Nael Nadif Kasri, PhD

Dr. Heather C. Mefford, MD, PhD.

Dr. Bert de Vries, MD, PhD.

Dr. David A. Koolen, MD, PhD.

Nael Nadif Kasri, PhD

Group leader, assistant professor
Neurobiologist
Radboud University Medical Centre
Department of Human Genetics

Contact Information

Radboud University Medical Centre
PO Box 9101, 6500 HB, The Netherlands
Email: n.nadif@donders.ru.nl
Telephone Number: 0031 24 3614242

Education:

Postdoctoral fellow: Cold Spring Harbor Laboratory, US 2005-2010
PhD: Catholic University Leuven, Belgium, 2000-2004
Master’s: Catholic University Leuven, Belgium, 1996-2000

Research Interests

Dr. Nael Nadif Kasri, is a neurobiologist who has extensive experience with the molecular mechanisms underlying synaptic plasticity, including imaging and electrophysiological methods in cellular and animal models. Since the start of his postdoctoral studies he has been interested in understanding the molecular mechanisms of neurodevelopmental disorders. In his postdoc he mainly focused on understanding the function of Intellectual disability (ID) genes related to the RhoGTPase pathway and he was among the first to posit that ID disorders are disorders of the synapse.

When starting his lab in 2011 at the Radboudumc, he joined the Human Genetics department (Nijmegen, the Netherlands) where he started several collaborations to understand the synaptic basis of ID. As such he has focused his research on several syndromes that were initially discovered in Nijmegen, being Kleefstra syndrome and Koolen-de Vries Syndrome. One of his recent contributions is the implementation of multi-electrode recordings in human induced pluripotent stem cells. This technique enables the stratification of patients who suffer from autism, which may lead to more specific therapies.

Dr. Nael Nadif Kasri was awarded with a Human Frontiers fellowship at Cold Spring Harbor Laboratories (USA), where he performed his second postdoctoral study. Since 2011 he has his own research group at the Radboudumc, and became part of the Donders Institute in Nijmegen, the Netherlands. There he was granted a prestigious Hypatia fellowship and a Marie Curie Career Integration Grant.

Publications

Total number of publications: 54 H index: 21

1. Frega M, van Gestel S, Linda K, van der Raadt J, Keller J, van Rhijn JR, Schubert D, Albers CA, Nadif Kasri N. Rapid neuronal differentiation of induced pluripotent stem cells for measuring network activity on micro-electrode arrays 2017 JOVE, doi: 10.3791/54900.

2. Martens M, Frega M, Classen J, Epping L, Bijvank E, Benevento M, van Bokhoven H, Tiesinga P, Schubert D, Nadif Kasri N. Euchromatin histone methyltransferase 1 regulates cortical neuronal network development. Sci Rep. 2016 6:35756.

3. Benevento M, Iacono G, Selten M, Ba W, Oudakker A, Frega M, Keller J, Mancini M, Lewerissa E, Kleefstra T, Stunnenberg HG, Zhou H, van Bokhoven H and Nadif Kasri N. Histone methylation by the Kleefstra syndrome protein EHMT1 mediates homeostatic synaptic scaling. Neuron 2016, 91:341-55.

4. Ba W, Selten MM, van der Raadt J, van Veen H, Li LL, Benevento M, Oudakker AR, Lasabuda RSE, Letteboer SJ, Roepman R, van Wezel RJA, Courtney MJ, van Bokhoven H and Nadif Kasri N. ARHGAP12 functions as a developmental brake on excitatory synapse function. Cell Reports 2016, 4:1355-68

5. Ba W, Yan Y, Reijnders MR, Schuurs-Hoeijmakers JH, Feenstra I, Bongers EM, Bosch DG, de Leeuw N, Pfundt R, Gilissen C, de Vries PF, Veltman JA, Hoischen A, Mefford HC, Eichler EE, Vissers LE, Nadif Kasri N.#*, de Vries BB TRIO loss of function is associated with mild intellectual disability and affects dendritic branching and synapse function. Hum Mol Genet. 2016 25:892-902

6. Rivero O, Selten M, Sich S, Popp S, Bacmeister L, Amendola E, Negwer M, Schubert D, Proft F, Kiser D, Schmitt A, Gross C, Kolk SM, Strekalova T, van den Hove D, J. Resink T, Nael Nadif Kasri#, Klaus-Peter Lesch Cadherin-13, a risk gene for neurodevelopmental and psychiatric disorders, impacts cognition and GABAergic function in hippocampus. Transl Psychiatry 2015, 5:e655

7. Nikkie FM Olde Loohuis, Ba W, Peter Stoerchel, Aron Kos, Amanda Jager, Gerhard Schratt, Gerard JM Martens, Hans van Bokhoven, Nael Nadif Kasri#* and Armaz Aschrafi#. MicroRNA-137 Controls Synaptic Efficacy and mGluR-Dependent LTD by Targeting AMPA-Receptor Subunit GluA1. Cell Reports, 2015 11:1876-84.

8. Nakano-Kobayashi A, Tai Y, Nadif Kasri N#, Van Aelst L# The X-linked Mental Retardation Protein OPHN1 Interacts with Homer1b/c to Control Spine Endocytic Zone Positioning and Expression of Synaptic Potentiation. J Neurosci. 2014 ;34:8665-71.

