Johan T den Dunnen

Leiden University Medical Centre, Leyden, South Holland, Netherlands

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Publications (350)2404.83 Total impact

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    ABSTRACT: This manuscript provides nomenclature recommendations developed by an international workgroup to increase transparency and standardization of pharmacogenetic (PGx) result reporting. Presently, sequence variants identified by PGx tests are described using different nomenclature systems. In addition, PGx analysis may detect different sets of variants for each gene, which can affect interpretation of results. This practice has caused confusion and may thereby impede the adoption of clinical PGx testing. Standardization is critical to move PGx forward. This article is protected by copyright. All rights reserved.
    Clinical Pharmacology &#38 Therapeutics 10/2015; DOI:10.1002/cpt.280 · 7.90 Impact Factor
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    ABSTRACT: Gastrointestinal tumor growth is thought to be promoted by gastrointestinal bacteria and their inflammatory products. We observed that intestine-specific conditional Apc mutant mice (FabplCre;Apc(15lox/+)) developed many more colorectal tumors under conventional than under pathogen-low housing conditions. Shotgun metagenomic sequencing plus quantitative PCR analysis of feces DNA revealed the presence of two bacterial species in conventional mice, absent from pathogen-low mice. One, Helicobacter typhlonius, has not been associated with cancer in man, nor in immune-competent mice. The other species, mucin-degrading Akkermansia muciniphila, is abundantly present in healthy humans, but reduced in patients with inflammatory gastrointestinal diseases and in obese and type 2 diabetic mice. Eradication of H. typhlonius in young conventional mice by antibiotics decreased the number of intestinal tumors. Additional presence of A. muciniphila prior to the antibiotic treatment reduced the tumor number even further. Colonization of pathogen-low FabplCre;Apc(15lox/+) mice with H. typhlonius or A. muciniphila increased the number of intestinal tumors, the thickness of the intestinal mucus layer, and A. muciniphila colonization without H. typhlonius increased the density of mucin-producing goblet cells. However, dual colonization with H. typhlonius and A. muciniphila significantly reduced the number of intestinal tumors, the mucus layer thickness, and goblet cell density to that of control mice. By global microbiota composition analysis, we found a positive association of A. muciniphila, and of H. typhlonius, and a negative association of unclassified Clostridiales with increased tumor burden. We conclude that A. muciniphila and H. typhlonius can modulate gut microbiota composition and intestinal tumor development in mice.
    Carcinogenesis 08/2015; DOI:10.1093/carcin/bgv120 · 5.33 Impact Factor
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    ABSTRACT: There are few better examples of the need for data sharing than in the rare disease community, where patients, physicians, and researchers must search for “the needle in a haystack” to uncover rare, novel causes of disease within the genome. Impeding the pace of discovery has been the existence of many small siloed datasets within individual research or clinical laboratory databases and/and disease-specific organizations, hoping for serendipitous occasions when two distant investigators happen to learn they have a rare phenotype in common and can “match” these cases to build evidence for causality. However, serendipity has never proven to be a reliable or scalable approach in science. As such, the Matchmaker Exchange (MME) was launched to provide a robust and systematic approach to rare disease gene discovery through the creation of a federated network connecting databases of genotypes and rare phenotypes using a common application programming interface (API). The core building blocks of the MME have been defined and assembled. Three MME services have now been connected through the API and are available for community use. Additional databases that support internal matching are anticipated to join the MME network as it continues to grow. This article is protected by copyright. All rights reserved
    Human Mutation 08/2015; 36(10). DOI:10.1002/humu.22858 · 5.14 Impact Factor
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    ABSTRACT: Collembola (springtails) represent a soil-living lineage of hexapods in between insects and crustaceans. Consequently, their genomes may hold key information on the early processes leading to evolution of Hexapoda from a crustacean ancestor. We assembled and annotated transcriptomes of the Collembola Folsomia candida and Orchesella cincta, and performed comparative analysis with protein-coding gene sequences of three crustaceans and three insects to identify adaptive signatures associated with the evolution of hexapods within the pancrustacean clade. Assembly of the springtail transcriptomes resulted in 37,730 transcripts with predicted open reading frames for F. candida and 32,154 for O. cincta, of which 34.2% were functionally annotated for F. candida and 38.4% for O. cincta. Subsequently, we predicted orthologous clusters among eight species and applied the branch-site test to detect episodic positive selection in the Hexapoda and Collembola lineages. A subset of 250 genes showed significant positive selection along the Hexapoda branch and 57 in the Collembola lineage. Gene Ontology categories enriched in these genes include metabolism, stress response (i.e. DNA repair, immune response), ion transport, ATP metabolism, regulation and development-related processes (i.e. eye development, neurological development). We suggest that the identified gene families represent processes that have played a key role in the divergence of hexapods within the pancrustacean clade that eventually evolved into the most species-rich group of all animals, the hexapods. Furthermore, some adaptive signatures in collembolans may provide valuable clues to understand evolution of hexapods on land.
