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

• Published in: American journal of human genetics Vol. 106; no. 4; pp. 570 - 583
• Main Authors: Mao, Dongxue, Reuter, Chloe M., Farrow, Emily G., Rosenfeld, Jill A., Mackenzie, Katherine M., Küry, Sébastien, Genetti, Casie A., Alejandro, Mercedes, Agrawal, Pankaj B., Alvey, Justin, Ashley, Euan A., Balasubramanyam, Ashok, Beck, Anita, Bellen, Hugo J., Berg-Rood, Beverly, Bernier, Raphael, Bivona, Stephanie, Bohnsack, John, Briere, Lauren C., Burke, Elizabeth A., Butte, Manish J., Carrasquillo, Olveen, Cogan, Joy D., Cole, F. Sessions, Colley, Heather A., Cooper, Cynthia M., Craigen, William J., Cunningham, Michael, Dasari, Surendra, Dayal, Jyoti G., Dhar, Shweta U., Emrick, Lisa T., Estwick, Tyra, Ferreira, Carlos, Fieg, Elizabeth L., Fogel, Brent L., Forghani, Irman, Gahl, William A., Godfrey, Rena A., Goldman, Alica M., Hahn, Sihoun, Hanchard, Neil A., Hing, Anne, Holm, Ingrid A., Huang, Yong, Jamal, Fariha, Jayadev, Suman, Karaviti, Lefkothea, Kelley, Emily G., Kohane, Isaac S., Kohler, Jennefer N., Krakow, Deborah, Korrick, Susan, Koziura, Mary, Krier, Joel B., Lam, Byron, Lanpher, Brendan C., Lanza, Ian R., Lee, Brendan H., Lewis, Richard A., Loo, Sandra K., Majcherska, Marta M., Malicdan, May Christine V., Mamounas, Laura A., Markello, Thomas C., Martin, Martin G., Martínez-Agosto, Julian A., McCormack, Colleen E., Merritt, J. Lawrence, Moretti, Paolo M., Mulvihill, John J., Murdock, David R., Nickerson, Deborah, Pallais, J. Carl, Posey, Jennifer E., Potocki, Lorraine, Raja, Archana N., Renteria, Genecee, Samson, Susan L., Schedl, Timothy, Shakachite, Lisa, Signer, Rebecca, Silverman, Edwin K., Sybert, Virginia, Tekin, Mustafa, Thorson, Willa, Tran, Alyssa A., Urv, Tiina K., Wahl, Colleen E., Wegner, Daniel, Wheeler, Matthew T., Yamamoto, Shinya, Yang, John, Yoon, Amanda J., Yu, Guoyun, Zastrow, Diane B., Zhao, Chunli, Bernstein, Jonathan A., Chao, Hsiao-Tuan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02.04.2020; Elsevier
• Subjects: abnormal myelination; Adolescent; Ataxia - genetics; Child; Child, Preschool; cognitive impairment; Developmental Disabilities - genetics; eIF-2 Kinase - genetics; EIF2S1; EIF2α; febrile illnesses; Female; Genetic Variation - genetics; Hereditary Central Nervous System Demyelinating Diseases - genetics; Humans; hypomyelination; hypotonia; Infant; integrated stress response; Leukoencephalopathies - genetics; Male; movement disorders; Nervous System Malformations - genetics; regression; White Matter - pathology; febrile illnesses; regression; abnormal myelination; cognitive impairment; hypomyelination; movement disorders; EIF2S1; hypotonia; integrated stress response; EIF2α
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2020.02.016

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.