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

Tanja Mederer, Stefanie Schmitteckert, Julia Volz, Cristina Martínez, Ralph Röth, Thomas Thumberger, Volker Eckstein, Jutta Scheuerer, Cornelia Thöni, Felix Lasitschka, Leonie Carstensen, Patrick Günther, Stefan Holland-Cunz, Robert Hofstra, Erwin Brosens, Jill A Rosenfeld, Christian P Schaaf, Duco Schriemer, Isabella Ceccherini, Marta RusminiJoseph Tilghman, Berta Luzón-Toro, Ana Torroglosa, Salud Borrego, Clara Sze-Man Tang, Mercè Garcia-Barceló, Paul Tam, Nagarajan Paramasivam, Melanie Bewerunge-Hudler, Carolina De La Torre, Norbert Gretz, Gudrun A Rappold, Philipp Romero, Beate Niesler

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)e1009106
JournalPLoS Genetics
Issue number11
Publication statusPublished - Nov 2020


  • ATP Binding Cassette Transporter, Subfamily D, Member 1/genetics
  • Animals
  • Cell Differentiation/genetics
  • Cell Line
  • Cell Proliferation/genetics
  • Cell Survival/genetics
  • Computer Simulation
  • Copper-Transporting ATPases/genetics
  • Disease Models, Animal
  • Gene Expression Profiling
  • Gene Knockout Techniques
  • Hirschsprung Disease/genetics
  • Humans
  • Infant
  • Male
  • Mice
  • Protein Inhibitors of Activated STAT/genetics
  • Sterol Regulatory Element Binding Protein 1/genetics
  • Whole Exome Sequencing

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