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OUR RESEARCH

We work on: rare diseases (RD), inborn errors of immunity (IEI); genomic technologies: optical genome mapping (OGM), long-read sequencing (LRS), molecular inversion probes (MIPs), long-read RNA-seq (IsoSeq); somatic mutations, clonal hematopoiesis; RD data re-analysis; innovating diagnostics of RD.

 

Our research group ‘Genomic Technologies and Immuno-Genomics’ has built expertise in the identification of rare disease genes using latest genomic tools. This multi-disciplinary group is led by Alex Hoischen, since June 2024 “Professor Genomic Technologies for Immune-Mediated and Infectious Diseases”. We have been the first identifying a disease causing dominant de novo mutation for a Mendelian disorder by exome sequencing [1], followed by the identification of several disease genes for rare diseases [2-6]. Following a six months’ research stint in 2013 in the laboratories of our collaborators Prof. Eichler and Prof. Shendure (UW, Seattle; USA), Alex established the latest technology for accurate and large scale targeted re-sequencing (smMIPs) in Nijmegen [7,8]. In recent years we started to apply long-read technologies such as HiFi long-read sequencing (PacBio) and optical genome mapping (OGM) to unsolved rare disease cases [9-16]. Our research group now focuses on the genetic basis of immune diseases, so-called inborn errors of immunity (IEI) [e.g.: 17-26], with an important identification of a novel immunodeficiency that predisposes men to severe COVID-19 [19, 22, 25].

Especially in the context of rare immune diseases, we increasingly expand our efforts beyond disease gene identification also to epigenome and transcriptome analyses, utilizing single-cell and long-read RNA sequencing efforts [26,27]. Additionally, the accurate detection of somatic mutations, in part as drivers of clonal hematopoiesis, is studied by our group as well [8, 30-33].

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Beyond strict research use, we aim to implement and apply latest genomic technologies successfully in the clinic for rare diseases, often in collaboration with colleagues from the human genetics department, the Radboudumc and beyond, e.g. WES [e.g.:18,25]; MIPs [e.g.: 7]; OGM [14,15] and LRS [11]. Some aspects of our work have been summarized in review articles or perspectives [9, 33-35].

 

In the last years we have shown that applications of novel and disruptive technologies allows new scientific insights and rapid translation into clinical and diagnostic practice at unprecedented speed. As part of our role in rare disease genomics Alex co-led a work package in the EU-funded H2020 project SOLVE-RD (2018-2024) [27,28,29]. This work of joining forces to innovate research and care for rare diseases on pan-European and global scale will be continued as part of the ERDERA project, in which Alex co-leads WP8 on “Innovations to shorten time to RD diagnosis”. In 2024 Alex received a VICI grant entitled “SOLVE-IEI: Solving Enigmas of Undiagnosed Inborn Errors of Immunity”, this enables his group to further push latest genomic innovations for an improved understanding of IEIs.

 

References: 

  1. Hoischen A*, van Bon BW*, Gilissen C*, et al.; De novo mutations of SETBP1 cause Schinzel-Giedion syndrome; Nat Genet. 2010 Jun;42(6):483-5. doi: 10.1038/ng.581. Epub 2010 May 2.; 10.1038/ng.581

  2. Becker J, Semler O, Gilissen C, […] Hoischen A*, Netzer C*.; Exome sequencing identifies truncating mutations in human SERPINF1 in autosomal-recessive osteogenesis imperfecta; Am J Hum Genet. 2011 Mar 11;88(3):362-71. doi: 10.1016/j.ajhg.2011.01.015. Epub 2011 Feb 25.; 10.1016/j.ajhg.2011.01.015

  3. Hoischen A*, van Bon BW*, Rodríguez-Santiago B*, et al.; De novo nonsense mutations in ASXL1 cause Bohring-Opitz syndrome; Nat Genet. 2011 Jun 26;43(8):729-31. doi: 10.1038/ng.868.; 10.1038/ng.868

  4. van Bon BW, […] Hoischen A.; Cantú syndrome is caused by mutations in ABCC9; Am J Hum Genet. 2012 Jun 8;90(6):1094-101. doi: 10.1016/j.ajhg.2012.04.014. Epub 2012 May 17.; 10.1016/j.ajhg.2012.04.014

  5. Stránecký V*, Hoischen A*, et al.; Mutations in ANTXR1 cause GAPO syndrome; Am J Hum Genet. 2013 May 2;92(5):792-9. doi: 10.1016/j.ajhg.2013.03.023. Epub 2013 Apr 18.; 10.1016/j.ajhg.2013.03.023

  6. Acuna-Hidalgo R*, Schanze D*, […], 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. doi: 10.1016/j.ajhg.2014.07.012. Epub 2014 Aug 21.; 10.1016/j.ajhg.2014.07.012

  7. Neveling K, […] Hoischen A.; BRCA Testing by Single-Molecule Molecular Inversion Probes; Clin Chem. 2017 Feb;63(2):503-512. doi: 10.1373/clinchem.2016.263897. Epub 2016 Dec 14.; 10.1373/clinchem.2016.263897

