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Copia De 2019 Tesis Drmed INDICE UNIVERSIDAD AUTÓNOMA DE NUEVO LEÓN FACULTAD DE MEDICINA ANÁLISIS DE EXOMA EN DOS FAMILIAS NUCLEARES CON GASTROSQUISIS RECURRENTE: ESTUDIO PILOTO PARA LA IDENTIFICACIÓN DE GENES CANDIDATOS POR VÍCTOR MICHAEL SALINAS TORRES COMO REQUISITO PARA OBTENER EL GRADO DE DOCTOR EN MEDICINA JULIO, 2019 UNIVERSIDAD AUTÓNOMA DE NUEVO LEÓN FACULTAD DE MEDICINA DEPARTAMENTO DE GENÉTICA ANÁLISIS DE EXOMA EN DOS FAMILIAS NUCLEARES CON GASTROSQUISIS RECURRENTE: ESTUDIO PILOTO PARA LA IDENTIFICACIÓN DE GENES CANDIDATOS POR VÍCTOR MICHAEL SALINAS TORRES COMO REQUISITO PARA OBTENER EL GRADO DE DOCTOR EN MEDICINA JULIO, 2019 ANÁLISIS DE EXOMA EN DOS FAMILIAS NUCLEARES CON GASTROSQUISIS RECURRENTE: ESTUDIO PILOTO PARA LA IDENTIFICACIÓN DE GENES CANDIDATOS Aprobación de la tesis: ___________________________________ Dr. med. Laura Elia Martínez de Villarreal Directora de la tesis ___________________________________ Dr. med. Luis Daniel Campos Acevedo Miembro ___________________________________ Dr. med. María Esthela Morales Pérez Miembro ____________________________________ Dr. med. Erika del Carmen Ochoa Correa Miembro ____________________________________ Dr. C. Hugo Leonid Gallardo Blanco Miembro ____________________________________ Dr. med. Felipe Arturo Morales Martínez Subdirector de Estudios de Posgrado ii! FINANCIAMIENTO El presente proyecto de investigación fue financiado con recursos económicos propios del Departamento de Genética. Responsable: Dr. med. Laura Elia Martínez de Villarreal. APROBACIÓN DEL COMITÉ DE ÉTICA Y COMITÉ DOCTORAL El presente proyecto de investigación fue aprobado por el Comité de Ética y el Comité Doctoral de la Facultad de Medicina y Hospital Universitario “Dr. José Eleuterio González” de la Universidad Autónoma de Nuevo León. No. GN17-00002 (21 de septiembre de 2017). No. FMSEPG-3322/1017 (25 de octubre de 2017). iii! AGRADECIMIENTOS A Dios por permitirme tener y disfrutar a mi Familia, gracias a todos y cada uno de Ustedes por apoyarme en cada decisión y proyecto, por permitirme cumplir con excelencia en el desarrollo de esta tesis. Gracias por creer en mí y gracias a Dios por permitirme vivir y disfrutar de cada día. No ha sido sencillo el camino hasta ahora, pero gracias a sus aportes, a su amor, a su inmensa bondad y apoyo, lo complicado de lograr esta meta se ha notado menos. Les agradezco, y hago presente mi gran afecto hacia ustedes, mi hermosa Familia. En particular, a la más completa, mejor e idónea compañía que Dios me regaló: mis Padres. Rafael Salinas y Rosa María Torres (y así generacionalmente sus padres y los padres de ellos) han sabido sembrar naturalmente en mi persona diversas virtudes como el amor, la paciencia, la sabiduria, la honorabilidad, la responsabilidad, la gratitud, el positivismo y una gran actitud hacia la vida para caminar por ella con la frente en alto y con el orgullo de poseer (posiblemente) la mejor expresión diferencial de alelos heredados por ellos. A la Dra. Laura Martínez, quien por su entrega como Directora de Tesis me compartió conocimientos con excelencia y disposición. Gracias por haber tomado la decisión de instruirme, hago patente mi admiración por