Regulome-seq: a novel approach for the identification of non-coding variants associated with human disease. Assessment of its applicability in 89 brugada syndrome individuals
- Autores: Mel·lina Pinsach Abuin
- Directores de la Tesis: Sara Pagans Lista (dir. tes.), Ivan Garcia-Bassets (codir. tes.), Ramón Brugada Terradellas (codir. tes.)
- Lectura: En la Universitat de Girona ( España ) en 2019
- Idioma: español
- Tribunal Calificador de la Tesis: Arthur P Arnold (presid.), Jordi Viñas de Puig (secret.), Julia di lulio (voc.)
- Programa de doctorado: Programa de Doctorado en Biología Molecular, Biomedicina y Salud por la Universidad de Girona
- Materias:
- Enlaces
- Tesis en acceso abierto en: TDX
- Resumen
Brugada syndrome (BrS) is a cardiac electrical disease with high susceptibility to sudden cardiac death. Approximately 25-30% of BrS patients are explained by pathogenic variants in coding sequences of cardiac ion channels, especially in the cardiac sodium channel gene SCN5A. However, the role of genetic variants in regulatory elements affecting cardiac ion channels remains largely unknown. We integrated ENCODE information of topological organization, chromatin accessibility, histone marks, and transcription factor binding in human cardiac cells to define 1,293 putative regulatory regions of six BrS-associated genes (SCN5A, SCN2B, SCN3B, CACNA1C, CACNB2 and CACNA2D). We selectively captured and sequenced these regions in 89 BrS patients and compared the genetic variation identified to that present in a cohort of 200 healthy-aging individuals. Finally, we scored the variants based on the tolerance to variation and other parameters, allowing us to propose candidate regulatory variants that may explain the molecular basis of some BrS cases.
