Identifikation genetischer Marker bei Kindern mit VACTERL-Assoziation

Ritter, Jessica (2022): Identifikation genetischer Marker bei Kindern mit VACTERL-Assoziation. Dissertation, LMU München: Medizinische Fakultät

Abstract

The VACTERL association is a rare malformation complex consisting of vertebral defects, anorectal malformation, cardiovascular defects, tracheoesophageal fistulae with esophageal atresia, renal malformation, and limb anomalies. As far as currently known, VACTERL is based on a multifactorial pathogenesis including genomic alterations. The aim of this study was to improve our understanding of the genetic processes involved in the development of VACTERL. For this purpose, the genetic background was investigated with a focus on cardiovascular development, signalling pathways and cilia function. The study was designed as a genetic association study. Whole-exome sequencing (WES) followed by functional enrichment analysis was performed in 21 patients with VACTERL or VACTERL-like phenotype. To investigate the inheritance, the parents were examined by WES respectively Sanger sequencing. In this study a genetic background for vascular disorders was identified in patients with VACTERL. This supports the theory, that congenital vascular defects may indicate other malformations in the spectrum of the VACTERL association. Additionally, this study indicates three more damage mechanisms for VACTERL. These are a general disruption of Shh- and Wnt signalling pathway by changes in signalling pathway activity, a structural cilia defect and a disruption of the ciliary signal transduction. Our work unites these damage mechanisms in different, partly hereditary combinations and thus offers an explanation for the heterogeneity of the VACTERL association. Follow-up studies in cell and animal models should further address these combined damage mechanisms.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Fakultäten: Medizinische Fakultät
• Sprache der Hochschulschrift: Deutsch
• Datum der mündlichen Prüfung: 1. Dezember 2022
• 1. Bericht­erstatter:in: Hubertus, Jochen