LEO1 – Neurodevelopmental Disorder

LEO1 has emerged as a strong candidate gene for neurodevelopmental disorder (MONDO_0700092), a condition characterized by autism (HP:0000717) and intellectual disability (HP:0001249). Two independent large‐scale studies have converged on LEO1, providing compelling clinical evidence for its involvement in neurodevelopmental phenotypes.

In a re‑analysis of trio exome sequencing data, six new individuals with de novo or inherited LEO1 variants were identified in an unsolved cohort of neurodevelopmental disorder patients (PMID:38965372). A complementary large‑scale targeted sequencing study further supported the candidate role of LEO1 by demonstrating a significant burden of ultra‑rare variants in this gene when compared to controls (PMID:33004838). These findings underpin a strong overall gene‑disease association with neurodevelopmental disorder.

Genetic evidence indicates that LEO1 variants contribute to disease by occurring in a predominantly de novo pattern, with some inherited cases also reported. Although a specific HGVS‐coded sequence change could not be isolated from the available data, the aggregate evidence from multiple probands (6 probands [PMID:38965372]) underscores its pathogenic relevance. The diversity of variant types supports the interpretation of LEO1 as playing a critical role in neural development.

The observed inheritance pattern is consistent with an autosomal dominant mode, with pathogenic variants most often arising de novo. This observation aligns with known genetic mechanisms in neurodevelopmental disorders, where a dominant effect in transcription‐regulatory genes is frequently implicated.

Functional investigations of LEO1 have predominantly focused on its role in transcription and chromatin regulation. Studies have shown that LEO1 interacts with Cockayne syndrome protein B (CSB) during transcription‐associated DNA repair (PMID:34096589) and functions as a member of the PAF1 complex, as confirmed by genetic and biochemical assays (PMID:11927560; PMID:27678520). However, these experimental models do not directly recapitulate neurodevelopmental phenotypes, leaving the functional evidence for the LEO1‑neurodevelopmental disorder association as limited.

Integrating the genetic and experimental findings, multiple independent studies provide strong support for the role of LEO1 in neurodevelopmental disorder. While the genetic evidence is robust, additional studies directly modeling neurodevelopment are warranted to further elucidate the pathogenic mechanism. Key take‑home: Incorporating LEO1 into diagnostic panels for autism and intellectual disability has significant clinical utility.

References

• European journal of human genetics : EJHG • 2024 • Burden re‑analysis of neurodevelopmental disorder cohorts for prioritization of candidate genes PMID:38965372
• Nature communications • 2020 • Large‑scale targeted sequencing identifies risk genes for neurodevelopmental disorders PMID:33004838
• Nucleic acids research • 2021 • LEO1 is a partner for Cockayne syndrome protein B (CSB) in response to transcription‑blocking DNA damage PMID:34096589
• The EMBO journal • 2002 • The Paf1 complex physically and functionally associates with transcription elongation factors in vivo PMID:11927560
• G3 (Bethesda, Md.) • 2016 • Drosophila CG2469 Encodes a Homolog of Human CTR9 and Is Essential for Development PMID:27678520

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