2. Academic Validation
  3. Cohesin complex-associated holoprosencephaly

Cohesin complex-associated holoprosencephaly

  • Brain. 2019 Sep 1;142(9):2631-2643. doi: 10.1093/brain/awz210.
Paul Kruszka 1,  Seth I Berger 1,  Valentina Casa 2,  Mike R Dekker 2,  Jenna Gaesser 3,  Karin Weiss 1,  Ariel F Martinez 1,  David R Murdock 1,  Raymond J Louie 4,  Eloise J Prijoles 4,  Angie W Lichty 4,  Oebele F Brouwer 5,  Evelien Zonneveld-Huijssoon 6,  Mark J Stephan 7,  Jacob Hogue 8,  Ping Hu 1,  Momoko Tanima-Nagai 1,  Joshua L Everson 9 10,  Chitra Prasad 11,  Anna Cereda 12,  Maria Iascone 13,  Allison Schreiber 14,  Vickie Zurcher 14,  Nicole Corsten-Janssen 6,  Luis Escobar 15,  Nancy J Clegg 16,  Mauricio R Delgado 16 17,  Omkar Hajirnis 18,  Meena Balasubramanian 19 20,  Hülya Kayserili 21,  Matthew Deardorff 22 23,  Raymond A Poot 2,  Kerstin S Wendt 2,  Robert J Lipinski 9 10,  Maximilian Muenke 1
Affiliations

Affiliations

  • 1 Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
  • 2 Department of Cell Biology, Erasmus MC, Rotterdam, The Netherlands.
  • 3 Department of Pediatrics, Division of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
  • 4 Greenwood Genetic Center, JC Self Research Institute of Human Genetics, Greenwood, SC, USA.
  • 5 Department of Neurology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
  • 6 Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
  • 7 Department of Pediatrics, University of Washington, Seattle, WA, USA.
  • 8 Division of Clinical Genetics, Department of Pediatrics, Madigan Army Hospital, Tacoma, WA, USA.
  • 9 Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA.
  • 10 Molecular and Environmental Toxicology Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.
  • 11 Children's Health Research Institute, London, ON, Canada.
  • 12 Department of Pediatrics, ASST Papa Giovanni XXIII, Bergamo, Italy.
  • 13 Laboratorio di Genetica Medica, ASST Papa Giovanni XXIII, Bergamo, Italy.
  • 14 Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH, USA.
  • 15 Peyton Manning Children's Hospital at St. Vincent, Medical Genetics and Neurodevelopment Center, Indianapolis, IN, USA.
  • 16 Texas Scottish Rite Hospital for Children, Dallas, TX, USA.
  • 17 Department of Neurology and Neurotherapeutics UT Southwestern Medical Center Dallas, TX, USA.
  • 18 Pediatric Neurology, Synapses Child Neurology and Development Centre, Thane, Maharashtra, India.
  • 19 Sheffield Clinical Genetics Service, Sheffield Children's, NHS Foundation Trust, Sheffield, UK.
  • 20 Academic Unit of Child Health, University of Sheffield, Sheffield, UK.
  • 21 Medical Genetics, Medical Faculty, Koç University, Istanbul, Turkey.
  • 22 The Division of Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • 23 The Department of Pediatrics, The Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA, USA.
PMID: 31334757 DOI: 10.1093/brain/awz210
Abstract

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.

Keywords

X-linked inheritance; cohesin complex; forebrain division; holoprosencephaly.

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