Between Monogenic and Complex Genetics: Lessons from Keratoconus and Otosclerosis Research

Date: 13 March 2018

Venue: Promotiezaal (UAntwerp, Campus Drie Eiken, Building Q) - Universiteitsplein 1 - 2610 Wilrijk (Antwerp) (route: UAntwerpen, Campus Drie Eiken)

Time: 4:00 PM - 6:00 PM

PhD candidate: Hanne Valgaeren

Principal investigator: Guy Van Camp, Carina Koppen

Short description: PhD defence Hanne Valgaeren - Department of Biomedical Sciences

Genetic factors play a role in the pathogenesis of both keratoconus (KC) and otosclerosis. These two diseases are phenotypically distinct, but on a genetic level there are similarities between both disorders. Both diseases can be present in a purely genetic (monogenic) form or in a complex form, where the disease is caused by the interplay between genetic and environmental risk factors.

Next Generation Sequencing (NGS) strategies allow investigating the genetic causes of disease in a hypothesis-free manner (using whole exome sequencing (WES)) as well as sequencing of large sets of patients in a relatively quick way, using the hypothesis-based targeted resequencing. During this PhD project, we aimed to unravel the genetic cause of KC and otosclerosis using NGS-based strategies. We implemented both the hypothesis-free WES strategy and the hypothesis-based targeted resequencing strategy.

In the first part of this thesis, we aimed to identify the genetic cause of KC using WES in Iranian and Belgian KC families, as well as using targeted resequencing of candidate genes in a large population of KC patients and controls. WES did not enable us to pinpoint the disease-causing mutation in any of the families, and led to a list of genes that might play a role in the pathogenesis. In the targeted resequencing experiment, we detected enrichment of genetic variation in genes with a known role in Ehlers-Danlos Syndrome (EDS). This study demonstrates that KC and EDS share etiological genetic factors.

In the second part of the thesis, we aimed to unravel the genetics of otosclerosis. In a large family with Hereditary Congenital Facial Paresis and HL resembling otosclerosis, a truncating mutation in MEPE was identified using WES. Since the HL-phenotype in this family resembled otosclerosis, we performed targeted resequencing of MEPE in a large population of otosclerosis families, patients and controls. We detected significant enrichment of truncating variants in patients versus controls, indicating that truncating variants are large effect risk factors for otosclerosis. Finally, we also examined the contribution of genetic variation in SERPINF1 in otosclerosis, since this gene had been published as the first gene for familial otosclerosis (Ziff et al., 2016). When we analyzed this gene in a large population of otosclerosis families, patients and controls, we were not able to detect enrichment of any type of variation in this gene in the patients and we conclude that there is insufficient evidence for a role of genetic variation in SERPINF1 in otosclerosis.