Increased STAG2 dosage defines a novel cohesinopathy with intellectual disability and behavioral problems

Raman Kumar, Mark A. Corbett, Bregje W.M. Van Bon, Alison Gardner, Joshua A.Woenig, Lachlan A. Jolly, Evelyn Douglas, Kathryn Friend, Chuan Tan, Hilde Van Esch, Maureen Holvoet, Martine Raynaud, Michael Field, Melanie Leffler, Bartlomiej Budny, Marzena Wisniewska, Magdalena Badura-Stronka, Anna Latos-Bieleńska, Jacqueline Batanian, Jill A. Rosenfeld & 16 others Lina Basel-Vanagaite, Corinna Jensen, Melanie Bienek, Guy Froyen, Reinhard Ullmann, Hao Hu, Michael I. Love, Stefan A. Haas, Pawel Stankiewicz, Sau Wai Cheung, Anne Baxendale, Jillian Nicholl, Elizabeth M. Thompson, Eric Haan, Vera M. Kalscheuer, Jozef Gecz

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Next generation genomic technologies have made a significant contribution to the understanding of the genetic architecture of human neurodevelopmental disorders. Copy number variants (CNVs) play an important role in the genetics of intellectual disability (ID). For many CNVs, and copy number gains in particular, the responsible dosage-sensitive gene(s) have been hard to identify. We have collected 18 different interstitial microduplications and 1 microtriplication of Xq25. There were 15 affected individuals from 6 different families and 13 singleton cases, 28 affected males in total. The critical overlapping region involved the STAG2 gene, which codes for a subunit of the cohesin complex that regulates cohesion of sister chromatids and gene transcription. We demonstrate that STAG2 is the dosage-sensitive gene within these CNVs, as gains of STAG2 mRNA and protein dysregulate disease-relevant neuronal gene networks in cells derived from affected individuals.We also show that STAG2 gains result in increased expression of OPHN1, a known X-chromosome ID gene. Overall, we define a novel cohesinopathy due to copy number gain of Xq25 and STAG2 in particular.

LanguageEnglish
Pages7171-7181
Number of pages11
JournalHuman Molecular Genetics
Volume24
Issue number25
DOIs
Publication statusPublished - 1 Jan 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Kumar, Raman ; Corbett, Mark A. ; Van Bon, Bregje W.M. ; Gardner, Alison ; A.Woenig, Joshua ; Jolly, Lachlan A. ; Douglas, Evelyn ; Friend, Kathryn ; Tan, Chuan ; Van Esch, Hilde ; Holvoet, Maureen ; Raynaud, Martine ; Field, Michael ; Leffler, Melanie ; Budny, Bartlomiej ; Wisniewska, Marzena ; Badura-Stronka, Magdalena ; Latos-Bieleńska, Anna ; Batanian, Jacqueline ; Rosenfeld, Jill A. ; Basel-Vanagaite, Lina ; Jensen, Corinna ; Bienek, Melanie ; Froyen, Guy ; Ullmann, Reinhard ; Hu, Hao ; Love, Michael I. ; Haas, Stefan A. ; Stankiewicz, Pawel ; Cheung, Sau Wai ; Baxendale, Anne ; Nicholl, Jillian ; Thompson, Elizabeth M. ; Haan, Eric ; Kalscheuer, Vera M. ; Gecz, Jozef. / Increased STAG2 dosage defines a novel cohesinopathy with intellectual disability and behavioral problems. In: Human Molecular Genetics. 2015 ; Vol. 24, No. 25. pp. 7171-7181.
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abstract = "Next generation genomic technologies have made a significant contribution to the understanding of the genetic architecture of human neurodevelopmental disorders. Copy number variants (CNVs) play an important role in the genetics of intellectual disability (ID). For many CNVs, and copy number gains in particular, the responsible dosage-sensitive gene(s) have been hard to identify. We have collected 18 different interstitial microduplications and 1 microtriplication of Xq25. There were 15 affected individuals from 6 different families and 13 singleton cases, 28 affected males in total. The critical overlapping region involved the STAG2 gene, which codes for a subunit of the cohesin complex that regulates cohesion of sister chromatids and gene transcription. We demonstrate that STAG2 is the dosage-sensitive gene within these CNVs, as gains of STAG2 mRNA and protein dysregulate disease-relevant neuronal gene networks in cells derived from affected individuals.We also show that STAG2 gains result in increased expression of OPHN1, a known X-chromosome ID gene. Overall, we define a novel cohesinopathy due to copy number gain of Xq25 and STAG2 in particular.",
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Kumar, R, Corbett, MA, Van Bon, BWM, Gardner, A, A.Woenig, J, Jolly, LA, Douglas, E, Friend, K, Tan, C, Van Esch, H, Holvoet, M, Raynaud, M, Field, M, Leffler, M, Budny, B, Wisniewska, M, Badura-Stronka, M, Latos-Bieleńska, A, Batanian, J, Rosenfeld, JA, Basel-Vanagaite, L, Jensen, C, Bienek, M, Froyen, G, Ullmann, R, Hu, H, Love, MI, Haas, SA, Stankiewicz, P, Cheung, SW, Baxendale, A, Nicholl, J, Thompson, EM, Haan, E, Kalscheuer, VM & Gecz, J 2015, 'Increased STAG2 dosage defines a novel cohesinopathy with intellectual disability and behavioral problems', Human Molecular Genetics, vol. 24, no. 25, pp. 7171-7181. https://doi.org/10.1093/hmg/ddv414

