Thesis defense Daniel Lôpo Polla (Donders series 467)

4 December 2020

Intellectual disability (ID) is a collective term for a large number of highly heterogeneous disorders that impair the intellectual abilities. To date, genetic variants have been identified in more than 1,000 genes, which collectively account for over 1,600 distinct ID disorders. Every year, three million children worldwide are born with ID, and even though ID is one of the main reasons patients are referred to pediatric and genetic centers, accurate diagnosis and genetic counseling can be complicated, and treatment is limited to rare single cases. The identification of the genetic cause of ID in a patient has positive impact for the patient and their family, generating data that can provide a prognosis for other patients with similar genetic variants, information about current treatment options and enables the development and application of personalized therapeutic interventions.

To provide further insight into the genetic, clinical, and biological aspects of ID patients, in my doctoral thesis I used state-of-the-art molecular tools, cellular and animal model approaches and international collaborations to elucidate the basis of ID in affected families.This strategy allowed the identification of three novel ID genes: METTL5, EDEM3 and TMEM222. Furthermore, I was able to describe a founder variant for an autosomal recessive ID gene, CRADD, defining the phenotypic spectrum associated with this founder variant in the Finnish population, and I described novel de novo variants resulting in distinct syndromes in females in two known X-linked ID genes, CNKSR2 and MED12.

Future work using model systems derived from patient material may aid in elucidate the defect in the molecular networks of the brain and the phenotypical spectrum of these disorders. This could ultimately lead to an effective targeted therapy.