9. Nadif Kasri N#, Nakano-Kobayashi# A and van Aelst, L. Rapid synthesis of the X-linked mental retardation protein OPHN1 mediates mGluR-dependent LTD through interaction with the endocytic machinery. Neuron 2011, 72, 300–315

10. Nadif Kasri N, Nakano-Kobayashi A, Malinow R, Li B and van Aelst L. The Rho-linked mental retardation protein oligophrenin-1 controls synapse maturation and plasticity by stabilizing AMPA receptors. Genes Dev 2009, 23, 1289–1302

Dr. Heather C. Mefford, MD, PhD.

Associate Professor of Pediatrics, University of Washington, Division of Genetic Medicine
Attending physician, Seattle Children’s Hospital, Genetic Medicine Clinic.

Contact Information

University of Washington
Department of Pediatrics
1959 NE Pacific St, Box 356320
Seattle, WA 98195
Email: hmefford@uw.edu
Telephone Number: (206) 543-4748
Fax Number: (206) 543-3184

Education

MD – University of Washington School of Medicine (2003)
PhD – University of Washington, Department of Genetics (2001) with Dr. Barbara Trask
Thesis: Evolution & biology of a subtelomeric repeat containing an expressed olfactory receptor gene
Residency – Department of Pediatrics, University of Washington, 2003-2006
Fellowship – Division of Medical Genetics, University of Washington, 2005-2008

Research Interests

Dr. Mefford’s research laboratory devoted to the discovery of novel genetic and genomic causes of pediatric disease. A major focus of their current work is to identify causes of pediatric epilepsy. To do this, they employ state-of-the-art technologies including whole exome sequencing, targeted gene panel sequencing and custom array comparative genomic hybridization (aCGH). The Mefford lab has discovered numerous new epilepsy genes and copy number variants. Dr. Mefford has also been involved in the discovery and characterization of several new genomic disorders, including deletions of chromosomes 1q21, 15q13 and 17q12, each of which cause a range of clinical features. She is continuing to investigate individuals with these conditions to better understand the variable outcomes. Dr. Mefford’s clinical interests parallel her research interests and include seeing patients with genomic disorders and patients with severe epilepsies and neurocognitive defects of unknown etiology.

Selected Publications

1: Myers CT, Mefford HC^ (2015) Advancing epilepsy genetics in the genomic era. Genome Medicine 7:91

2: Carvill GL, Crompton DE, Regan BM, McMahon JM, Saykally J, Zemel M, Schneider AL, Dibbens L, Howell KB, Mandelstam S, Leventer FJ, Harvey AS, Mullen SA, Berkovic SF, Sullivan J, Scheffer IE, Mefford HC^ (2015) Epileptic spasms are a feature of DEPDC5 mTORopathy. Neurology: Genetics (in press).

3: Jones K, Schwarze U, Adam M, Byers PH, Mefford HC^ (2015) A homozygous B3GAT3 mutation causes a severe syndrome with multiple fractures, expanding the phenotype of linkeropathy syndromes. Am J Med Gen doi:10.1002/ajmg.a.37209 [Epub ahead of print].

4: Bernier R, Steinman KJ, Reilly B, Wallace AS, Sherr EH, Pojman N, Mefford HC, Gerdts J, Earl R, Hanson E, Goin-Kochel RP, Berry L, Kanne S, Snyder LAG, Spence S, Ramocki MB, Evans DW, Spiro JE, Martin CL, Ledbetter DH, Chunk WK, Simons VIP Consortium (2015) Clinical phenotype of the recurrent 1q21.1 copy number variation. Genet Med doi: 10.1038/gim.2015.78 [epub ahead of print].

5: Carvill GL, McMahon JM, Schneider A, Zemel M, Myers CT, Saykally J, Nguyen J, Robbiano A, Zara F, Specchio N, Mecarelli O, Smith RL, Leventer RJ, Møller RS, Nikanorova M, Dimova P, Jordanova A, Petrou S, Euroepinomics RES, Helbig I, Striano P, Weckhuysen S, Berkovic SF, Scheffer IE, Mefford HC^. Mutations in the GABA transporter GAT-1 cause epilepsy with myoclonic astatic seizures. American Journal of Human Genetics 96:808-15.

6: van Bon BW, Coe BP, Bernier R, Green C, Gerdts J, Witherspoon K, Kleefstra T, Willemsen MH, Kumar R, Bosco P, Fichera M, Li D, Amaral D, Cristofoli F, Peeters H, Haan E, Romano C, Mefford HC, Scheffer I, Gecz J, de Vries BB, Eichler EE. Disruptive de novo mutations in DYRK1A lead to a syndromic form of autism and ID (2015) Mol Psych doi:10.1038/mp.2015.5 [Epub ahead of print].

7: Larsen J, Carvill GL, Gardella E, Kluger G, Schmiedel G, Barisic N, Depienne C, Brilstra E, Mang Y, Nielsen JEK, Kirkpatrick M, Goudie D, Goldman R, Jähn JA, Jepsen B, Gill D, Döcker M, Biskup S, McMahon JM, Koeleman B, Harris M, Braun K, de Kovel CGF, Marini C, Specchio N, Djémié T, Weckhuysen S, Tommerup N, Troncoso M, Troncoso L, EuroEPINOMICS RES CRP, Bevot A, Wolff M, Hjalgrim H, Guerrini R, Scheffer IE, Mefford HC^, Møller RS (2015) The phenotypic spectrum of SCN8A encephalopathy. Neurology 84:480-9.

