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

Michael D. Fountain, Emmelien Aten, Megan T. Cho, Jane Juusola, Magdalena A. Walkiewicz, Joseph W. Ray, Fan Xia, Yaping Yang, Brett H. Graham, Carlos A. Bacino, Lorraine Potocki, Arie van Haeringen, Claudia A. L. Ruivenkamp, Pedro Mancias, Hope Northrup, Mary K. Kukolich, Marjan M. Weiss, Conny M. A. van Ravenswaaij-Arts, Inge B. Mathijssen, Sebastien LevesqueNaomi Meeks, Jill A. Rosenfeld, Danielle Lemke, Ada Hamosh, Suzanne K. Lewis, Simone Race, Laura L. Stewart, Beverly Hay, Andrea M. Lewis, Rita L. Guerreiro, Jose T. Bras, Marcia P. Martins, Gerarda Derksen-Lubsen, Els Peeters, Connie Stumpel, Sander Stegmann, Levinus A. Bok, Gijs W. E. Santen*, Christian P. Schaaf*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

56 Citations (Web of Science)


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.1996deIC (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.

Original languageEnglish
Pages (from-to)45-52
Number of pages8
JournalGenetics in Medicine
Issue number1
Publication statusPublished - Jan 2017


  • MAGEL2
  • neurodevelopment
  • Prader-Willi syndrome
  • Schaaf-Yang syndrome
  • GENE

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