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@ARTICLE{Mederer:165816,
      author       = {T. Mederer and S. Schmitteckert and J. Volz and C.
                      Martínez and R. Röth and T. Thumberger and V. Eckstein and
                      J. Scheuerer and C. Thöni and F. Lasitschka and L.
                      Carstensen and P. Günther and S. Holland-Cunz and R.
                      Hofstra and E. Brosens and J. A. Rosenfeld and C. P. Schaaf
                      and D. Schriemer and I. Ceccherini and M. Rusmini and J.
                      Tilghman and B. Luzón-Toro and A. Torroglosa and S. Borrego
                      and C. Sze-Man Tang and M. Garcia-Barceló and P. Tam and N.
                      Paramasivam$^*$ and M. Bewerunge-Hudler$^*$ and C. De La
                      Torre and N. Gretz and G. A. Rappold and P. Romero and B.
                      Niesler},
      title        = {{A} complementary study approach unravels novel players in
                      the pathoetiology of {H}irschsprung disease.},
      journal      = {PLoS Genetics},
      volume       = {16},
      number       = {11},
      issn         = {1553-7404},
      address      = {San Francisco, Calif.},
      publisher    = {Public Library of Science},
      reportid     = {DKFZ-2020-02396},
      pages        = {e1009106 -},
      year         = {2020},
      abstract     = {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.},
      cin          = {B080 / W110},
      ddc          = {610},
      cid          = {I:(DE-He78)B080-20160331 / I:(DE-He78)W110-20160331},
      pnm          = {312 - Functional and structural genomics (POF3-312)},
      pid          = {G:(DE-HGF)POF3-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:33151932},
      doi          = {10.1371/journal.pgen.1009106},
      url          = {https://inrepo02.dkfz.de/record/165816},
}