8: EuroEPINOMICS-RES Consortium, Epilepsy Phenome/Genome Project, and Epi4K Consortium (2014) De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies. Am J Hum Genet 95:360-70. PMCID PMC4185114.

9: Mefford HC^ (2014) CNVs in epilepsy. Current Genetic Medicine Reports. 2:162-7.

10: Bernier R, Golzio C, Xiong B, Stessman H, Coe BP, Penn O, Witherspoon K, Gerdts J, Baker C, Vulto-van Silfhout AT, Schuurs-Hoeijmakers JH, Fichera M, Bosco P, Buono S, Alberti A, Failla P, Peeters H, Steyaert J, Vissers LELM, Francescatto L, Mefford HC, Rosenfeld JA, Bakken T, O’Roak BJ, Pawlus M, Moon R, Shendure J, Amaral DG, Lein E, Rankin J, Romano C, de Vries BBA, Katsanis N, Eichler EE (2014) Disruptive CHD8 mutations define a subtype of autism early in development. Cell 158:263-76. PMCID: PMC4136921.

11: Reinthaler EM, Lal D, Lebon S, Hildebrand MS, Dahl HH, Regan BM, Feucht M, Steinböck H, Neophytou B, Ronen GM, Roche L, Gruber-Sedlmayr U, Geldner J, Haberlandt E, Hoffmann P, Herms S, Gieger C, Waldenberger M, Franke A, Wittig M, Schoch S, Becker AJ, Hahn A, Männik K, Toliat MR, Winterer G; The 16p11.2 European Consortium, Lerche H, Nürnberg P, Mefford H, Scheffer IE, Berkovic SF, Beckmann JS; The EPICURE Consortium; The EuroEPINOMICS Consortium, Sander T, Jacquemont S, Reymond A, Zimprich F, Neubauer BA (2014) 16p11.2 600 kb Duplications Confer Risk for Typical and Atypical Rolandic Epilepsy. Hum Mol Gen 23:6069-80.

12: Watson CT, Marques-Bonet T, Sharp AJ, Mefford HC^ (2014) The genetics of microdeletion and microduplication syndromes: an update. Annu Rev Genomics Hum Genet 15:215-44.

13: Carvill GL, Weckhuysen S, McMahon JM, Hartmann C, Moller RS, Hjalgrim H, Cook J, Geraghty E, O’Roak BJ, Petrou S, Clarke A, Gill D, Sadleir LG, Muhle H, von Spiczak S, Nikanorova M, Gazina EV, Suls A, Shendure J, De Jonghe P, Helbig I, Berkovic SF, Scheffer IE, Mefford HC^ (2013) GABRA1 and STXBP1: novel genetic causes of Dravet syndrome. Neurology

14: Mullen SA#, Carvill GL#, Bellows S, Bayly MA, Trucks H, Lal D, Sander T, Berkovic SF, Dibbens LM, Scheffer IE, Mefford HC^ (2013) Copy number variants are frequent in genetic generalized epilepsy with intellectual disability. Neurology 81:1507-14.

15: Carvill GL, Regan BM, Yendle SC, O’Roak BJ, Lozovaya N, Bruneau N, Burnashev N, Khan A, Cook J, Sadleir LG, Turner SJ, Tsai MH, Webster R, Ouvrier R, Damiano J, Berkovic SF, Shendure J, Hildebrand M, Szepetowski P, Scheffer IE, Mefford HC^ (2013) GRIN2A mutations cause epilepsy-aphasia spectrum disorders. Nature Genetics 45:1073-6. PMCID: PMC3868952.

16: Epi4K Consortium; Epilepsy Phenome/Genome Project. (2013) De novo mutation in epileptic encephalopathies. Nature 501:217-21. PMCID: PMC3773011.

17: Carvill GL, Heavin SB, Yendle SC, McMahon JM, O’Roak BJ, Cook J, Khan A, Dorschner MO, Weaver M, Calvery S, Malone S, Wallace G, Stanley T, Bye AME, Bleasel A, Howell KB, Kivity S, Mackey MT, Rodriguez-Casero V, Webster R, Korczyn A, Afawi Z, Zelnick N, Lerman-Sagie T, Lev D, Møller RS, Gill D, Andrade DM, Freeman JL, Sadleir LG, Shendure J, Berkovic SF, Scheffer IE, Mefford HC^ (2013) Targeted resequencing in epileptic encephalopathies reveals marked genetic heterogeneity and novel genes including CHD2 and SYNGAP1. Nature Genetics 45:825-30. PMCID: PMC3704157.

18: Carvill GL, Mefford HC^ (2013) Microdeletion syndromes. Curr Opin Genet Dev 23:232-9.

19: O’Roak BJ, Vives L, Fu W, Egertson JD, Stanaway IB, Phelps IG, Carvill GL, Kumar K, Lee C, Ankenman K, Munson J, Hiatt JB, Turner EH, Levy R, O’Day DR, Krumm N, Coe BP, Martin BK, Borenstein E, Nickerson DA, Mefford HC, Doherty D, Akey JM, Bernier R, Eichler EE, Shendure J (2012) Massively multiplex targeted sequencing identified genes recurrently disrupted in autism spectrum disorders. Science 338:1619-22. PMCID: PMC3528801.

