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Haploinsufficiency of KDM6A is associated with severe psychomotor retardation, global growth restriction, seizures and cleft palate

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Abstract

We describe a female subject (DGAP100) with a 46,X,t(X;5)(p11.3;q35.3)inv(5)(q35.3q35.1)dn, severe psychomotor retardation with hypotonia, global postnatal growth restriction, microcephaly, globally reduced cerebral volume, seizures, facial dysmorphia and cleft palate. Fluorescence in situ hybridization and whole-genome sequencing demonstrated that the X chromosome breakpoint disrupts KDM6A in the second intron. No genes were directly disrupted on chromosome 5. KDM6A is a histone 3 lysine 27 demethylase and a histone 3 lysine 4 methyltransferase. Expression of KDM6A is significantly reduced in DGAP100 lymphoblastoid cells compared to control samples. We identified nine additional cases with neurodevelopmental delay and various other features consistent with the DGAP100 phenotype with copy number variation encompassing KDM6A from microarray databases. We evaluated haploinsufficiency of kdm6a in a zebrafish model. kdm6a is expressed in the pharyngeal arches and ethmoid plate of the developing zebrafish, while a kdm6a morpholino knockdown exhibited craniofacial defects. We conclude KDM6A dosage regulation is associated with severe and diverse structural defects and developmental abnormalities.

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Acknowledgments

We would like to thank DGAP100 and her family for participating in our research study and all of the healthcare professionals that contributed to this effort. We would also like to thank Mary Anne Anderson for her technical assistance at the Massachusetts General Hospital Genomics Core Facility in the Center for Human Genetic Research, Tammy Gillis and the MGH NextGen Sequencing Core, and the Cytogenetics Core of Dana Farber Harvard Cancer Center (P30 CA006516). This work was supported by PO1GM061354 (CCM), HD065286 (JFG) and MH095867 (MET) from the National Institutes of Health and the National Institute of General Medical Sciences, and March of Dimes and Shriners Hospitals for Children (ECL).

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Authors and Affiliations

  1. Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women’s Hospital, Boston, MA, USA

    Amelia M. Lindgren, Shahrin Pereira & Zehra Ordulu

  2. Department of Plastic and Reconstructive Surgery, Center for Regenerative Medicine, Massachusetts General Hospital, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA, USA

    Tatiana Hoyos & Eric C. Liao

  3. Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA

    Michael E. Talkowski, Carrie Hanscom, Ian Blumenthal, Colby Chiang, Carl Ernst & James F. Gusella

  4. Departments of Neurology and Genetics, Harvard Medical School, Boston, MA, USA

    Michael E. Talkowski & James F. Gusella

  5. Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA

    Michael E. Talkowski, James F. Gusella & Cynthia C. Morton

  6. Department of Pediatrics/Genetics, University of New Mexico, Albuquerque, NM, USA

    Carol Clericuzio & Joanne M. Drautz

  7. Signature Genomic Laboratories, PerkinElmer Inc., Spokane, WA, USA

    Jill A. Rosenfeld & Lisa G. Shaffer

  8. Northwestern Ontario Regional Genetics Program, Thunder Bay, ON, Canada

    Lea Velsher & Tania Pynn

  9. University of Leuven, Gasthuisberg, The Netherlands

    Joris Vermeesch

  10. Division of Genetics, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA

    David J. Harris

  11. Autism Consortium of Boston, Boston, MA, USA

    James F. Gusella

  12. Departments of Obstetrics, Gynecology and Reproductive Biology and Pathology, Brigham and Women’s Hospital and Harvard Medical School, New Research Building, Room 160D, 77 Avenue Louis Pasteur, Boston, MA, 02115, USA

    Cynthia C. Morton

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  1. Amelia M. Lindgren
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  2. Tatiana Hoyos
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  3. Michael E. Talkowski
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  4. Carrie Hanscom
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  6. Colby Chiang
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  7. Carl Ernst
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  8. Shahrin Pereira
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  9. Zehra Ordulu
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  10. Carol Clericuzio
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  15. Tania Pynn
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  16. Joris Vermeesch
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  17. David J. Harris
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  18. James F. Gusella
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  19. Eric C. Liao
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  20. Cynthia C. Morton
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Corresponding author

Correspondence to Cynthia C. Morton.

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Lindgren, A.M., Hoyos, T., Talkowski, M.E. et al. Haploinsufficiency of KDM6A is associated with severe psychomotor retardation, global growth restriction, seizures and cleft palate. Hum Genet 132, 537–552 (2013). https://doi.org/10.1007/s00439-013-1263-x

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  • DOI: https://doi.org/10.1007/s00439-013-1263-x

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