Caracterización funcional de variantes (SNV, Indels, CNVs) analizadas por medios computacionales en 5 familias dominicanas con labio y/o paladar hendido no sindrómico

dc.contributor.advisorCatalina María, Arévalo Caro
dc.contributor.advisorPinzón Velasco, Andrés Mauricio
dc.contributor.authorOcampo Mahecha, Sandra Jhoana
dc.contributor.orcidSandra Jhoana Ocampo [0000-0003-2171-6000]spa
dc.contributor.researchgroupGrupo de Investigación en Crecimiento y desarrollo Craneofacialspa
dc.contributor.researchgroupGenética Clínicaspa
dc.date.accessioned2023-05-29T16:52:37Z
dc.date.available2023-05-29T16:52:37Z
dc.date.issued2023
dc.descriptionilustraciones, fotografías, graficasspa
dc.description.abstractIntroducción: El labio y/o paladar hendido es una anomalía congénita, la más frecuente a nivel facial. Puede tener una etiología multifactorial o genética. En República Dominicana y en particular la región de Cibao, se identifica una alta frecuencia diagnóstica de hendiduras orofaciales; sin embargo, son pocos los estudios alrededor de la anomalía. Objetivo: Determinar la estructura y funcionalidad de variantes (SNV, Indels, CNVs) asociadas con labio y/o paladar hendido no sindrómico en cinco familias dominicanas con herencia autosómica dominante, a través de secuenciación masiva y análisis computacional. Metodología: Se reclutaron cinco familias dominicanas mediante la base de datos de la Fundación Niños que Ríen, a quienes se les realizó árboles genealógicos con datos clínicos y poblacionales sobre tres generaciones en cada familia. Se hizo una revisión clínica sistémica y orofacial, análisis de genoma completo en trío mediante el uso de tecnología Illumina por medio de la plataforma HiSeqX con profundidad promedio de 30X. Se tuvieron en cuenta elementos de la historia clínica y los criterios de clasificación de variantes para la definición final. Se hizo un análisis integral mediante herramientas bioinformáticas a las variantes relacionadas a labio y/o paladar hendido no sindrómico con el fin de entender sus mecanismos biológicos con relación a su funcionamiento y al desarrollo de fisuras orofaciales en los seres humanos, mediante modelamiento de proteínas, construcción de red de genes y acoplamiento molecular. Resultados: Se encontraron ocho variantes relacionadas con riesgo de enfermedades; solo una de ellas fue asociada al desarrollo de fisuras orofaciales: una variante tipo CNV en el gen del factor 6 regulador de interferón (IRF6) con clasificación patogénica identificada en una familia afectada. Los factores ambientales identificados no fueron concluyentes. Se crearon tres modelos de IRF6, uno del dominio a unión a ADN sin cambios patogénicos, otro de la variante con pérdida de los primero tres exones y un último de la proteína completa. Mediante herramientas bioinformáticas se obtuvo un modelo de acoplamiento ADN-Dominio unión ADN de IRF6, no publicado en la literatura previamente. Se construyó una red de genes relacionados a IRF6 y el desarrollo de labio y/o paladar hendido no sindrómico. Conclusiones: Se detectó una variante tipo CNV consistente en una deleción de una copia de los exones 1-3 del gen IRF6 asociada a fisuras orofaciales no reportada previamente en la literatura. Se creó un modelo de acoplamiento de ADN-proteína con IRF6 no publicado en la literatura científica. Se hizo un modelo nuevo de red de genes relacionado a IRF6 y labio y/o paladar hendido no sindrómico. Por otro lado, se resalta la importancia de la realización de pruebas moleculares para ofrecer asesoramiento genético a las familias y pacientes. (Texto tomado de la fuente)spa
dc.description.abstractIntroduction: Cleft lip and/or palate is a congenital anomaly, the most frequent at the facial level. It may have a multifactorial or genetic etiology. In the Dominican Republic and in particular the Cibao region, a high diagnostic frequency of orofacial clefts is identified; however, there are few studies around the anomaly. Objective: To determine the structure and functionality of variants (SNV, Indels, CNVs) associated with non-syndromic cleft lip and/or palate in five Dominican families with autosomal dominant inheritance, through massive sequencing and computational analysis. Methodology: Five Dominican families were recruited through the database of the Niños que Ríen Foundation, to whom family trees were made with clinical and population data on three generations in each family. A systemic and orofacial clinical review was made, complete genome analysis in trio using Illumina technology through the HiSeqX platform with average depth of 30X. Elements of the clinical history and the variant classification criteria were taken into account for the final definition. A comprehensive analysis was made using bioinformatic tools of the variants