Cohesin complex-associated holoprosencephaly

Author:

Kruszka Paul1ORCID,Berger Seth I1,Casa Valentina2,Dekker Mike R2,Gaesser Jenna3,Weiss Karin1,Martinez Ariel F1,Murdock David R1,Louie Raymond J4,Prijoles Eloise J4,Lichty Angie W4,Brouwer Oebele F5,Zonneveld-Huijssoon Evelien6,Stephan Mark J7,Hogue Jacob8,Hu Ping1,Tanima-Nagai Momoko1,Everson Joshua L910,Prasad Chitra11,Cereda Anna12,Iascone Maria13,Schreiber Allison14,Zurcher Vickie14,Corsten-Janssen Nicole6,Escobar Luis15,Clegg Nancy J16,Delgado Mauricio R1617,Hajirnis Omkar18,Balasubramanian Meena1920,Kayserili Hülya21,Deardorff Matthew2223,Poot Raymond A2,Wendt Kerstin S2,Lipinski Robert J910,Muenke Maximilian1

Affiliation:

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

Abstract

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.

Funder

National Human Genome Research Institute Intramural Research Program

Dutch Cancer Society

Netherlands Organisation of Scientific Research

NWO

National Institute of Environmental Health Sciences

National Institutes of Health

Publisher

Oxford University Press (OUP)

Subject

Neurology (clinical)

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