su dedicación y que junto con el Comité de Tesis (Dr. Daniel Campos, Dra. María Esthela Morales, Dra. Erika del Carmen Ochoa y Dr. Hugo Gallardo) me compartieron valiosos conocimientos, gracias por creer en la educación y el desarrollo de la sociedad a través de sus enseñanzas. Dr. Hugo Gallardo, gracias en lo particular por instruirme con diversidad, disposición, calidad de conocimientos, actitudes y respuestas hacia la vida. iv! A mis pacientes, una gran parte significativa de esta tesis, gracias por su disposición y cooperación, puedo afirmar que disfruté mucho este tipo de investigación y fue porque en los procesos que se realizaron siempre estuvieron disponibles para la realización de esta tesis, gracias. A la Subdirección de Estudios de Posgrado, a los Comités de Ética e Investigación, a los Profesores del Doctorado en Medicina y a la Universidad Autónoma de Nuevo León gracias por creer en mi potencial como alumno para cumplir con excelencia en el desarrollo de esta tesis. Gracias por haberme permitido formarme en ella, gracias a todas las personas que fueron participes de este proceso, ya sea de manera directa o indirecta, gracias por ser responsables de realizar su pequeño aporte, que el día de hoy se vería reflejado en la culminación de esta tesis. A todos los compañeros y personal del Departamento de Genética por su colaboración y ayuda para la realización de la presente investigación. v! CONTENIDO ÍNDICE DE TABLAS ………………………………………………………………… IX ÍNDICE DE FIGURAS ………………………………………………………………. XI ABREVIATURAS …………………………………………………………………… XII CAPÍTULO I: RESUMEN ……………………………………………………………. 1 CAPÍTULO II: Introducción ………………………………………………………… 2 2.1 Gastrosquisis (definición) …………………………………………………….. 2 2.1.1 Embriología de la pared abdominal …………………………………….. 2 2.1.2 Epidemiología y factores de riesgo …………………………………….. 6 2.1.3 Etiología y patogénesis ………………………………………………….. 8 2.1.4 Diagnóstico pre y posnatal …………………………………………….. 27 2.1.5 Presentación clínica …………………………………………………….. 28 2.2 Estrategias para la identificación de genes candidatos ………………….. 30 2.2.1 Secuenciación de exoma ………………………………………………. 38 2.3 Originalidad y contribución del proyecto de investigación ………………. 39 CAPÍTULO III: Hipótesis ………………………………………………………….. 41 CAPÍTULO IV: Objetivos ………………………………………………………….. 42 4.1 Objetivo general ……………………………………………………………… 42 4.2 Objetivos particulares ……………………………………………………….. 42 CAPÍTULO V: Material y métodos ………………………………………………. 43 5.1 Diseño metodológico del estudio …………………………………………… 4 3 5.2 Tipo de estudio ……………………………………………………………….. 43 vi! 5.3 Población de estudio ………………………………………………………… 43 5.3.1 Número de sujetos incluidos y calculo del tamaño de la muestra …. 44 5.3.2 Características de la población ………………………………………… 4 4 5.3.3 Criterios de inclusión ……………………………………………………. 44 5.3.4 Criterios de exclusión …………………………………………………… 44 5.3.5 Criterios de eliminación …………………………………………………. 44 5.3.6 Lugar de referencia y método de reclutamiento ……………………… 4 5 5.4 Estrategia del diseño metodológico ………………………………………… 4 6 5.5 Naturaleza de la muestra y secuenciación de exoma ……………………. 47 5.6 Análisis bioinformático integral de los datos ………………………………. 48 CAPÍTULO VI: Resultados ……………………………………………………….. 