Damaging de novo missense variants in EEF1A2 lead to a developmental and degenerative epileptic-dyskinetic encephalopathy

Gemma L. Carvill; Katherine L. Helbig; Candace T. Myers; Marcello Scala; Robert Huether; Sara Lewis; Tyler N. Kruer; Brandon S. Guida; Somayeh Bakhtiari; Joy Sebe; Sha Tang; Heather Stickney; Sehribani Ulusoy Oktay; Ashwin A. Bhandiwad; Keri Ramsey; Vinodh Narayanan; Timothy Feyma; Luis O. Rohena; Andrea Accogli; Mariasavina Severino; Georgina Hollingsworth; Deepak Gill; Christel Depienne; Caroline Nava; Lynette G. Sadleir; Paul A. Caruso; Angela E. Lin; Floor E. Jansen; Bobby Koeleman; Eva Brilstra; Marjolein H. Willemsen; Tjitske Kleefstra; Joaquim Sa; Marie Laure Mathieu; Laurine Perrin; Gaetan Lesca; Pasquale Striano; Giorgio Casari; Ingrid E. Scheffer; David Raible; Evelyn Sattlegger; Valeria Capra; Sergio Padilla-Lopez; Heather C. Mefford; Michael C. Kruer

doi:10.1002/humu.24015

Damaging de novo missense variants in EEF1A2 lead to a developmental and degenerative epileptic-dyskinetic encephalopathy

Gemma L. Carvill, Katherine L. Helbig, Candace T. Myers, Marcello Scala, Robert Huether, Sara Lewis, Tyler N. Kruer, Brandon S. Guida, Somayeh Bakhtiari, Joy Sebe, Sha Tang, Heather Stickney, Sehribani Ulusoy Oktay, Ashwin A. Bhandiwad, Keri Ramsey, Vinodh Narayanan, Timothy Feyma, Luis O. Rohena, Andrea Accogli, Mariasavina SeverinoGeorgina Hollingsworth, Deepak Gill, Christel Depienne, Caroline Nava, Lynette G. Sadleir, Paul A. Caruso, Angela E. Lin, Floor E. Jansen, Bobby Koeleman, Eva Brilstra, Marjolein H. Willemsen, Tjitske Kleefstra, Joaquim Sa, Marie Laure Mathieu, Laurine Perrin, Gaetan Lesca, Pasquale Striano, Giorgio Casari, Ingrid E. Scheffer, David Raible, Evelyn Sattlegger, Valeria Capra, Sergio Padilla-Lopez, Heather C. Mefford^*, Michael C. Kruer^*

^*Corresponding author for this work

Neurology

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

28 Scopus citations

Abstract

Heterozygous de novo variants in the eukaryotic elongation factor EEF1A2 have previously been described in association with intellectual disability and epilepsy but never functionally validated. Here we report 14 new individuals with heterozygous EEF1A2 variants. We functionally validate multiple variants as protein-damaging using heterologous expression and complementation analysis. Our findings allow us to confirm multiple variants as pathogenic and broaden the phenotypic spectrum to include dystonia/choreoathetosis, and in some cases a degenerative course with cerebral and cerebellar atrophy. Pathogenic variants appear to act via a haploinsufficiency mechanism, disrupting both the protein synthesis and integrated stress response functions of EEF1A2. Our studies provide evidence that EEF1A2 is highly intolerant to variation and that de novo pathogenic variants lead to an epileptic-dyskinetic encephalopathy with both neurodevelopmental and neurodegenerative features. Developmental features may be driven by impaired synaptic protein synthesis during early brain development while progressive symptoms may be linked to an impaired ability to handle cytotoxic stressors.

Original language	English (US)
Pages (from-to)	1263-1279
Number of pages	17
Journal	Human mutation
Volume	41
Issue number	7
DOIs	https://doi.org/10.1002/humu.24015
State	Published - Jul 1 2020

