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MEF2C Haploinsufficiency features consistent hyperkinesis, variable epilepsy, and has a role in dorsal and ventral neuronal developmental pathways

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Abstract

MEF2C haploinsufficiency syndrome is an emerging neurodevelopmental disorder associated with intellectual disability, autistic features, epilepsy, and abnormal movements. We report 16 new patients with MEF2C haploinsufficiency, including the oldest reported patient with MEF2C deletion at 5q14.3. We detail the neurobehavioral phenotype, epilepsy, and abnormal movements, and compare our subjects with those previously reported in the literature. We also investigate Mef2c expression in the developing mouse forebrain. A spectrum of neurofunctional deficits emerges, with hyperkinesis a consistent finding. Epilepsy varied from absent to severe, and included intractable myoclonic seizures and infantile spasms. Subjects with partial MEF2C deletion were statistically less likely to have epilepsy. Finally, we confirm that Mef2c is present both in dorsal primary neuroblasts and ventral gamma-aminobutyric acid(GABA)ergic interneurons in the forebrain of the developing mouse. Given interactions with several key neurodevelopmental genes such as ARX, FMR1, MECP2, and TBR1, it appears that MEF2C plays a role in several developmental stages of both dorsal and ventral neuronal cell types.

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Acknowledgments

We wish to thank the families of the subjects for sharing the details of their children’s condition with us. We recognize Natasha Vedage and Molly Bourke for their assistance with the immunohistochemistry, Erin Dodge for assistance with figure design, and Hailly Butler for assistance with subject consents.

Disclosures

WBD is funded by NINDS R01 NS058721; JAR and RAS are employees of Signature Genomic Laboratories, PerkinElmer; ANL is an employee of ARUP Laboratories; and RJV is an employee of Lineagen, Inc. The other authors have no disclosures.

Author information

Author notes

  1. Lisa G. Shaffer & Blake C. Ballif

    Present address: Paw Print Genetics, Genetic Veterinary Sciences, Inc., Spokane, WA, USA

Authors and Affiliations

  1. Departments of Neurology, Pediatrics, and Biomedical Genetics, Center for Neural Development & Disease, University of Rochester Medical Center, 601 Elmwood Ave, Rochester, NY, 14642, USA

    Alex R. Paciorkowski

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

    Ryan N. Traylor, Jill A. Rosenfeld, Roger A. Schultz, Lisa G. Shaffer & Blake C. Ballif

  3. Department of Medical Genetics, Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA

    Jacqueline M. Hoover

  4. Division of Medical Genetics, Department of Child Health, University of Missouri, Columbia, MO, USA

    Catharine J. Harris

  5. Department of Medical Genetics/Metabolism, Children’s Hospital of Central California, Madera, CA, USA

    Susan Winter

  6. Department of Pediatrics, Louisiana State University Health Sciences Center, New Orleans, LA and Children’s Hospital, New Orleans, LA, USA

    Yves Lacassie

  7. Division of Medical Genetics, North Shore Long Island Jewish Health System, New Hyde Park, NY, USA

    Martin Bialer

  8. ARUP Laboratories, University of Utah, Salt Lake City, UT, USA

    Allen N. Lamb

  9. Departments of Pediatrics, Neurological Sciences & Biochemistry, Rush University Medical Center, Chicago, IL, USA

    Elizabeth Berry-Kravis

  10. Department of Neurology, Stanford University, Stanford, CA, USA

    Brenda E. Porter

  11. Department of Medical Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Marni Falk

  12. Department of Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Anu Venkat & Eric D. Marsh

  13. Lineagen, Inc., Salt Lake City, UT, USA

    Rena J. Vanzo

  14. Division of Neurogenetics, Kennedy Krieger Institute, Johns Hopkins Medical Institutions, Baltibmore, MD, USA

    Julie S. Cohen & Ali Fatemi

  15. Division of Genetic Medicine, Department of Pediatrics, University of Washington and Seattle Children’s Research Institute, Seattle, WA, USA

    William B. Dobyns

Authors
  1. Alex R. Paciorkowski
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  2. Ryan N. Traylor
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  9. Allen N. Lamb
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  20. Blake C. Ballif
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  21. Eric D. Marsh
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Corresponding author

Correspondence to Alex R. Paciorkowski.

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Video 1

Subject LR11-325 at 5 months, showing paroxysms of hyperkinetic movements of the arms and legs. These were not associated with epileptiform discharges on EEG. (MPG 7636 kb)

Subject IS09-024 at 12 years, showing stereotypic hyperkinetic movements of the distal upper extremities. (AVI 6156 kb)

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Paciorkowski, A.R., Traylor, R.N., Rosenfeld, J.A. et al. MEF2C Haploinsufficiency features consistent hyperkinesis, variable epilepsy, and has a role in dorsal and ventral neuronal developmental pathways. Neurogenetics 14, 99–111 (2013). https://doi.org/10.1007/s10048-013-0356-y

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  • DOI: https://doi.org/10.1007/s10048-013-0356-y

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