related to non-syndromic cleft lip and/or palate in order to understand their biological mechanisms in relation to their functioning and the development of orofacial clefts in humans, through protein modeling. Gene network construction and molecular docking. Results: Eight variants related to disease risk were found; only one of them was associated with the development of orofacial clefts: a CNV-type variant in the Interferon Regulatory Factor 6 (IRF6) gene with a pathogenic classification identified in an affected family. The environmental factors identified were not conclusive. Three models of IRF6 were created, one of the DNA-binding domain without pathogenic changes, another of the variant with loss of the first three exons, and a last one of the complete protein. Using bioinformatic tools, a DNA-DNA binding domain coupling model of IRF6 was obtained, not previously published in the literature. A network of genes related to IRF6 and the development of non-syndromic cleft lip and/or palate was constructed. Conclusions: A CNV-type variant consisting of a deletion of one copy of exons 1-3 of the IRF6 gene associated with orofacial clefts not previously reported in the literature was detected. A model of DNA-protein docking with IRF6 not published in the scientific literature was created. A new model of gene network related to IRF6 and non-syndromic cleft lip and/or palate was made. On the other hand, the importance of performing molecular tests to offer genetic counseling to families and patients is highlighted.eng
dc.description.degreelevelMaestríaspa
dc.description.degreenameMagister en Genética Humanaspa
dc.description.researchareaLínea de investigación en genética del crecimiento y malformacionesspa
dc.format.extent203 páginasspa
dc.format.mimetypeapplication/pdfspa
dc.identifier.instnameUniversidad Nacional de Colombiaspa
dc.identifier.reponameRepositorio Institucional Universidad Nacional de Colombiaspa
dc.identifier.repourlhttps://repositorio.unal.edu.co/spa
dc.identifier.urihttps://repositorio.unal.edu.co/handle/unal/83895
dc.language.isospaspa
dc.publisherUniversidad Nacional de Colombiaspa
dc.publisher.branchUniversidad Nacional de Colombia - Sede Bogotáspa
dc.publisher.facultyFacultad de Medicinaspa
dc.publisher.placeBogotá, Colombiaspa
dc.publisher.programBogotá - Medicina - Maestría en Genética Humanaspa
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dc.rights.accessrightsinfo:eu-repo/semantics/openAccessspa
dc.rights.licenseAtribución-SinDerivadas 4.0 Internacionalspa
dc.rights.urihttp://creativecommons.org/licenses/by-nd/4.0/spa
dc.subject.ddc570 - Biología::576 - Genética y evoluciónspa
dc.subject.decsFisura del Paladarspa
dc.subject.decsCleft Palateeng
dc.subject.decsMutación INDELspa
dc.subject.decsINDEL Mutationeng
dc.subject.decsPatrón de Herenciaspa
dc.subject.decsInheritance Patternseng
dc.subject.proposalLabio hendidospa
dc.subject.proposalPaladar hendidospa
dc.subject.proposalNo sindrómicospa
dc.subject.proposalSecuenciación del genoma completospa
dc.subject.proposalIRF6spa
dc.subject.proposalSimulación computacionalspa
dc.subject.proposalSimulación acoplamiento molecularspa
dc.subject.proposalRed de genesspa
dc.subject.proposalCleft lipeng
dc.subject.proposalCleft palateeng
dc.subject.proposalNon-syndromiceng
dc.subject.proposalWhole genome sequencingeng
dc.subject.proposalMolecular docking simulationeng
dc.subject.proposalComputer simulationeng
dc.subject.proposalGene networkeng
dc.titleCaracterización funcional de variantes (SNV, Indels, CNVs) analizadas por medios computacionales en 5 familias dominicanas con labio y/o paladar hendido no sindrómicospa
dc.title.translatedFunctional characterization of variants (SNV, Indels, CNVs) analyzed by computational means in 5 Dominican families with non-syndromic cleft lip and/or palateeng
dc.typeTrabajo de grado - Maestríaspa
dc.type.coarhttp://purl.org/coar/resource_type/c_bdccspa
dc.type.coarversionhttp://purl.org/coar/version/c_ab4af688f83e57aaspa
dc.type.contentTextspa
dc.type.driverinfo:eu-repo/semantics/masterThesisspa
dc.type.redcolhttp://purl.org/redcol/resource_type/TMspa
dc.type.versioninfo:eu-repo/semantics/acceptedVersionspa
dcterms.audience.professionaldevelopmentEstudiantesspa
dcterms.audience.professionaldevelopmentInvestigadoresspa
dcterms.audience.professionaldevelopmentMaestrosspa
dcterms.audience.professionaldevelopmentMedios de comunicaciónspa
dcterms.audience.professionaldevelopmentPadres y familiasspa
dcterms.audience.professionaldevelopmentPúblico generalspa
oaire.accessrightshttp://purl.org/coar/access_right/c_abf2spa
oaire.fundernameFondo Nacional de Innovación y Desarrollo Científico y Tecnológico (FONDOCyT No. 2018-19-2A5-236) de República Dominicanaspa

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