    PLoS ONE 06/2015; 10(6). DOI:10.1371/journal.pone.0130600 · 3.23 Impact Factor
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    ABSTRACT: Mutations create variation in the population, fuel evolution and cause genetic diseases. Current knowledge about de novo mutations is incomplete and mostly indirect. Here we analyze 11,020 de novo mutations from the whole genomes of 250 families. We show that de novo mutations in the offspring of older fathers are not only more numerous but also occur more frequently in early-replicating, genic regions. Functional regions exhibit higher mutation rates due to CpG dinucleotides and show signatures of transcription-coupled repair, whereas mutation clusters with a unique signature point to a new mutational mechanism. Mutation and recombination rates independently associate with nucleotide diversity, and regional variation in human-chimpanzee divergence is only partly explained by heterogeneity in mutation rate. Finally, we provide a genome-wide mutation rate map for medical and population genetics applications. Our results provide new insights and refine long-standing hypotheses about human mutagenesis.
    Nature Genetics 05/2015; DOI:10.1038/ng.3292 · 29.35 Impact Factor
  • Johan T den Dunnen ·
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    ABSTRACT: With the cost of genome sequencing decreasing every day, DNA information has the potential of affecting the lives of everyone. Surprisingly, an individual has little knowledge about his own DNA information, can rarely access it and has hardly any control over its use. This may result in preventable, life threatening situations and also significantly inhibits scientific progress. What we urgently need is a "DNA bank", a resource providing a secure personal account where, similar to a financial institution, you can store your DNA sequence. Using this private and secure DNA bank account, you govern your sequence-related business. For any genetic study performed the data generated must be transferred (paid) to your DNA account. Using your account you regulate access, knowing for what purpose (informed consent) and only for the genetic data you are willing to share. The DNA account ensures you are in the driver's seat, know what's known, and control what's happening with it. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Human Mutation 05/2015; 36(7). DOI:10.1002/humu.22810 · 5.14 Impact Factor
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    ABSTRACT: Small insertions and deletions (indels) and large structural variations (SVs) are major contributors to human genetic diversity and disease. However, mutation rates and characteristics of de novo indels and SVs in the general population have remained largely unexplored. We report 332 validated de novo structural changes identified in whole genomes of 250 families, including complex indels, retrotransposon insertions and interchromosomal events. These data indicate a mutation rate of 2.94 indels (1-20bp) and 0.16 SVs (>20bp) per generation. De novo structural changes affect on average 4.1kbp of genomic sequence and 29 coding bases per generation, which is 91 and 52 times more nucleotides than de novo substitutions, respectively. This contrasts with the equal genomic footprint of inherited SVs and substitutions. An excess of structural changes originated on paternal haplotypes. Additionally, we observed a non-uniform distribution of de novo SVs across offspring. These results reveal the importance of different mutational mechanisms to changes in human genome structure across generations. Published by Cold Spring Harbor Laboratory Press.
