Cohesin complex-associated holoprosencephaly

Paul Kruszka; Seth Berger; Valentina Casa; Mike R. Dekker; Jenna Gaesser; Karin Weiss; Ariel F. Martinez; David R. Murdock; Raymond J. Louie; Eloise J. Prijoles; Angie W. Lichty; Oebele F. Brouwer; Evelien Zonneveld-Huijssoon; Mark J. Stephan; Jacob Hogue; Ping Hu; Momoko Tanima-Nagai; Joshua L. Everson; Chitra Prasad; Anna Cereda; Maria Iascone; Allison Schreiber; Vickie Zurcher; Nicole Corsten-Janssen; Luis Escobar; Nancy J. Clegg; Mauricio R. Delgado; Omkar Hajirnis; Meena Balasubramanian; Hulya Kayserili; Matthew Deardorff; Raymond A. Poot; Kerstin S. Wendt; Robert J. Lipinski; Maximilian Muenke

doi:10.1093/brain/awz210

Cohesin complex-associated holoprosencephaly

Paul Kruszka, Seth Berger, Valentina Casa, Mike R. Dekker, Jenna Gaesser, Karin Weiss, Ariel F. Martinez, David R. Murdock, Raymond J. Louie, Eloise J. Prijoles, Angie W. Lichty, Oebele F. Brouwer, Evelien Zonneveld-Huijssoon, Mark J. Stephan, Jacob Hogue, Ping Hu, Momoko Tanima-Nagai, Joshua L. Everson, Chitra Prasad, Anna CeredaMaria Iascone, Allison Schreiber, Vickie Zurcher, Nicole Corsten-Janssen, Luis Escobar, Nancy J. Clegg, Mauricio R. Delgado, Omkar Hajirnis, Meena Balasubramanian, Hulya Kayserili, Matthew Deardorff, Raymond A. Poot, Kerstin S. Wendt, Robert J. Lipinski, Maximilian Muenke

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Abstract

Marked by incomplete division of the embryonic forebrain, holoprosencephaly is one of the most common human developmental disorders. Despite decades of phenotype-driven research, 80-90% of aneuploidy-negative holoprosencephaly individuals with a probable genetic aetiology do not have a genetic diagnosis. Here we report holoprosencephaly associated with variants in the two X-linked cohesin complex genes, STAG2 and SMC1A, with loss-of-function variants in 10 individuals and a missense variant in one. Additionally, we report four individuals with variants in the cohesin complex genes that are not X-linked, SMC3 and RAD21. Using whole mount in situ hybridization, we show that STAG2 and SMC1A are expressed in the prosencephalic neural folds during primary neurulation in the mouse, consistent with forebrain morphogenesis and holoprosencephaly pathogenesis. Finally, we found that shRNA knockdown of STAG2 and SMC1A causes aberrant expression of HPE-associated genes ZIC2, GLI2, SMAD3 and FGFR1 in human neural stem cells. These findings show the cohesin complex as an important regulator of median forebrain development and X-linked inheritance patterns in holoprosencephaly.

Original language	English
Pages (from-to)	2631-2643
Number of pages	13
Journal	Brain
Volume	142
DOIs	https://doi.org/10.1093/brain/awz210
Publication status	Published - Sept-2019

Keywords

holoprosencephaly
cohesin complex
X-linked inheritance
forebrain division
DE-LANGE-SYNDROME
OF-FUNCTION MUTATIONS
SONIC-HEDGEHOG
DEVELOPMENTAL DELAY
RAD21 MUTATIONS
SMC1A CAUSE
CORNELIA
EPILEPSY
VARIANT
INDIVIDUALS

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Kruszka, P., Berger, S., Casa, V., Dekker, M. R., Gaesser, J., Weiss, K., Martinez, A. F., Murdock, D. R., Louie, R. J., Prijoles, E. J., Lichty, A. W., Brouwer, O. F., Zonneveld-Huijssoon, E., Stephan, M. J., Hogue, J., Hu, P., Tanima-Nagai, M., Everson, J. L., Prasad, C., ... Muenke, M. (2019). Cohesin complex-associated holoprosencephaly. Brain, 142, 2631-2643. https://doi.org/10.1093/brain/awz210

