup.spa.fl_str_mv Patología Molecular
dc.subject.ddc.spa.fl_str_mv 610 - Medicina y salud::612 - Fisiología humana
570 - Biología::576 - Genética y evolución
610 - Medicina y salud
topic 610 - Medicina y salud::612 - Fisiología humana
570 - Biología::576 - Genética y evolución
610 - Medicina y salud
Miocardiopatía
Canalopatía
Miocardiopatía hipertrófica
Miocardiopatía arritmogénica
Síndrome de QT largo
Síndrome de Brugada
Colombia
Genética
Cardiomyopathy
Channelopathy
Hypertrophic cardiomyopathy
Arrhythmogenic cardiomyopathy
Long QT syndrome
Brugada syndrome
Genetics
Genética humana
Ciencias médicas
dc.subject.proposal.spa.fl_str_mv Miocardiopatía
Canalopatía
Miocardiopatía hipertrófica
Miocardiopatía arritmogénica
Síndrome de QT largo
Síndrome de Brugada
Colombia
Genética
dc.subject.proposal.eng.fl_str_mv Cardiomyopathy
Channelopathy
Hypertrophic cardiomyopathy
Arrhythmogenic cardiomyopathy
Long QT syndrome
Brugada syndrome
Genetics
dc.subject.unesco.none.fl_str_mv Genética humana
Ciencias médicas
description iustraciones, fotografías, graficas, tablas
publishDate 2020
dc.date.issued.none.fl_str_mv 2020
dc.date.accessioned.none.fl_str_mv 2021-05-03T20:19:55Z
dc.date.available.none.fl_str_mv 2021-05-03T20:19:55Z
dc.type.spa.fl_str_mv Trabajo de grado - Maestría
dc.type.driver.spa.fl_str_mv info:eu-repo/semantics/masterThesis
dc.type.version.spa.fl_str_mv info:eu-repo/semantics/acceptedVersion
dc.type.content.spa.fl_str_mv Text
dc.type.redcol.spa.fl_str_mv http://purl.org/redcol/resource_type/TM
status_str acceptedVersion
dc.identifier.uri.none.fl_str_mv https://repositorio.unal.edu.co/handle/unal/79466
dc.identifier.instname.spa.fl_str_mv Universidad Nacional de Colombia
dc.identifier.reponame.spa.fl_str_mv Repositorio Institucional Universidad Nacional de Colombia
dc.identifier.repourl.spa.fl_str_mv https://repositorio.unal.edu.co/
url https://repositorio.unal.edu.co/handle/unal/79466
https://repositorio.unal.edu.co/
identifier_str_mv Universidad Nacional de Colombia
Repositorio Institucional Universidad Nacional de Colombia
dc.language.iso.spa.fl_str_mv spa
language spa
dc.relation.indexed.spa.fl_str_mv RedCol
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dc.format.extent.spa.fl_str_mv 1 recurso en linea (113 paginas)
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spelling Atribución-NoComercial-SinDerivadas 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2Yunis Londoño, Juan José900883724ed1be45c24ef9e18a9f99dbRucinski Calderón, Cynthia79dea895358261e405240b1b98138144Patología Molecular2021-05-03T20:19:55Z2021-05-03T20:19:55Z2020https://repositorio.unal.edu.co/handle/unal/79466Universidad Nacional de ColombiaRepositorio Institucional Universidad Nacional de Colombiahttps://repositorio.unal.edu.co/iustraciones, fotografías, graficas, tablasLa más importante manifestación de las canalopatías y miocardiopatías es la muerte súbita cardiaca; por ello la evaluación de estas patologías es de gran importancia. Las canalopatías cardíacas congénitas son causadas por mutaciones que afectan los genes que codifican canales iónicos de la membrana (canales iónicos de sodio, potasio o calcio) o las estructuras celulares que afectan la disponibilidad de calcio. Las miocardiopatías están relacionadas principalmente con anomalías estructurales cardíacas que conducen a arritmias y dependen de alteraciones genéticas en las proteínas estructurales, incluidas las de sarcómeros, desmosomas y el citoesqueleto. Este proyecto busca determinar las variantes genéticas por medio de secuenciación de siguiente generación en una muestra piloto de pacientes colombianos diagnosticados con miocardiopatías hereditarias: síndrome de QT largo, síndrome de Brugada, miocardiopatía hipertrófica y miocardiopatía arritmogénica. En este estudio se incluyeron 25 pacientes no relacionados con edades de inicio de síntomas entre los 9 y los 55 años. La media de diagnóstico para la miocardiopatía hipertrófica fue de 2 años, y para síndrome de QT largo fue de 10.1 años. Existe una diferencia importante en el intervalo de tiempo que lleva diagnosticar una miocardiopatía hipertrófica y un síndrome de QT largo (p<0,01). La edad de presentación de eventos