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

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

  • Am J Hum Genet. 2020 Apr 2;106(4):570-583. doi: 10.1016/j.ajhg.2020.02.016.
Dongxue Mao 1,  Chloe M Reuter 2,  Maura R Z Ruzhnikov 3,  Anita E Beck 4,  Emily G Farrow 5,  Lisa T Emrick 6,  Jill A Rosenfeld 7,  Katherine M Mackenzie 8,  Laurie Robak 9,  Matthew T Wheeler 10,  Lindsay C Burrage 11,  Mahim Jain 12,  Pengfei Liu 7,  Daniel Calame 13,  Sébastien Küry 14,  Martin Sillesen 15,  Klaus Schmitz-Abe 16,  Davide Tonduti 17,  Luigina Spaccini 18,  Maria Iascone 19,  Casie A Genetti 16,  Mary K Koenig 20,  Madeline Graf 21,  Alyssa Tran 7,  Mercedes Alejandro 7,  Undiagnosed Diseases Network,  Brendan H Lee 11,  Isabelle Thiffault 22,  Pankaj B Agrawal 16,  Jonathan A Bernstein 23,  Hugo J Bellen 24,  Hsiao-Tuan Chao 25
Affiliations

Affiliations

  • 1 Department 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.
  • 2 Stanford 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.
  • 3 Department of Neurology and Neurological Sciences, Stanford, CA 94305, USA; Division of Medical Genetics, Department of Pediatrics, Stanford Medicine, Stanford, CA 94305, USA.
  • 4 Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA 98195, USA.
  • 5 Center 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.
  • 6 Department 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.
  • 7 Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA.
  • 8 Department of Neurology and Neurological Sciences, Stanford, CA 94305, USA.
  • 9 Jan 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.
  • 10 Stanford Center for Undiagnosed Diseases, Stanford University, Stanford, CA 94305, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • 11 Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
  • 12 Department of Bone and Osteogenesis Imperfecta, Kennedy Krieger Institute, Baltimore, MD 21205, USA.
  • 13 Division of Neurology and Developmental Neuroscience, Department of Pediatrics, BCM, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
  • 14 Centre Hospitalier Universitaire de Nantes, Service de Génétique Médicale, Nantes 44007, France; INSERM, CNRS, UNIV Nantes, l'institut du thorax, Nantes 44007, France.
  • 15 Department of Surgical Gastroenterology, Copenhagen University Hospital, Copenhagen 2100, Denmark.
  • 16 Division 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.
  • 17 Unit of Child Neurology, V. Buzzi Children's Hospital, Milan 20154, Italy.
  • 18 Clinical Genetics Unit, Department of Obstetrics and Gynecology, V. Buzzi Children's Hospital, University of Milan, Milan 20154, Italy.
  • 19 Laboratorio di Genetica Medica, ASST Papa Giovanni XXIII, Bergamo 24127, Italy.
  • 20 Department of Pediatrics, McGovern Medical School, The University of Texas Health Sciences Center at Houston, Houston, TX 77030, USA.
  • 21 Stanford Cancer Genetics, Stanford Healthcare, Stanford, CA 94305, USA.
  • 22 Center 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.
  • 23 Stanford Center for Undiagnosed Diseases, Stanford University, Stanford, CA 94305, USA; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • 24 Jan 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: [email protected].
  • 25 Department 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: [email protected].
PMID: 32197074 DOI: 10.1016/j.ajhg.2020.02.016
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.

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