T. (Tjitske) Kleefstra, Professor, MD

General ambition

I have always been driven by the aim to bridge fundamental research to patient care and vice versa. This is reflected by my graduation (Msc) in both medical biology and medicine, and by my interdisciplinary research collaborations ranging from clinical to pre-clinical studies in understanding underlying biology of genetic causes for (rare) diseases.

Current activities and goals

As Head of the Department and professor in Clinical Genetics, my current activities are overarching the entire genomic medicine field to broaden impact in clinical genetics. This ranges from ethical and clinical studies to molecular mechanistic studies and therapeutic strategies related to genetic (rare) diseases.

Previous and current research

I started my professional career at Human Genetics Department Radboudumc Nijmegen. There, for 25 years, I have studied numerous aspects of genetic neurodevelopmental disorders (NDDs). During my thesis studies, I identified mutations in EHMT1 as cause for a novel disorder, now known as ‘Kleefstra syndrome’. Ever since, (personal) grants allowed me to continue studies to understand underlying mechanisms and clinical consequences of Kleefstra syndrome and also substantial additional Mendelian epigenetic machinery syndromes. 

Since my transition to Erasmus MC in 2023, I continued studying the potential of DNA methylation in genetic and non-genetic disorders, by implementing innovative translational genomics efforts using long read nanopore sequencing. This also resulted in a novel research line: Translational Epigenetics (dr Rots).

As Head of the Department, I am involved and responsible for the broad field of research activities. My personal expertise are genetic neurodevelopmental disorders, in particular the chromatinopathes and related epigenetics biology relevant for clinical application.

1994 MSc. Medical Biology, University Utrecht 
1994 MSc. Medicine, University Utrecht
1997 MD.  Medicine, University Utrecht
2005 PhD Faculty Medical Sciences, Radboud University Nijmegen:
‘X-linked mental retardation: from families to genes and back’
2007 Staff member in Clinical Genetics, Radboud UMC 
2023 Department Head Clinical Genetics Erasmus MC 

Over 275 publications; see Pub Med  kleefstra t - Search Results - PubMed

Selection 10:
1. Comprehensive EHMT1 variants analysis broadens genotype-phenotype associations and molecular mechanisms in Kleefstra syndrome.  Rots D, et al.
 Am J Hum Genet. 2024 Aug;111(8):1605-1625. doi: 10.1016/j.ajhg.2024.06.008
2. Pathogenic variants in KMT2C result in a neurodevelopmental disorder distinct from Kleefstra and Kabuki syndromes.  Rots D, et al. Am J Hum Genet. 2024 Aug 8;111(8):1626-1642. doi: 10.1016/j.ajhg.2024.06.009. 
3. The clinical and molecular spectrum of the KDM6B-related neurodevelopmental disorder.  Rots D, et al.  Am J Hum Genet. 2023 Jun 1;110(6):963-978. doi: 10.1016/j.ajhg.2023.04.008
4. Characterization of SETD1A haploinsufficiency in humans and Drosophila defines a novel neurodevelopmental syndrome.  Kummeling J, et al.  Mol Psychiatry. 26(6):2013-2024 (2021).
5. Haploinsufficiency of MECP2-interacting transcriptional co-repressor SIN3A causes mild intellectual disability by affecting the development of cortical integrity. Witteveen JS, et al.  Nature Genet. 48 (8), 877-87 (2016).
6. De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific Recognizable Syndrome with Developmental Delay and Congenital Malformations.  Reijnders MR, et al. American Journal of Human Genetics. 98(2):373- 81 (2016).
7. Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling. Snijders Blok, L et al,   Am J Hum Genet. 97, 343-52 (2015).
8. Disruption of an EHMT1-associated chromatin-modification module causes intellectual disability. Kleefstra T, et al.  Am J Hum Genet. 91, 73-82 (2012).
9. Diagnostic exome sequencing in persons with severe intellectual disability.  de Ligt J, et al. The New England Journal of Medicine. 367(20):1921-9 (2012).
10. Loss-of-function mutations in euchromatin histone methyl transferase 1 (EHMT1) cause the 9q34 subtelomeric deletion syndrome.  Kleefstra T, et al. American Journal of Human Genetics. 79(2):370-7 (2006).

2020 Endowed Professor, Clinical genetics and psychopathology of rare syndromes Radboudumc Nijmegen & Vincent van Gogh Center for Neuropsychiatry Venray
2023 Full Professor, Clinical Genetics Erasmus MC Rotterdam
Supervision of over 30 finalized- and ongoing theses 

2025-2029 SPC European Society Human Genetics
2024 Member and chair of Strategy and Evaluation Protocol RI AR&D, AUMC, the Dutch Research Council (NWO)
2023-2026 Chair SPC Euro NDD
2015-2025 Executive board member ERN ITHACA
2016-2023 PI Donders Centre for Medical Neuroscience Nijmegen
2015-2023 Head Radboudumc expert center rare neurodevelopmental disorders

SAB several patient organizations, such as ZeldSamen, IDefine (Kleefstra syndrome foundation)

Selection of grants as PI and co-PI:
2022 Unravelling immune deregulation in neurodevelopmental disorders caused by single gene mutations in the epigenetic machinery (ZonMW Open)
2021  An all human iPSC-based neuronal network platform for functional validation of ASD-linked variants SFARI (Simons Foundation Autism Research Initiative)
2020 BRAIN MODEL Programme Pluripotent Stem cells for Inherited Diseases and Embryonic Research, PSIDER (ZonMw)
2019 Creating a phenotypic ASD landscape using human models of ASD (Simons Foundation Autism Research Initiative, SFARI)
2019 ProMiSe: Tackling defective Prefrontal development in Mendelian Syndromes (NWO Dutch National Research Agenda Research along Routes by Consortia)

Scientific personal grants:
2019  Aspasia stipendium for excellent female researchers (NWO)
2018  VIDI Tackling defective epigenetic assembly in psychopathology: Towards personalized intervention in rare genetic syndromes (ZonMw)
2011  Clinical Fellowship: ‘Compiling a chromatin modification module for Intellectual disability’ (ZonMw)
2002 AGIKO: Genotypes and phenotypes in X-linked mental retardation (ZonMw)

Scientific personal awards:
2010 Ben ter Haar Prize: bi-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), Utrecht
2006 Isabelle Oberlé Award: for outstanding research in the field of genetics of mental retardation, European Congress of Human Genetics, Amsterdam (presented by Prof. Dr. S. Brenner, Nobel Prize winner 2002

Expertise and global network on Kleefstra syndrome and other chromatinopathies
Epigenetic clinic
Patient foundation and networks:
IDefine USA en EU