severos, divididos en pérdida de la conciencia (19.3 años) y sin pérdida de la conciencia (33 años) tienen una diferencia significativa (p<0,01). Se realizó aislamiento de ADN de sangre periférica con posterior secuenciación genética masiva en paralelo. Los datos obtenidos se compararon con la secuencia de referencia y las variantes encontradas se cotejaron con bases de datos internacionales y literatura científica. Se identificaron las variantes patogénicas causales en 52% de los pacientes estudiados, 13/25 en total. De ellas dos variantes no han sido reportadas; una variante tipo nonsense en el gen DSP en un paciente con miocardiopatía arritmogénica y otra variante tipo frameshift en el gen KCNE1 en dos pacientes con síndrome de QT largo. Se evidenció un rendimiento superior de la prueba a menor edad de presentación de síntomas, rendimiento de 66.6%, 50% y 20% en menores de edad, 18 a 39 años y mayores de 40 años, respectivamente. El rendimiento de la prueba para síndrome de QT largo fue de 62.5%. Los pacientes con este diagnóstico tuvieron 4 veces más eventos con pérdida de la conciencia, y la muerte súbita reanimada fue más representativa frente a otras patologías. Asimismo, todos los pacientes que presentaron un evento severo mientras realizaban ejercicio tienen una variante patogénica detectada por secuenciación. Para la miocardiopatía hipertrófica el rendimiento de la prueba fue de 45.4%. Los genes sarcoméricos fueron los implicados en la mayoría de las variantes patogénicas o probablemente patogénicas y se reportó una variante en un gen no sarcomérico. Se identificaron 2 cambios missense y 1 variante intrónica catalogadas como variantes de significado incierto; una hallada en el gen fenocopia LAMP2. Este estudio es el primero en Colombia en evaluar canalopatías y miocardiopatías de forma conjunta. Resalta la necesidad de realizar el análisis mutacional en este grupo de enfermedades, para así brindar un adecuado asesoramiento genético a las familias y poder identificar pacientes en riesgo de eventos severos. Se considera que la principal barrera es encontrar una muestra significativa y representativa de todas las regiones del país. Creemos en la importancia de tener grupos con experticia clínica y molecular, con información centralizada de los pacientes, por medio de alianzas estratégicas entre instituciones cardiovasculares y laboratorios de diagnóstico molecular del país.The most relevant outcome of channelopathies and cardiomyopathies is sudden cardiac death. For this reason, the study of this conditions is of great importance. Congenital cardiac channelopathies are caused by mutations that affect genes that encode membrane ion channels (sodium, potassium, or calcium ion channels) or cellular structures that affect calcium availability. Cardiomyopathies are primarily related to cardiac structural abnormalities that lead to arrhythmias and depend on genetic alterations in structural proteins, including those of sarcomeres, desmosomes, and cytoskeleton. This project seeks to determine genetic variants using next generation sequencing in a pilot sample of Colombian patients diagnosed with inherited cardiac conditions: long QT syndrome, Brugada syndrome, hypertrophic cardiomyopathy, and arrhythmogenic cardiomyopathy. Twenty-five unrelated patients with ages of disease onset between 9 and 55 years were included in this study. The mean time to diagnose hypertrophic cardiomyopathy was 2 years and for long QT syndrome it was 10.1 years. There is a significant difference in the time interval that it takes to diagnose hypertrophic cardiomyopathy and long QT syndrome (p <0.01). The age at which severe events occur, divided into, loss of consciousness (19.3 years) and without loss of consciousness (33 years) shows a significant difference (p <0.01). Peripheral blood DNA isolation and subsequent massive parallel sequencing were performed. The data obtained were compared with the reference sequence, and the variants found were checked against international databases and scientific literature. Causative mutations were identified in 52% of the subjects, 13 in total. Two novel mutations were found, a nonsense variant in the DSP gene in