20: Mefford HC^, Batshaw ML, Hoffman EP (2012) Genomics, Intellectual Disability and Autism. New England Journal of Medicine 366:733-43.

21: Mefford HC, Shur N, Rosenfeld J (2012) 15q24 Microdeletion. In GeneReviews at GeneTests: Medical Genetics Information Resource. Copyright, University of Washington, Seattle, 1997-2011. Available at http://www.genetests.org.

22: Mefford HC^, Rosenfeld JA, Shur N, Slavotinek AM, Cox VA, Hennekam RC, Firth HV, Willatt L, Wheeler P, Morrow EM, Cook J, Sullivan R, Oh A, McDonald MT, Zonana J, Keller K, Hannibal MC, Ball S, Kussmann J, Gorski J, Zelewski S, Banks V, Smith W, Smith R, Paull L, Rosenbaum KN, Amor DJ, Silva J, Lamb A, Eichler EE (2011) Further clinical and molecular delineation of the 15q24 microdeletion syndrome. J Med Genet 49:110-8. PMCID: PMC3261729

23: *Mefford HC^, Yendle SC, Hsu C, Cook J, Geraghty E, McMahon JM, Eeg-Olofsson O, Sadleir LG, Gill D, Ben-Zeev B, Lerman-Sagie T, Mackay M, Freeman JL, Andermann E, Pelakanos J, Andrews I, Wallace G, Eichler EE, Berkovic SF, Scheffer IE (2011) Rare copy number variants are an important cause of epileptic encephalopathies. Annals of Neurology 70:974-85. PMCID: PMC3245646

24: van Bon BWM, Mefford HC, de Vries BBA (2010) 15q13.3 Microdeletion. In GeneReviews at GeneTests: Medical Genetics Information Resource (http://www.genetests.org). Copyright University of Washington, Seattle. 1997-2011.

25: Bachmann-Gagescu R*, Mefford HC*^, Cowan C, Glew GM, Hing AV, Wallace S, Bader PI, Hamati A, Reitnauer PJ, Smith R, Stockton SW, Muhle H, Helbig I, Eichler EE, Ballif BC, Rosenfeld J, Tsuchiya KD (2010) Recurrent 200-kb deletions of 16p11.2 that include the SH2B1 gene are associated with developmental delay and obesity. Genetics in Medicine 12:641-7

26: Mefford HC^, Muhle H, Ostertag P, von Spiczak S, Buysse K, Baker C, Franke A, Malafosse A, Genton P, Thomas P, Gurnett CA, Schreiber S, Bassuk AG, Guipponi M, Stephani U, Helbig I, Eichler EE. (2010) Genome-wide copy number variation in epilepsy: novel susceptibility loci in idiopathic generalized and focal epilepsies. PLoS Genetics 6:e1000962. PMCID: PMC2873910.

27: Mefford HC. (2009) Genotype to phenotype discovery and characterization of novel genomic disorders in a genotype-first era. Genetics in Medicine 11:836-42.

28: Mefford HC, Cooper GM, Zerr T, Smith J, Baker C, Shafer N, Thorland E, Skinner C, Schwartz CE, Nickerson DA, Eichler EE (2009) A high-throughput and cost-effective method for CNV genotyping Genome Research 19:1579-85.

29: Mefford HC, Eichler EE (2009) Duplication Hotspots, Rare Genomic Disorders and Common Disease. Current Opinion in Genetics & Development 19:196-204.

30: van Bon BWM, Mefford HC, Menten B, Koolen DA, Sharp AJ, Nillesen WM, Innis JW, de Ravel TJL, Mercer C, Fichera M, Stewart H, Connell LE, Ounap K, Castle B, et al. (2009) Further delineation of the 15q13 micro-deletion and duplication syndrome: A clinical spectrum varying from non-pathogenic to a severe outcome. Journal of Medical Genetics 46:511-23.

31: Helbig I, Mefford HC, Sharp AJ, Guipponi M, Fichera M, Franke A, Muhle H, de Kovel C, Baker C, von Spiczak S, Kron KL, Steinich I, Kleefuß-Lie AA, Leu C, Gaus V, Schmitz B, Klein KM, Reif PS, Rosenow F, Weber Y, Lerche H, Zimprich F, Urak L, Fuchs K, Feucht M, Genton P, Thomas P, Visscher F, de Haan G, Møller RS, Hjalgrim H, Luciano D, Wittig M, Nothnagel M, Elger CE, Nuernberg P, Romano C, Malafosse A, Koeleman BPC, Lindhout D, Stephani U, Schreiber D, Eichler EE, Sander T (2009) 15q13.3 microdeletions increase risk of idiopathic generalized epilepsy. Nature Genetics 41:160-2.

32: Mefford HC, Sharp AJ, Baker C, Itsara A, Jiang Z, Buysse K, Huang S, Maloney VK, Crolla JA, Baralle D, Collins A, Mercer C, Norga K, de Ravel T, et al. (2008) Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. New England Journal of Medicine 359: 1685-99.