Increased STAG2 dosage defines a novel cohesinopathy with intellectual disability and behavioral problems. / Kumar, Raman; Corbett, Mark A.; Van Bon, Bregje W.M.; Gardner, Alison; A.Woenig, Joshua; Jolly, Lachlan A.; Douglas, Evelyn; Friend, Kathryn; Tan, Chuan; Van Esch, Hilde; Holvoet, Maureen; Raynaud, Martine; Field, Michael; Leffler, Melanie; Budny, Bartlomiej; Wisniewska, Marzena; Badura-Stronka, Magdalena; Latos-Bieleńska, Anna; Batanian, Jacqueline; Rosenfeld, Jill A.; Basel-Vanagaite, Lina; Jensen, Corinna; Bienek, Melanie; Froyen, Guy; Ullmann, Reinhard; Hu, Hao; Love, Michael I.; Haas, Stefan A.; Stankiewicz, Pawel; Cheung, Sau Wai; Baxendale, Anne; Nicholl, Jillian; Thompson, Elizabeth M.; Haan, Eric; Kalscheuer, Vera M.; Gecz, Jozef.

In: Human Molecular Genetics, Vol. 24, No. 25, 01.01.2015, p. 7171-7181.

Research output: Contribution to journalArticle

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T1 - Increased STAG2 dosage defines a novel cohesinopathy with intellectual disability and behavioral problems

AU - Kumar, Raman

AU - Corbett, Mark A.

AU - Van Bon, Bregje W.M.

AU - Gardner, Alison

AU - A.Woenig, Joshua

AU - Jolly, Lachlan A.

AU - Douglas, Evelyn

AU - Friend, Kathryn

AU - Tan, Chuan

AU - Van Esch, Hilde

AU - Holvoet, Maureen

AU - Raynaud, Martine

AU - Field, Michael

AU - Leffler, Melanie

AU - Budny, Bartlomiej

AU - Wisniewska, Marzena

AU - Badura-Stronka, Magdalena

AU - Latos-Bieleńska, Anna

AU - Batanian, Jacqueline

AU - Rosenfeld, Jill A.

AU - Basel-Vanagaite, Lina

AU - Jensen, Corinna

AU - Bienek, Melanie

AU - Froyen, Guy

AU - Ullmann, Reinhard

AU - Hu, Hao

AU - Love, Michael I.

AU - Haas, Stefan A.

AU - Stankiewicz, Pawel

AU - Cheung, Sau Wai

AU - Baxendale, Anne

AU - Nicholl, Jillian

AU - Thompson, Elizabeth M.

AU - Haan, Eric

AU - Kalscheuer, Vera M.

AU - Gecz, Jozef

PY - 2015/1/1

Y1 - 2015/1/1

N2 - Next generation genomic technologies have made a significant contribution to the understanding of the genetic architecture of human neurodevelopmental disorders. Copy number variants (CNVs) play an important role in the genetics of intellectual disability (ID). For many CNVs, and copy number gains in particular, the responsible dosage-sensitive gene(s) have been hard to identify. We have collected 18 different interstitial microduplications and 1 microtriplication of Xq25. There were 15 affected individuals from 6 different families and 13 singleton cases, 28 affected males in total. The critical overlapping region involved the STAG2 gene, which codes for a subunit of the cohesin complex that regulates cohesion of sister chromatids and gene transcription. We demonstrate that STAG2 is the dosage-sensitive gene within these CNVs, as gains of STAG2 mRNA and protein dysregulate disease-relevant neuronal gene networks in cells derived from affected individuals.We also show that STAG2 gains result in increased expression of OPHN1, a known X-chromosome ID gene. Overall, we define a novel cohesinopathy due to copy number gain of Xq25 and STAG2 in particular.

AB - Next generation genomic technologies have made a significant contribution to the understanding of the genetic architecture of human neurodevelopmental disorders. Copy number variants (CNVs) play an important role in the genetics of intellectual disability (ID). For many CNVs, and copy number gains in particular, the responsible dosage-sensitive gene(s) have been hard to identify. We have collected 18 different interstitial microduplications and 1 microtriplication of Xq25. There were 15 affected individuals from 6 different families and 13 singleton cases, 28 affected males in total. The critical overlapping region involved the STAG2 gene, which codes for a subunit of the cohesin complex that regulates cohesion of sister chromatids and gene transcription. We demonstrate that STAG2 is the dosage-sensitive gene within these CNVs, as gains of STAG2 mRNA and protein dysregulate disease-relevant neuronal gene networks in cells derived from affected individuals.We also show that STAG2 gains result in increased expression of OPHN1, a known X-chromosome ID gene. Overall, we define a novel cohesinopathy due to copy number gain of Xq25 and STAG2 in particular.

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U2 - 10.1093/hmg/ddv414

DO - 10.1093/hmg/ddv414

M3 - Article

VL - 24

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EP - 7181

JO - Human molecular genetics

T2 - Human molecular genetics

JF - Human molecular genetics

SN - 0964-6906

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