51 6.1 Descripción clínica de la familia nuclear con gastrosquisis recurrente … 51 6.2 Árbol genealógico ……………………………………………………………. 53 6.3 Naturaleza de la muestra y secuenciación de exoma …………………… 53 6.4 Análisis bioinformático integral de los datos ………………………………. 55 6.5 Clasificación de genes y variantes genéticas de acuerdo a su impacto/ efecto deletéreo …………………………………………………………………… 5 5 6.6 Clasificación de genes y variantes genéticas de acuerdo a los modelos de herencia ……………………………………………………………………………. 72 6.7 Plausibilidad biológica e identificación de vías patogenéticas ………….. 73 CAPÍTULO VII: Discusión ………………………………………………………… 80 7.1 Modelo multigénico/multifactorial en gastrosquisis ………………………. 81 7.2 Nuevos genes candidatos y vías patogenéticas para gastrosquisis …… 83 vii! 7.3 Teorías sobre el defecto del cierre de la pared abdominal en humanos y su implicación para la gastrosquisis ………………………………………….. 104 7.4 Susceptibilidad clínica en gastrosquisis …………………………………. 108 CAPÍTULO VIII: Conclusión …………………………………………………….. 112 CAPÍTULO IX: Anexos …………………………………………………………… 114 9.1 Formato de consentimiento informado …………………………………… 114 9.2 Formato de consentimiento informado dirigido hacia los padres ……… 119 9.3 Cuestionario suministrado a los sujetos de investigación ……………… 1 2 4 9.4 Priorización funcional e identificación de genes de acuerdo al fenotipo investigado ……………………………………………………………………….. 126 9.5 Clasificación de genes y variantes genéticas de acuerdo al modelo de herencia ………………………………………………………………………….. 128 9.6 Producción científica y distinciones ………………………………………. 131 CAPÍTULO X: Bibliografía ………………………………………………………. 133 CAPÍTULO XI: RESUMEN AUTOBIOGRÁFICO ……………………………… 164 viii! ÍNDICE DE TABLAS TABLA 1 RIESGO DE RECURRENCIA Y DISTRIBUCIÓN GEOGRÁFICA DE GASTROSQUISIS POR PROBANDO (UN PROBANDO POR FAMILIA) OBTENIDO DE 11 ESTUDIOS POBLACIONALES .....................................................................................................9 TABLA 2 DISTRIBUCIÓN DE ABERRACIONES CROMOSÓMICAS Y PATRONES DE ANOMALÍAS MÚLTIPLES ASOCIADOS A GASTROSQUISIS .....................................11 TABLA 3 GENES Y VARIANTES GENÉTICAS INVESTIGADAS EN GASTROSQUISIS .........13 TABLA 4 DISTRIBUCIÓN DE GENOTIPOS Y ASOCIACIONES SIGNIFICATIVAS ENTRE VARIANTES GENÉTICAS Y RIESGOS CRUDOS PARA GASTROSQUISIS ...................18 TABLA 5 DISTRIBUCIÓN DE GENOTIPOS Y ASOCIACIONES SIGNIFICATIVAS ENTRE LAS VARIANTES GENÉTICAS Y EL RIESGO DE GASTROSQUISIS ESTRATIFICADO POR ETNIA, EDAD MATERNA, EXPOSICIÓN AL TABACO Y USO DE VITAMINAS ..............20 TABLA 6 REGIONES CRÍTICAS Y GENES CANDIDATOS PARA GASTROSQUISIS A PARTIR DE SÍNDROMES CROMOSÓMICOS ....................................................................24 TABLA 7 ALGUNAS CARACTERÍSTICAS SOCIODEMOGRÁFICAS Y CLÍNICAS DE LOS CASOS DE GASTROSQUISIS ESTRATIFICADOS POR ANOMALÍAS AISLADAS Y ASOCIADAS ...................................................................................................29 TABLA 8 RESUMEN DE DIVERSOS SOFTWARES DE APLICACIÓN Y HERRAMIENTAS EN LÍNEA RELACIONADAS CON EL ENFOQUE DEL GEN CANDIDATO DIGITAL ..............34 TABLA 9 RESUMEN DE LOS CONTROLES DE CALIDAD VALIDADOS DEL WES ..............54 TABLA
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