33: Sharp AJ, Mefford HC, Li KE, Broomer AJ, Wang Y, Xiao C, Barbacioru C, Baker C, Skinner C, Stevenson RE, Schroer R, Novara F, De Gregori M, Ciccone R, Gimelli G, Bernardina BD, Torniero C, Giorda R, Regan R, Murday V, Mansour S, Fichera M, Castiglia L, Failla P, Cooper GM, Knight SJL, Romano C, Zuffardi O, Chen C, Schwartz C, Eichler EE (2008) A recurrent 15q13.3 microdeletion syndrome associated with mental retardation and seizures. Nature Genetics 40:322-8.

34: Hannes F, Sharp AJ, Mefford HC, de Ravel T, Ruivenkamp CA, Breuning MH, Fryns J-P, Devriendt K, Van Buggenhout G, Vogels A, Stewart H, Hennekam RC, Cooper GM, Regan R, Knight JSL, Eichler EE, Vermeesch JR. (2009) Recurrent reciprocal deletions and duplications of 16p13.11: The deletion is a risk factor for MR/MCA while the duplication may be a rare benign variant. Journal of Medical Genetics 46:223-32 [Epub 2008 Jun 11].

35: Mefford HC, Clauin S, Sharp AJ, Moller RS, Ullman R, Kapur R, Pinkel D, Cooper GM, Ropers HH, Tommerup N, Eichler EE, Bellanne-Chantelot C. (2007) Recurrent reciprocal genomic rearrangements of 17q12 are involved in renal disease, diabetes and epilepsy. American Journal of Human Genetics 81:1057-69.

Bert B.A. de Vries, MD, PhD.

Clinical Geneticist
Radboud University Medical Centre
Department of Human Genetics

Contact Information

Radboud University Medical Centre
PO Box 9101, 6500 HB, The Netherlands
Email: bert.devries@radboudumc.nl
Telephone Number: 0031 24 3613946
Fax Number: 0031 24 3668753

Education

MD – Medical School, Erasmus University Rotterdam, The Netherlands (1990)
Residency – Department of Clinical Genetics, Erasmus University Medical Centre, Rotterdam, The Netherlands (1990-1997)
PhD – Erasmus University Rotterdam, The Netherlands (1997)
Fellowship – Institute of Child Health, Great Ormond Street Hospital, London (1999-2000)

Research Interests

Since his start at the Radboud UMC in 2001, Bert B.A. de Vries and his team were involved in the introduction of the novel diagnostic techniques for intellectual disability. Within his group, new deletion/duplication syndromes were identified, and subsequent gene identifications in the defined genomic areas became a reality, as in the CHARGE syndrome with the CHD7 gene, the 9q34 deletion syndrome with the EHMT1 gene and the 17q21.31 microdeletion syndrome with the KANSL1.

Subsequently, he was involved in the introduction of whole exome/genome sequencing which led to identification of the causative genes for Schinzel-Giedion syndrome, Bohring-Opitz syndrome, Cantu syndrome and de novo mutations in various genes for intellectual disability. In recent years the clinical interpretation of novel genetic mutations (genotype first approach) has led to extensive studies (clinical, functional and as animal models) leading to novel insights for various genes not only linked to ID but to autism as well, e.g. TDP2, DEAF1, NR2F1 and, respectively, ADNP and CHD8.

Since 2011, he is a Principal Investigator (PI) at the Radboud UMC which allows him to perform his research next to his clinical work. Previously, he received two personal grants from Netherlands Organisation for Scientific Research (Clinical Fellows, 2002 and VIDI 2007) and took part in various European projects (Ecaruca, Aneuploidy, GENCODYS) over the years. Recently his work was supported by a TOPsubsidy grant (2013) from the Netherlands Organisation for Scientific Research.

Publications

Selection out over 200 papers:

1. Koolen DA, Pfundt R, Linda K, Beunders G, Veenstra-Knol HE, Conta JH, Fortuna AM, Gillessen-Kaesbach G, Dugan S, Halbach S, Abdul-Rahman OA, Winesett HM, Chung WK, Dalton M, Dimova PS, Mattina T, Prescott K, Zhang HZ, Saal HM, Hehir-Kwa JY, Willemsen MH, Ockeloen CW, Jongmans MC, Van der Aa N, Failla P, Barone C, Avola E, Brooks AS, Kant SG, Gerkes EH, Firth HV, Õunap K, Bird LM, Masser-Frye D, Friedman JR, Sokunbi MA, Dixit A, Splitt M; DDD Study, Kukolich MK, McGaughran J, Coe BP, Flórez J, Nadif Kasri N, Brunner HG, Thompson EM, Gecz J, Romano C, Eichler EE, de Vries BB. The Koolen-de Vries syndrome: a phenotypic comparison of patients with a 17q21.31 microdeletion versus a KANSL1 sequence variant. Eur J Hum Genet. 2015 Aug 26.

