title: The phenotypic spectrum of Schaaf-Yang syndrome: 18 new affected individuals from 14 families.
abstract: 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.
authors.affiliation: Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas, USA.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Fountain
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Emmelien
authors.initials: E
authors.lastname: Aten
authors.affiliation: GeneDX, Gaithersburg, Maryland, USA.
authors.forename: Megan T
authors.initials: MT
authors.lastname: Cho
authors.affiliation: GeneDX, Gaithersburg, Maryland, USA.
authors.forename: Jane
authors.identifier: 0000-0002-4476-1309
authors.initials: J
authors.lastname: Juusola
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Magdalena A
authors.initials: MA
authors.lastname: Walkiewicz
authors.affiliation: Division of Medical Genetics, University of Texas Medical Branch, Galveston, Texas, USA.|Department of Pediatrics, The University of Texas Medical School at Houston, Houston, Texas, USA.
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Ray
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Xia
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Texas Children's Hospital, Houston, Texas, USA.
authors.forename: Brett H
authors.identifier: 0000-0001-8451-8154
authors.initials: BH
authors.lastname: Graham
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Texas Children's Hospital, Houston, Texas, USA.
authors.forename: Carlos A
authors.identifier: 0000-0002-4342-5012
authors.initials: CA
authors.lastname: Bacino
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Texas Children's Hospital, Houston, Texas, USA.
authors.forename: Lorraine
authors.initials: L
authors.lastname: Potocki
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Arie
authors.initials: A
authors.lastname: van Haeringen
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Claudia A L
authors.initials: CA
authors.lastname: Ruivenkamp
authors.affiliation: Department of Pediatrics, The University of Texas Medical School at Houston, Houston, Texas, USA.
authors.forename: Pedro
authors.initials: P
authors.lastname: Mancias
authors.affiliation: Department of Pediatrics, The University of Texas Medical School at Houston, Houston, Texas, USA.
authors.forename: Hope
authors.initials: H
authors.lastname: Northrup
authors.affiliation: Genetic Services, Cook Children's Health Care System, Fort Worth, Texas, USA.
authors.forename: Mary K
authors.identifier: 0000-0002-1184-6226
authors.initials: MK
authors.lastname: Kukolich
authors.affiliation: Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Marjan M
authors.initials: MM
authors.lastname: Weiss
authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Conny M A
authors.initials: CM
authors.lastname: van Ravenswaaij-Arts
authors.affiliation: Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Inge B
authors.initials: IB
authors.lastname: Mathijssen
authors.affiliation: Département de pédiatrie, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada.
authors.forename: Sebastien
authors.identifier: 0000-0002-0009-7952
authors.initials: S
authors.lastname: Levesque
authors.affiliation: Children's Hospital Colorado, Aurora, Colorado, USA.
authors.forename: Naomi
authors.identifier: 0000-0001-5355-3811
authors.initials: N
authors.lastname: Meeks
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Jill A
authors.identifier: 0000-0001-5664-7987
authors.initials: JA
authors.lastname: Rosenfeld
authors.affiliation: Children's Hospital Colorado, Aurora, Colorado, USA.
authors.forename: Danielle
authors.initials: D
authors.lastname: Lemke
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Ada
authors.initials: A
authors.lastname: Hamosh
authors.affiliation: Department of Medical Genetics, BC Children's and Women's Health Center of British Columbia, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Suzanne K
authors.identifier: 0000-0002-6300-5381
authors.initials: SK
authors.lastname: Lewis
authors.affiliation: Department of Medical Genetics, BC Children's and Women's Health Center of British Columbia, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Simone
authors.initials: S
authors.lastname: Race
authors.affiliation: Department of Pediatrics, BC Children's and Women's Health Center of British Columbia, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Laura L
authors.initials: LL
authors.lastname: Stewart
authors.affiliation: Division of Genetics, UMass Memorial Children's Medical Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Beverly
authors.identifier: 0000-0001-8294-0087
authors.initials: B
authors.lastname: Hay
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Texas Children's Hospital, Houston, Texas, USA.
authors.forename: Andrea M
authors.identifier: 0000-0002-1116-4276
authors.initials: AM
authors.lastname: Lewis
authors.affiliation: Department of Molecular Neuroscience, University College London Institute of Neurology, London, UK.
authors.forename: Rita L
authors.initials: RL
authors.lastname: Guerreiro
authors.affiliation: Department of Molecular Neuroscience, University College London Institute of Neurology, London, UK.
authors.forename: Jose T
authors.identifier: 0000-0001-8186-0333
authors.initials: JT
authors.lastname: Bras
authors.affiliation: Centro Hospitalar de Trás-os-Montes e Alto Douro, Unidade Hospital de Vila Real, Vila Real, Portugal.
authors.forename: Marcia P
authors.initials: MP
authors.lastname: Martins
authors.affiliation: Department of Pediatrics, Juliana Children's Hospital-Haga Teaching Hospital, The Hague, The Netherlands.
authors.forename: Gerarda
authors.initials: G
authors.lastname: Derksen-Lubsen
authors.affiliation: Department of Child Neurology, Juliana Children's Hospital-Haga Teaching Hospital, The Hague, The Netherlands.
authors.forename: Els
authors.initials: E
authors.lastname: Peeters
authors.affiliation: Department of Clinical Genetics and School for Oncology and Developmental Biology, Maastricht UMC+, Maastricht, The Netherlands.
authors.forename: Connie
authors.initials: C
authors.lastname: Stumpel
authors.affiliation: Department of Clinical Genetics and School for Oncology and Developmental Biology, Maastricht UMC+, Maastricht, The Netherlands.
authors.forename: Sander
authors.initials: S
authors.lastname: Stegmann
authors.affiliation: Department of Pediatrics, Máxima Medical Center, Veldhoven, The Netherlands.
authors.forename: Levinus A
authors.initials: LA
authors.lastname: Bok
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Gijs W E
authors.initials: GW
authors.lastname: Santen
authors.affiliation: Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas, USA.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, USA.
authors.forename: Christian P
authors.identifier: 0000-0002-2148-7490
authors.initials: CP
authors.lastname: Schaaf
mesh_terms: D000293:Adolescent; D000328:Adult; D000067877:Autism Spectrum Disorder / Q000235:genetics* / Q000503:physiopathology; D002648:Child; D002675:Child, Preschool; D002884:Chromosomes, Human, Pair 15; D002658:Developmental Disabilities / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D015870:Gene Expression; D018392:Genomic Imprinting; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008607:Intellectual Disability / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D009154:Mutation; D010641:Phenotype; D011218:Prader-Willi Syndrome / Q000235:genetics* / Q000503:physiopathology; D011506:Proteins / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins; D064267:Intrinsically Disordered Proteins
chemical_list: D011506:Proteins; C510822:MAGEL2 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D064267:Intrinsically Disordered Proteins