About our research group/lab
Our research
Innovation in genomic medicine
Clinical genetics is a rapidly developing field that demands continuous innovation. The goal of the Translational and Functional Genomics group is to stay at the forefront of diagnostic innovations by testing, optimizing, validating, developing and translating novel genetic technologies, and bioinformatic tools to deliver state-of-the art and rapid patient diagnostics.
Long-read sequencing implementation
The Translational and Functional Genomics group is utilising long-read sequencing for various diagnostic and innovative research applications. For example, our team already successfully validated and implemented the ultrarapid long-read genome sequencing for critically ill patients as a routine diagnostic service, enabling swift clinical decision making, while replacing multiple tests with one. Diagnostic long-read sequencing for other indications, including repeat expansion and imprinting disorders, is currently underway.
Solving the unsolved
Despite the improvement of the currently available diagnostic tests, a significant proportion of patients remains undiagnosed. To address this, we apply innovative molecular technologies - including long-read DNA and RNA sequencing - to uncover the genetic basis of unresolved cases. Our focus includes neurodevelopmental disorders (particularly chromatinopathies), cardiogenetic conditions, and neurodegenerative diseases, including frontotemporal dementia. Furthermore, we systematized genetic data from our department to perform in-depth re-analysis of the unsolved cases (including via "Solvathons”) to identify novel disease-causing mechanisms and variants in known genes, as well as novel morbid genes (‘the discovery unit’).
Translating Epigenetics to the clinics
DNA methylation and other epigenetic modifications are powerful biomarkers that can reveal disorder biology, and support diagnosis - not only for genetic conditions but also for non-genetic causes such as prenatal exposures. We developed an approach to train DNA methylation-based classifiers with no access to patient data and a user-friendly, publicly available tool called “MethaDory”, compatible with various DNA methylation platforms, including arrays and long-read sequencing.
We integrated DNA methylation analysis into the ultra-rapid long-read sequencing, leading to increased diagnostic yield, reduced turnaround time, and the detection of imprinting disorders and epigenetic gene silencing without separate testing - highlighting the potential of epigenetics for both diagnostics and discovery.
Uncovering DNA effects with transcriptome analysis
Transcriptome sequencing (RNA-seq) provides a functional read-out of DNA, enabling precise interpretation of genetic variant, providing transcriptomic signatures of certain syndromes (like spliceosome disorders) and detecting molecular causes of rare disorders that are missed due to the complex nature of genomic variant interpretation (e.g., noncoding region). We have demonstrated that long read RNA sequencing, in particular, provides isoform-level resolution. Our team develops and applies novel tools and long-read RNA sequencing methods to enhance the diagnostic power of transcriptomics.
Related Groups / Labs
- KLGN Genoomdiagnostiek.
- Kleefstra group (Chromatinopathies).
- Cardiogenetics group (J.Verhoeven & W. te Rijdt).
- Neurodegenerative disorder group (L. Donker Kaat).
- Barakat group.
- Gribnau group.
Key Publications
- Training with synthetic data provides accurate and openly-available DNA methylation classifiers for developmental disorders and congenital anomalies via MethaDory
Authors: Federico Ferraro, Mark Drost, Herma van der Linde, Livija Bardina, Daphne Smits, Bianca M. de Graaf, Rachel Schot, Yolande van Bever, Alice Brooks, Laura Donker Kaat, Erwin Brosens, Ruizhi Deng, Tahsin Stefan Barakat, Virginie J.M. Verhoeven, Tjakko J. van Ham, Tjitske Kleefstra, Dmitrijs Rots
Available at: medRxiv 2025; doi: https://doi.org/10.1101/2025.03.28.25324859.
- Nanopore long-read sequencing for the critically ill facilitates ultrarapid diagnostics and urgent clinical decision making.
Authors: Daphne J. Smits, Federico Ferraro, Mark Drost, Herma C. van der Linde, Bianca M. de Graaf, Yolande van Bever, Alice S. Brooks, Livija Bardina, Hennie T. Brüggenwirth, Christophe Debuy, Laura Donker Kaat, Bastiaan T. van Dijk, Nienke van Engelen, Geert Geeven, Raoul van de Graaf, Désirée Y. van Haaften-Visser, Peter M. van Hasselt, Daphne Heijsman, Yvonne M.C. Hendriks, Rebekkah J. Hitti-Malin, Lies H. Hoefsloot, Glenn Huijbregts, Hanna IJspeert, Sander Lamballais, Jona Mijalkovic, Merel O. Mol, Diënna Nawawi, Nadine Nederpelt, Esther A.R. Nibbeling, Wouter te Rijdt, Rachel Schot, Marjon van Slegtenhorst, Frank Sleutels, Eva L.M. Ulenkate, Monique Van Veghel – Plandsoen, Judith M.A. Verhagen, David Vos, Erwin Wauters, Martina Wilke, Marc Sylva, Tahsin Stefan Barakat, Tjakko J. van Ham, Tjitske Kleefstra, Dmitrijs Rots, Virginie J.M. Verhoeven
Available at: submitted.
