MED27 Variants Cause Developmental Delay, Dystonia, and Cerebellar Hypoplasia

Linyan Meng; Pirjo Isohanni; Yunru Shao; Brett H. Graham; Scott E. Hickey; Stephanie Brooks; Anu Suomalainen; Pascal Joset; Katharina Steindl; Anita Rauch; Annette Hackenberg; Frances A. High; Amy Armstrong-Javors; Niccolò E. Mencacci; Paulina Gonzàlez-Latapi; Walaa A. Kamel; Jasem Y. Al-Hashel; Bernabé I. Bustos; Alejandro V. Hernandez; Dimitri Krainc; Steven J. Lubbe; Hilde Van Esch; Chiara De Luca; Katleen Ballon; Claudia Ravelli; Lydie Burglen; Leila Qebibo; Daniel G. Calame; Tadahiro Mitani; Dana Marafi; Davut Pehlivan; Nebal W. Saadi; Yavuz Sahin; Reza Maroofian; Stephanie Efthymiou; Henry Houlden; Shazia Maqbool; Fatima Rahman; Shen Gu; Jennifer E. Posey; James R. Lupski; Jill V. Hunter; Michael F. Wangler; Christopher J. Carroll; Yaping Yang

doi:10.1002/ana.26019

MED27 Variants Cause Developmental Delay, Dystonia, and Cerebellar Hypoplasia

Linyan Meng, Pirjo Isohanni, Yunru Shao, Brett H. Graham, Scott E. Hickey, Stephanie Brooks, Anu Suomalainen, Pascal Joset, Katharina Steindl, Anita Rauch, Annette Hackenberg, Frances A. High, Amy Armstrong-Javors, Niccolò E. Mencacci, Paulina Gonzàlez-Latapi, Walaa A. Kamel, Jasem Y. Al-Hashel, Bernabé I. Bustos, Alejandro V. Hernandez, Dimitri KraincSteven J. Lubbe, Hilde Van Esch, Chiara De Luca, Katleen Ballon, Claudia Ravelli, Lydie Burglen, Leila Qebibo, Daniel G. Calame, Tadahiro Mitani, Dana Marafi, Davut Pehlivan, Nebal W. Saadi, Yavuz Sahin, Reza Maroofian, Stephanie Efthymiou, Henry Houlden, Shazia Maqbool, Fatima Rahman, Shen Gu, Jennifer E. Posey, James R. Lupski, Jill V. Hunter, Michael F. Wangler, Christopher J. Carroll, Yaping Yang^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

17 Scopus citations

Abstract

The Mediator multiprotein complex functions as a regulator of RNA polymerase II–catalyzed gene transcription. In this study, exome sequencing detected biallelic putative disease-causing variants in MED27, encoding Mediator complex subunit 27, in 16 patients from 11 families with a novel neurodevelopmental syndrome. Patient phenotypes are highly homogeneous, including global developmental delay, intellectual disability, axial hypotonia with distal spasticity, dystonic movements, and cerebellar hypoplasia. Seizures and cataracts were noted in severely affected individuals. Identification of multiple patients with biallelic MED27 variants supports the critical role of MED27 in normal human neural development, particularly for the cerebellum. ANN NEUROL 2021;89:828–833.

Original language	English (US)
Pages (from-to)	828-833
Number of pages	6
Journal	Annals of neurology
Volume	89
Issue number	4
DOIs	https://doi.org/10.1002/ana.26019
State	Published - Apr 2021

