Evidence map›Paper›PMID 32197074›Full record

ArticleAmerican journal of human genetics2020

De novo EIF2AK1 and EIF2AK2 Variants Are Associated with Developmental Delay, Leukoencephalopathy, and Neurologic Decompensation.

Dongxue Mao, Chloe M Reuter, Maura R Z Ruzhnikov, Anita E Beck, Emily G Farrow, Lisa T Emrick, Jill A Rosenfeld, Katherine M Mackenzie, Laurie Robak, Matthew T Wheeler and 22 more

Registry-linked trialOpen access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in American journal of human genetics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT02450851 (Clinical and Genetic Evaluation of Patients With Undiagnosed Disorders Through the Undiagnosed Diseases Network), which is not on this map. Cited by 45 papers.

0numbers the graph read from it
0cells of the map it votes in
45citing papers in PubMed
2.9field-weighted citation impact, top 8% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT02450851 recruitingnot on this map

Clinical and Genetic Evaluation of Patients With Undiagnosed Disorders Through the Undiagnosed Diseases Network

TypeobservationalSponsorNational Human Genome Research Institute (NHGRI)Ran2015 to 2028Enrolled20,000ConditionsGenetic Disease
3 · Its place in the literature

Who cites it

45 citing papers in PubMed, 69 citations in OpenAlex.

  1. Article
  2. Article
  3. Article
  4. ComplexFrontiers in pediatrics · 2026
    Article
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  6. Article
  7. Article
  8. Article
  9. Article
  10. Cell-Autonomous Immunity: From Cytosolic Sensing to Self-Defense.International journal of molecular sciences · 2025
    Review
  11. Article
  12. Review
  13. Article
  14. ISR Modulators in Neurological Diseases.Current neuropharmacology · 2025
    Review
  15. Article
  16. Considerations for reporting variants in novel candidate genes identified during clinical genomic testing.Genetics in medicine : official journal of the American College of Medical Genetics · 2024
    Article
  17. Article
  18. Review
  19. Article
  20. A frameshift mutation in the murinebioRxiv : the preprint server for biology · 2024
    Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

32 authors at 18 institutions in 4 countries.

Dongxue MaoDepartment of Pediatrics, Baylor College of Medicine (BCM), Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
Chloe M ReuterStanford Center for Undiagnosed Diseases, Stanford University, Stanford, CA 94305, USA; Stanford Center for Inherited Cardiovascular Disease, Division of Cardiovascular Medicine, Stanford School of Medicine, Stanford, CA 94305, USA.
Maura R Z RuzhnikovDepartment of Neurology and Neurological Sciences, Stanford, CA 94305, USA; Division of Medical Genetics, Department of Pediatrics, Stanford Medicine, Stanford, CA 94305, USA.
Anita E BeckDepartment of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA 98195, USA.
Emily G FarrowCenter for Pediatric Genomic Medicine, Children's Mercy Hospital, Kansas City, MO 64108, USA; University of Missouri-Kansas City School of Medicine, Kansas City, MO 64108, USA; Department of Pediatrics, Children's Mercy Hospitals, Kansas City, MO 64108, USA.
Lisa T EmrickDepartment of Pediatrics, Baylor College of Medicine (BCM), Houston, TX 77030, USA; Division of Neurology and Developmental Neuroscience, Department of Pediatrics, BCM, Houston, TX 77030, USA; Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
Jill A RosenfeldDepartment of Molecular and Human Genetics, BCM, Houston, TX 77030, USA.
Katherine M MackenzieDepartment of Neurology and Neurological Sciences, Stanford, CA 94305, USA.
Laurie RobakJan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
Matthew T WheelerStanford Center for Undiagnosed Diseases, Stanford University, Stanford, CA 94305, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
Lindsay C BurrageDepartment of Molecular and Human Genetics, BCM, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
Mahim JainDepartment of Bone and Osteogenesis Imperfecta, Kennedy Krieger Institute, Baltimore, MD 21205, USA.
Pengfei LiuDepartment of Molecular and Human Genetics, BCM, Houston, TX 77030, USA.
Daniel CalameDivision of Neurology and Developmental Neuroscience, Department of Pediatrics, BCM, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
Sébastien KüryCentre Hospitalier Universitaire de Nantes, Service de Génétique Médicale, Nantes 44007, France; INSERM, CNRS, UNIV Nantes, l'institut du thorax, Nantes 44007, France.
Martin SillesenDepartment of Surgical Gastroenterology, Copenhagen University Hospital, Copenhagen 2100, Denmark.
Klaus Schmitz-AbeDivision of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA; Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA; The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Davide TondutiUnit of Child Neurology, V. Buzzi Children's Hospital, Milan 20154, Italy.
Luigina SpacciniClinical Genetics Unit, Department of Obstetrics and Gynecology, V. Buzzi Children's Hospital, University of Milan, Milan 20154, Italy.
Maria IasconeLaboratorio di Genetica Medica, ASST Papa Giovanni XXIII, Bergamo 24127, Italy.
Casie A GenettiDivision of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA; Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA; The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Mary K KoenigDepartment of Pediatrics, McGovern Medical School, The University of Texas Health Sciences Center at Houston, Houston, TX 77030, USA.
Madeline GrafStanford Cancer Genetics, Stanford Healthcare, Stanford, CA 94305, USA.
Alyssa TranDepartment of Molecular and Human Genetics, BCM, Houston, TX 77030, USA.
Mercedes AlejandroDepartment of Molecular and Human Genetics, BCM, Houston, TX 77030, USA.
Undiagnosed Diseases Network
Brendan H LeeDepartment of Molecular and Human Genetics, BCM, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
Isabelle ThiffaultCenter for Pediatric Genomic Medicine, Children's Mercy Hospital, Kansas City, MO 64108, USA; University of Missouri-Kansas City School of Medicine, Kansas City, MO 64108, USA; Department of Pathology and Laboratory Medicine, Children's Mercy Hospitals, Kansas City, MO 64108, USA.
Pankaj B AgrawalDivision of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA; Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA; The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Jonathan A BernsteinStanford Center for Undiagnosed Diseases, Stanford University, Stanford, CA 94305, USA; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA.
Hugo J BellenJan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA; Program in Development, Disease Models, and Therapeutics, BCM, Houston, TX 77030, USA; Department of Neuroscience, BCM, Houston, TX 77030, USA; Howard Hughes Medical Institute, BCM, Houston, TX 77030, USA. Electronic address: hbellen@bcm.edu.
Hsiao-Tuan ChaoDepartment of Pediatrics, Baylor College of Medicine (BCM), Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Division of Neurology and Developmental Neuroscience, Department of Pediatrics, BCM, Houston, TX 77030, USA; Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA; Program in Development, Disease Models, and Therapeutics, BCM, Houston, TX 77030, USA; Department of Neuroscience, BCM, Houston, TX 77030, USA; McNair Medical Institute, The Robert and Janice McNair Foundation, Houston, TX 77030, USA. Electronic address: hc140077@bcm.edu.
Baylor College of Medicine · USStanford Medicine · USTexas Children's Hospital · USBoston Children's Hospital · USStanford University · USChildren's Mercy Hospital · USCopenhagen University Hospital · DKNeurological Research Institute · USHoward Hughes Medical Institute · USOspedale dei Bambini Vittore Buzzi · ITThe University of Texas Health Science Center at Houston · USUniversity of Washington · USCentre National de la Recherche Scientifique · FRKennedy Krieger Institute · USNeurological Surgery · USOspedale Papa Giovanni XXIII · ITStanford Health Care · USUniversity of Milan · IT

