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<p>Pathogenic variants of genes encoding initiation factors can cause neurological diseases, including neurodevelopmental disorders and brain abnormalities. The eukaryotic translation initiation factor 1 A, X-linked (<i>EIF1AX</i>) is a gene located at Xp22.12 that plays an important role in the regulation of translation initiation. Here, we identified de novo hemizygous <i>EIF1AX</i> variants in male individuals with neurodevelopmental disorders and explored their possible involvement in these neurological disorders. We performed trio-based exome or whole genome sequencing in four families. The pathogenicity of <i>EIF1AX</i> variants was evaluated using a molecular dynamic simulation and transgenic <i>Drosophila</i> models. We identified four de novo hemizygous <i>EIF1AX</i> variants in four male individuals with variable neurodevelopmental delay, dysmorphic features, behavioral problems, ophthalmological abnormalities, and structural abnormalities in the brain. One variant was predicted to cause a splicing alteration, and minigene analysis confirmed exon skipping leading to the generation of a premature termination codon. In transgenic <i>Drosophila</i> harboring wild-type (WT) <i>EIF1AX</i> or the three other <i>EIF1AX</i> missense variants, overexpression of WT and the p.(Asn17Asp) variant caused structural abnormalities in the compound eye, whereas the p.(Lys64Glu) and p.(Asp90Gly) variants significantly reduced these eye abnormalities. In addition, WT overexpression resulted in significant axonal toxicity in the <i>Drosophila</i> optic nerve, causing a significant reduction in the number of axons, whereas all mutants showed only a mild reduction in axonal number. Our findings indicated that all variants resulted in different degrees of EIF1AX loss-of-function. Overall, <i>EIF1AX</i> is a novel gene for which loss-of-function variants appear to produce syndromic neurodevelopmental disorders in males.</p>

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Hemizygous loss-of-function variants of EIF1AX are associated with a syndromic neurodevelopmental disorder

  • 期刊论文

  • 发表日期：

    2026年6月24日

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  • Kazuyuki Komatsu,
  • Atsushi Sugie,
  • Yohei Nitta,
  • Jiro Osaka,
  • Ummul Halilunnisa Mansoor Hussain,
  • Mitsuru Kubota,
  • Nobuyuki Shimozawa,
  • Melissa T. Carter,
  • Petra J. G. Zwijnenburg,
  • Quinten Waisfisz,
  • Felix Boschann,
  • Denise Horn,
  • Mitsuko Nakashima,
  • Hirotomo Saitsu

摘要

Pathogenic variants of genes encoding initiation factors can cause neurological diseases, including neurodevelopmental disorders and brain abnormalities. The eukaryotic translation initiation factor 1 A, X-linked (EIF1AX) is a gene located at Xp22.12 that plays an important role in the regulation of translation initiation. Here, we identified de novo hemizygous EIF1AX variants in male individuals with neurodevelopmental disorders and explored their possible involvement in these neurological disorders. We performed trio-based exome or whole genome sequencing in four families. The pathogenicity of EIF1AX variants was evaluated using a molecular dynamic simulation and transgenic Drosophila models. We identified four de novo hemizygous EIF1AX variants in four male individuals with variable neurodevelopmental delay, dysmorphic features, behavioral problems, ophthalmological abnormalities, and structural abnormalities in the brain. One variant was predicted to cause a splicing alteration, and minigene analysis confirmed exon skipping leading to the generation of a premature termination codon. In transgenic Drosophila harboring wild-type (WT) EIF1AX or the three other EIF1AX missense variants, overexpression of WT and the p.(Asn17Asp) variant caused structural abnormalities in the compound eye, whereas the p.(Lys64Glu) and p.(Asp90Gly) variants significantly reduced these eye abnormalities. In addition, WT overexpression resulted in significant axonal toxicity in the Drosophila optic nerve, causing a significant reduction in the number of axons, whereas all mutants showed only a mild reduction in axonal number. Our findings indicated that all variants resulted in different degrees of EIF1AX loss-of-function. Overall, EIF1AX is a novel gene for which loss-of-function variants appear to produce syndromic neurodevelopmental disorders in males.