    Genome Research 04/2015; 25(6). DOI:10.1101/gr.185041.114 · 14.63 Impact Factor
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    ABSTRACT: Alternative splicing is a powerful mechanism present in eukaryotic cells to obtain a wide range of transcripts and protein isoforms from a relatively small number of genes. The mechanisms regulating (alternative) splicing and the paradigm of consecutive splicing have recently been challenged, especially for genes with a large number of introns. RNA-Seq, a powerful technology using deep sequencing in order to determine transcript structure and expression levels, is usually performed on mature mRNA, therefore not allowing detailed analysis of splicing progression. Sequencing pre-mRNA at different stages of splicing potentially provides insight into mRNA maturation. Although the number of tools that analyze total and cytoplasmic RNA in order to elucidate the transcriptome composition is rapidly growing, there are no tools specifically designed for the analysis of nuclear RNA (which contains mixtures of pre- and mature mRNA). We developed dedicated algorithms to investigate the splicing process. In this paper, we present a new classification of RNA-Seq reads based on three major stages of splicing: pre-, intermediate- and post-splicing. Applying this novel classification we demonstrate the possibility to analyze the order of splicing. Furthermore, we uncover the potential to investigate the multi-step nature of splicing, assessing various types of recursive splicing events. We provide the data that gives biological insight into the order of splicing, show that non-sequential splicing of certain introns is reproducible and coinciding in multiple cell lines. We validated our observations with independent experimental technologies and showed the reliability of our method. The pipeline, named SplicePie, is freely available at: The example data can be found at: © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.
    Nucleic Acids Research 03/2015; 43(12). DOI:10.1093/nar/gkv242 · 9.11 Impact Factor
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    ABSTRACT: The formation of skeletal muscles is associated with drastic changes in protein requirements known to be safeguarded by tight control of gene transcription and mRNA processing. The contribution of regulation of mRNA translation during myogenesis has not been studied so far. We monitored translation during myogenic differentiation of C2C12 myoblasts, using a simplified protocol for ribosome footprint profiling. Comparison of ribosome footprints to total RNA showed that gene expression is mostly regulated at the transcriptional level. However, a subset of transcripts, enriched for mRNAs encoding for ribosomal proteins, was regulated at the level of translation. Enrichment was also found for specific pathways known to regulate muscle biology. We developed a dedicated pipeline to identify translation initiation sites (TISs) and discovered 5333 unannotated TISs, providing a catalog of upstream and alternative open reading frames used during myogenesis. We identified 298 transcripts with a significant switch in TIS usage during myogenesis, which was not explained by alternative promoter usage, as profiled by DeepCAGE. Also these transcripts were enriched for ribosomal protein genes. This study demonstrates that differential mRNA translation controls protein expression of specific subsets of genes during myogenesis. Experimental protocols, analytical workflows, tools and data are available through public repositories ( © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.
    Nucleic Acids Research 03/2015; 43(1). DOI:10.1093/nar/gkv281 · 9.11 Impact Factor
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    ABSTRACT: Although the benefits of next generation sequencing (NGS) for the diagnosis of heterogeneous diseases such as intellectual disability (ID) are undisputed, there is little consensus on the relative merits of targeted enrichment, whole exome sequencing (WES) or whole genome sequencing (WGS). To answer this question, WES and WGS data from the same nine samples were compared, and WES was shown not to miss any variants identified by WGS in a gene panel including ∼500 genes linked to ID (500GP). Additionally, deeply sequenced WES data was shown to adequately cover ∼99% of the 500GP, thus little additional benefit was to be expected from a targeted enrichment approach. To reduce costs, minimal sequencing criteria were determined by investigating the relation between sequenced reads and outcome parameters such as coverage and variant yield. Our analysis indicated that 60 million reads yielded a mean coverage of ∼60x: ∼97% of the 500GP sequences were sufficiently covered to exclude variants, while variant yield was ∼99.5% and false positive and false negative rates were controlled. Our findings indicate that WES is currently the optimal approach to ID diagnostics. This result depends on the capture kit and sequencing strategy used. The developed framework however is amenable to other sequencing approaches. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Human Mutation 03/2015; 36(6). DOI:10.1002/humu.22783 · 5.14 Impact Factor
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    ABSTRACT: With several therapeutic approaches in development for Huntington's disease, there is a need for easily accessible biomarkers to monitor disease progression and therapy response. We performed next-generation sequencing-based transcriptome analysis of total RNA from peripheral blood of 91 mutation carriers (27 presymptomatic and, 64 symptomatic) and 33 controls. Transcriptome analysis by DeepSAGE identified 167 genes significantly associated with clinical total motor score in Huntington's disease patients. Relative to previous studies, this yielded novel genes and confirmed previously identified genes, such as H2AFY, an overlap in results that has proven difficult in the past. Pathway analysis showed enrichment of genes of the immune system and target genes of miRNAs, which are downregulated in Huntington's disease models. Using a highly parallelized microfluidics array chip (Fluidigm), we validated 12 of the top 20 significant genes in our discovery cohort and 7 in a second independent cohort. The five genes (PROK2, ZNF238, AQP9, CYSTM1 and ANXA3) that were validated independently in both cohorts present a candidate biomarker panel for stage determination and therapeutic readout in Huntington's disease. Finally we suggest a first empiric formula predicting total motor score from the expression levels of our biomarker panel. Our data support the view that peripheral blood is a useful source to identify biomarkers for Huntington's disease and monitor disease progression in future clinical trials.European Journal of Human Genetics advance online publication, 28 January 2015; doi:10.1038/ejhg.2014.281.
