Neurodevelopmental disorder in an Egyptian family with a biallelic ALKBH8 variant.

TitleNeurodevelopmental disorder in an Egyptian family with a biallelic ALKBH8 variant.
Publication TypeJournal Article
Year of Publication2021
AuthorsSaad, AK, Marafi, D, Mitani, T, Du, H, Rafat, K, Fatih, JM, Jhangiani, SN, Coban-Akdemir, Z, Gibbs, RA, Pehlivan, D, Hunter, JV, Posey, JE, Zaki, MS, Lupski, JR
Corporate AuthorsBaylor-Hopkins Center for Mendelian Genomics
JournalAm J Med Genet A
Date Published2021 Apr
KeywordsAdolescent, AlkB Homolog 8, tRNA Methyltransferase, Brain, Child, Child, Preschool, Female, Genetic Predisposition to Disease, Humans, Infant, Magnetic Resonance Imaging, Male, Neurodevelopmental Disorders, Pedigree

Alkylated DNA repair protein AlkB homolog 8 (ALKBH8) is a member of the AlkB family of dioxygenases. ALKBH8 is a methyltransferase of the highly variable wobble nucleoside position in the anticodon loop of tRNA and thus plays a critical role in tRNA modification by preserving codon recognition and preventing errors in amino acid incorporation during translation. Moreover, its activity catalyzes uridine modifications that are proposed to be critical for accurate protein translation. Previously, two distinct homozygous truncating variants in the final exon of ALKBH8 were described in two unrelated large Saudi Arabian kindreds with intellectual developmental disorder and autosomal recessive 71 (MRT71) syndrome (MIM# 618504). Here, we report a third family-of Egyptian descent-harboring a novel homozygous frame-shift variant in the last exon of ALKBH8. Two affected siblings in this family exhibit global developmental delay and intellectual disability as shared characteristic features of MRT71 syndrome, and we further characterize their observed dysmorphic features and brain MRI findings. This description of a third family with a truncating ALKBH8 variant from a distinct population broadens the phenotypic and genotypic spectrum of MRT71 syndrome, affirms that perturbations in tRNA biogenesis can contribute to neurogenetic disease traits, and firmly establishes ALKBH8 as a novel neurodevelopmental disease gene.

Alternate JournalAm J Med Genet A
PubMed ID33544954
PubMed Central IDPMC8450764
Grant ListT32 GM007526 / GM / NIGMS NIH HHS / United States
R35 NS105078 / NS / NINDS NIH HHS / United States
K08 HG008986 / HG / NHGRI NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States

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