Funding

Neuropathogenesis of Retroviral InfectionsZIANS003130 · NINDS · NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE · PI NATH, AVINDRA · 2011 to 2025
$73.7M
Joint Center for Mendelian GenomicsUM1HG008900 · NHGRI · BROAD INSTITUTE, INC. · PI O'DONNELL-LURIA, ANNE, REHM, HEIDI L · 2016 to 2020
$16.5M
Pilot of New Technologies to Increase the Genomic Diagnosis of Undiagnosed Disease Network (UDN) PatientsU01HG007709 · NHGRI · BAYLOR COLLEGE OF MEDICINE · PI BACINO, CARLOS A., LEE, BRENDAN · 2014 to 2022
$14.3M
Clinical Sequencing Core Facility for the Undiagnosed Diseases Network (UDN)U01HG007942 · NHGRI · BAYLOR COLLEGE OF MEDICINE · PI ENG, CHRISTINE · 2014 to 2021
$10.2M
Stanford Center for Undiagnosed DiseasesU01HG007708 · NHGRI · STANFORD UNIVERSITY · PI ASHLEY, EUAN A, BERNSTEIN, JONATHAN ADAM · 2014 to 2018
$8.0M
Zebrafish CoreU54NS093793 · NINDS · BAYLOR COLLEGE OF MEDICINE · PI BELLEN, HUGO J · 2015 to 2022
$7.5M
What comes next? Engaging stakeholders in governance of participant data and relationships during the sunset of large genomic medicine research initiativesU01HG010218 · NHGRI · STANFORD UNIVERSITY · PI ASHLEY, EUAN A, BERNSTEIN, JONATHAN ADAM · 2018 to 2022
$6.3M
A powerful web-based discovery platform for rare disease geneticsR01HG009141 · NHGRI · BROAD INSTITUTE, INC. · PI QUINLAN, AARON R, REHM, HEIDI L · 2017 to 2020
$2.9M
Illuminating GABAergic Signaling in Neurodevelopmental DisordersDP5OD026428 · OD · BAYLOR COLLEGE OF MEDICINE · PI CHAO, HSIAO-TUAN · 2018 to 2022
$2.0M
NHGRI NIH HHS R01 HG009141NHGRI NIH HHS U01 HG007708NHGRI NIH HHS U01 HG007709NHGRI NIH HHS U01 HG007942NHGRI NIH HHS U01 HG010218NHGRI NIH HHS UM1 HG008900NIH HHS DP5 OD026428NINDS NIH HHS U54 NS093793
6 · The paper itself

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.

Indexed as

AdolescentAtaxiaChildChild, PreschoolDevelopmental DisabilitieseIF-2 KinaseFemaleGenetic VariationHereditary Central Nervous System Demyelinating DiseasesHumansInfantLeukoencephalopathiesMaleNervous System MalformationsWhite MatterEIF2AK1 protein, humanEIF2AK2 protein, humaneIF-2 Kinaseabnormal myelinationcognitive impairmentEIF2S1EIF2αfebrile illnesseshypomyelinationhypotoniaintegrated stress responsemovement disordersregression

Identifiers

PMID32197074
PMCPMC7118694
OpenAlexW3012400786

What OpenQuestion holds

Textmetadata
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Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.