    European journal of human genetics: EJHG 01/2015; 23(10). DOI:10.1038/ejhg.2014.281 · 4.35 Impact Factor
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    ABSTRACT: We describe an open-source kPAL package that facilitates an alignment-free assessment of the quality and comparability of sequencing datasets by analyzing k-mer frequencies. We show that kPAL can detect technical artefacts such as high duplication rates, library chimeras, contamination and differences in library preparation protocols. kPAL also successfully captures the complexity and diversity of microbiomes and provides a powerful means to study changes in microbial communities. Together, these features make kPAL an attractive and broadly applicable tool to determine the quality and comparability of sequence libraries even in the absence of a reference sequence. kPAL is freely available at Electronic supplementary material The online version of this article (doi:10.1186/s13059-014-0555-3) contains supplementary material, which is available to authorized users.
    Genome Biology 12/2014; 15(12):555. DOI:10.1186/PREACCEPT-1559595347144548 · 10.81 Impact Factor
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    ABSTRACT: Success rates for genomic analyses of highly heterogeneous disorders can be greatly improved if a large cohort of patient data is assembled to enhance collective capabilities for accurate sequence variant annotation, analysis, and interpretation. Indeed, molecular diagnostics requires the establishment of robust data resources to enable data sharing that informs accurate understanding of genes, variants, and phenotypes. The "Mitochondrial Disease Sequence Data Resource (MSeqDR) Consortium" is a grass-roots effort facilitated by the United Mitochondrial Disease Foundation to identify and prioritize specific genomic data analysis needs of the global mitochondrial disease clinical and research community. A central Web portal ( facilitates the coherent compilation, organization, annotation, and analysis of sequence data from both nuclear and mitochondrial genomes of individuals and families with suspected mitochondrial disease. This Web portal provides users with a flexible and expandable suite of resources to enable variant-, gene-, and exome-level sequence analysis in a secure, Web-based, and user-friendly fashion. Users can also elect to share data with other MSeqDR Consortium members, or even the general public, either by custom annotation tracks or through the use of a convenient distributed annotation system (DAS) mechanism. A range of data visualization and analysis tools are provided to facilitate user interrogation and understanding of genomic, and ultimately phenotypic, data of relevance to mitochondrial biology and disease. Currently available tools for nuclear and mitochondrial gene analyses include an MSeqDR GBrowse instance that hosts optimized mitochondrial disease and mitochondrial DNA (mtDNA) specific annotation tracks, as well as an MSeqDR locus-specific database (LSDB) that curates variant data on more than 1300 genes that have been implicated in mitochondrial disease and/or encode mitochondria-localized proteins. MSeqDR is integrated with a diverse array of mtDNA data analysis tools that are both freestanding and incorporated into an online exome-level dataset curation and analysis resource ( that is being optimized to support needs of the MSeqDR community. In addition, MSeqDR supports mitochondrial disease phenotyping and ontology tools, and provides variant pathogenicity assessment features that enable community review, feedback, and integration with the public ClinVar variant annotation resource. A centralized Web-based informed consent process is being developed, with implementation of a Global Unique Identifier (GUID) system to integrate data deposited on a given individual from different sources. Community-based data deposition into MSeqDR has already begun. Future efforts will enhance capabilities to incorporate phenotypic data that enhance genomic data analyses. MSeqDR will fill the existing void in bioinformatics tools and centralized knowledge that are necessary to enable efficient nuclear and mtDNA genomic data interpretation by a range of shareholders across both clinical diagnostic and research settings. Ultimately, MSeqDR is focused on empowering the global mitochondrial disease community to better define and explore mitochondrial diseases. Copyright © 2014 Elsevier Inc. All rights reserved.