  8. Acuna-Hidalgo R, […], 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. doi: 10.1016/j.ajhg.2017.05.013. Epub 2017 Jun 29.; 10.1016/j.ajhg.2017.05.013

  9. Mantere T, Kersten S, Hoischen A.; Long-Read Sequencing Emerging in Medical Genetics; Front Genet. 2019 May 7;10:426. doi: 10.3389/fgene.2019.00426. eCollection 2019.; 10.3389/fgene.2019.00426

  10. Kucuk E*, van der Sanden BPGH*, […], Vissers LELM*, Hoischen A*, Gilissen C*.; Comprehensive de novo mutation discovery with HiFi long-read sequencing; Genome Med. 2023 May 8;15(1):34. doi: 10.1186/s13073-023-01183-6.; 10.1186/s13073-023-01183-6

  11. Höps W*, Weiss MM*, […], Hoischen A*, Gilissen C*, Vissers LELM*.; HiFi long-read genomes for difficult-to-detect, clinically relevant variants; Am J Hum Genet. 2025 Jan 4:S0002-9297(24)00455-5. doi: 10.1016/j.ajhg.2024.12.013. Online ahead of print.; 10.1016/j.ajhg.2024.12.013

  12. Steyaert W*, Sagath L*, […], Gilissen C*, Hoischen A*; Solve-RD consortium.; Unraveling undiagnosed rare disease cases by HiFi long-read genome sequencing; Genome Res. 2025 Mar 26. doi: 10.1101/gr.279414.124. Online ahead of print.; 10.1101/gr.279414.124

  13. Sabatella M*, Mantere T*, […], Hoischen A*, Jongmans MC*, Kuiper RP*.; Optical genome mapping identifies a germline retrotransposon insertion in SMARCB1 in two siblings with atypical teratoid rhabdoid tumors; J Pathol. 2021 Oct;255(2):202-211. doi: 10.1002/path.5755. Epub 2021 Jul 29.; 10.1002/path.5755

  14. Mantere T*, Neveling K*, [...], Hoischen A*, Schluth-Bolard C*, El Khattabi L*.; Optical genome mapping enables constitutional chromosomal aberration detection; Am J Hum Genet. 2021 Aug 5;108(8):1409-1422. doi: 10.1016/j.ajhg.2021.05.012. Epub 2021 Jul 7.; 10.1016/j.ajhg.2021.05.012

  15. Neveling K*, Mantere T*, […], Hoischen A.; Next-generation cytogenetics: Comprehensive assessment of 52 hematological malignancy genomes by optical genome mapping; Am J Hum Genet. 2021 Aug 5;108(8):1423-1435. doi: 10.1016/j.ajhg.2021.06.001. Epub 2021 Jul 7.; 10.1016/j.ajhg.2021.06.001

  16. van der Sanden B, […], Hoischen A.; Optical genome mapping enables accurate testing of large repeat expansions; Genome Res. 2025 Mar 20. doi: 10.1101/gr.279491.124. Online ahead of print.; 10.1101/gr.279491.124

  17. van de Veerdonk FL*, Plantinga TS*, Hoischen A*, et al.; STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis; N Engl J Med. 2011 Jul 7;365(1):54-61. doi: 10.1056/NEJMoa1100102. Epub 2011 Jun 29.; 10.1056/NEJMoa1100102

  18. Arts P, […] Hoischen A.; Exome sequencing in routine diagnostics: a generic test for 254 patients with primary immunodeficiencies; Genome Med. 2019 Jun 17;11(1):38. doi: 10.1186/s13073-019-0649-3.; 10.1186/s13073-019-0649-3

  19. van der Made CI, […], Veerdonk FL*, Hoischen A*.; Presence of Genetic Variants Among Young Men With Severe COVID-19; JAMA. 2020 Aug 18;324(7):663-673. doi: 10.1001/jama.2020.13719.; 10.1001/jama.2020.13719

  20. van Deuren RC, […], Hoischen A.; Impact of rare and common genetic variation in the interleukin-1 pathway on human cytokine responses; Genome Med. 2021 May 25;13(1):94. doi: 10.1186/s13073-021-00907-w.; 10.1186/s13073-021-00907-w

  21. van der Made CI, et al.; Adult-onset autoinflammation caused by somatic mutations in UBA1: A Dutch case series of patients with VEXAS; J Allergy Clin Immunol. 2022 Jan;149(1):432-439.e4. doi: 10.1016/j.jaci.2021.05.014. Epub 2021 May 25.; 10.1016/j.jaci.2021.05.014

  22. Solanich X*, Vargas-Parra G*, van der Made CI*, […], Hoischen A*, Lázaro C*.; Genetic Screening for TLR7 Variants in Young and Previously Healthy Men With Severe COVID-19; Front Immunol. 2021 Jul 23;12:719115. doi: 10.3389/fimmu.2021.719115. eCollection 2021.; 10.3389/fimmu.2021.719115

  23. Hebert A, […], Hoischen A*, van der Made CI*.; Trio-based whole exome sequencing in patients with suspected sporadic inborn errors of immunity: A retrospective cohort study; Elife. 2022 Oct 17;11:e78469. doi: 10.7554/eLife.78469.; 10.7554/eLife.78469

