Research group Genomic technologies immuno-genomics

Discoveries

Successful identification of novel genes associated with primary immunodeficiencies

• van de Veerdonk FL*, Plantinga TS*, Hoischen A*, Smeekens SP, Joosten LA, Gilissen C, Arts P, Rosentul DC, Carmichael AJ, Smits-van der Graaf CA, Kullberg BJ, van der Meer JW, Lilic D, Veltman JA, Netea MG. STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis. N Engl J Med. 2011 Jul 7;365(1):54-61. See publication
• Plantinga TS, Arts P, Knarren GH, Mulder AH, Wakelkamp IM, Hermus AR, Joosten LA, Netea MG, Bisschop PH, de Herder WW, Beijers HJ, de Bruin IJ, Gilissen C, Veltman JA, Hoischen A, Smit JW, Netea-Maier RT. Rare NOX3 Variants Confer Susceptibility to Agranulocytosis During Thyrostatic Treatment of Graves' Disease. Clin Pharmacol Ther. 2017 May 9. See publication
• Becker KL, Arts P, Jaeger M, Plantinga TS, Gilissen C, van Laarhoven A, van Ingen J, Veltman JA, Joosten LA, Hoischen A, Netea MG, Iseman MD, Chan ED, van de Veerdonk FL. MST1R mutation as a genetic cause of Lady Windermere syndrome. Eur Respir J. 2017 Jan 18;49(1). pii: 1601478. See publication
• Arts P, van de Veerdonk FL, van der Lee R, Langereis MA, Gilissen C, van Zelst-Stams WA, Huynen MA, van der Meer JW, van Kuppeveld FJ, Veltman JA, Kullberg BJ, Hoischen A, Netea MG. Immunologic defects in severe mucocutaneous HSV-2 infections: Response to IFN-γ therapy. J Allergy Clin Immunol. 2016 Apr 7. See publication
• van der Kolk NM, Arts P, van Uden IW, Hoischen A, van de Veerdonk FL, Netea MG, de Jong BA. Progressive multifocal leukoencephalopathy in an immunocompetent patient. Ann Clin Transl Neurol. 2016 Jan 8;3(3):226-32. See publication
• Arts P, Plantinga TS, van den Berg JM, Gilissen C, Veltman JA, van Trotsenburg AS, van de Veerdonk FL, Kuijpers TW, Hoischen A, Netea MG. A missense mutation underlies defective SOCS4 function in a family with autoimmunity. J Intern Med. 2015 Jan 31. See publication

