Cohesin complex-associated holoprosencephaly

Paul Kruszka, Seth I. Berger, Valentina Casa, Mike R. Dekker, Jenna Gaesser, Karin Weiss, Ariel F. Martinez, David R. Murdock, Raymond J. Louie, Eloise J. Prijoles, Angie W. Lichty, Oebele F. Brouwer, Evelien Zonneveld-Huijssoon, Mark J. Stephan, Jacob Hogue, Ping Hu, Momoko Tanima-Nagai, Joshua L. Everson, Chitra Prasad, Anna CeredaMaria Iascone, Allison Schreiber, Vickie Zurcher, Nicole Corsten-Janssen, Luis Escobar, Nancy J. Clegg, Mauricio R. Delgado, Omkar Hajirnis, Meena Balasubramanian, Hülya Kayserili, Matthew Deardorff, Raymond A. Poot, Kerstin S. Wendt, Robert J. Lipinski, Maximilian Muenke

Research output: Contribution to journalArticlepeer-review

31 Scopus citations


Marked by incomplete division of the embryonic forebrain, holoprosencephaly is one of the most common human developmental disorders. Despite decades of phenotype-driven research, 80–90% of aneuploidy-negative holoprosencephaly individuals with a probable genetic aetiology do not have a genetic diagnosis. Here we report holoprosencephaly associated with variants in the two X-linked cohesin complex genes, STAG2 and SMC1A, with loss-of-function variants in 10 individuals and a missense variant in one. Additionally, we report four individuals with variants in the cohesin complex genes that are not X-linked, SMC3 and RAD21. Using whole mount in situ hybridization, we show that STAG2 and SMC1A are expressed in the prosencephalic neural folds during primary neurulation in the mouse, consistent with forebrain morphogenesis and holoprosencephaly pathogenesis. Finally, we found that shRNA knockdown of STAG2 and SMC1A causes aberrant expression of HPE-associated genes ZIC2, GLI2, SMAD3 and FGFR1 in human neural stem cells. These findings show the cohesin complex as an important regulator of median forebrain development and X-linked inheritance patterns in holoprosencephaly.

Original languageEnglish (US)
Pages (from-to)2631-2643
Number of pages13
Issue number9
StatePublished - Sep 1 2019
Externally publishedYes


  • Cohesin complex
  • Forebrain division
  • Holoprosencephaly
  • X-linked inheritance

ASJC Scopus subject areas

  • Clinical Neurology


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