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

De novo hemizygous loss-of-function *EIF1AX* variants impairing translation initiation

Four de novo hemizygous EIF1AX variants, located at Xp22.12 and encoding a translation initiation factor, were identified by trio exome or whole-genome sequencing in four boys with variable neurodevelopmental delay, dysmorphic features, behavioral problems, ophthalmological abnormalities, and structural brain malformations. One variant caused exon skipping confirmed by minigene assay, generating a premature termination codon. Transgenic Drosophila models showed that missense variants reduced the eye abnormalities and axonal toxicity induced by wild-type overexpression, indicating variable degrees of loss of function. These data establish EIF1AX as a novel syndromic neurodevelopmental disorder gene in males.

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Linking an X-linked neurodevelopmental disorder to a translation initiation factor enriches the already substantial group of neurodevelopmental ribosomopathies and translation-opathies. The convergence of evidence — de novo recurrence, demonstrated splicing effect, Drosophila model — is convincing despite the small cohort. EIF1AX is already captured by WES/WGS; the challenge now is its correct annotation and the recognition of hypomorphic missense variants during interpretation.