    Molecular Genetics and Metabolism 12/2014; 114(3). DOI:10.1016/j.ymgme.2014.11.016 · 2.63 Impact Factor
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    ABSTRACT: A mutation update on the nebulin gene (NEB) is necessary because of recent developments in analysis methodology, the identification of increasing numbers and novel types of variants and a widening in the spectrum of clinical and histological phenotypes associated with this gigantic, 183 exons containing gene. Recessive pathogenic variants in NEB are the major cause of nemaline myopathy (NM), one of the most common congenital myopathies. Moreover, pathogenic NEB variants have been identified in core-rod myopathy and in distal myopathies. In this update, we present the disease-causing variants in NEB in 159 families, 143 families with NM and 16 families with NM-related myopathies. Eighty-eight families are presented here for the first time. We summarize 86 previously published and 126 unpublished variants identified in NEB. Furthermore, we have analyzed the NEB variants deposited in the Exome Variant Server (, identifying that pathogenic variants are a minor fraction of all coding variants (∼7%). This indicates that nebulin tolerates substantial changes in its amino acid sequence, providing an explanation as to why variants in such a large gene result in relatively rare disorders. Lastly, we discuss the difficulties of drawing reliable genotype-phenotype correlations in NEB-associated disease.This article is protected by copyright. All rights reserved
    Human Mutation 12/2014; 35(12). DOI:10.1002/humu.22693 · 5.14 Impact Factor
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    ABSTRACT: A recent review identified 60 common inherited renal diseases caused by DNA variants in 132 different genes. These diseases can be diagnosed with DNA sequencing, but each gene probably also has a thousand normal variants. Many more normal variants have been characterised by individual laboratories than are reported in the literature or found in publicly accessible collections. At present, testing laboratories must assess each novel change they identify for pathogenicity, even when this has been done elsewhere previously, and the distinction between normal and disease-associated variants is particularly an issue with the recent surge in exomic sequencing and gene discovery projects. The Human Variome Project recommends the establishment of gene-specific DNA variant databases to facilitate the sharing of DNA variants and decisions about likely disease causation. Databases improve diagnostic accuracy and testing efficiency, and reduce costs. They also help with genotype-phenotype correlations and predictive algorithms. The Human Variome Project advocates databases that use standardised descriptions, are up-to-date, include clinical information and are freely available. Currently, the genes affected in the most common inherited renal diseases correspond to 350 different variant databases, many of which are incomplete or have insufficient clinical details for genotype-phenotype correlations. Assistance is needed from nephrologists to maximise the usefulness of these databases for the diagnosis and management of inherited renal disease.
    Pediatric Nephrology 11/2014; 30(11). DOI:10.1007/s00467-014-2994-1 · 2.86 Impact Factor
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    ABSTRACT: Background Aerobic methanotrophs can grow in hostile volcanic environments and use methane as their sole source of energy. The discovery of three verrucomicrobial Methylacidiphilum strains has revealed diverse metabolic pathways used by these methanotrophs, including mechanisms through which methane is oxidized. The basis of a complete understanding of these processes and of how these bacteria evolved and are able to thrive in such extreme environments partially resides in the complete characterization of their genome and its architecture. Results In this study, we present the complete genome sequence of Methylacidiphilum fumariolicum SolV, obtained using Pacific Biosciences single-molecule real-time (SMRT) sequencing technology. The genome assembles to a single 2.5 Mbp chromosome with an average GC content of 41.5%. The genome contains 2,741 annotated genes and 314 functional subsystems including all key metabolic pathways that are associated with Methylacidiphilum strains, including the CBB pathway for CO2 fixation. However, it does not encode the serine cycle and ribulose monophosphate pathways for carbon fixation. Phylogenetic analysis of the particulate methane mono-oxygenase operon separates the Methylacidiphilum strains from other verrucomicrobial methanotrophs. RNA-Seq analysis of cell cultures growing in three different conditions revealed the deregulation of two out of three pmoCAB operons. In addition, genes involved in nitrogen fixation were upregulated in cell cultures growing in nitrogen fixing conditions, indicating the presence of active nitrogenase. Characterization of the global methylation state of M. fumariolicum SolV revealed methylation of adenines and cytosines mainly in the coding regions of the genome. Methylation of adenines was predominantly associated with 5′-m6ACN4GT-3′ and 5′-CCm6AN5CTC-3′ methyltransferase recognition motifs whereas methylated cytosines were not associated with any specific motif. Conclusions Our findings provide novel insights into the global methylation state of verrucomicrobial methanotroph M. fumariolicum SolV. However, partial conservation of methyltransferases between M. fumariolicum SolV and M. infernorum V4 indicates potential differences in the global methylation state of Methylacidiphilum strains. Unravelling the M. fumariolicum SolV genome and its epigenetic regulation allow for robust characterization of biological processes that are involved in oxidizing methane. In turn, they offer a better understanding of the evolution, the underlying physiological and ecological properties of SolV and other Methylacidiphilum strains. Electronic supplementary material The online version of this article (doi:10.1186/1471-2164-15-914) contains supplementary material, which is available to authorized users.
