Genetics of disease, diagnosis and treatment

Our goals are to identify the genetic causes of disease, understand the pathomechanisms, define phenotypic disease spectra  and identify disease modifiers. In this way we expect to contribute to the identification of therapeutic targets and develop therapeutic strategies and prevention for the genetic disease areas within our scope. Our research focus is directly aligned with our areas of diagnostic and clinical expertise, to achieve synergy between research and the clinic. Our aim is that our patients will ultimately benefit from the results of our research efforts, by receiving genetic diagnoses, learning more about prognosis and eventually open up possibilities for treatment. Our disease areas are historically determined and aligned to the LUMC research profiles Translational Neuroscience  (TN) and Innovation in Health Strategy and Quality of Care (IHQC).  We focus on genetic nerve and brain disorders, specifically developmental disorders and hereditary small vessel diseases (hSVD) such as CADASIL, as well as disorders of growth, haemoglobin and clinical translation of pharmacogenetics. All work is done in close collaboration with the department of Human Genetics.

Our research is translational, from the patient to the lab and back. We apply and develop genomics technology, genome and RNA sequencing in daily patient care, and are supported by high-quality bioinformatics and gene variant databases. In this way we capitalize on the novel developments in genetics and bioinformatics.

Our department has always been at the forefront of introducing new technologies in genetic diagnostics, from MLPA,  array to whole exome sequencing. Furthermore, we are considered international expertise centers in the areas of hemoglobinopathies, CADASIL and Coffin-Siris syndrome, leading to a significant number of publications, invited presentations and workshops at international symposia. This research line has significant international collaborations with groups in the UK, US and several European countries. Considerable research grants have been obtained from for example The Dutch Brain Foundation and ZonMW.

We participate in European and nation initiative, such as the ERN Hematological diseases and national studies on the feasibility of WGS in routine diagnostics.

Recently, breakthroughs have been achieved in the CADASIL/NOTCH3 research area, with recent papers in internationally acclaimed journals providing in vitro proof of concept for the genetic therapeutic approach of 'NOTCH3 cysteine correction', as well as the discovery that CADASIL-associated NOTCH3 variants are highly frequent in population biobanks (1:300) and the finding of the first clinically significant NOTCH3 genotype-phenotype correlation.

The entire whole exome sequencing (WES) flow has been implemented in the routine DNA diagnostic service. We offer targeted panel, exomes and even "high priority" WES/WGS for rapid diagnostics in pre- and perinatal care. Turn around times can be as short as 7 days. Innovation focussed mainly on Next Generation Sequencing (NGS). Technological developments here were breathtaking, demanding continuous investment of equipment. Latest developments are label-free sequencing (Ion Torrent technology), real-time single molecule sequencing (Pacific Biosciences) and long range phasing technologies (10x Genomics). These technological developments go together with the development of ways to analyse the data, pipelines and bioinformatic tools. Many publications report the successful implementation of NGS in research and diagnosis. Most focus was on finding the cause of (rare) genetic diseases and detailed studies of RNA-expression. In parallel we strengthened the Leiden position in the field of gene variant databases, LOVD is the source of information required to evaluate the consequences of variants found in patient, is it disease-causing or not?

For diagnostics we will focus on improved analysis by NGS haplotyping and copy-number analysis from exomes.  We will implement even faster pre- and perinatal WES/WGS earlier/faster diagnosis (neonatal, prenatal).

We will align our diagnostics with the priority areas in order to improve the link with the other LUMC departments, such as Human Genetics, Pathology, Immunology and Oncology.

We already started a collaboration with the department MCB for the development of genetic replacement therapies for Hb-pathies. Crsipr/Cas9 technology will be used to repair intronic mutation that affect splicing of globin genes. In this way we expect to be able to replace defective hematopoietic stem cells with genetically corrected autologous cells.

The research line of the group of Prof. Frank Baas focussed on Neurogenetic research with emphasis on neurodegeneration and associated neuroinflammation. Animal models for neurogenetic disorders will be implement for research on pathomechanisms. We will continue our successful research for modelling neurogenetic diseases in zebrafish (Schaeffer et al, Cell 2015, Lardelli et al, Nature Genetics 2017).