JUN 26, 2020 8:00 AM PDT

Next-Generation Cytogenetics: international, multi-center study of chromosomal aberrations in constitutional diseases and leukemia with Bionano genome imaging

Sponsored by: Bionano Genomics
C.E. Credits: P.A.C.E. CE Florida CE
  • PHD - Assistant Professor, Immuno-Genomics - Radboud Medical Center, Nijmegen, The Netherlands
      My research group 'Genomic Technologies and Immuno-Genomics' (https://www.radboudumc.nl/en/immuno-genomics) has expertise in the identification of rare disease genes using latest genomics tools - since recently with a particular focus on immune disease genes. 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. Recently we started to apply long-read sequencing and long-read mapping to unsolved rare disease cases.

      After we applied latest genomic technologies successfully in the research of rare diseases, e.g. WES [e.g.:1-5]; and MIPs [e.g.:6-9]; these were subsequently integrated into routine diagnostics, e.g. WES [e.g.:10-11]; and MIPs [12-13]. My research group now focuses on the genetic basis of immune diseases [e.g.:14-16].

      In the last years we have shown that applications of novel and disruptive technologies allows new scientific insights and rapid translation into clinical/diagnostic practice at unprecedented speed. As part of my role in rare disease genomics I co-lead a work package in the EU-funded H2020 project SOLVE-RD (www.solve-rd.eu). I was also awarded the full PI status at the Radboudumc from 2019 onwards.


      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.

      2. Acuna-Hidalgo R [...] 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.

      3. Hoischen A, Krumm N, Eichler EE. Prioritization of neurodevelopmental disease genes by discovery of new mutations. Nat Neurosci. 2014 Jun;17(6):764-72.

      4. Stránecký V, Hoischen A, et al. Mutations in ANTXR1 cause GAPO syndrome. Am J Hum Genet. 2013 May 2;92(5):792-9.

      5. van Bon BW, [...] Hoischen A. Cantú syndrome is caused by mutations in ABCC9. Am J Hum Genet. 2012 Jun 8;90(6):1094-101.

      6. Jansen S, Hoischen A, et al. A genotype-first approach identifies an intellectual disability-overweight syndrome caused by PHIP haploinsufficiency. Eur J Hum Genet. 2017 Dec 5.

      7. Ockeloen CW, [...] Hoischen A, Carels CEL. Novel mutations in LRP6 highlight the role of WNT signaling in tooth agenesis. Genet Med. 2016 Nov;18(11):1158-1162.

      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.

      9. Arts P, [...] Hoischen A, Albers CA. Quantification of differential gene expression by multiplexed targeted resequencing of cDNA. Nat Commun. 2017 May 5;8:15190.

      10. de Ligt J, [...] 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.

      11. Gilissen C [...] Hoischen A, [...] Veltman JA. Genome sequencing identifies major causes of severe intellectual disability. Nature. 2014 Jul 17;511(7509):344-7.

      12. Neveling K [...] Shendure J, Nelen MR, Hoischen A. BRCA Testing by Single-Molecule Molecular Inversion Probes. Clin Chem. 2017 Feb;63(2):503-512.

      13. Eijkelenboom A, [...] Hoischen A, Nelen MR, Ligtenberg MJ, Tops BB. Reliable Next-Generation Sequencing of Formalin-Fixed, Paraffin-Embedded Tissue Using Single Molecule Tags. J Mol Diagn. 2016 Nov;18(6):851-863.

      14. 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.

      15. Arts P [...] Hoischen A, Netea MG. Immunologic defects in severe mucocutaneous HSV-2 infections: Response to IFN-γ therapy. J Allergy Clin Immunol. 2016 Sep;138(3):895-898.

      16. 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.
    • PharmD PHD - Associate Professor, APHP Cochin - Paris Descartes University, Paris, France
        Dr Laïla El Khattabi is an associate professor in Cytogenetics at Paris Descartes University and Cochin Hospital in Paris. She is in charge of the Laboratory of non-invasive prenatal screening of fetal aneuploidies for Parisian public hospitals. She is also involved in the diagnosis of chromosomal abnormalities related to developmental and reproductive disorders. In addition to the diagnosis activity, Dr El Khattabi leads research at Cochin Institute to understand how gene transcription is regulated and how this is altered in case of chromosomal abnormalities.

      Join us June 26th at 8am PT, 11am ET as Dr. Laila El Khattabi and Dr. Alexander Hoischen discuss Next-Generation Cytogenetics: international, multi-center study of chromosomal aberrations in constitutional diseases and leukemia with Bionano genome imaging
      Dr. El Khattabi:  Genome-mapping using Bionano allows for comprehensive detection of chromosomal aberrations in constitutional diseases and leukemia.
      Dr. Hoischen:  Next generation cytogenetics: Optical mapping identifies hidden germline structural variant in rare disease cases and allows comprehensive somatic SV detection in leukemia. 
      Structural variants (SVs) are an important source of genetic variation in the human genome and they are involved in a multitude of human diseases as well as cancer. SVs are enriched in repeat-rich regions of the human genome, and several remain undetected by conventional short-read sequencing technologies.  Here we applied Bionano Genomics’ high-resolution optical mapping to comprehensively identify SVs, leveraging the most recent improvements: a) deep-genome coverage (400x) to enable somatic mutation detection in leukemia samples; b) highest resolution (≥500bp) and no sequencing bias allows detection of SVs refractory to sequencing in rare disease cases.  Deep-genome coverage was used to comprehensively detect somatic SVs on 52 leukemia samples, and allowed the 100% concordance for all aberrations with >10% variant allele fraction that previously required a combination of karyotyping, FISH and/or CNV-microarray. In addition, optical mapping allowed the identification of SVs that remained refractory to detection by classical methods including MLPA, Sanger sequencing, exome and/or genome sequencing. This allowed the identification of likely disease causing SVs in 5/20 research cases. Including a) a partial deletion of the NSF gene located in the distal segmental-duplication in 17q21.31, which likely disrupts NSF in a patients with intellectual disability; this event remained undetected even by long-read SMRT sequencing; b) a retrotransposon insertion in patient with a tumor-predisposition syndrome
      In summary, the full concordance with diagnostic standard assays in leukemia demonstrates the potential to replace classical cytogenetic tests. We furthermore show how the complementary use of mapping rather than sequencing approaches can unmask hidden SVs.
      Learning objectives:
      • Develop awareness of new long read technologies for whole genome study
      • Review findings in complex Cancer/constitutional cases in a clinical or research setting
      Webinars will be available for unlimited on-demand viewing after live event.
      LabRoots is approved as a provider of continuing education programs in the clinical laboratory sciences by the ASCLS P.A.C.E. ® Program. By attending this webinar, you can earn 1 Continuing Education credit once you have viewed the webinar in its entirety.

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