2. Academic Validation
  3. The phenotypic spectrum of Schaaf-Yang syndrome: 18 new affected individuals from 14 families

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

  • Genet Med. 2017 Jan;19(1):45-52. doi: 10.1038/gim.2016.53.
Michael D Fountain 1 2 3,  Emmelien Aten 4,  Megan T Cho 5,  Jane Juusola 5,  Magdalena A Walkiewicz 2,  Joseph W Ray 6 7,  Fan Xia 2,  Yaping Yang 2,  Brett H Graham 2 8,  Carlos A Bacino 2 8,  Lorraine Potocki 2 8,  Arie van Haeringen 4,  Claudia A L Ruivenkamp 4,  Pedro Mancias 7,  Hope Northrup 7,  Mary K Kukolich 9,  Marjan M Weiss 10,  Conny M A van Ravenswaaij-Arts 11,  Inge B Mathijssen 12,  Sebastien Levesque 13,  Naomi Meeks 14,  Jill A Rosenfeld 2,  Danielle Lemke 14,  Ada Hamosh 15,  Suzanne K Lewis 16,  Simone Race 16,  Laura L Stewart 17,  Beverly Hay 18,  Andrea M Lewis 2 8,  Rita L Guerreiro 19,  Jose T Bras 19,  Marcia P Martins 20,  Gerarda Derksen-Lubsen 21,  Els Peeters 22,  Connie Stumpel 23,  Sander Stegmann 23,  Levinus A Bok 24,  Gijs W E Santen 4,  Christian P Schaaf 1 2 3
Affiliations

Affiliations

  • 1 Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas, USA.
  • 2 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
  • 3 Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, USA.
  • 4 Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
  • 5 GeneDX, Gaithersburg, Maryland, USA.
  • 6 Division of Medical Genetics, University of Texas Medical Branch, Galveston, Texas, USA.
  • 7 Department of Pediatrics, The University of Texas Medical School at Houston, Houston, Texas, USA.
  • 8 Texas Children's Hospital, Houston, Texas, USA.
  • 9 Genetic Services, Cook Children's Health Care System, Fort Worth, Texas, USA.
  • 10 Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
  • 11 Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
  • 12 Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.
  • 13 Département de pédiatrie, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada.
  • 14 Children's Hospital Colorado, Aurora, Colorado, USA.
  • 15 McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
  • 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.
  • 17 Department of Pediatrics, BC Children's and Women's Health Center of British Columbia, The University of British Columbia, Vancouver, British Columbia, Canada.
  • 18 Division of Genetics, UMass Memorial Children's Medical Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
  • 19 Department of Molecular Neuroscience, University College London Institute of Neurology, London, UK.
  • 20 Centro Hospitalar de Trás-os-Montes e Alto Douro, Unidade Hospital de Vila Real, Vila Real, Portugal.
  • 21 Department of Pediatrics, Juliana Children's Hospital-Haga Teaching Hospital, The Hague, The Netherlands.
  • 22 Department of Child Neurology, Juliana Children's Hospital-Haga Teaching Hospital, The Hague, The Netherlands.
  • 23 Department of Clinical Genetics and School for Oncology and Developmental Biology, Maastricht UMC+, Maastricht, The Netherlands.
  • 24 Department of Pediatrics, Máxima Medical Center, Veldhoven, The Netherlands.
PMID: 27195816 DOI: 10.1038/gim.2016.53
Abstract

Purpose: 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.

Methods: 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.

Results: 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.

Conclusion: 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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