LEO1 haploinsufficiency is associated with developmental delays and autism spectrum disorder.

Researchers studied a gene called LEO1 and found that when this gene doesn't work properly, it can cause developmental delays and autism. They looked at a new case of a boy with a change in this gene, plus reviewed other similar cases. The study suggests that problems with the LEO1 gene may be an important cause of autism and developmental delays, and recommends including this gene in genetic testing.

This case report describes a novel de novo LEO1 gene variant (c.446dup) in a male child and provides a comprehensive analysis of all previously reported LEO1 patients. LEO1 encodes a component of the PAF1 complex that regulates gene expression. The study found that developmental delays and autism spectrum disorder were core features consistently observed across patients with truncating LEO1 variants, though other manifestations were also noted. The authors propose LEO1 haploinsufficiency as the underlying mechanism causing neurodevelopmental disorders and recommend including LEO1 in genetic testing panels, despite acknowledging that more research is needed to fully characterize the phenotype and penetrance.

Results support including LEO1 in neurodevelopmental genetic testing panels. Clinicians should consider LEO1 testing for patients with developmental delays and autism, particularly when other genetic causes have been excluded. However, more research is needed to establish complete phenotype and penetrance.

Small sample size limits definitive conclusions. The study acknowledges that more research is needed to completely ascertain associated features and penetrance. Paucity of reported cases has previously prevented definitive phenotype characterization.

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.