Original Research Article | Published:

The phenotypic spectrum of Schaaf-Yang syndrome: 18 new affected individuals from 14 families

Genetics in Medicine volume 19, pages 4552 (2017) | Download Citation

  • A Corrigendum to this article was published on 29 September 2016



Truncating mutations in the maternally imprinted, paternally expressed gene MAGEL2, which is located in the Prader-Willi critical region 15q11–13, have recently been reported to cause Schaaf-Yang syndrome, a Prader-Willi-like disease that manifests as developmental delay/intellectual disability, hypotonia, feeding difficulties, and autism spectrum disorder. The causality of the reported variants in the context of the patients’ phenotypes was questioned, as MAGEL2 whole-gene deletions seem to cause little or no clinical phenotype.


Here we report a total of 18 newly identified individuals with Schaaf-Yang syndrome from 14 families, including 1 family with 3 individuals found to be affected with a truncating variant of MAGEL2, 11 individuals who are clinically affected but were not tested molecularly, and a presymptomatic fetal sibling carrying the pathogenic MAGEL2 variant.


All cases harbor truncating mutations of MAGEL2, and nucleotides c.1990–1996 arise as a mutational hotspot, with 10 individuals and 1 fetus harboring a c.1996dupC (p.Q666fs) mutation and 2 fetuses harboring a c.1996delC (p.Q666fs) mutation. The phenotypic spectrum of Schaaf-Yang syndrome ranges from fetal akinesia to neurobehavioral disease and contractures of the small finger joints.


This study provides strong evidence for the pathogenicity of truncating mutations of the paternal allele of MAGEL2, refines the associated clinical phenotypes, and highlights implications for genetic counseling for affected families.

Genet Med 19 1, 45–52.

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This work was supported by the Joan and Stanford Alexander Family (C.P.S.), and the Foundation for Prader-Willi Research (C.P.S.). This research is supported by the Intellectual and Developmental Disabilities Research Center (1U54 HD083092). The authors are indebted to the patients and their families for their willingness to participate in this study.

A Facebook group for affected families is at http://www.facebook.com/MAGEL2.

Author information

Author notes


  1. Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas, USA

    • Michael D. Fountain
    •  & Christian P. Schaaf
  2. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA

    • Michael D. Fountain
    • , Magdalena A. Walkiewicz
    • , Fan Xia
    • , Yaping Yang
    • , Brett H. Graham
    • , Carlos A. Bacino
    • , Lorraine Potocki
    • , Jill A. Rosenfeld
    • , Andrea M. Lewis
    •  & Christian P. Schaaf
  3. Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, Texas, USA

    • Michael D. Fountain
    •  & Christian P. Schaaf
  4. Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands

    • Emmelien Aten
    • , Arie van Haeringen
    • , Claudia A.L. Ruivenkamp
    •  & Gijs W.E. Santen
  5. GeneDX, Gaithersburg, Maryland, USA

    • Megan T. Cho
    •  & Jane Juusola
  6. Division of Medical Genetics, University of Texas Medical Branch, Galveston, Texas, USA

    • Joseph W. Ray
  7. Department of Pediatrics, The University of Texas Medical School at Houston, Houston, Texas, USA

    • Joseph W. Ray
    • , Pedro Mancias
    •  & Hope Northrup
  8. Texas Children’s Hospital, Houston, Texas, USA

    • Brett H. Graham
    • , Carlos A. Bacino
    • , Lorraine Potocki
    •  & Andrea M. Lewis
  9. Genetic Services, Cook Children’s Health Care System, Fort Worth, Texas, USA

    • Mary K. Kukolich
  10. Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands

    • Marjan M. Weiss
  11. Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    • Conny M.A. van Ravenswaaij-Arts
  12. Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands

    • Inge B. Mathijssen
  13. Département de pédiatrie, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada

    • Sebastien Levesque
  14. Children’s Hospital Colorado, Aurora, Colorado, USA

    • Naomi Meeks
    •  & Danielle Lemke
  15. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    • Ada Hamosh
  16. Department of Medical Genetics, BC Children’s and Women’s Health Center of British Columbia, The University of British Columbia, Vancouver, British Columbia, Canada

    • Suzanne K. Lewis
    •  & Simone Race
  17. Department of Pediatrics, BC Children’s and Women’s Health Center of British Columbia, The University of British Columbia, Vancouver, British Columbia, Canada

    • Laura L. Stewart
  18. Division of Genetics, UMass Memorial Children’s Medical Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA

    • Beverly Hay
  19. Department of Molecular Neuroscience, University College London Institute of Neurology, London, UK

    • Rita L. Guerreiro
    •  & Jose T. Bras
  20. Centro Hospitalar de Trás-os-Montes e Alto Douro, Unidade Hospital de Vila Real, Vila Real, Portugal

    • Marcia P. Martins
  21. Department of Pediatrics, Juliana Children’s Hospital-Haga Teaching Hospital, The Hague, The Netherlands

    • Gerarda Derksen-Lubsen
  22. Department of Child Neurology, Juliana Children’s Hospital–Haga Teaching Hospital, The Hague, The Netherlands

    • Els Peeters
  23. Department of Clinical Genetics and School for Oncology and Developmental Biology, Maastricht UMC+, Maastricht, The Netherlands

    • Connie Stumpel
    •  & Sander Stegmann
  24. Department of Pediatrics, Máxima Medical Center, Veldhoven, The Netherlands

    • Levinus A. Bok


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Corresponding authors

Correspondence to Gijs W.E. Santen or Christian P. Schaaf.

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