LEO1 haploinsufficiency is associated with developmental delays and autism spectrum disorder

Sep 29, 2026

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LEO1 encodes a core subunit of PAF1C, a key regulator of eukaryotic gene expression. Although burden analyses suggest rare LEO1 variants increase risk for neurodevelopmental disorders, limited case reports have restricted phenotype definition. This brief communication describes a male child with a novel de novo frameshift variant (c.446dup) and compares features across previously reported patients with truncating LEO1 variants. Developmental delay and autism spectrum disorder are common, supporting LEO1 haploinsufﬁciency as an underlying mechanism. Further studies are needed to clarify associated features and penetrance, and recognition in multigene panels is encouraged.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages3

Reading Time8 min

AccessFree to download

LEO1 and PAF1C function

Model organism evidence and neurodevelopmental context

Clinical evidence from reported cases

Novel de novo frameshift variant case

Phenotype comparison across patients

Conclusions and implications for diagnosis

[www.nature.com/jhg](www.nature.com/jhg) BRIEF COMMUNICATION OPEN LEO1 haploinsufﬁciency is associated with developmental delays and autism spectrum disorder Emilie C. Ung 1 and Nicholas A. Borja 2 ✉ © The Author(s) 2025 | | | | | --- | --- | --- | | | 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. | | | | | Journal of Human Genetics (2026) 71:109–111; [https://doi.org/10.1038/s10038-025-01410-5](https://doi.org/10.1038/s10038-025-01410-5) | | | | | | LEO1 encodes a core subunit of the evolutionarily conserved RNA polymerase associated factor 1 complex (PAF1C), a key regulator of eukaryotic gene expression [1] . PAF1C physically associates with RNA polymerase II and is integral to the transcription cycle, including elongation, mRNA 3’ end formation, processing, and chromatin modiﬁcation [2] . The complex also orchestrates RNA polymerase II degradation in response to DNA damage [3] . Despite their operating as a complex, each PAF1C subunit has functional specialization, with LEO1 regulating heterochromatin stability and histone H3 turnover during cellular quiescence [4] . In addition, LEO1 is critical during embryogenesis in model organisms, where homozygous knockout of leo1 in zebraﬁsh leads to severe defects in cardiac and neural crest development and in mice is associated with preweaning lethality [5, 6] . Burden analyses in cohorts of neurodevelopmental disorder patients have identiﬁed signiﬁcant enrichment for rare variants in LEO1 [7–9] . This association is supported by the substantial fraction of neurodevelopmental disorders in humans occurring in genes within transcription and chromatin remodeling pathways, including other PAF1C subunits [8, 10, 11] . Nevertheless, the reported LEO1 variants to date have included a combination of truncating variants expected to result in a loss-of-function, missense variants, and paternally inherited promoter deletions that paradoxically appear to cause gene overexpression [9, 12, 13] . In addition to the paucity of reported cases, the limited clinical data available for each proband has prevented a more deﬁnitive characterization of the resulting phenotype. Here, we report the case of a male child with a de novo frameshift variant in LEO1, providing further evidence that haploinsufﬁciency of this gene is associated with an increased risk for neurodevelopmental impairment. This is reinforced by the comprehensive phenotype delineation we undertake of all previously reported patients. The proband is the ﬁrst liveborn child to a nonconsanguineous couple of Cuban and Japanese descent. He was born at 30 weeks gestation following a pregnancy complicated by intrauterine growth restriction, with a weight of 1.0 kg (z = −1.24), length of 38 cm (z = -0 .48), and head circumference of 28 cm (z = 0.32) . During his admission to the NICU he developed respiratory distress and apnea of prematurity, wh

FAQs

What role does LEO1 play in gene regulation?

LEO1 encodes a core subunit of PAF1C, which associates with RNA polymerase II and regulates multiple steps of the transcription cycle including elongation, mRNA 3’ end formation, processing, and chromatin modification.

What genetic variant was reported in the described patient?

The study reports a male child with a novel de novo frameshift variant in LEO1, specified as c.446dup (p.Asp149Glus2), and evaluates how it relates to previously reported LEO1 cases.

Which clinical features were most common among patients with LEO1 truncating variants?

Across previously reported truncating LEO1 variants, developmental delay and autism spectrum disorder were core features, with additional rarer manifestations also observed.

Sep 29, 2026

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