Use of WES/WGS for rare disease gene identification

• Tylki-Szymańska A, Acuna-Hidalgo R, Krajewska-Walasek M, Lecka-Ambroziak A, Steehouwer M, Gilissen C, Brunner HG, Jurecka A, Różdżyńska-Świątkowska A, Hoischen A, Chrzanowska KH. Thyroid hormone resistance syndrome due to mutations in the thyroid hormone receptor α gene (THRA). J Med Genet. 2015 Feb 10. See publication
• Acuna-Hidalgo R, Schanze D, Kariminejad A, Nordgren A, Kariminejad MH, Conner P, Grigelioniene G, Nilsson D, Nordenskjöld M, Wedell A, Freyer C, Wredenberg A, Wieczorek D, Gillessen-Kaesbach G, Kayserili H, Elcioglu N, Ghaderi-Sohi S, Goodarzi P, Setayesh H, van de Vorst M, Steehouwer M, Pfundt R, Krabichler B, Curry C, MacKenzie MG, Boycott KM, Gilissen C, Janecke AR*, Hoischen A*, Zenker M*. Neu-Laxova syndrome is a heterogeneous metabolic disorder caused by defects in enzymes of the L-serine biosynthesis pathway. Am J Hum Genet. 2014 Sep 4;95(3):285-93. See publication
• Gilissen C, Hehir-Kwa JY, Thung DT, van de Vorst M, van Bon BW, Willemsen MH, Kwint M, Janssen IM, Hoischen A, Schenck A, Leach R, Klein R, Tearle R, Bo T, Pfundt R, Yntema HG, de Vries BB, Kleefstra T, Brunner HG, Vissers LE, Veltman JA. Genome sequencing identifies major causes of severe intellectual disability. Nature. 2014 Jul 17;511(7509):344-7. See publication
• Stránecký V*, Hoischen A*, Hartmannová H*, Zaki MS, Chaudhary A, Zudaire E, Nosková L, Barešová V, Přistoupilová A, Hodaňová K, Sovová J, Hůlková H, Piherová L, Hehir-Kwa JY, de Silva D, Senanayake MP, Farrag S, Zeman J, Martásek P, Baxová A, Afifi HH, St Croix B, Brunner HG, Temtamy S, Kmoch S. Mutations in ANTXR1 cause GAPO syndrome. Am J Hum Genet. 2013 May 2;92(5):792-9. See publication
• 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. See publication
• van Bon BWM, Gilissen C, Grange DK, Hennekam RCM, 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 BBA, Hoischen A. Cantú Syndrome Is Caused by Mutations in ABCC9. Am J Hum Genet. 2012 Jun 8;90(6):1094-101. See publication
• Gilissen C, Hoischen A, Brunner HG, Veltman JA. Disease gene identification strategies for exome sequencing. Eur J Hum Genet. 2012 May;20(5):490-7. See publication
• Rivière JB, van Bon BW, Hoischen A, Kholmanskikh SS, O'Roak BJ, Gilissen C, Gijsen S, Sullivan CT, Christian SL, Abdul-Rahman OA, Atkin JF, Chassaing N, Drouin-Garraud V, Fry AE, Fryns JP, Gripp KW, Kempers M, Kleefstra T, Mancini GM, Nowaczyk MJ, van Ravenswaaij-Arts CM, Roscioli T, Marble M, Rosenfeld JA, Siu VM, de Vries BB, Shendure J, Verloes A, Veltman JA, Brunner HG, Ross ME, Pilz DT, Dobyns WB. De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome. Nat Genet. 2012 Feb 26;44(4):440-4. See publication
• Gilissen C, Hoischen A, Brunner HG, Veltman JA. Unlocking Mendelian disease using exome sequencing. Genome Biol. 2011 Sep 14;12(9):228. See publication
• 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. See publication
• Becker J, Semler O, Gilissen C, Li Y, Bolz HJ, Giunta C, Bergmann C, Rohrbach M, Zimmermann K, de Vries P, Wirth B, Schoenau E, Wollnik B,Veltman JA, Hoischen A, Netzer C. Exome Sequencing Identifies Truncating Mutations in Human SERPINF1 in Autosomal-Recessive Osteogenesis Imperfecta. Am J Hum Genet. 2011 Feb 23. See publication
• Vissers LELM, de Ligt J, Gilissen C, Janssen I, Steehouwer M, de Vries P, van Lier B, Arts P, Wieskamp N, del Rosario M, van Bon BWM, Hoischen A, de Vries BBA, Brunner HG, Veltman JA. A de novo paradigm for mental retardation. Nat Genet. 2010 Dec;42(12):1109-12. See publication
• Vermeer S, Hoischen A, Meijer RPP, Gilissen G, Neveling K, Wieskamp N, de Brouwer A, Koenig M, Assoum M, Drouot N, Todorovic S, Milic-Rasic V, Lochmuller H, Anheim M,  Stevanin G, Goizet C, David A, Durr A, Brice A, Kremer B, van de Warrenburg BPC, Schijvenaars M, HeisterA, Kwint MP, Arts P, van der Wijst J, Veltman J, Kamsteeg EJ, Scheffer H, Knoers N. Targeted next generation sequencing of a 12.5 Mb homozygous region reveals mutations in the ANO10 gene in patients with autosomal recessive cerebellar ataxia. Am J Hum Genet. 2010 Dec 10;87(6):813-9. See publication
• Gilissen C*, Arts HH*, Hoischen A*, Spruijt L, Mans DA, Arts P, van Lier B, Steehouwer M, van Reeuwijk J, Kant SG, Roepman R, Knoers NV, Veltman JA, Brunner HG. Exome sequencing identifies WDR35 variants involved in Sensenbrenner syndrome. Am J Hum Genet. 2010 Sep 10;87(3):418-23. (IF: 10.362) See publication
• 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. See publication

