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 Levesque; Naomi 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

doi:10.1038/gim.2016.53

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 journal › Article › Academic › peer-review

56 Citations (Web of Science)

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.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 language	English
Pages (from-to)	45-52
Number of pages	8
Journal	Genetics in Medicine
Volume	19
Issue number	1
DOIs	https://doi.org/10.1038/gim.2016.53
Publication status	Published - Jan 2017

Keywords

MAGEL2
neurodevelopment
Prader-Willi syndrome
Schaaf-Yang syndrome
PRADER-WILLI-SYNDROME
TRUNCATING MUTATIONS
FETAL PHENOTYPE
AUTISM
GENE

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Cite this

Fountain, M. D., Aten, E., Cho, M. T., Juusola, J., Walkiewicz, M. A., Ray, J. W., Xia, F., Yang, Y., Graham, B. H., Bacino, C. A., Potocki, L., van Haeringen, A., Ruivenkamp, C. A. L., Mancias, P., Northrup, H., Kukolich, M. K., Weiss, M. M., van Ravenswaaij-Arts, C. M. A., Mathijssen, I. B., ... Schaaf, C. P. (2017). The phenotypic spectrum of Schaaf-Yang syndrome: 18 new affected individuals from 14 families. Genetics in Medicine, 19(1), 45-52. https://doi.org/10.1038/gim.2016.53

@article{191698bbeb7944f5b6252da603cc38bc,

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

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.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.",

keywords = "MAGEL2, neurodevelopment, Prader-Willi syndrome, Schaaf-Yang syndrome, PRADER-WILLI-SYNDROME, TRUNCATING MUTATIONS, FETAL PHENOTYPE, AUTISM, GENE",

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

year = "2017",

month = jan,

doi = "10.1038/gim.2016.53",

language = "English",

volume = "19",

pages = "45--52",

journal = "Genetics in Medicine",

issn = "1098-3600",

publisher = "Nature Publishing Group",

number = "1",

}

Fountain, MD, Aten, E, Cho, MT, Juusola, J, Walkiewicz, MA, Ray, JW, Xia, F, Yang, Y, Graham, BH, Bacino, CA, Potocki, L, van Haeringen, A, Ruivenkamp, CAL, Mancias, P, Northrup, H, Kukolich, MK, Weiss, MM, van Ravenswaaij-Arts, CMA, Mathijssen, IB, Levesque, S, Meeks, N, Rosenfeld, JA, Lemke, D, Hamosh, A, Lewis, SK, Race, S, Stewart, LL, Hay, B, Lewis, AM, Guerreiro, RL, Bras, JT, Martins, MP, Derksen-Lubsen, G, Peeters, E, Stumpel, C , Stegmann, S, Bok, LA, Santen, GWE & Schaaf, CP 2017, 'The phenotypic spectrum of Schaaf-Yang syndrome: 18 new affected individuals from 14 families', Genetics in Medicine, vol. 19, no. 1, pp. 45-52. https://doi.org/10.1038/gim.2016.53

TY - JOUR

T1 - The phenotypic spectrum of Schaaf-Yang syndrome

T2 - 18 new affected individuals from 14 families

AU - Fountain, Michael D.

AU - Aten, Emmelien

AU - Cho, Megan T.

AU - Juusola, Jane

AU - Walkiewicz, Magdalena A.

AU - Ray, Joseph W.

AU - Xia, Fan

AU - Yang, Yaping

AU - Graham, Brett H.

AU - Bacino, Carlos A.

AU - Potocki, Lorraine

AU - van Haeringen, Arie

AU - Ruivenkamp, Claudia A. L.

AU - Mancias, Pedro

AU - Northrup, Hope

AU - Kukolich, Mary K.

AU - Weiss, Marjan M.

AU - van Ravenswaaij-Arts, Conny M. A.

AU - Mathijssen, Inge B.

AU - Levesque, Sebastien

AU - Meeks, Naomi

AU - Rosenfeld, Jill A.

AU - Lemke, Danielle

AU - Hamosh, Ada

AU - Lewis, Suzanne K.

AU - Race, Simone

AU - Stewart, Laura L.

AU - Hay, Beverly

AU - Lewis, Andrea M.

AU - Guerreiro, Rita L.

AU - Bras, Jose T.

AU - Martins, Marcia P.

AU - Derksen-Lubsen, Gerarda

AU - Peeters, Els

AU - Stumpel, Connie

AU - Stegmann, Sander

AU - Bok, Levinus A.

AU - Santen, Gijs W. E.

AU - Schaaf, Christian P.

PY - 2017/1

Y1 - 2017/1

N2 - 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.

AB - 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.

KW - MAGEL2

KW - neurodevelopment

KW - Prader-Willi syndrome

KW - Schaaf-Yang syndrome

KW - PRADER-WILLI-SYNDROME

KW - TRUNCATING MUTATIONS

KW - FETAL PHENOTYPE

KW - AUTISM

KW - GENE

U2 - 10.1038/gim.2016.53

DO - 10.1038/gim.2016.53

M3 - Article

VL - 19

SP - 45

EP - 52

JO - Genetics in Medicine

JF - Genetics in Medicine

SN - 1098-3600

IS - 1

ER -