Funding

N.E.M. is supported by a Parkinson's Foundation grant. P.I. is supported by the Foundation for Pediatric Research. D.K. is supported by the Simpson Querrey Center for Neurogenetics. Biospecimens used in the analyses presented in this article were obtained from the Northwestern University Movement Disorders Center (MDC) Biorepository. As such, the investigators within MDC Biorepository contributed to the design and implementation of the MDC Biorepository and/or provided data and collected biospecimens but did not participate in the analysis or writing of this report. MDC Biorepository investigators include Tanya Simuni, MD; Dimitri Krainc, MD, PhD; Opal Puneet, MD, PhD; Cindy Zadikoff, MD; Onur Melen, MD; Danny Bega, MD; Roneil G. Malkani, MD; Steven Lubbe, PhD; Niccolo E. Mencacci, MD, PhD; Christina Zelano, PhD; Joanna Blackburn, MD; Firas Wehbe, MD, PhD; Lisa Kinsley, MS, CGC; and Tina Ward, MS. A gift from the Malkin family generously supported the work of the MDC Biorepository. J.R.L. is supported by a grant from the National Human Genome Research Institute (NHGRI) and National Heart, Lung, and Blood Institute (NHLBI) to the Baylor–Hopkins Center for Mendelian Genomics (UM1 HG006542); a National Institute of Neurological Disorders and Stroke grant (R35NS105078); and an Muscular Dystrophy Association grant (512848). T.M. is supported by the Uehara Memorial Foundation. D.M. is supported by a Medical Genetics Research Fellowship Program through the National Institute of General Medical Sciences (NIGMS) at US NIH (T32 GM007526‐42). D.P. is supported by a Clinical Research Training Scholarship in Neuromuscular Disease partnered by the American Brain Foundation and Muscle Study Group, and the International Rett Syndrome Foundation (grant #3701‐1). J.E.P. was supported by NHGRI K08 HG008986. N.E.M. is supported by a Parkinson's Foundation grant. P.I. is supported by the Foundation for Pediatric Research. D.K. is supported by the Simpson Querrey Center for Neurogenetics. Biospecimens used in the analyses presented in this article were obtained from the Northwestern University Movement Disorders Center (MDC) Biorepository. As such, the investigators within MDC Biorepository contributed to the design and implementation of the MDC Biorepository and/or provided data and collected biospecimens but did not participate in the analysis or writing of this report. MDC Biorepository investigators include Tanya Simuni, MD; Dimitri Krainc, MD, PhD; Opal Puneet, MD, PhD; Cindy Zadikoff, MD; Onur Melen, MD; Danny Bega, MD; Roneil G. Malkani, MD; Steven Lubbe, PhD; Niccolo E. Mencacci, MD, PhD; Christina Zelano, PhD; Joanna Blackburn, MD; Firas Wehbe, MD, PhD; Lisa Kinsley, MS, CGC; and Tina Ward, MS. A gift from the Malkin family generously supported the work of the MDC Biorepository. J.R.L. is supported by a grant from the National Human Genome Research Institute (NHGRI) and National Heart, Lung, and Blood Institute (NHLBI) to the Baylor?Hopkins Center for Mendelian Genomics (UM1 HG006542); a National Institute of Neurological Disorders and Stroke grant (R35NS105078); and an Muscular Dystrophy Association grant (512848). T.M. is supported by the Uehara Memorial Foundation. D.M. is supported by a Medical Genetics Research Fellowship Program through the National Institute of General Medical Sciences (NIGMS) at US NIH (T32 GM007526-42). D.P. is supported by a Clinical Research Training Scholarship in Neuromuscular Disease partnered by the American Brain Foundation and Muscle Study Group, and the International Rett Syndrome Foundation (grant #3701-1). J.E.P. was supported by NHGRI K08 HG008986. We thank the Finnish Institute for Molecular Medicine for whole-exome sequencing, and A. Harju and M. Pohjanpelto for technical assistance.

ASJC Scopus subject areas

Neurology
Clinical Neurology

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10.1002/ana.26019

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Meng, L., Isohanni, P., Shao, Y., Graham, B. H., Hickey, S. E., Brooks, S., Suomalainen, A., Joset, P., Steindl, K., Rauch, A., Hackenberg, A., High, F. A., Armstrong-Javors, A., Mencacci, N. E., Gonzàlez-Latapi, P., Kamel, W. A., Al-Hashel, J. Y., Bustos, B. I., Hernandez, A. V., ... Yang, Y. (2021). MED27 Variants Cause Developmental Delay, Dystonia, and Cerebellar Hypoplasia. Annals of neurology, 89(4), 828-833. https://doi.org/10.1002/ana.26019

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title = "MED27 Variants Cause Developmental Delay, Dystonia, and Cerebellar Hypoplasia",

abstract = "The Mediator multiprotein complex functions as a regulator of RNA polymerase II–catalyzed gene transcription. In this study, exome sequencing detected biallelic putative disease-causing variants in MED27, encoding Mediator complex subunit 27, in 16 patients from 11 families with a novel neurodevelopmental syndrome. Patient phenotypes are highly homogeneous, including global developmental delay, intellectual disability, axial hypotonia with distal spasticity, dystonic movements, and cerebellar hypoplasia. Seizures and cataracts were noted in severely affected individuals. Identification of multiple patients with biallelic MED27 variants supports the critical role of MED27 in normal human neural development, particularly for the cerebellum. ANN NEUROL 2021;89:828–833.",