2. Andrews T, Meader S, Vulto-van Silfhout A, Taylor A, Steinberg J, Hehir-Kwa J, Pfundt R, de Leeuw N, de Vries BB, Webber C. Gene networks underlying convergent and pleiotropic phenotypes in a large and systematically-phenotyped cohort with heterogeneous developmental disorders. PLoS Genet. 2015 Mar 17;11(3):e1005012

3. van Bon BW, Coe BP, Bernier R, Green C, Gerdts J, Witherspoon K, Kleefstra T, Willemsen MH, Kumar R, Bosco P, Fichera M, Li D, Amaral D, Cristofoli F, Peeters H, Haan E, Romano C, Mefford HC, Scheffer I, Gecz J, de Vries BB, Eichler EE. Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID. Mol Psychiatry. 2015 Feb 24

4. Coe BP, Witherspoon K, Rosenfeld JA, van Bon BW, Vulto-van Silfhout AT, Bosco P, Friend KL, Baker C, Buono S, Vissers LE, Schuurs-Hoeijmakers JH, Hoischen A, Pfundt R, Krumm N, Carvill GL, Li D, Amaral D, Brown N, Lockhart PJ, Scheffer IE, Alberti A, Shaw M, Pettinato R, Tervo R, de Leeuw N, Reijnders MR, Torchia BS, Peeters H, Thompson E, O’Roak BJ, Fichera M, Hehir-Kwa JY, Shendure J, Mefford HC, Haan E, Gécz J, de Vries BB, Romano C, Eichler EE. Refining analyses of copy number variation identifies specific genes associated with developmental delay. Nat Genet. 2014 Oct;46(10):1063-71

5. Bernier R, Golzio C, Xiong B, Stessman HA, Coe BP, Penn O, Witherspoon K, Gerdts J, Baker C, Vulto-van Silfhout AT, Schuurs-Hoeijmakers JH, Fichera M, Bosco P, Buono S, Alberti A, Failla P, Peeters H, Steyaert J, Vissers LE, Francescatto L, Mefford HC, Rosenfeld JA, Bakken T, O’Roak BJ, Pawlus M, Moon R, Shendure J, Amaral DG, Lein E, Rankin J, Romano C, de Vries BB, Katsanis N, Eichler EE. Disruptive CHD8 mutations define a subtype of autism early in development. Cell. 2014 Jul 17;158(2):263-76.

6. Vulto-van Silfhout AT, Rajamanickam S, Jensik PJ, Vergult S, de Rocker N, Newhall KJ, Raghavan R, Reardon SN, Jarrett K, McIntyre T, Bulinski J, Ownby SL, Huggenvik JI, McKnight GS, Rose GM, Cai X, Willaert A, Zweier C, Endele S, de Ligt J, van Bon BW, Lugtenberg D, de Vries PF, Veltman JA, van Bokhoven H, Brunner HG, Rauch A, de Brouwer AP, Carvill GL, Hoischen A, Mefford HC, Eichler EE, Vissers LE, Menten B,Collard MW, de Vries BB. Mutations affecting the SAND domain of DEAF1 cause intellectual disability with severe speech impairment and behavioral problems. Am J Hum Genet. 2014 May 1;94(5):649-61.

7. Gómez-Herreros F, Schuurs-Hoeijmakers JH, McCormack M, Greally MT, Rulten S, Romero-Granados R, Counihan TJ, Chaila E, Conroy J, Ennis S, Delanty N, Cortés-Ledesma F, de Brouwer AP, Cavalleri GL, El-Khamisy SF, de Vries BB, Caldecott KW. TDP2 protects transcription from abortive topoisomerase activity and is required for normal neural function. Nat Genet. 2014 May;46(5):516-21.

8. Bosch DG, Boonstra FN, Gonzaga-Jauregui C, Xu M, de Ligt J, Jhangiani S, Wiszniewski W, Muzny DM, Yntema HG, Pfundt R, Vissers LE, Spruijt L, Blokland EA, Chen CA; Baylor-Hopkins Center for Mendelian Genomics, Lewis RA, Tsai SY, Gibbs RA, Tsai MJ, Lupski JR, Zoghbi HY, Cremers FP, de Vries BB, Schaaf CP. NR2F1 mutations cause optic atrophy with intellectual disability. Am J Hum Genet. 2014 Feb 6;94(2):303-9.

9. Schuurs-Hoeijmakers JH, Geraghty MT, Kamsteeg EJ, Ben-Salem S, de Bot ST, Nijhof B, van de Vondervoort II, van der Graaf M, Nobau AC, Otte-Höller I, Vermeer S, Smith AC, Humphreys P, Schwartzentruber J; FORGE Canada Consortium, Ali BR, Al-Yahyaee SA, Tariq S, Pramathan T, Bayoumi R, Kremer HP, van de Warrenburg BP, van den Akker WM, Gilissen C, Veltman JA, Janssen IM, Vulto-van Silfhout AT, van der Velde-Visser S, Lefeber DJ, Diekstra A, Erasmus CE, Willemsen MA, Vissers LE, Lammens M, van Bokhoven H, Brunner HG, Wevers RA, Schenck A, Al-Gazali L, de Vries BB, de Brouwer AP. Mutations in DDHD2, Encoding an Intracellular Phospholipase A(1), Cause a Recessive Form of Complex Hereditary Spastic Paraplegia. Am J Hum Genet. 2012 91(6):1073-81.

