PhD defence E. (Elena) Perenthaler

Dissertation in short:

Neurodevelopmental disorders (NDDs) are complex disorders that affect more than 3% of the children worldwide, presenting with various forms of developmental delay, behavioural issues such as autism and sometimes epilepsy. There are many potential causes leading to NDDs ranging from environmental to genetic alterations that are encoded in the human DNA. Establishing a diagnosis is important, as this allows family counselling, reproductive choices for parents and personalized medicine for patients. At present however, we fail to find a genetic diagnosis for >50% of patients, even if we suspect them of a genetic disorder. 

The human genome is formed by regions of DNA carrying the recipe for the synthesis of proteins (genes) and regions that do not carry information for protein synthesis (non-coding regions). Among these non-coding regions are enhancers, regulatory elements crucial for determining when, where, and at what level genes are activated. At present, virtually all diagnostic for patients only focus on coding genes, even though these represent less than 2% of all our DNA. With my PhD work we aimed at improving our knowledge on the molecular causes of NDDs by investigating both genes and non-coding regulatory elements such enhancers.

Focussing on genes, we identified a novel variant in the gene UGP2 as causative of severe developmental and epileptic encephalopathy, discovering a novel biological pathway that can lead to epilepsy. Up to now we could identify 40 patients worldwide with this new syndrome, which others have named Barakat-Perenthaler syndrome, starting with a single patient at Erasmus MC. By now, based on these findings, we are working on a therapy for this novel rare disorder, highlighting the importance of rare disease research.  

Our understanding of the non-coding genome has deepened over the last decade, but we still lack a way to identify relevant and active enhancers. Therefore, these regions are often neglected in the clinic, as we simply do not know how to interpret genetic variants in such non-coding regions. To improve this, we developed a method to identify functional enhancers in the whole human genome with which we could identify enhancers active in neural stem cells, the precursors of nearly all the cells of the human brain.  This now offers new possibilities to diagnose patients, and hopefully results in improved diagnosis and therapies for patients with NDDs.