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<p><i>LEO1</i> encodes a core subunit of the evolutionarily conserved RNA polymerase associated factor 1 complex (PAF1C), a key regulator of eukaryotic gene expression. While burden analyses suggest an association between rare <i>LEO1</i> variants and an increased risk for neurodevelopmental disorder, the paucity of reported cases has prevented a definitive characterization of the resulting phenotype. We describe a male child with a novel de novo frameshift variant in <i>LEO1</i> c.446dup (p.Asp149Gluf s*2) and undertake a comprehensive phenotype delineation of all previously reported patients. Developmental delay and autism spectrum disorder were core features common across patients with truncating variants, though rarer manifestations were also observed. This analysis supports <i>LEO1</i> haploinsufficiency as a mechanism for this neurodevelopmental disorder. Further research is needed to more completely ascertain its associated features and penetrance. We nevertheless encourage its recognition as a definitive disease gene and inclusion in multigene panels.</p>

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LEO1 haploinsufficiency is associated with developmental delays and autism spectrum disorder

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  • 发表日期：

    2025年9月24日

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  • Emilie C. Ung,
  • Nicholas A. Borja

摘要

LEO1 encodes a core subunit of the evolutionarily conserved RNA polymerase associated factor 1 complex (PAF1C), a key regulator of eukaryotic gene expression. While burden analyses suggest an association between rare LEO1 variants and an increased risk for neurodevelopmental disorder, the paucity of reported cases has prevented a definitive characterization of the resulting phenotype. We describe a male child with a novel de novo frameshift variant in LEO1 c.446dup (p.Asp149Gluf s*2) and undertake a comprehensive phenotype delineation of all previously reported patients. Developmental delay and autism spectrum disorder were core features common across patients with truncating variants, though rarer manifestations were also observed. This analysis supports LEO1 haploinsufficiency as a mechanism for this neurodevelopmental disorder. Further research is needed to more completely ascertain its associated features and penetrance. We nevertheless encourage its recognition as a definitive disease gene and inclusion in multigene panels.