PhD defence S. (Soheil) Yousefi

Summary: As sequencing costs decrease, whole genome sequencing (WGS) will be more often routinely employed for diagnostics of patients with presumed genetic diseases in the field of human genetics. These studies provide the opportunity to investigate regions of our genome that currently used routine methods, such as whole exome sequencing (WES) fail to assess, such as non-coding regions outside of protein-coding genes. Variants in these regions beyond the exome, are excellent candidates in which genetic variants might contribute to the phenomena of missing heritability. Namely, independent of the precise indication for genetic testing, in general a molecular diagnosis is not achieved in around 50% of individuals suspected of a genetic disorder, including neurodevelopmental disorders, and it seems likely that at least part of this missing heritability is caused by alterations of the non-coding genome. Particular interesting parts of that non-coding genome are enhancers, which are non-coding elements that ensure correct spatio-temporal expression of their target genes. An increasing number of studies have linked alterations of such enhancers to human disease, but still, their wide-spread investigation in a clinical setting is hampered. One of the key reasons is that it is still challenging to predict the location and the activity of functional enhancers genome-wide. Given these hurdles, it is even more challenging to interpret the effect of genetic variants in such non-coding regulatory elements. It is thus of crucial relevance to better functionally annotate non-coding regulatory elements as this will greatly facilitate the interpretation of genetic variants identified outside of the exome in WGS studies.
In this thesis, I aimed to solve part of the missing heritability in neurodevelopmental disorders, using computational approaches. Next to the investigations of a novel epilepsy syndrome and investigations aiming to elucidate the regulation of the gene involved, I investigated and prioritized genomic sequences that have implications in gene regulation during the developmental stages of human brain, with the goal to create an atlas of high confidence non-coding regulatory elements that future studies can assess for genetic variants in genetically unexplained individuals suffering from neurodevelopmental disorders that are of suspected genetic origin.