@article{f3e5962978a7467a918a87f96f8ef5ef,

title = "Cohesin complex-associated holoprosencephaly",

abstract = "Marked by incomplete division of the embryonic forebrain, holoprosencephaly is one of the most common human developmental disorders. Despite decades of phenotype-driven research, 80-90% of aneuploidy-negative holoprosencephaly individuals with a probable genetic aetiology do not have a genetic diagnosis. Here we report holoprosencephaly associated with variants in the two X-linked cohesin complex genes, STAG2 and SMC1A, with loss-of-function variants in 10 individuals and a missense variant in one. Additionally, we report four individuals with variants in the cohesin complex genes that are not X-linked, SMC3 and RAD21. Using whole mount in situ hybridization, we show that STAG2 and SMC1A are expressed in the prosencephalic neural folds during primary neurulation in the mouse, consistent with forebrain morphogenesis and holoprosencephaly pathogenesis. Finally, we found that shRNA knockdown of STAG2 and SMC1A causes aberrant expression of HPE-associated genes ZIC2, GLI2, SMAD3 and FGFR1 in human neural stem cells. These findings show the cohesin complex as an important regulator of median forebrain development and X-linked inheritance patterns in holoprosencephaly.",

keywords = "holoprosencephaly, cohesin complex, X-linked inheritance, forebrain division, DE-LANGE-SYNDROME, OF-FUNCTION MUTATIONS, SONIC-HEDGEHOG, DEVELOPMENTAL DELAY, RAD21 MUTATIONS, SMC1A CAUSE, CORNELIA, EPILEPSY, VARIANT, INDIVIDUALS",

author = "Paul Kruszka and Seth Berger and Valentina Casa and Dekker, {Mike R.} and Jenna Gaesser and Karin Weiss and Martinez, {Ariel F.} and Murdock, {David R.} and Louie, {Raymond J.} and Prijoles, {Eloise J.} and Lichty, {Angie W.} and Brouwer, {Oebele F.} and Evelien Zonneveld-Huijssoon and Stephan, {Mark J.} and Jacob Hogue and Ping Hu and Momoko Tanima-Nagai and Everson, {Joshua L.} and Chitra Prasad and Anna Cereda and Maria Iascone and Allison Schreiber and Vickie Zurcher and Nicole Corsten-Janssen and Luis Escobar and Clegg, {Nancy J.} and Delgado, {Mauricio R.} and Omkar Hajirnis and Meena Balasubramanian and Hulya Kayserili and Matthew Deardorff and Poot, {Raymond A.} and Wendt, {Kerstin S.} and Lipinski, {Robert J.} and Maximilian Muenke",

year = "2019",

month = sep,

doi = "10.1093/brain/awz210",

language = "English",

volume = "142",

pages = "2631--2643",

journal = "Brain",

issn = "0006-8950",

publisher = "Oxford University Press",

}

Kruszka, P, Berger, S, Casa, V, Dekker, MR, Gaesser, J, Weiss, K, Martinez, AF, Murdock, DR, Louie, RJ, Prijoles, EJ, Lichty, AW, Brouwer, OF , Zonneveld-Huijssoon, E, Stephan, MJ, Hogue, J, Hu, P, Tanima-Nagai, M, Everson, JL, Prasad, C, Cereda, A, Iascone, M, Schreiber, A, Zurcher, V, Corsten-Janssen, N, Escobar, L, Clegg, NJ, Delgado, MR, Hajirnis, O, Balasubramanian, M, Kayserili, H, Deardorff, M, Poot, RA, Wendt, KS, Lipinski, RJ & Muenke, M 2019, 'Cohesin complex-associated holoprosencephaly', Brain, vol. 142, pp. 2631-2643. https://doi.org/10.1093/brain/awz210

TY - JOUR

T1 - Cohesin complex-associated holoprosencephaly

AU - Kruszka, Paul

AU - Berger, Seth

AU - Casa, Valentina

AU - Dekker, Mike R.

