BACKGROUND

Our research group ‘Genomic Technologies and Immuno-Genomics’ has built expertise in the identification of rare disease genes using the 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 [2-5]. Following a six months’ research stint in 2013 in the laboratories of my collaborators Prof. Eichler and Prof. Shendure (UW, Seattle; USA), I established the latest technology for accurate and large scale targeted re-sequencing (smMIPs) in Nijmegen.

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 [6-10]. Especially in the context of rare immune diseases, we increasingly expand our efforts also to epigenome and transcriptome analyses, utilizing single-cell and long-read RNA sequencing efforts.

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We implemented and applied latest genomic technologies successfully in the research of rare diseases, often in collaboration with colleagues from the human genetics department, the RadboudUMC and beyond, e.g. WES [e.g.:1-5]; MIPs [e.g.:11-14]; OGM and LRS. Importantly, these were subsequently integrated into routine diagnostics, e.g. WES [e.g.:15-17]; and MIPs [18-19]. Our research group now focuses on the genetic basis of immune diseases, so-called inborn errors of immunity (IEI) [e.g.:20-22], with an important identification of a novel immunodeficiency that predisposes men to severe COVID-19 [22].

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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 (www.solve-rd.eu, 2018-2024). 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 (www.erdera.eu), 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 et al. Nat Genet. 2010 Jun;42(6):483-5. 

2. Acuna-Hidalgo R et al. Am J Hum Genet. 2014 Sep 4;95(3):285-93. 

3. Hoischen A, Krumm N, Eichler EE. Nat Neurosci. 2014 Jun;17(6):764-72. 

4. Hoischen A, et al.Nat Genet. 2011 Jun 26;43(8):729-31. 

5. van Bon BW, et al. Am J Hum Genet. 2012 Jun 8;90(6):1094-101. 

6. Pauper M, et al. Eur J Hum Genet. 2020 Nov 30. 

7. Mantere T, Kersten S, Hoischen A. Front Genet. 2019 May 7;10:426 

8. Mantere et al. Am J Hum Genet. 2021 Aug 5;108(8):1409-1422 

9. Neveling et al. Am J Hum Genet. 2021 Aug 5;108(8):1423-1435 

10. Sabatella et al. J Pathol. 2021 Oct;255(2):202-211 

11. Jansen S, Hoischen A, et al. Eur J Hum Genet. 2017 Dec 5. 

12. Ockeloen CW et al. Genet Med. 2016 Nov;18(11):1158-1162. 

13. Acuna-Hidalgo R et al. Am J Hum Genet. 2017 Jul 6;101(1):50-64. 

14. Arts P, et al. Nat Commun. 2017 May 5;8:15190. 

15. de Ligt J, et al. N Engl J Med. 2012 Nov 15;367(20):1921-9. 

16. Gilissen C et al. Nature. 2014 Jul 17;511(7509):344-7. 

17. Arts P et al. Genome Med. 2019 Jun 17;11(1):38. 

18. Neveling K et al. Clin Chem. 2017 Feb;63(2):503-512. 

19. Eijkelenboom A, et al. J Mol Diagn. 2016 Nov;18(6):851-863. 

20. van de Veerdonk FL, Plantinga TS, Hoischen A, et al. N Engl J Med. 2011 Jul 7;365(1):54-61. 

21. Arts et al. J Allergy Clin Immunol. 2016 Sep;138(3):895-898. 

22. van der Made CI, et al. JAMA. 2020 Jul 24;324(7):1–11