Use of molecular inversion probes (MIPs) for rare disease gene identification

• Ockeloen CW, Khandelwal KD, Dreesen K, Ludwig KU, Sullivan R, van Rooij IA, Thonissen M, Swinnen S, Phan M, Conte F, Ishorst N, Gilissen C, Roa Fuentes L, van de Vorst M, Henkes A, Steehouwer M, van Beusekom E, Bloemen M, Vankeirsbilck B, Bergé S, Hens G, Schoenaers J, Vander Poorten V, Roosenboom J, Verdonck A, Devriendt K, Roeleveldt N, Jhangiani SN, Vissers LE, Lupski JR, de Ligt J, Von den Hoff JW, Pfundt R, Brunner HG, Zhou H, Dixon J, Mangold E, van Bokhoven H, Dixon MJ, Kleefstra T, Hoischen A*, Carels CE*. Novel mutations in LRP6 highlight the role of WNT signaling in tooth agenesis. Genet Med. 2016 Mar 10. 2016 (IF: 7.437) See publication
• Khandelwal KD, Ishorst N, Zhou H, Ludwig KU, Venselaar H, Gilissen C, Thonissen M, van Rooij IA, Dreesen K, Steehouwer M, van de Vorst M, Bloemen M, van Beusekom E, Roosenboom J, Borstlap W, Admiraal R, Dormaar T, Schoenaers J, Vander Poorten V, Hens G, Verdonck A, Bergé S, Roeleveldt N, Vriend G, Devriendt K, Brunner HG, Mangold E, Hoischen A, van Bokhoven H, Carels CE. Novel IRF6 Mutations Detected in Orofacial Cleft Patients by Targeted Massively Parallel Sequencing. J Dent Res. 2017 Feb;96(2):179-185. See publication
• 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, 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. doi: 10.1038/ng.3092. See publication

Use of molecular inversion probes (MIPs) for diagnostics

• Neveling K, Mensenkamp AR, Derks R, Kwint M, Ouchene H, Steehouwer M, van Lier B, Bosgoed E, Rikken A, Tychon M, Zafeiropoulou D, Castelein S, Hehir-Kwa J, Tjwan Thung D, Hofste T, Lelieveld SH, Bertens SM, Adan IB, Eijkelenboom A, Tops  BB, Yntema H, Stokowy T, Knappskog PM, Høberg-Vetti H, Steen VM, Boyle E, Martin B, Ligtenberg MJ, Shendure J*, Nelen MR*, Hoischen A*. BRCA Testing by Single-Molecule Molecular Inversion Probes. Clin Chem. 2017 Feb;63(2):503-512. See publication
• Weren RD, Mensenkamp AR, Simons M, Eijkelenboom A, Sie AS, Ouchene H, van Asseldonk M, Gomez-Garcia EB, Blok MJ, de Hullu JA, Nelen MR, Hoischen A, Bulten  J, Tops BB, Hoogerbrugge N, Ligtenberg MJ. Novel BRCA1 and BRCA2 Tumor Test as Basis for Treatment Decisions and Referral for Genetic Counselling of Patients with Ovarian Carcinomas. Hum Mutat. 2017 Feb;38(2):226-235. See publication
• Eijkelenboom A, Kamping E, Kastner-van Raaij A, Hendriks-Cornelissen S, Neveling K, Kuiper R, Hoischen A, Nelen M, Ligtenberg M, Tops B. Reliable Next-Generation Sequencing of Formalin-Fixed, Paraffin-Embedded Tissue Using Single Molecule Tags. J Mol Diagn. 2016 Nov;18(6):851-863. See publication

 
Novel method development and application

• Acuna-Hidalgo R, Sengul H, Steehouwer M, van de Vorst M, Vermeulen SH, Kiemeney LALM, Veltman JA, Gilissen C, Hoischen A. Ultra-sensitive Sequencing Identifies High Prevalence of Clonal Hematopoiesis-Associated Mutations throughout Adult Life. Am J Hum Genet. 2017 Jul 6;101(1):50-64. See publication
• Arts P, van der Raadt J, van Gestel SHC, Steehouwer M, Shendure J, Hoischen A*, Albers CA*. Quantification of differential gene expression by multiplexed targeted resequencing of cDNA. Nat Commun. 2017 May 5;8:15190. See publication

De novo mutation biology

• Acuna-Hidalgo R, Sengul H, Steenhouwer M, van de Vorst M, Vermeulen SH, Kiemeny LALM, Veltman JA, Gilissen C, Hoischen A. Ultra-sensitive Sequencing Identifies High Prevalence of Clonal Hematopoiesis-Associated Mutations throughout Adult Life. Am J Hum Genet. 2017 Jul 6;101(1):50-64. (see image 1 below) See publication
• Acuna-Hidalgo R, Veltman JA, Hoischen A. New insights into the generation and role of de novo mutations in health and disease. Genome Biol. 2016 Nov 28;17(1):241. Review. (see image 2 below) See publication
• Acuna-Hidalgo R, Bo T, Kwint MP, van de Vorst M, Pinelli M, Veltman JA, Hoischen A*, Vissers LE*, Gilissen C*. Post-zygotic Point Mutations Are an Underrecognized Source of De Novo Genomic Variation. Am J Hum Genet. 2015 Jul 2;97(1):67-74. See publication

Image 1: Clonal Hematopoiesis-Driver Mutations per age group. Mutation variant allele fraction per age of the individual in which the mutation was identified. Note: the y axis is in logarithmic scale.


Image 2: Mechanisms of de novo mutations.