Funding

The authors wish to thank the patients and their families for participating in this work. Portions of this work were supported by a Phoenix Children's Hospital RAC award (Sergio Padilla-Lopez), by a Doris Duke Clinical Scientist Development Award (MCK), and by NIH NINDS 1R01NS106298 (Michael C. Kruer). The authors thank Joseph A. Sisneros for his contributions. Giorgio Casari, Marcello Scala, and Valeria Capra are members of the Telethon Undiagnosed Diseases Program (TUDP) consortium. Gemma L. Carvill is supported by NIH NINDS R00 NS089858. Heather C. Mefford is supported by NIH NINDS R01NS069605. Ingrid E. Scheffer is supported by the NHMRC of Australia Program grant and Practitioner Fellowship. Lynette G Sadleir is supported by the Health Research Council of New Zealand and Cure Kids New Zealand. The authors wish to thank the patients and their families for participating in this work. Portions of this work were supported by a Phoenix Children's Hospital RAC award (Sergio Padilla‐Lopez), by a Doris Duke Clinical Scientist Development Award (MCK), and by NIH NINDS 1R01NS106298 (Michael C. Kruer). The authors thank Joseph A. Sisneros for his contributions. Giorgio Casari, Marcello Scala, and Valeria Capra are members of the Telethon Undiagnosed Diseases Program (TUDP) consortium. Gemma L. Carvill is supported by NIH NINDS R00 NS089858. Heather C. Mefford is supported by NIH NINDS R01NS069605. Ingrid E. Scheffer is supported by the NHMRC of Australia Program grant and Practitioner Fellowship. Lynette G Sadleir is supported by the Health Research Council of New Zealand and Cure Kids New Zealand.

Keywords

EEF1A2
de novo
dyskinesia
epilepsy
yeast complementation assay

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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10.1002/humu.24015

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Carvill, G. L., Helbig, K. L., Myers, C. T., Scala, M., Huether, R., Lewis, S., Kruer, T. N., Guida, B. S., Bakhtiari, S., Sebe, J., Tang, S., Stickney, H., Oktay, S. U., Bhandiwad, A. A., Ramsey, K., Narayanan, V., Feyma, T., Rohena, L. O., Accogli, A., ... Kruer, M. C. (2020). Damaging de novo missense variants in EEF1A2 lead to a developmental and degenerative epileptic-dyskinetic encephalopathy. Human mutation, 41(7), 1263-1279. https://doi.org/10.1002/humu.24015

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title = "Damaging de novo missense variants in EEF1A2 lead to a developmental and degenerative epileptic-dyskinetic encephalopathy",

abstract = "Heterozygous de novo variants in the eukaryotic elongation factor EEF1A2 have previously been described in association with intellectual disability and epilepsy but never functionally validated. Here we report 14 new individuals with heterozygous EEF1A2 variants. We functionally validate multiple variants as protein-damaging using heterologous expression and complementation analysis. Our findings allow us to confirm multiple variants as pathogenic and broaden the phenotypic spectrum to include dystonia/choreoathetosis, and in some cases a degenerative course with cerebral and cerebellar atrophy. Pathogenic variants appear to act via a haploinsufficiency mechanism, disrupting both the protein synthesis and integrated stress response functions of EEF1A2. Our studies provide evidence that EEF1A2 is highly intolerant to variation and that de novo pathogenic variants lead to an epileptic-dyskinetic encephalopathy with both neurodevelopmental and neurodegenerative features. Developmental features may be driven by impaired synaptic protein synthesis during early brain development while progressive symptoms may be linked to an impaired ability to handle cytotoxic stressors.",

keywords = "EEF1A2, de novo, dyskinesia, epilepsy, yeast complementation assay",

author = "Carvill, {Gemma L.} and Helbig, {Katherine L.} and Myers, {Candace T.} and Marcello Scala and Robert Huether and Sara Lewis and Kruer, {Tyler N.} and Guida, {Brandon S.} and Somayeh Bakhtiari and Joy Sebe and Sha Tang and Heather Stickney and Oktay, {Sehribani Ulusoy} and Bhandiwad, {Ashwin A.} and Keri Ramsey and Vinodh Narayanan and Timothy Feyma and Rohena, {Luis O.} and Andrea Accogli and Mariasavina Severino and Georgina Hollingsworth and Deepak Gill and Christel Depienne and Caroline Nava and Sadleir, {Lynette G.} and Caruso, {Paul A.} and Lin, {Angela E.} and Jansen, {Floor E.} and Bobby Koeleman and Eva Brilstra and Willemsen, {Marjolein H.} and Tjitske Kleefstra and Joaquim Sa and Mathieu, {Marie Laure} and Laurine Perrin and Gaetan Lesca and Pasquale Striano and Giorgio Casari and Scheffer, {Ingrid E.} and David Raible and Evelyn Sattlegger and Valeria Capra and Sergio Padilla-Lopez and Mefford, {Heather C.} and Kruer, {Michael C.}",