- Long-read DNA and RNA sequencing reveal an intronic retrotransposon insertion in TCOF1 causing Treacher Collins syndrome.
Authors: Federico Ferraro, Nikolas Kühn, Dmitrijs Rots, Herma C. van der Linde, Banin Mohseni, Leontine van Unen, Mark Drost, Mark Nellist, Marieke Koekkoek, Rachel Schot, Henriette W. de Gier, Mieke Pleumeekers, Tahsin Stefan Barakat, Tjitske Kleefstra, Marjolein Weerts, Marieke F. van Dooren, Tjakko J. van Ham
Available at: medRxiv; doi:https://doi.org/10.1101/2025.04.24.25326319
- Web-accessible application for identifying pathogenic transcripts with RNA-seq: Increased sensitivity in diagnosis of neurodevelopmental disorders.
Authors: Dekker J, Schot R, Bongaerts M, de Valk WG, van Veghel-Plandsoen MM, Monfils K, Douben H, Elfferich P, Kasteleijn E, van Unen LMA, Geeven G, Saris JJ, van Ierland Y, Verheijen FW, van der Sterre MLT, Sadeghi Niaraki F, Smits DJ, Huidekoper HH, Williams M, Wilke M, Verhoeven VJM, Joosten M, Kievit AJA, van de Laar IMBH, Hoefsloot LH, Hoogeveen-Westerveld M, Nellist M, Mancini GMS, van Ham TJ.
Available at: Am J Hum Genet. 2023 Feb 2;110(2):251-272. doi: 10.1016/j.ajhg.2022.12.015.
- Functional Assays Combined with Pre-mRNA-Splicing Analysis Improve Variant Classification and Diagnostics for Individuals with Neurofibromatosis Type 1 and Legius Syndrome.
Authors: Douben H, Hoogeveen-Westerveld M, Nellist M, Louwen J, Haan MK, Punt M, van Ommeren B, van Unen L, Elfferich P, Kasteleijn E, van Bever Y, van Vliet M, Oostenbrink R, Saris JJ, Wagner A, van Ierland Y, van Ham T, van Minkelen R.
Available at: Hum Mutat. 2023 Feb 15;2023:9628049. doi: 10.1155/2023/9628049.
- High-yield identification of pathogenic NF1 variants by skin fibroblast transcriptome screening after apparently normal diagnostic DNA testing.
Authors: Douben HCW, Nellist M, van Unen L, Elfferich P, Kasteleijn E, Hoogeveen-Westerveld M, Louwen J, van Veghel-Plandsoen M, de Valk W, Saris JJ, Hendriks F, Korpershoek E, Hoefsloot LH, van Vliet M, van Bever Y, van de Laar I, Aten E, Lachmeijer AMA, Taal W, van den Bersselaar L, Schuurmans J, Oostenbrink R, van Minkelen R, van Ierland Y, van Ham TJ.
Available at: Hum Mutat. 2022 Dec;43(12):2130-2140. doi: 10.1002/humu.24487.
Collaborations
Collaboration outside of Erasmus MC
We are part of the The European lrGS innovation network (ELRIN).
We are part of the ERDERA – the European Rare Diseases Research Alliance (via Erasmus MC).
Funding & Grants
1. “Ultrarapid Genomic Medicine to improve health management for critically ill children at Sophia's Children's Hospital (UR-SOPHIA)” (Vrienden van Sophia; main applicant: V.Verhoeven).
2. “Unlocking hearts: accelerating pediatric cardiogenetic diagnoses” (Vrienden van Sophia; main applicant: J.Verhagen).
3. “Dissecting the genomic architecture in frontotemporal dementia (FTD)” (Alzheimer Nederland, main applicant: L.Donker Kaat).
Career opportunities
If you are a GPU-based computing tower, please join our team.
Our team
- Tjakko van Ham, PhD.
- Herma C. van der Linde, MSc, analyst.
- Federico Ferraro, MSc, PhD student.
- Livija Bardina, MSc, PhD student.
- Christophe Debuy, MSc, PhD student.
- Sander Lamballais Tessensohn, PhD, bioinformatician.
- Mark Drost, PhD, labspecialist.
- Rachel Schot, MSc, analyst, lead of the discovery unit.
- Prof.Tjitske Kleefstra, MD, PhD, head of Clinical genetics department.