AU - Gaesser, Jenna

AU - Weiss, Karin

AU - Martinez, Ariel F.

AU - Murdock, David R.

AU - Louie, Raymond J.

AU - Prijoles, Eloise J.

AU - Lichty, Angie W.

AU - Brouwer, Oebele F.

AU - Zonneveld-Huijssoon, Evelien

AU - Stephan, Mark J.

AU - Hogue, Jacob

AU - Hu, Ping

AU - Tanima-Nagai, Momoko

AU - Everson, Joshua L.

AU - Prasad, Chitra

AU - Cereda, Anna

AU - Iascone, Maria

AU - Schreiber, Allison

AU - Zurcher, Vickie

AU - Corsten-Janssen, Nicole

AU - Escobar, Luis

AU - Clegg, Nancy J.

AU - Delgado, Mauricio R.

AU - Hajirnis, Omkar

AU - Balasubramanian, Meena

AU - Kayserili, Hulya

AU - Deardorff, Matthew

AU - Poot, Raymond A.

AU - Wendt, Kerstin S.

AU - Lipinski, Robert J.

AU - Muenke, Maximilian

PY - 2019/9

Y1 - 2019/9

N2 - Marked by incomplete division of the embryonic forebrain, holoprosencephaly is one of the most common human developmental disorders. Despite decades of phenotype-driven research, 80-90% of aneuploidy-negative holoprosencephaly individuals with a probable genetic aetiology do not have a genetic diagnosis. Here we report holoprosencephaly associated with variants in the two X-linked cohesin complex genes, STAG2 and SMC1A, with loss-of-function variants in 10 individuals and a missense variant in one. Additionally, we report four individuals with variants in the cohesin complex genes that are not X-linked, SMC3 and RAD21. Using whole mount in situ hybridization, we show that STAG2 and SMC1A are expressed in the prosencephalic neural folds during primary neurulation in the mouse, consistent with forebrain morphogenesis and holoprosencephaly pathogenesis. Finally, we found that shRNA knockdown of STAG2 and SMC1A causes aberrant expression of HPE-associated genes ZIC2, GLI2, SMAD3 and FGFR1 in human neural stem cells. These findings show the cohesin complex as an important regulator of median forebrain development and X-linked inheritance patterns in holoprosencephaly.

AB - Marked by incomplete division of the embryonic forebrain, holoprosencephaly is one of the most common human developmental disorders. Despite decades of phenotype-driven research, 80-90% of aneuploidy-negative holoprosencephaly individuals with a probable genetic aetiology do not have a genetic diagnosis. Here we report holoprosencephaly associated with variants in the two X-linked cohesin complex genes, STAG2 and SMC1A, with loss-of-function variants in 10 individuals and a missense variant in one. Additionally, we report four individuals with variants in the cohesin complex genes that are not X-linked, SMC3 and RAD21. Using whole mount in situ hybridization, we show that STAG2 and SMC1A are expressed in the prosencephalic neural folds during primary neurulation in the mouse, consistent with forebrain morphogenesis and holoprosencephaly pathogenesis. Finally, we found that shRNA knockdown of STAG2 and SMC1A causes aberrant expression of HPE-associated genes ZIC2, GLI2, SMAD3 and FGFR1 in human neural stem cells. These findings show the cohesin complex as an important regulator of median forebrain development and X-linked inheritance patterns in holoprosencephaly.

KW - holoprosencephaly

KW - cohesin complex

KW - X-linked inheritance

KW - forebrain division

KW - DE-LANGE-SYNDROME

KW - OF-FUNCTION MUTATIONS

KW - SONIC-HEDGEHOG

KW - DEVELOPMENTAL DELAY

KW - RAD21 MUTATIONS

KW - SMC1A CAUSE

KW - CORNELIA

KW - EPILEPSY

KW - VARIANT

KW - INDIVIDUALS

U2 - 10.1093/brain/awz210

DO - 10.1093/brain/awz210

M3 - Article

SN - 0006-8950

VL - 142

SP - 2631

EP - 2643

JO - Brain

JF - Brain

ER -

Cohesin complex-associated holoprosencephaly

Abstract

Keywords

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