Theme 3: Plasticity and Memory

Psychopathology in rare genetic neurodevelopmental disorders

Donders Institute for Brain, Cognition and Behaviour

Our aim is to improve the care and management of rare genetic NDs by constructing a concept of personalized healthcare. To achieve this, we aim to better understand the underlying neurocognitive and biological mechanisms to open doors for investigating new therapeutic interventions.

Next generation genetic studies in rare neurodevelopmental disorders (NDs) have spectacularly increased diagnostic yield.^. The majority of Mendelian causes of NDs as intellectual disability (ID) and autism spectrum disorders (ASD) can now be identified. This enables detailed characterization and identification of syndromes based on their genetic etiology.

One of the major issues we experience in dealing with patients affected by ND syndromes is related to their psychopathology and behavioral problems, which have a great impact on quality of life of patients and their families.

In order to create tailored interventions, there is a strong need for research into the specific developmental and behavioral problems accompanying these syndromes.

We want to translate new knowledge of ND causation into better care for ND patients. Therefore I am dedicated to coordinate patient care and research activities at the approved Radboudumc Expert Centre for Rare Genetic Neurodevelopmental Disorders. Our research on rare ND disorders is shifting from syndrome discovery to development of etiology-based strategies for personalized management and therapy.

We recently defined several novel syndromes mainly based on the somatic and developmental phenotype (f.i SIN3A, POGZ, DDX3X, USP9X). The next challenge is to establish procedures for a more complete assessment of the clinical profile of these patients by systematically collecting measures on development, behaviour, and cognition. Understanding the natural course of NDs is mandatory to identify key milestones in disease progression, which is crucial to the design of clinical trials or other intervention tools.

We established vulnerability to psychotic disorders for the Kleefstra syndrome and published recent intervention recommendations. Neurocognitive and psychiatric studies related to other syndromes SIN3A-, KBG-, CTNNB1- and Kabuki syndromes is ongoing.

The Clinical Neurogenetics is closely affiliated with the following research groups:

Molecular Neurogenetics (Prof. Dr. Hans van Bokhoven)
Drosophila models of brain disorders (Dr. Annette Schenck)
Genomic technologies and bioinformatics (Dr. C. Gillissen)
Human Genetics (Prof. H. Brunner)
Molecular Neurophysiology (Dr. Nael Nadif Kasri)
Contextual neuropsychology (Prof. Jos Egger)
Translational Genomics (Dr. L. Vissers)
Translational research in Autism Spectrum Disorders (Prof. W. Staal)

Contact
Name:	Tjitske Kleefstra
Telephone:	0031 (0)24-36 13946
Email:	tjitske.kleefstra@radboudumc.nl
Visiting address:	Radboud University Medical Centre Department of Human Genetics route 855 Geert Grooteplein 10 6525 GA Nijmegen The Netherlands
Postal address:	Radboud University Medical Centre HP 855 Department of Human Genetics P.O. Box 9101 6500 HB Nijmegen The Netherlands

Projects

AGIKO grant Donders (to Drs. K. Vermeulen, childpsychiatrist in training): ’Endophynotyping: on the intersection of Psychiatry and Genetics’. 171k Euro, October 2012

Clinical Fellowship ZonMw: ‘Compiling a chromatin modification module for Intellectual disability’ Personal grant 160k Euro, June 2011

Dutch Brain foundation: Identification of genes regulated by EHMT1-protein transcription complexes in brain cells by comparative expression profiling; 35k Euro. Main applicant, June 2009

Diagnostics and diagnostic related research on novel genetic causes of intellectual disability: PhD study and co-promotor (PhD student Mrs. W.H Willemsen). Consortium VG-Oost Netherlands “Stronger on your own feet”; 450k Euro. February 2008, shared application.

AGIKO Stipendium ZonMw: ‘Genotypes and phenotypes in X-linked mental retardation’ Personal grant, 128k Euro, October

Key grants and prizes

Kleefstra: Ben ter Haar prize: two-annual prize for a young clinical geneticist for outstanding patient based research in the preceding 2 years from the Dutch Society of Clinical Genetics (VKGN), January 2010, Utrecht

Kleefstra: Isabelle Oberlé Award: presented by Prof.Dr.S. Brenner, Nobel prize winner 2002, for outstanding presentation in the field of genetics of mental retardation, European Congress of Human Genetics, 6-9 may 2006, Amsterdam

Kleefstra: Young investigator award for the best oral presentation Genotype-phenotype studies in three families with mutations in the polyglutamine-binding protein 1 gene (PQBP1) Fifteenth European meeting on dysmorphology, 2-3 september 2004, Strassbourg

Willemsen:Isabelle Oberlé award, for outstanding presentation in the field of genetics of mental retardation, European Congress of Human Genetics 13 June 2012, Nurnberg

Willemsen:Young investigator award for the best oral presentation, 6 september 2011, MR Workshop Berlin

Key publications

de Ligt, J., et al., Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med, 2012. 367(20): p. 1921-9.

Willemsen, M.H., et al., Mutations in DYNC1H1 cause severe intellectual disability with neuronal migration defects. J Med Genet, 2012. 49(3): p. 179-83.

Kleefstra, T., et al., Disruption of an EHMT1-associated chromatin-modification module causes intellectual disability. Am J Hum Genet, 2012. 91(1): p. 73-82.

Balemans, M.C., et al., Hippocampal dysfunction in the Euchromatin histone methyltransferase 1 heterozygous knockout mouse model for Kleefstra syndrome. Hum Mol Genet, 2012.

Kleefstra, T., et al., Loss-of-function mutations in euchromatin histone methyl transferase 1 (EHMT1) cause the 9q34 subtelomeric deletion syndrome. Am J Hum Genet, 2006. 79(2): p. 370-7.

Links

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Theme 3:
Plasticity and Memory

Research Group
Psychopathology in rare genetic neurodevelopmental disorders
Principal Investigator
Prof. dr. T. Kleefstra

Group members

PhDs
Elke de Boer
Linde van Dongen (promotie dec '20)
Joost Kummeling
Lot Snijders Blok
Lara van Renssen
Dmitrijs Rots
Jet van der Spek

update OCT 20 EL