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year = "2020",

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doi = "10.1002/humu.24015",

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Carvill, GL, Helbig, KL, Myers, CT, Scala, M, Huether, R, Lewis, S, Kruer, TN, Guida, BS, Bakhtiari, S, Sebe, J, Tang, S, Stickney, H, Oktay, SU, Bhandiwad, AA, Ramsey, K, Narayanan, V, Feyma, T, Rohena, LO, Accogli, A, Severino, M, Hollingsworth, G, Gill, D, Depienne, C, Nava, C, Sadleir, LG, Caruso, PA, Lin, AE, Jansen, FE, Koeleman, B, Brilstra, E, Willemsen, MH, Kleefstra, T, Sa, J, Mathieu, ML, Perrin, L, Lesca, G, Striano, P, Casari, G, Scheffer, IE, Raible, D, Sattlegger, E, Capra, V, Padilla-Lopez, S, Mefford, HC & Kruer, MC 2020, 'Damaging de novo missense variants in EEF1A2 lead to a developmental and degenerative epileptic-dyskinetic encephalopathy', Human mutation, vol. 41, no. 7, pp. 1263-1279. https://doi.org/10.1002/humu.24015

TY - JOUR

T1 - Damaging de novo missense variants in EEF1A2 lead to a developmental and degenerative epileptic-dyskinetic encephalopathy

AU - Carvill, Gemma L.

AU - Helbig, Katherine L.

AU - Myers, Candace T.

AU - Scala, Marcello

AU - Huether, Robert

AU - Lewis, Sara

AU - Kruer, Tyler N.

AU - Guida, Brandon S.

AU - Bakhtiari, Somayeh

AU - Sebe, Joy

AU - Tang, Sha

AU - Stickney, Heather

AU - Oktay, Sehribani Ulusoy

AU - Bhandiwad, Ashwin A.

AU - Ramsey, Keri

AU - Narayanan, Vinodh

AU - Feyma, Timothy

AU - Rohena, Luis O.

AU - Accogli, Andrea

AU - Severino, Mariasavina

AU - Hollingsworth, Georgina

AU - Gill, Deepak

AU - Depienne, Christel

AU - Nava, Caroline

AU - Sadleir, Lynette G.

AU - Caruso, Paul A.

AU - Lin, Angela E.

AU - Jansen, Floor E.

AU - Koeleman, Bobby

AU - Brilstra, Eva

AU - Willemsen, Marjolein H.

AU - Kleefstra, Tjitske

AU - Sa, Joaquim

AU - Mathieu, Marie Laure

AU - Perrin, Laurine

AU - Lesca, Gaetan

AU - Striano, Pasquale

AU - Casari, Giorgio

AU - Scheffer, Ingrid E.

AU - Raible, David

AU - Sattlegger, Evelyn

AU - Capra, Valeria

AU - Padilla-Lopez, Sergio

AU - Mefford, Heather C.

AU - Kruer, Michael C.

PY - 2020/7/1

Y1 - 2020/7/1

N2 - Heterozygous de novo variants in the eukaryotic elongation factor EEF1A2 have previously been described in association with intellectual disability and epilepsy but never functionally validated. Here we report 14 new individuals with heterozygous EEF1A2 variants. We functionally validate multiple variants as protein-damaging using heterologous expression and complementation analysis. Our findings allow us to confirm multiple variants as pathogenic and broaden the phenotypic spectrum to include dystonia/choreoathetosis, and in some cases a degenerative course with cerebral and cerebellar atrophy. Pathogenic variants appear to act via a haploinsufficiency mechanism, disrupting both the protein synthesis and integrated stress response functions of EEF1A2. Our studies provide evidence that EEF1A2 is highly intolerant to variation and that de novo pathogenic variants lead to an epileptic-dyskinetic encephalopathy with both neurodevelopmental and neurodegenerative features. Developmental features may be driven by impaired synaptic protein synthesis during early brain development while progressive symptoms may be linked to an impaired ability to handle cytotoxic stressors.

AB - Heterozygous de novo variants in the eukaryotic elongation factor EEF1A2 have previously been described in association with intellectual disability and epilepsy but never functionally validated. Here we report 14 new individuals with heterozygous EEF1A2 variants. We functionally validate multiple variants as protein-damaging using heterologous expression and complementation analysis. Our findings allow us to confirm multiple variants as pathogenic and broaden the phenotypic spectrum to include dystonia/choreoathetosis, and in some cases a degenerative course with cerebral and cerebellar atrophy. Pathogenic variants appear to act via a haploinsufficiency mechanism, disrupting both the protein synthesis and integrated stress response functions of EEF1A2. Our studies provide evidence that EEF1A2 is highly intolerant to variation and that de novo pathogenic variants lead to an epileptic-dyskinetic encephalopathy with both neurodevelopmental and neurodegenerative features. Developmental features may be driven by impaired synaptic protein synthesis during early brain development while progressive symptoms may be linked to an impaired ability to handle cytotoxic stressors.

KW - EEF1A2

KW - de novo

KW - dyskinesia

KW - epilepsy

KW - yeast complementation assay

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ER -

Damaging de novo missense variants in EEF1A2 lead to a developmental and degenerative epileptic-dyskinetic encephalopathy

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