10. van Bon BW, Gilissen C, Grange DK, Hennekam RC, Kayserili H, Engels H, Reutter H, Ostergaard JR, Morava E, Tsiakas K, Isidor B, Le Merrer M, Eser M, Wieskamp N, de Vries P, Steehouwer M, Veltman JA, Robertson SP, Brunner HG, de Vries BB, Hoischen A. Cantú Syndrome Is Caused by Mutations in ABCC9. Am J Hum Genet. 2012 May 16

11. Koolen DA, Kramer JM, Neveling K, Nillesen WM, Moore-Barton HL, Elmslie FV, Toutain A, Amiel J, Malan V, Tsai AC, Cheung SW, Gilissen C, Verwiel ET, Martens S, Feuth T, Bongers EM, de Vries P, Scheffer H, Vissers LE, de Brouwer AP, Brunner HG, Veltman JA, Schenck A, Yntema HG, de Vries BB. Mutations in the chromatin modifier gene KANSL1 cause the 17q21.31 microdeletion syndrome. Nat Genet. 2012 Apr 29;44(6):639-41

12. Koolen DA, Dupont J, de Leeuw N, Vissers LE, van den Heuvel SP, Bradbury A, Steer J, de Brouwer AP, Ten Kate LP, Nillesen WM, de Vries BB, Parker MJ. Two families with sibling recurrence of the 17q21.31 microdeletion syndrome due to low-grade mosaicism.Eur J Hum Genet. 2012 Jul;20(7):729-33.

13. Hoischen A, van Bon BW, Rodríguez-Santiago B, Gilissen C, Vissers LE, de Vries P, Janssen I, van Lier B, Hastings R, Smithson SF, Newbury-Ecob R, Kjaergaard S, Goodship J, McGowan R, Bartholdi D, Rauch A, Peippo M, Cobben JM, Wieczorek D, Gillessen-Kaesbach G, Veltman JA, Brunner HG, de Vries BB. De novo nonsense mutations in ASXL1 cause Bohring-Opitz syndrome. Nat Genet. 2011 Jun 26;43(8):729-31

14. Vissers LE, de Ligt J, Gilissen C, Janssen I, Steehouwer M, de Vries P, van Lier B, Arts P, Wieskamp N, del Rosario M, van Bon BW, Hoischen A, de Vries BB, Brunner HG, Veltman JA. A de novo paradigm for mental retardation. Nat Genet. 2010 Dec;42(12):1109-12.

15. Hoischen A, van Bon BW, Gilissen C, Arts P, van Lier B, Steehouwer M, de Vries P, de Reuver R, Wieskamp N, Mortier G, Devriendt K, Amorim MZ, Revencu N, Kidd A, Barbosa M, Turner A, Smith J, Oley C, Henderson A, Hayes IM, Thompson EM, Brunner HG, de Vries BB, Veltman JA. De novo mutations of SETBP1 cause Schinzel-Giedion syndrome. Nat Genet. 2010 Jun;42(6):483-5.

Dr. David A. Koolen, MD, PhD.

Clinical Geneticist
Radboud University Medical Centre
Department of Human Genetics

Contact Information

Radboud University Medical Centre
PO Box 9101, 6500 HB, The Netherlands
Email: david.koolen@radboudumc.nl
Telephone Number: 0031 24 3613946
Fax Number: 0031 24 3668753

Education

MD – Medical School, Radboud University Nijmegen, The Netherlands (2002)
Residency – Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands (2003-2011)
Doctorate – Radboud University Nijmegen, The Netherlands (2008) (cum laude)
Thesis: Copy number variation and mental retardation

Research Interests

Over the last ten years I’ve been involved in the identification of various novel syndromes associated with neurodevelopmental disorders, such as the Koolen-de Vries syndrome (KdVS), thereby substantiating the “genome first‟ paradigm in clinical genetics as a genuine and successful concept. Since the recognition of the KdVS in 2006, this syndrome is my main focus of research. We keep collecting clinical data on individuals with KdVS. Based on these clinical data we will generate specific management protocols, including proposals for clinical evaluations following the initial diagnosis, treatment of manifestations, prevention of secondary complications, and surveillance. The protocols will provide accurate information for monitoring of co-morbidity to medical professionals and counseling of patients and families. Moreover, in collaboration with others, we perform fundamental research in order to unravel the underlying molecular mechanisms of the KdVS.

Interestingly, with the implementation of next-generation sequencing novel syndromes will be identified and as such, for the years to come, my goal is to unravel neurodevelopmental disorders and to reach clinically well-defined diagnoses.

Publications

Selection out 43 papers:

1: Koolen DA, Pfundt R, Linda K, Beunders G, Veenstra-Knol HE, Conta JH, Fortuna AM, Gillessen-Kaesbach G, Dugan S, Halbach S, Abdul-Rahman OA, Winesett HM, Chung WK, Dalton M, Dimova PS, Mattina T, Prescott K, Zhang HZ, Saal HM, Hehir-Kwa JY, Willemsen MH, Ockeloen CW, Jongmans MC, Van der Aa N, Failla P, Barone C, Avola E, Brooks AS, Kant SG, Gerkes EH, Firth HV, Õunap K, Bird LM, Masser-Frye D, Friedman JR, Sokunbi MA, Dixit A, Splitt M; DDD Study, Kukolich MK, McGaughran J, Coe BP, Flórez J, Nadif Kasri N, Brunner HG, Thompson EM, Gecz J, Romano C, Eichler EE, de Vries BB. The Koolen-de Vries syndrome: a phenotypic comparison of patients with a 17q21.31 microdeletion versus a KANSL1 sequence variant. Eur J Hum Genet. 2015 Aug 26.

2: Wortmann SB, Koolen DA, Smeitink JA, van den Heuvel L, Rodenburg RJ. Whole exome sequencing of suspected mitochondrial patients in clinical practice. J Inherit Metab Dis. 2015 May;38(3):437-43. doi: 10.1007/s10545-015-9823-y. Epub 2015 Mar 4.

