Neurodevelopmental disorder in an Egyptian family with a biallelic ALKBH8 variant

Abstract

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.

Centers for Mendelian Genomics: A decade of facilitating gene discovery

“…Many of the CMG discoveries are still in the process of gathering cases, functional data, or going through the peer review publication process. 26 South Africa, Kenya, Egypt, 27,28 Iraq, 29 Chile 30,31 , Turkey, [32][33][34] and Lithuania. For some, this has involved training opportunities within a CMG-affiliated laboratory, while for others learning happened through collaborative meetings to discuss analysis results on teleconferences.…”

“…A special week-long Genomics course is incorporated into the medical school curriculum at Johns Hopkins and will be developed into an on-line training module. The CMGs have enabled researchers and clinicians investigating rare Mendelian diseases in the US and around the world to access gene discovery techniques, including those in countries where access to research opportunities is limited, such as the Democratic Republic of the Congo, 26 South Africa, Kenya, Egypt, 27, 28 Iraq, 29 Chile 30, 31 , Turkey, 32–34 and Lithuania. For some, this has involved training opportunities within a CMG-affiliated laboratory, while for others learning happened through collaborative meetings to discuss analysis results on teleconferences.…”

Case Report: Biallelic Variant in the tRNA Methyltransferase Domain of the AlkB Homolog 8 Causes Syndromic Intellectual Disability

“…Homozygous loss-of-function variants in the ALKBH8 gene were first associated with syndromic ID ( Monies et al, 2019 ). Saad et al (2021) reported a novel ALKBH8 variant in an Egyptian family associated with a neurodevelopmental disorder. We report, to the best of our knowledge, on the fourth novel variant in ALKBH8 associated with syndromic ID.…”

Integrative analysis of proteome-wide association and transcriptome-wide association study identifies candidate brain proteins associated with insomnia

“…Several signi cant genes in this study have been found to be associated with brain-related disorders. For instances, there is a close relationship between ALKBH8 and neurodevelopmental disorder including autosomal recessive nonsyndromic intellectual disability, and non-syndromic x-linked intellectual disability (30). Besides, INPP4A has a strong expression in the central nervous system and plays a vital role in the pathogenesis of intellectual disability, mental retardation syndrome and mental disorder (31).…”