De Duve Institute

Description of the legal entity:

DDUV (https://www.deduveinstitute.be/) is a multidisciplinary biomedical research institute hosting the Brussels branch of the Ludwig Institute and several laboratories of the faculty of medicine of UCLouvain, the largest French-speaking University of Belgium. DDUV counts 260 employees and has a turnover of 20 million €.

The Laboratory of Human Molecular Genetics, headed by Prof Miikka Vikkula, MD, PhD, focuses on characterization of the underlying pathophysiology of vascular anomalies, such as lymphedema, as well as cleft lip and palate, and selected cancers. The long-term goal is to develop molecular precision therapies for these disorders. The lab is specialized in evaluating the contribution of genetic variation to human disease. This research is based on blood and tissue samples collected from patients in collaboration with clinicians and multidisciplinary centers worldwide, and especially with the highly-specialized Vascular Anomaly Center (including primary lymphedema) and the Cancer Center (for secondary lymphedema) at the University Clinics Saint-Luc, UCLouvain, Brussels. The lab analyses patients’ genomes using high-throughput (NGS) sequencing, including targeted panels, WES (whole exome sequencing), WGS (whole genome sequencing) and RNAseq. With its full-time bioinformatician, the group has developed an in-house software called Highlander implementing specialized bioinformatic tools for NGS analyses. Recently, a large powerful computational cluster to run and store such data was also installed. A mathematician in the group develops novel algorithms for genome analyses, and a bioinformatic programmer now works tightly with the bioinformatician to test and develop existing and novel analytical tools. The group also hosts and runs the UCLouvain Genomics Platform.

Curriculum Vitae:

Prof. M. Vikkula, MD, PhD (Male): Co-director of the de Duve Institute, PI with over 20 years of expertise in human genetics, as well as lymphatic and vascular biology. Also, specialized in generation and characterisation of mouse models for studying vascular development and disease, and their pre-clinical testing. H-index: 57 (Scopus), 64 (Google Scholar). Selected awards: First Generet Prize for the study of Rare Diseases (Belgium) (2018) (1M€), INBEV-BAILLET LATOUR Clinical Research Award, Belgium (2013) (150K€).

Dr Pascal Brouillard, PhD (Male): Senior researcher and manager of the Genomics platform of UCLouvain. Expert in genetic analysis of vascular anomalies, with a strong focus on lymphedema. Has extensive expertise in using Highlander to search for mutations and genomic signatures. H-index: 14.

Dr Raphaël Helaers, PhD (Male): Bioinformatician who developed the NGS analysis software Highlander (http://sites.uclouvain.be/highlander/) and continues to implement it with new tools. Co-promoter of the ongoing PhD thesis work of a mathematician to develop tools to study oligogenic inheritance. Supervises the groups bioinformatic programmer. H-index:10.

Audrey Debue (Female): Laboratory technician in molecular biology and NGS sample preparation. Dominique Cottem (Female): Laboratory technician in molecular biology and NGS sample preparation.

DDUV Main tasks in the project per WP

• WP2: Gene expression analysis (Task 2.3)

WP9 DDUV will contribute to dissemination and communication activities

List of up to 5 relevant publications, and/or products, services (including widely-used datasets or software), or other achievements relevant to the call content

• Amyere M, Revencu N, Helaers R, Pairet E, Baselga E, Cordisco M, …, Mulliken JB, Boon LM, Vikkula M. Germline loss-of-function mutations in EPHB4 cause a second form of capillary malformation–arteriovenous malformation (CM-AVM2) deregulating RAS-MAPK signaling. Circulation 2017, 136(11) :1037-48. IF=18.88

• Brouillard P, Dupont L, Helaers R, Coulie R, Tiller GE, Peeden J, Colige A, Vikkula M (2017). Loss of ADAMTS3 activity causes Hennekam lymphangiectasia-lymphedema syndrome 3. Hum Mol Genet 26, 4095-4104.
• Brouillard P, Boon L and Vikkula M. (2014). Genetics of lymphatic anomalies. J Clin Invest 124, 898-904.