  24. van der Made CI*, Kersten S*, Chorin O*, […], Hambleton S*, Henriet SSV*, Hoischen A*.; Expanding the PRAAS spectrum: De novo mutations of immunoproteasome subunit β-type 10 in six infants with SCID-Omenn syndrome; Am J Hum Genet. 2024 Apr 4;111(4):791-804. doi: 10.1016/j.ajhg.2024.02.013. Epub 2024 Mar 18.; 10.1016/j.ajhg.2024.02.013

  25. van der Made CI, Netea MG, van der Veerdonk FL, Hoischen A.; Clinical implications of host genetic variation and susceptibility to severe or critical COVID-19; Genome Med. 2022 Aug 19;14(1):96. doi: 10.1186/s13073-022-01100-3.;

  26. Vorsteveld EE*, Van der Made CI*, […], Hoischen A.; Clinical exome sequencing data from patients with inborn errors of immunity: Cohort level diagnostic yield and the benefit of systematic reanalysis; Clin Immunol. 2024 Nov;268:110375. doi: 10.1016/j.clim.2024.110375. Epub 2024 Oct 5.; 10.1016/j.clim.2024.110375

  27. Arts P, […], Hoischen A*, Albers CA*.; Quantification of differential gene expression by multiplexed targeted resequencing of cDNA; Nat Commun. 2017 May 5;8:15190. doi: 10.1038/ncomms15190.; 10.1038/ncomms15190

  28. Graessner H, Zurek B, Hoischen A, Beltran S.; Solving the unsolved rare diseases in Europe; Eur J Hum Genet. 2021 Sep;29(9):1319-1320. doi: 10.1038/s41431-021-00924-8.; 10.1038/s41431-021-00924-8

  29. Salz R*, Vorsteveld EE*, et al.; Multi-omic profiling of pathogen-stimulated primary immune cells; iScience. 2024 Jul 6;27(8):110471. doi: 10.1016/j.isci.2024.110471. eCollection 2024 Aug 16.; 10.1016/j.isci.2024.110471

  30. Steyaert W, […], Hoischen A*, Gilissen C*.; Systematic analysis of paralogous regions in 41,755 exomes uncovers clinically relevant variation; Nat Commun. 2023 Oct 27;14(1):6845. doi: 10.1038/s41467-023-42531-9.; 10.1038/s41467-023-42531-9

  31. Laurie S*, Steyaert W*, de Boer E*, Polavarapu K*, Schuermans N*, Sommer AK*, […], Lohmann K*, de Voer RM*, Töpf A*, Vissers LELM*, Beltran S*, Hoischen A*.; Genomic reanalysis of a pan-European rare-disease resource yields new diagnoses; Nat Med. 2025 Feb;31(2):478-489. doi: 10.1038/s41591-024-03420-w. Epub 2025 Jan 17.; 10.1038/s41591-024-03420-w

  32. Acuna-Hidalgo R, […], 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. doi: 10.1016/j.ajhg.2015.05.008. Epub 2015 Jun 6.; 10.1016/j.ajhg.2015.05.008

  33. Acuna-Hidalgo R, […], Fisher SE*, Hoischen A*, van Bon BW*.; Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies; PLoS Genet. 2017 Mar 27;13(3):e1006683. doi: 10.1371/journal.pgen.1006683. eCollection 2017 Mar.; 10.1371/journal.pgen.1006683

  34. Nicolas G*, Acuña-Hidalgo R*, […], Hoischen A.; Somatic variants in autosomal dominant genes are a rare cause of sporadic Alzheimer's disease; Alzheimers Dement. 2018 Dec;14(12):1632-1639. doi: 10.1016/j.jalz.2018.06.3056. Epub 2018 Aug 13.; 10.1016/j.jalz.2018.06.3056

  35. Andersson-Assarsson JC*, van Deuren RC*, […], Hoischen A*, Carlsson LMS*.; Evolution of age-related mutation-driven clonal haematopoiesis over 20 years is associated with metabolic dysfunction in obesity; EBioMedicine. 2023 Jun;92:104621. doi: 10.1016/j.ebiom.2023.104621. Epub 2023 May 18.; 10.1016/j.ebiom.2023.104621

  36. Hoischen A, Krumm N, Eichler EE.; Prioritization of neurodevelopmental disease genes by discovery of new mutations; Nat Neurosci. 2014 Jun;17(6):764-72. doi: 10.1038/nn.3703. Epub 2014 May 27.; 10.1038/nn.3703

  37. 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. doi: 10.1186/s13059-016-1110-1.; 10.1186/s13059-016-1110-1

  38. Vorsteveld EE, Hoischen A, van der Made CI.; Next-Generation Sequencing in the Field of Primary Immunodeficiencies: Current Yield, Challenges, and Future Perspectives; Clin Rev Allergy Immunol. 2021 Oct;61(2):212-225. doi: 10.1007/s12016-021-08838-5. Epub 2021 Mar 5.; 10.1007/s12016-021-08838-5

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