3: Maley AM, Spraker MK, de Vries BB, Koolen DA. Vitiligo in the Koolen-de Vries or 17q21.31 microdeletion syndrome. Clin Dysmorphol. 2015 Apr;24(2):86-7.

4: Ockeloen CW, Cobben JM, Marcelis CL, Koolen DA. A rare complex malformation of the hand in split hand foot malformation type 3 (SHFM3). Clin Dysmorphol. 2013 Jul;22(3):106-8.

5: de Ligt J, Willemsen MH, van Bon BW, Kleefstra T, Yntema HG, Kroes T, Vulto-van Silfhout AT, Koolen DA, de Vries P, Gilissen C, del Rosario M, Hoischen A, Scheffer H, de Vries BB, Brunner HG, Veltman JA, Vissers LE. Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med. 2012 Nov 15;367(20):1921-9.

6: Koolen DA, Kramer JM, Neveling K, Nillesen WM, Moore-Barton HL, Elmslie FV, Toutain A, Amiel J, Malan V, Tsai AC, Cheung SW, Gilissen C, Verwiel ET, Martens S, Feuth T, Bongers EM, de Vries P, Scheffer H, Vissers LE, de Brouwer AP, Brunner HG, Veltman JA, Schenck A, Yntema HG, de Vries BB. Mutations in the chromatin modifier gene KANSL1 cause the 17q21.31 microdeletion syndrome. Nat Genet. 2012 Apr 29;44(6):639-41.

7: Itsara A, Vissers LE, Steinberg KM, Meyer KJ, Zody MC, Koolen DA, de Ligt J, Cuppen E, Baker C, Lee C, Graves TA, Wilson RK, Jenkins RB, Veltman JA, Eichler EE. Resolving the breakpoints of the 17q21.31 microdeletion syndrome with next-generation sequencing. Am J Hum Genet. 2012 Apr 6;90(4):599-613.

8: Koolen DA, Dupont J, de Leeuw N, Vissers LE, van den Heuvel SP, Bradbury A, Steer J, de Brouwer AP, Ten Kate LP, Nillesen WM, de Vries BB, Parker MJ. Two families with sibling recurrence of the 17q21.31 microdeletion syndrome due to low-grade mosaicism. Eur J Hum Genet. 2012 Jul;20(7):729-33.

9: Koolen DA,, de Vries BBA. KANSL1-Related Intellectual Disability Syndrome. 2010 Jan 26 [updated 2013 Jan 10]. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Fong CT, Mefford HC, Smith RJH, Stephens K, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015. Available from http://www.ncbi.nlm.nih.gov/books/NBK24676/ PubMed PMID: 20301783.

10: van Bon BW, Koolen DA, Brueton L, McMullan D, Lichtenbelt KD, Adès LC, Peters G, Gibson K, Moloney S, Novara F, Pramparo T, Dalla Bernardina B, Zoccante L, Balottin U, Piazza F, Pecile V, Gasparini P, Guerci V, Kets M, Pfundt R, de Brouwer AP, Veltman JA, de Leeuw N, Wilson M, Antony J, Reitano S, Luciano D, Fichera M, Romano C, Brunner HG, Zuffardi O, de Vries BB. The 2q23.1 microdeletion syndrome: clinical and behavioural phenotype. Eur J Hum Genet. 2010 Feb;18(2):163-70.

11: Koolen DA, Pfundt R, de Leeuw N, Hehir-Kwa JY, Nillesen WM, Neefs I, Scheltinga I, Sistermans E, Smeets D, Brunner HG, van Kessel AG, Veltman JA, de Vries BB. Genomic microarrays in mental retardation: a practical workflow for diagnostic applications. Hum Mutat. 2009 Mar;30(3):283-92.

12: Koolen DA, Sharp AJ, Hurst JA, Firth HV, Knight SJ, Goldenberg A, Saugier-Veber P, Pfundt R, Vissers LE, Destrée A, Grisart B, Rooms L, Van der Aa N, Field M, Hackett A, Bell K, Nowaczyk MJ, Mancini GM, Poddighe PJ, Schwartz CE, Rossi E, De Gregori M, Antonacci-Fulton LL, McLellan MD 2nd, Garrett JM, Wiechert MA, Miner TL, Crosby S, Ciccone R, Willatt L, Rauch A, Zenker M, Aradhya S, Manning MA, Strom TM, Wagenstaller J, Krepischi-Santos AC, Vianna-Morgante AM, Rosenberg C, Price SM, Stewart H, Shaw-Smith C, Brunner HG, Wilkie AO, Veltman JA, Zuffardi O, Eichler EE, de Vries BB. Clinical and molecular delineation of the 17q21.31 microdeletion syndrome. J Med Genet. 2008 Nov;45 (11):710-20.

13: Koolen DA, Vissers LE, Pfundt R, de Leeuw N, Knight SJ, Regan R, Kooy RF, Reyniers E, Romano C, Fichera M, Schinzel A, Baumer A, Anderlid BM, Schoumans J, Knoers NV, van Kessel AG, Sistermans EA, Veltman JA, Brunner HG, de Vries BB. A new chromosome 17q21.31 microdeletion syndrome associated with a common inversion polymorphism. Nat Genet. 2006 Sep;38(9):999-1001.