• Alders M, Hogan BM, Gjini E, Salehi F, Al-Gazali L, Hennekam EA, Holmberg EE, Mannens MM, Mulder MF, Offerhaus GJ, Prescott TE, Schroor EJ, Verheij JB, Witte M, Zwijnenburg PJ, Vikkula M, Schulte-Merker S, and Hennekam RC (2009). Mutations in CCBE1 cause generalized lymph vessel dysplasia in humans. Nat Genet. 41: 1272-1274.
• Irrthum A, Devriendt K, Chitayat D, Matthijs G, Glade C, Steijlen PM, Fryns JP, Van Steensel MA, and Vikkula M(2003). Mutations in the transcription factor gene SOX18 underlie recessive and dominant forms of hypotrichosis-lymphedema-telangiectasia. Am J Hum Genet 72, 1470-1478.

List of up to 5 relevant previous projects or activities, connected to the subject of this proposal

• 2019-2024 EU MSCA-ITN-2018, Co-ordinator of the VA Cure Network (512K/4 years)
• 2019-2022 FNRS PDR Belgium (vascular anomalies)(PI)(320K/4 years)
• 2019-2020 First Generet Prize for the study of Rare Diseases (Belgium)(PI)(1M/4 years)
• 2015-2019 FRFS-WELBIO 2015, Walloon Excellence in Lifesciences and Biotechnology, Belgium (PI) (600K/4 years)

2011-2015  WELBIO-CR-2010-15, Walloon Excellence in Lifesciences and Biotechnology, Belgium (PI) (600K/4 years)

Infrastructure and/or major items of technical equipment

The laboratory is located in the de Duve Institute at the medical faculty of UCLouvain. It comprises 3 laboratories (6 double-sided benches), one cold room, one completely equipped cell culture room, five office rooms, and one library/meeting room shared by other groups on the floor. Besides basic requirements, the major equipment include: a King Fisher Flex for DNA extraction; a LightCycler 480 System for qPCR; a Sanger sequencer; an Agilent TapeStation, the Genomics Platform of UCL composed of an Affymetrix station, an Ion Torrent PGM, an Ion Proton with Ion Chef and a large cluster (450 processors, 10 GPU, 1,8 Tb of RAM, 1,5 Pb of storage) for data analysis and storage. The lab developed “Highlander” (http://sites.uclouvain.be/highlander/), a software for easy NGS-data analysis. All of the computers and clusters are connected to a high-speed network. The Institute has local IT support and a firewall protects the network.

A number of equipment is also available in the de Duve Institute, e.g. confocal microscopy, dual photon microscopy, FACS, an Orbitrap Fusion Lumos mass spec (3 analyzers & 4 MS/MS fragment analyzers), FRET, and a biological microanalysis station.

We work in close association with Prof. Laurence Boon, who co-ordinates the Vascular Anomalies Center at the University hospital, CUSL and with several other centers for vascular anomalies worldwide, such as with Dr. Arin Greene (Children’s Hospital, Boston, MA, USA), Anne Dompmartin (CHU Caen, France), Isabelle Quere (Montpellier, France) and Guido Giacalone (Belgium). For secondary lymphedema, we collaborate with Prof Martine Berlière from the University hospital, CUSL, Cancer Center. These invaluable collaborations have allowed us to collect a biobank of DNA samples from more than 3000 families (> 10 000 samples), including more than 750 lymphedemas, 1200 CL/Ps and over 1000 frozen tissues from various vascular anomalies. Besides the key personnel mentioned above, the laboratory currently includes one PhD student (on a Televie fellowship), one Postdoctoral researcher on institutional fellowship (de Duve Institute) and one Masters student, all working on the genetic bases and pathophysiology of lymphedema.

Operational capacity

Fully operational