Ivo Fokkema

Publications (13) View all

• Article: LOVD v.2.0: the next generation in gene variant databases.

  Ivo F A C Fokkema, Peter E M Taschner, Gerard C P Schaafsma, J Celli, Jeroen F J Laros, Johan T den Dunnen
  [show abstract] [hide abstract]
  ABSTRACT: Locus-Specific DataBases (LSDBs) store information on gene sequence variation associated with human phenotypes and are frequently used as a reference by researchers and clinicians. We developed the Leiden Open-source Variation Database (LOVD) as a platform-independent Web-based LSDB-in-a-Box package. LOVD was designed to be easy to set up and maintain and follows the Human Genome Variation Society (HGVS) recommendations. Here we describe LOVD v.2.0, which adds enhanced flexibility and functionality and has the capacity to store sequence variants in multiple genes per patient. To reduce redundancy, patient and sequence variant data are stored in separate tables. Tables are linked to generate connections between sequence variant data for each gene and every patient. The dynamic structure allows database managers to add custom columns. The database structure supports fast queries and allows storage of sequence variants from high-throughput sequence analysis, as demonstrated by the X-chromosomal Mental Retardation LOVD installation. LOVD contains measures to ensure database security from unauthorized access. Currently, the LOVD Website (http://www.LOVD.nl/) lists 71 public LOVD installations hosting 3,294 gene variant databases with 199,000 variants in 84,000 patients. To promote LSDB standardization and thereby database interoperability, we offer free server space and help to establish an LSDB on our Leiden server.
  Human Mutation 05/2011; 32(5):557-63. · 5.69 Impact Factor
• Article: Leiden Open Variation Database of the MUTYH gene.

  Astrid A Out, Carli M J Tops, Maartje Nielsen, Marjan M Weiss, Ivonne J H M van Minderhout, Ivo F A C Fokkema, Marie-Pierre Buisine, Kathleen Claes, Chrystelle Colas, Riccardo Fodde, [......], Rodney J Scott, Bruno Vankeirsbilck, Rikke Veggerby Grønlund, Juul T Wijnen, Friedrik P Wikman, Stefan Aretz, Julian R Sampson, Peter Devilee, Johan T den Dunnen, Frederik J Hes
  [show abstract] [hide abstract]
  ABSTRACT: The MUTYH gene encodes a DNA glycosylase involved in base excision repair (BER). Biallelic pathogenic MUTYH variants have been associated with colorectal polyposis and cancer. The pathogenicity of a few variants is beyond doubt, including c.536A4G/p.Tyr179Cys and c.1187G4A/p.Gly396Asp (previously c.494A4G/p.Tyr165Cys and c.1145G4A/p.Gly382Asp).However, for a substantial fraction of the detected variants, the clinical significance remains uncertain,compromising molecular diagnostics and thereby genetic counseling. We have established an interactive MUTYH gene sequence variant database (www.lovd.nl/MUTYH) with the aim of collecting and sharing MUTYH genotype and phenotype data worldwide. To support standard variant description, we chose NM_001128425.1 as the reference sequence. The database includes records with variants per individual, linked to available phenotype and geographic origin data as well as records with in vitro functional and in silico test data. As of April 2010, the database contains 1968 published and 423 unpublished submitted entries, and 230 and 61 unique variants,respectively. This open-access repository allows all involved to quickly share all variants encountered and communicate potential consequences, which will be especially useful to classify variants of uncertain significance.
  Human Mutation 11/2010; 31(11):1205-15. · 5.69 Impact Factor
• Article: Therapeutic exon skipping for dysferlinopathies?

  Annemieke Aartsma-Rus, Kavita H K Singh, Ivo F A C Fokkema, Ieke B Ginjaar, Gert-Jan van Ommen, Johan T den Dunnen, Silvère M van der Maarel
  [show abstract] [hide abstract]
  ABSTRACT: Antisense-mediated exon skipping is a promising therapeutic approach for Duchenne muscular dystrophy (DMD) currently tested in clinical trials. The aim is to reframe dystrophin transcripts using antisense oligonucleotides (AONs). These hide an exon from the splicing machinery to induce exon skipping, restoration of the reading frame and generation of internally deleted, but partially functional proteins. It thus relies on the characteristic of the dystrophin protein, which has essential N- and C-terminal domains, whereas the central rod domain is largely redundant. This approach may also be applicable to limb-girdle muscular dystrophy type 2B (LGMD2B), Myoshi myopathy (MM) and distal myopathy with anterior tibial onset (DMAT), which are caused by mutations in the dysferlin-encoding DYSF gene. Dysferlin has a function in repairing muscle membrane damage. Dysferlin contains calcium-dependent C2 lipid binding (C2) domains and an essential transmembrane domain. However, mildly affected patients in whom one or a large number of DYSF exons were missing have been described, suggesting that internally deleted dysferlin proteins can be functional. Thus, exon skipping might also be applicable as a LGMD2B, MM and DMAT therapy. In this study we have analyzed the dysferlin protein domains and DYSF mutations and have described what exons are promising targets with regard to applicability and feasibility. We also show that DYSF exon skipping seems to be as straightforward as DMD exon skipping, as AONs to induce efficient skipping of four DYSF exons were readily identified.
  European journal of human genetics: EJHG 02/2010; 18(8):889-94. · 3.56 Impact Factor
• Article: VarioML framework for comprehensive variation data representation and exchange.

  Myles G Byrne, Ivo Fac Fokkema, Owen Lancaster, Tomasz Adamusiak, Anni Ahonen-Bishopp, David Atlan, Christophe Beroud, Michael Cornell, Raymond Dalgeish, Andrew Devereau, George Patrinos, Morris A Swertz, Peter Em Taschner, Gudmundur A Thorisson, Mauno Vihinen, Anthony J Brookes, Juha Muilu
  [show abstract] [hide abstract]
  ABSTRACT: BACKGROUND: Sharing of data about variation and the associated phenotypes is a critical need, yet variant information can be arbitrarily complex, making a single standard vocabulary elusive and re-formatting difficult. Complex standards have proven too time-consuming to implement. RESULTS: The GEN2PHEN project addressed these difficulties by developing a comprehensive data model for capturing biomedical observations, Observ-OM, and building the VarioML format around it. VarioML pairs a simplified open specification for describing variants, with a toolkit for adapting the specification into one's own research workflow. Straightforward variant data can be captured, federated, and exchanged with no overhead; more complex data can be described, without loss of compatibility. The open specification enables push-button submission to gene variant databases (LSDB's) e.g., the Leiden Open Variation Database, using the Cafe Variome data publishing service, while VarioML bidirectionally transforms data between XML and web-application code formats, opening up new possibilities for open source web applications building on shared data. A Java implementation toolkit makes VarioML easily integrated into biomedical applications. VarioML is designed primarily for LSDB data submission and transfer scenarios, but can also be used as a standard variation data format for JSON and XML document databases and user interface components. CONCLUSIONS: VarioML is a set of tools and practices improving the availability, quality, and comprehensibility of human variation information. It enables researchers, diagnostic laboratories, and clinics to share that information with ease, clarity, and without ambiguity.
  BMC Bioinformatics 10/2012; 13(1):254. · 2.75 Impact Factor
• Article: Therapeutic exon skipping for dysferlinopathies?

  Annemieke Aartsma-Rus, Kavita Hk Singh, Ivo Fac Fokkema, Ieke B Ginjaar, Gert-Jan van Ommen, Johan T den Dunnen, Silvère M van der Maarel
  European journal of human genetics: EJHG 09/2010; 18(9):1072-3. · 3.56 Impact Factor