a patient with arrhythmogenic cardiomyopathy, and another frameshift variant in the KCNE1 gene in two patients with long QT syndrome. Younger individuals (i.e., those <18 years of age) had the highest yield of genetic testing (66.6%) compared with 50% and 20% in young adults and patients over 40 years, respectively. The test yield for long QT syndrome was 62.5%. Patients with this diagnosis had 4 times more events with loss of consciousness. Resuscitated sudden cardiac arrest was more representative compared to other conditions. Likewise, all patients who presented a severe event while exercising have a positive genetic test. For hypertrophic cardiomyopathy, the test yield was 45.4%. Sarcomeric genes were involved in four of the pathogenic or probably pathogenic variants while one subject had a non-sarcomeric causing variant. Two missense variants and 1 intronic mutation cataloged as variants of uncertain significance were identified; one found in a phenocopy gene, LAMP2. This study is the first in Colombia to evaluate altogether channelopathies and cardiomyopathies. It highlights the need to perform mutational analysis in this group of diseases, in order to provide adequate genetic counseling to families and to be able to identify patients at risk of severe events. Finding a significant and representative sample from all regions of the country is probably the main shortcoming of this kind of research. We believe in the importance of setting groups with clinical and molecular expertise, with centralized information on patients, through strategic alliances between cardiovascular institutions and molecular diagnostic laboratories in the country.MaestríaAlteraciones Moleculares en Miocardiopatías1 recurso en linea (113 paginas)application/pdfspaUniversidad Nacional de ColombiaBogotá - Medicina - Maestría en Genética HumanaFacultad de MedicinaBogotáUniversidad Nacional de Colombia - Sede Bogotá610 - Medicina y salud::612 - Fisiología humana570 - Biología::576 - Genética y evolución610 - Medicina y saludMiocardiopatíaCanalopatíaMiocardiopatía hipertróficaMiocardiopatía arritmogénicaSíndrome de QT largoSíndrome de BrugadaColombiaGenéticaCardiomyopathyChannelopathyHypertrophic cardiomyopathyArrhythmogenic cardiomyopathyLong QT syndromeBrugada syndromeGeneticsGenética humanaCiencias médicasDeterminación de variantes genéticas en una muestra de población colombiana con miocardiopatías hereditarias: Un estudio pilotoDetermination of genetic variants in a Colombian population sample with hereditary cardiomyopathies: A pilot studyTrabajo de grado - Maestríainfo:eu-repo/semantics/masterThesisinfo:eu-repo/semantics/acceptedVersionTexthttp://purl.org/redcol/resource_type/TMRedCol1. 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Resuscitation. 2014;85(9):1212-1218. doi:10.1016/j.resuscitation.2014.06.008Vicedecanaturas de Investigación y Extensión, Facultad de Medicina, Universidad Nacional de ColombiaORIGINALDeterminación de variantes genéticas en una muestra de población colombiana con miocardiopatías hereditarias- Un estudio piloto.pdfDeterminación de variantes genéticas en una muestra de población colombiana con miocardiopatías hereditarias- Un estudio piloto.pdfTesis de Maestría en Genética Humanaapplication/pdf11252630https://repositorio.unal.edu.co/bitstream/unal/79466/1/Determinaci%c3%b3n%20de%20variantes%20gen%c3%a9ticas%20en%20una%20muestra%20de%20poblaci%c3%b3n%20colombiana%20con%20miocardiopat%c3%adas%20hereditarias-%20Un%20estudio%20piloto.pdf576ceef16762ad698b366f7a4c936954MD51LICENSElicense.txtlicense.txttext/plain; charset=utf-83964https://repositorio.unal.edu.co/bitstream/unal/79466/2/license.txtcccfe52f796b7c63423298c2d3365fc6MD52THUMBNAILDeterminación de variantes genéticas en una muestra de 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GVyZWNob3MgZGUgYXV0b3IgcXVlIGNvbmxsZXZlIGxhIGRpc3RyaWJ1Y2nDs24gZGUgZXN0b3MgYXJjaGl2b3MgeSBtZXRhZGF0b3MuCkFsIGhhY2VyIGNsaWMgZW4gZWwgc2lndWllbnRlIGJvdMOzbiwgdXN0ZWQgaW5kaWNhIHF1ZSBlc3TDoSBkZSBhY3VlcmRvIGNvbiBlc3RvcyB0w6lybWlub3MuCgpVTklWRVJTSURBRCBOQUNJT05BTCBERSBDT0xPTUJJQSAtIMOabHRpbWEgbW9kaWZpY2FjacOzbiAyNy8yMC8yMDIwCg==

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