Specifieke onderzoeksstrategieën in de genetica van neurologische ontwikkelingsstoornissen
2 oktober 2017
UAntwerpen, Campus Drie Eiken, Gebouw R, Auditorium R1 - Universiteitsplein 1 - 2610 Wilrijk (Antwerpen) (route: UAntwerpen, Campus Drie Eiken
16 - 18 uur
Ilse van der Werf
Doctoraatsverdediging Ilse van der Werf - Departement Biomedische Wetenschappen
Genetic variation is a major contributor to the pathogenesis of neurodevelopmental disorders (NDDs). These disorders manifest during childhood and are the consequence of a disturbed development of the central nervous system, which results in deficits in personal, social and cognitive functioning. The NDD group encompasses among other disorders intellectual disability (ID), autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD).
Major technological advances in the last two decades have drastically increased the resolution of molecular detection methods, cumulating in an era of massive disease gene identification during which hundreds of genes have been linked to the different NDDs. Most of the genes were identified by microarray, targeted next-generation sequencing or whole exome sequencing studies, but whole genome sequencing is becoming more widely available as a result of the drop in sequencing costs. Standard diagnostics for NDDs today include Fragile-X testing, microarrays and targeted or whole exome sequencing. For multiple patients that could not be unequivocally diagnosed using these routine genetic screenings, we applied customized strategies and were able to identify the genetic cause of their disease. These included triplications on chromosome 1q21.1, a microdeletion and a complex structural variant on chromosome 14q32.2 as well as mutations in ZNF711.
Based on the observations that the same genetic abnormalities can cause multiple NDDs (e.g. ID or ASD) and that genes associated with NDDs converge to overlapping genetic networks, it is hypothesized that NDDs are part of a continuous phenotypic spectrum rather than separate disease entities. Building on this hypothesis, we investigated the ANK3 protein-protein interaction network and its role in the emergence of NDDs in more detail. The ANK3 network is a highly specified protein network essential for axon formation and maintenance and for proper action potential initiation and propagation. Using a mouse model with reduced Ank3 expression, we found a consistent elevation of anxiety-related behaviour in knockout mice. Besides, we identified minor neuroanatomical aberrations that may be involved in the behavioural abnormalities. To investigate the role of genetic variation in the ANK3 network in NDDs, we screened more than 1000 NDD patient-parent trios for variants in each of the network genes. This resulted in the identification of de novo potentially disease-causing variants in 14 patients in multiple genes of the network. The cumulative effect of multiple (less detrimental) variants in the ANK3 network in individuals with NDDs is currently under investigation.