PT  - JOURNAL ARTICLE
AU  - Dongxue Mao
AU  - Chloe M. Reuter
AU  - Maura R.Z. Ruzhnikov
AU  - Anita E. Beck
AU  - Emily G. Farrow
AU  - Lisa T. Emrick
AU  - Jill A. Rosenfeld
AU  - Katherine M. Mackenzie
AU  - Laurie Robak
AU  - Matthew T. Wheeler
AU  - Lindsay C. Burrage
AU  - Mahim Jain
AU  - Pengfei Liu
AU  - Daniel Calame
AU  - Sebastien Küry
AU  - Martin Sillesen
AU  - Klaus Schmitz-Abe
AU  - Davide Tonduti
AU  - Luigina Spaccini
AU  - Maria Iascone
AU  - Casie A. Genetti
AU  - Madeline Graf
AU  - Alyssa Tran
AU  - Mercedes Alejandro
AU  - Undiagnosed Diseases Network
AU  - Brendan H. Lee
AU  - Isabelle Thiffault
AU  - Pankaj B. Agrawal
AU  - Jonathan A. Bernstein
AU  - Hugo J. Bellen
AU  - Hsiao-Tuan Chao
TI  - <em>De novo EIF2AK1</em> and <em>EIF2AK2</em> variants are associated with developmental delay, leukoencephalopathy, and neurologic decompensation
AID  - 10.1101/757039
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 757039
4099  - http://biorxiv.org/content/early/2019/09/16/757039.short
4100  - http://biorxiv.org/content/early/2019/09/16/757039.full
AB  - 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 eight unrelated individuals with heterozygous de novo missense variants in EIF2AK1 (1/8) or EIF2AK2 (7/8). Features seen in these eight individuals include white matter alterations (8/8), developmental delay (8/8), impaired language (8/8), cognitive impairment (7/8), ataxia (6/8), dysarthria in probands with verbal ability (6/6), hypotonia (6/8), hypertonia (5/8), and involuntary movements (3/8). Individuals with EIF2AK2 variants also exhibit neurological regression in the setting of febrile illness or infection. We use mammalian cell lines and patient-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 disease (CACH/VWM), a leukoencephalopathy 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.