author = "Linyan Meng and Pirjo Isohanni and Yunru Shao and Graham, {Brett H.} and Hickey, {Scott E.} and Stephanie Brooks and Anu Suomalainen and Pascal Joset and Katharina Steindl and Anita Rauch and Annette Hackenberg and High, {Frances A.} and Amy Armstrong-Javors and Mencacci, {Niccol{\`o} E.} and Paulina Gonz{\`a}lez-Latapi and Kamel, {Walaa A.} and Al-Hashel, {Jasem Y.} and Bustos, {Bernab{\'e} I.} and Hernandez, {Alejandro V.} and Dimitri Krainc and Lubbe, {Steven J.} and {Van Esch}, Hilde and {De Luca}, Chiara and Katleen Ballon and Claudia Ravelli and Lydie Burglen and Leila Qebibo and Calame, {Daniel G.} and Tadahiro Mitani and Dana Marafi and Davut Pehlivan and Saadi, {Nebal W.} and Yavuz Sahin and Reza Maroofian and Stephanie Efthymiou and Henry Houlden and Shazia Maqbool and Fatima Rahman and Shen Gu and Posey, {Jennifer E.} and Lupski, {James R.} and Hunter, {Jill V.} and Wangler, {Michael F.} and Carroll, {Christopher J.} and Yaping Yang",

note = "Publisher Copyright: {\textcopyright} 2021 American Neurological Association",

year = "2021",

month = apr,

doi = "10.1002/ana.26019",

language = "English (US)",

volume = "89",

pages = "828--833",

journal = "Annals of neurology",

issn = "0364-5134",

publisher = "John Wiley & Sons Inc.",

number = "4",

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Meng, L, Isohanni, P, Shao, Y, Graham, BH, Hickey, SE, Brooks, S, Suomalainen, A, Joset, P, Steindl, K, Rauch, A, Hackenberg, A, High, FA, Armstrong-Javors, A, Mencacci, NE , Gonzàlez-Latapi, P, Kamel, WA, Al-Hashel, JY, Bustos, BI, Hernandez, AV, Krainc, D, Lubbe, SJ, Van Esch, H, De Luca, C, Ballon, K, Ravelli, C, Burglen, L, Qebibo, L, Calame, DG, Mitani, T, Marafi, D, Pehlivan, D, Saadi, NW, Sahin, Y, Maroofian, R, Efthymiou, S, Houlden, H, Maqbool, S, Rahman, F, Gu, S, Posey, JE, Lupski, JR, Hunter, JV, Wangler, MF, Carroll, CJ & Yang, Y 2021, 'MED27 Variants Cause Developmental Delay, Dystonia, and Cerebellar Hypoplasia', Annals of neurology, vol. 89, no. 4, pp. 828-833. https://doi.org/10.1002/ana.26019

TY - JOUR

T1 - MED27 Variants Cause Developmental Delay, Dystonia, and Cerebellar Hypoplasia

AU - Meng, Linyan

AU - Isohanni, Pirjo

AU - Shao, Yunru

AU - Graham, Brett H.

AU - Hickey, Scott E.

AU - Brooks, Stephanie

AU - Suomalainen, Anu

AU - Joset, Pascal

AU - Steindl, Katharina

AU - Rauch, Anita

AU - Hackenberg, Annette

AU - High, Frances A.

AU - Armstrong-Javors, Amy

AU - Mencacci, Niccolò E.

AU - Gonzàlez-Latapi, Paulina

AU - Kamel, Walaa A.

AU - Al-Hashel, Jasem Y.

AU - Bustos, Bernabé I.

AU - Hernandez, Alejandro V.

AU - Krainc, Dimitri

AU - Lubbe, Steven J.

AU - Van Esch, Hilde

AU - De Luca, Chiara

AU - Ballon, Katleen

AU - Ravelli, Claudia

AU - Burglen, Lydie

AU - Qebibo, Leila

AU - Calame, Daniel G.

AU - Mitani, Tadahiro

AU - Marafi, Dana

AU - Pehlivan, Davut

AU - Saadi, Nebal W.

AU - Sahin, Yavuz

AU - Maroofian, Reza

AU - Efthymiou, Stephanie

AU - Houlden, Henry

AU - Maqbool, Shazia

AU - Rahman, Fatima

AU - Gu, Shen

AU - Posey, Jennifer E.

AU - Lupski, James R.

AU - Hunter, Jill V.

AU - Wangler, Michael F.

AU - Carroll, Christopher J.

AU - Yang, Yaping

PY - 2021/4

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AB - The Mediator multiprotein complex functions as a regulator of RNA polymerase II–catalyzed gene transcription. In this study, exome sequencing detected biallelic putative disease-causing variants in MED27, encoding Mediator complex subunit 27, in 16 patients from 11 families with a novel neurodevelopmental syndrome. Patient phenotypes are highly homogeneous, including global developmental delay, intellectual disability, axial hypotonia with distal spasticity, dystonic movements, and cerebellar hypoplasia. Seizures and cataracts were noted in severely affected individuals. Identification of multiple patients with biallelic MED27 variants supports the critical role of MED27 in normal human neural development, particularly for the cerebellum. ANN NEUROL 2021;89:828–833.

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M3 - Article

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JO - Annals of neurology

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ER -

MED27 Variants Cause Developmental Delay, Dystonia, and Cerebellar Hypoplasia

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