@article{2c1c217ddb75434f8c8ead423a3ae28d,
title = "De novo EIF2AK1 and EIF2AK2 Variants Are Associated with Developmental Delay, Leukoencephalopathy, and Neurologic Decompensation",
abstract = "EIF2AK1 and EIF2AK2 encode members of the eukaryotic translation initiation factor 2 alpha kinase (EIF2AK) family that inhibits protein synthesis in response to physiologic stress conditions. EIF2AK2 is also involved in innate immune response and the regulation of signal transduction, apoptosis, cell proliferation, and differentiation. Despite these findings, human disorders associated with deleterious variants in EIF2AK1 and EIF2AK2 have not been reported. Here, we describe the identification of nine unrelated individuals with heterozygous de novo missense variants in EIF2AK1 (1/9) or EIF2AK2 (8/9). Features seen in these nine individuals include white matter alterations (9/9), developmental delay (9/9), impaired language (9/9), cognitive impairment (8/9), ataxia (6/9), dysarthria in probands with verbal ability (6/9), hypotonia (7/9), hypertonia (6/9), and involuntary movements (3/9). Individuals with EIF2AK2 variants also exhibit neurological regression in the setting of febrile illness or infection. We use mammalian cell lines and proband-derived fibroblasts to further confirm the pathogenicity of variants in these genes and found reduced kinase activity. EIF2AKs phosphorylate eukaryotic translation initiation factor 2 subunit 1 (EIF2S1, also known as EIF2α), which then inhibits EIF2B activity. Deleterious variants in genes encoding EIF2B proteins cause childhood ataxia with central nervous system hypomyelination/vanishing white matter (CACH/VWM), a leukodystrophy characterized by neurologic regression in the setting of febrile illness and other stressors. Our findings indicate that EIF2AK2 missense variants cause a neurodevelopmental syndrome that may share phenotypic and pathogenic mechanisms with CACH/VWM.",
keywords = "EIF2S1, EIF2α, abnormal myelination, cognitive impairment, febrile illnesses, hypomyelination, hypotonia, integrated stress response, movement disorders, regression",
author = "{Undiagnosed Diseases Network} and Dongxue Mao and Reuter, {Chloe M.} and Ruzhnikov, {Maura R.Z.} and Beck, {Anita E.} and Farrow, {Emily G.} and Emrick, {Lisa T.} and Rosenfeld, {Jill A.} and Mackenzie, {Katherine M.} and Laurie Robak and Wheeler, {Matthew T.} and Burrage, {Lindsay C.} and Mahim Jain and Pengfei Liu and Daniel Calame and S{\'e}bastien K{\"u}ry and Martin Sillesen and Klaus Schmitz-Abe and Davide Tonduti and Luigina Spaccini and Maria Iascone and Genetti, {Casie A.} and Koenig, {Mary K.} and Madeline Graf and Alyssa Tran and Mercedes Alejandro and Acosta, {Maria T.} and Margaret Adam and Adams, {David R.} and Agrawal, {Pankaj B.} and Alejandro, {Mercedes E.} and Patrick Allard and Justin Alvey and Laura Amendola and Ashley Andrews and Ashley, {Euan A.} and Azamian, {Mahshid S.} and Bacino, {Carlos A.} and Guney Bademci and Eva Baker and Ashok Balasubramanyam and Dustin Baldridge and Jim Bale and Michael Bamshad and Deborah Barbouth and Batzli, {Gabriel F.} and Surendra Dasari and Lanpher, {Brendan C.} and Lanza, {Ian R.} and Eva Morava-Kozicz and Devin Oglesbee",
note = "Funding Information: We thank the families and clinical staff at locations for participation in this study. We thank Seth Masters at the University of Melbourne, Australia for discussions and review of the manuscript. We thank Mingshan Xue, Fairouz Elsaeidi, Darrion Nguyen, Maimuna Sali Paul, and Cole Deisseroth at BCM for critical review and feedback on the manuscript. We thank Dr. Richard A. Lewis and Dr. Karen D. Evankovich at BCM for their input on the clinical findings. Research reported in this manuscript was supported by the NIH Common Fund , through the Office of Strategic Coordination/Office of the NIH Director under Award Number(s) U01HG007709 (BCM clinical site), U01HG007708 (Stanford clinical site), and U01HG007942 (BCM sequencing core). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This was work was supported in part by NIH U54NS093793 to H.J.B., by the Intramural Research Program of the National Human Genome Research Institute , and by the Common Fund, Office of the Director, NIH . H.J.B. is an investigator of the Howard Hughes Medical Institute. L.T.E., J.A.R., L.B., A.T., M.A., and H.-T.C are supported in part by NIH grant U01HG007709 . P.L. is supported in part by NIH grant U01HG007942 . H.-T.C.{\textquoteright}s research effort was also supported in part by the American Academy of Neurology , Child Neurology Foundation , Burroughs Wellcome Fund , NIH grant 1DP1OD026428 , and the McNair Medical Institute at The Robert and Janice McNair Foundation . Sequencing and analysis for proband 5 were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and was funded by the National Human Genome Research Institute , the National Eye Institute , and the National Heart, Lung, and Blood Institute grant UM1 HG008900 and in part by National Human Genome Research Institute grant R01 HG009141 . Funding Information: We thank the families and clinical staff at locations for participation in this study. We thank Seth Masters at the University of Melbourne, Australia for discussions and review of the manuscript. We thank Mingshan Xue, Fairouz Elsaeidi, Darrion Nguyen, Maimuna Sali Paul, and Cole Deisseroth at BCM for critical review and feedback on the manuscript. We thank Dr. Richard A. Lewis and Dr. Karen D. Evankovich at BCM for their input on the clinical findings. Research reported in this manuscript was supported by the NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Director under Award Number(s) U01HG007709 (BCM clinical site), U01HG007708 (Stanford clinical site), and U01HG007942 (BCM sequencing core). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This was work was supported in part by NIH U54NS093793 to H.J.B. by the Intramural Research Program of the National Human Genome Research Institute, and by the Common Fund, Office of the Director, NIH. H.J.B. is an investigator of the Howard Hughes Medical Institute. L.T.E. J.A.R. L.B. A.T. M.A. and H.-T.C are supported in part by NIH grant U01HG007709. P.L. is supported in part by NIH grant U01HG007942. H.-T.C.{\textquoteright}s research effort was also supported in part by the American Academy of Neurology, Child Neurology Foundation, Burroughs Wellcome Fund, NIH grant 1DP1OD026428, and the McNair Medical Institute at The Robert and Janice McNair Foundation. Sequencing and analysis for proband 5 were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and was funded by the National Human Genome Research Institute, the National Eye Institute, and the National Heart, Lung, and Blood Institute grant UM1 HG008900 and in part by National Human Genome Research Institute grant R01 HG009141. Publisher Copyright: {\textcopyright} 2020 American Society of Human Genetics",
year = "2020",
month = apr,
day = "2",
doi = "10.1016/j.ajhg.2020.02.016",
language = "English (US)",
volume = "106",
pages = "570--583",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "4",
}