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A complementary study approach unravels novel players in the pathoetiology of Hirschsprung disease.

  • Mederer T Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany.
  • Schmitteckert S Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany.
  • Volz J Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany.
  • Martínez C Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany.
  • Röth R Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany.
  • Thumberger T Centre for Organismal Studies, Heidelberg University, Heidelberg, Germany.
  • Eckstein V FACS Core Facility, Campus Heidelberg, Germany.
  • Scheuerer J Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
  • Thöni C Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
  • Lasitschka F Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
  • Carstensen L Pediatric Surgery Division, Heidelberg University Hospital, Heidelberg, Germany.
  • Günther P Pediatric Surgery Division, Heidelberg University Hospital, Heidelberg, Germany.
  • Holland-Cunz S Pediatric Surgery, University Children's Hospital, Basel, Switzerland.
  • Hofstra R Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
  • Brosens E Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
  • Rosenfeld JA Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
  • Schaaf CP Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
  • Schriemer D Department of Neuroscience, University Medical Center, Groningen, The Netherlands.
  • Ceccherini I UOSD Genetica e Genomica delle Malattie Rare, IRCCS, Instituto Giannina Gaslini, Genova, Italy.
  • Rusmini M UOSD Genetica e Genomica delle Malattie Rare, IRCCS, Instituto Giannina Gaslini, Genova, Italy.
  • Tilghman J Center for Human Genetics and Genomics, New York University School of Medicine, United States of America.
  • Luzón-Toro B Department of Maternofetal Medicine, Genetics and Reproduction, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain.
  • Torroglosa A Department of Maternofetal Medicine, Genetics and Reproduction, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain.
  • Borrego S Department of Maternofetal Medicine, Genetics and Reproduction, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain.
  • Sze-Man Tang C Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • Garcia-Barceló M Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • Tam P Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • Paramasivam N Division of Theoretical Bioinformatics, German Cancer Research Center, Heidelberg, Germany.
  • Bewerunge-Hudler M Genomics and Proteomic Core Facility, German Cancer Research Center, Heidelberg, Germany.
  • De La Torre C Center of Medical Research, Medical Faculty Mannheim, Mannheim, Germany.
  • Gretz N Center of Medical Research, Medical Faculty Mannheim, Mannheim, Germany.
  • Rappold GA Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany.
  • Romero P Pediatric Surgery Division, Heidelberg University Hospital, Heidelberg, Germany.
  • Niesler B Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany.
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  • 2020-11-05
Published in:
  • PLoS genetics. - 2020
Genetics(clinical)
Genetics
Cancer Research
Ecology, Evolution, Behavior and Systematics
Molecular Biology
English Hirschsprung disease (HSCR, OMIM 142623) involves congenital intestinal obstruction caused by dysfunction of neural crest cells and their progeny during enteric nervous system (ENS) development. HSCR is a multifactorial disorder; pathogenetic variants accounting for disease phenotype are identified only in a minority of cases, and the identification of novel disease-relevant genes remains challenging. In order to identify and to validate a potential disease-causing relevance of novel HSCR candidate genes, we established a complementary study approach, combining whole exome sequencing (WES) with transcriptome analysis of murine embryonic ENS-related tissues, literature and database searches, in silico network analyses, and functional readouts using candidate gene-specific genome-edited cell clones. WES datasets of two patients with HSCR and their non-affected parents were analysed, and four novel HSCR candidate genes could be identified: ATP7A, SREBF1, ABCD1 and PIAS2. Further rare variants in these genes were identified in additional HSCR patients, suggesting disease relevance. Transcriptomics revealed that these genes are expressed in embryonic and fetal gastrointestinal tissues. Knockout of these genes in neuronal cells demonstrated impaired cell differentiation, proliferation and/or survival. Our approach identified and validated candidate HSCR genes and provided further insight into the underlying pathomechanisms of HSCR.
Language
  • English
Open access status
gold
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Persistent URL
https://sonar.ch/global/documents/139257
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