    BMC Genomics 10/2014; 15(1):914. DOI:10.1186/1471-2164-15-914 · 3.99 Impact Factor
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    ABSTRACT: Huntington disease is caused by expansion of a CAG repeat in the huntingtin gene that is translated into an elongated polyglutamine stretch within the N-terminal domain of the huntingtin protein. The mutation is thought to introduce a gain-of-toxic function in the mutant huntingtin protein, and blocking this toxicity by antibody binding could alleviate Huntington disease pathology. Llama single domain antibodies (VHH) directed against mutant huntingtin are interesting candidates as therapeutic agents or research tools in Huntington disease because of their small size, high thermostability, low cost of production, possibility of intracellular expression, and potency of blood-brain barrier passage. We have selected VHH from llama phage display libraries that specifically target the N-terminal domain of the huntingtin protein. Our VHH are capable of binding wild-type and mutant human huntingtin under native and denatured conditions and can be used in Huntington disease studies as a novel antibody that is easy to produce and manipulate. Electronic supplementary material The online version of this article (doi:10.1007/s10072-014-1971-6) contains supplementary material, which is available to authorized users.
    Neurological Sciences 10/2014; 36(3). DOI:10.1007/s10072-014-1971-6 · 1.45 Impact Factor
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    Johan den Dunnen ·

    Human Mutation 10/2014; 35(10). DOI:10.1002/humu.22420 · 5.14 Impact Factor

Publication Stats

15k Citations
2,404.83 Total Impact Points


  • 1995-2015
    • Leiden University Medical Centre
      • • Department of Human Genetics
      • • Leiden Genome Technology Center
      Leyden, South Holland, Netherlands
    • University of Groningen
      • Department of Medical Genetics
      Groningen, Province of Groningen, Netherlands
  • 2014
    • Max Planck Institute for Evolutionary Anthropology
      Leipzig, Saxony, Germany
  • 1987-2014
    • Leiden University
      • Molecular Cell Biology Group
      Leyden, South Holland, Netherlands
  • 2013
    • Netherlands Bioinformatics Centre
      Nymegen, Gelderland, Netherlands
  • 2012
    • Royal Holloway, University of London
      Эгхем, England, United Kingdom
  • 2011
    • Newcastle University
      Newcastle-on-Tyne, England, United Kingdom
    • The Human Variome Project
      Melbourne, Victoria, Australia
    • VU University Medical Center
      Amsterdamo, North Holland, Netherlands
  • 2005-2011
    • Curium-LUMC
      Leyden, South Holland, Netherlands
    • University of Amsterdam
      • Faculty of Medicine AMC
      Amsterdamo, North Holland, Netherlands
  • 2008
    • Lomonosov Moscow State University
      Moskva, Moscow, Russia
  • 1985-2008
    • Radboud University Nijmegen
      • Department of Molecular Biology
      Nijmegen, Provincie Gelderland, Netherlands
    • Erasmus Universiteit Rotterdam
      Rotterdam, South Holland, Netherlands
  • 2006
    • Imperial College London
      Londinium, England, United Kingdom
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
  • 1991
    • SickKids
      Toronto, Ontario, Canada
    • Baylor College of Medicine
      Houston, Texas, United States