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Download (3MB) “Caracterización Molecular por aCGH de alteraciones genómicas en pacientes con discapacidad intelectual y malformaciones múltiples de etiología desconocida” UNIVERSIDAD AUTÓNOMA DE NUEVO LEÓN FACULTAD DE MEDICINA “CARACTERIZACIÓN MOLECULAR POR aCGH DE ALTERACIONES GENÓMICAS EN PACIENTES CON DISCAPACIDAD INTELECTUAL Y MALFORMACIONES MÚLTIPLES DE ETIOLOGÍA DESCONOCIDA” Por Q.C.B. Lizeth Alejandra Martínez Jacobo Como requisito parcial para obtener el Grado de MAESTRÍA EN CIENCIAS con Orientación en Biología Molecular e Ingeniería Genética Julio, 2013 i “Caracterización Molecular por aCGH de alteraciones genómicas en pacientes con discapacidad intelectual y malformaciones múltiples de etiología desconocida” El presente trabajo de tesis se llevó a cabo en el Laboratorio de Medicina Genómica de la Unidad de Diagnóstico Molecular del Departamento de Bioquímica y Medicina Molecular de la facultad de Medicina, así como en la Unidad de Biología Molecular Genómica y Secuenciación del Centro de investigación y Desarrollo en Ciencias de la Salud, ambos de la Universidad Autónoma de Nuevo León, bajo la dirección del Dr. Carlos Córdova Fletes, la co-dirección de la Dra. Rocío Ortiz López y como miembro de la comisión el Dr. Augusto Rojas Martínez. iii “Caracterización Molecular por aCGH de alteraciones genómicas en pacientes con discapacidad intelectual y malformaciones múltiples de etiología desconocida” AGRADECIMIENTOS Al CONACYT por la beca otorgada para realizar mi posgrado. A mi director de tesis, Dr. Carlos Córdova Fletes, Gracias por sus consejos, paciencia, apoyo y dedicación en este proyecto, por compartirme de sus conocimientos procurando siempre mi formación profesional; muchísimas gracias por confiar en mí. A la Dra. Rocío Ortiz López y al Dr. Augusto Rojas, por todo su apoyo para la realización de este proyecto y por permitirme formar parte de la UBMG y S. A los investigadores del CIBO por su valiosa colaboración en la captación de los pacientes y su apoyo en la parte clínica del proyecto. A la Dra. Herminia G. Martínez, por confiar en mí, por sus consejos y apoyarme en todo momento. A mis compañeros de generación: Geo, Junior, Alex, Erick, Mariel y Kame por vivir esta experiencia conmigo y brindarme su amistad. A Geo Clavo por su paciencia, consejos y apoyo en el laboratorio, por brindarme su amistad y sinceridad durante estos 2 años. A mis compañeros del CIDICS: Sandra, Laura, Adriana, Yadira, Ramsés y la Química Paty, por su apoyo y por hacerme sentir parte del equipo. A mi familia, por su apoyo incondicional y confianza para cumplir mis metas. A Pedrin Salas, por apoyarme siempre para lograr mi superación profesional y estar conmigo en los momentos buenos y en los no tan buenos. TA. iv “Caracterización Molecular por aCGH de alteraciones genómicas en pacientes con discapacidad intelectual y malformaciones múltiples de etiología desconocida” DEDICATORIA A mis padres: Por su amor y apoyo incondicional. Por todo el sacrificio puesto para que mis hermanas y yo pudiéramos estudiar, se merecen esto y mucho más. Estoy convencida que un día les compensare un poco de lo mucho que me han dado. A mis hermanas: Porque ustedes me han dado el ejemplo, siempre estudiando y trabajando para lograr sus metas. Porque me han apoyado incondicionalmente y siempre han creído en mí. Estoy orgullosa de ser su hermana menor, ustedes son mi inspiración y cuando sea grande quiero ser como ustedes. A mis sobrinos (Vale, Emi y Ernesto) y a Pedrín: Por motivarme a seguir estudiando, por creer en mí, jamás les voy a fallar. A todos ustedes, con Amor Liz “Después de escalar una montaña muy alta, descubrí que hay muchas otras montañas por escalar”….Nelson Mandela v “Caracterización Molecular por aCGH de alteraciones genómicas en pacientes con discapacidad intelectual y malformaciones múltiples de etiología desconocida” CONTENIDO ABREVIATURAS ..................................................................................................................... IX INDICE DE FIGURAS ................................................................................................................ X INDICE DE TABLAS ................................................................................................................. X RESUMEN ................................................................................................................................... 1 CAPÍTULO 1 ................................................................................................................................ 2 INTRODUCCIÓN ........................................................................................................................ 2 1.1 Malformaciones múltiples ............................................................................................... 3 1.2 DI .................................................................................................................................... 5 1.2.1 Epidemiología de la DI ............................................................................................. 6 1.2.2 Etiología de la DI ..................................................................................................... 8 1.3 Herramientas de Diagnóstico .......................................................................................... 9 1.3.1 Microarreglos genómicos ....................................................................................... 11 1.4 Variaciones en el número de copias .............................................................................. 13 1.5 JUSTIFICACIÓN ......................................................................................................... 15 CAPÍTULO 2 .............................................................................................................................. 16 OBJETIVOS ........................................................................................................................... 16 2.1 OBJETIVO GENERAL ............................................................................................... 16 2.2 OBJETIVOS ESPECÍFICOS ........................................................................................ 16 CAPÍTULO 3 .............................................................................................................................. 17 DISEÑO METODOLÓGICO ..................................................................................................... 17 3.1 Diseño de estudio .......................................................................................................... 17 3.2 Universo de estudio ....................................................................................................... 17 3.3 Muestra de estudio ........................................................................................................ 17 3.4 Criterios de inclusión .................................................................................................... 17 3.5 Criterios de no inclusión................................................................................................ 18 3.6 Criterios de exclusión .................................................................................................... 18 CAPÍTULO 4 .............................................................................................................................. 19 MATERIALES Y MÉTODOS ................................................................................................ 19 4.1 Estrategia General ......................................................................................................... 19 4.2 MATERIALES ............................................................................................................. 20 4.2.1 Reactivos ................................................................................................................ 20 4.2.2 Material Biológico .................................................................................................. 21 vi “Caracterización Molecular por aCGH de alteraciones genómicas en pacientes con discapacidad intelectual y malformaciones múltiples de etiología desconocida” 4.2.3 Equipo .................................................................................................................... 21 4.2.4 Programas computacionales ................................................................................... 21 4.3 MÉTODOS (ver anexos) ............................................................................................... 22 4.3.1 Escanéo Genómico ................................................................................................. 22 4.3.1.1 Naturaleza de la muestra .................................................................................. 22 4.3.1.2 Extracción de ADN ......................................................................................... 22 4.3.1.3 Calidad de ADN por electroforesis y espectrofotometría ................................ 23 4.3.1.4 Microarreglos de genotipificación (anexo 4) ................................................... 23 4.3.1.4 Control de calidad del escanéo genómico en plataforma Affymetrix .............. 25 4.3.1.5 Algoritmo Birdseed y Algoritmo Canary ......................................................... 25 4.3.2 Identificación de alteraciones genómicas ............................................................... 25 4.3.2.1 Variaciones en el número de copias (CNV) ..................................................... 25 4.3.2.2 Identificación de
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