Genetic alterations in SUPT6H are associated with neurodevelopmental disorders

Genetic variants affecting the RNA polymerase II complex have been associated with various neurodevelopmental disorders (NDDs). SUPT6H, an RNA polymerase II-associated elongation factor and a histone chaperone, plays a critical role in transcriptional regulation. However, the contribution of SUPT6H variants to human NDDs and the phenotypic consequences of its loss-of-function in vivo remain unexplored. Here, we have analyzed 18 published sporadic single-nucleotide variants (SNVs) of SUPT6H associated with human developmental disorders. Molecular modeling suggests that these variants are likely deleterious, leading to loss-of-function effects. Consistent with this, homozygous or heterozygous Supt6 null mice exhibit embryonic lethality, underscoring its essential role during development. To investigate the postnatal consequences of Supt6 deficiency, we generated conditional Supt6 knockout (KO) mice with targeted deletion in parvalbumin-expressing GABAergic interneurons (cKO PV ). Homozygous Supt6 cKO PV mice displayed motor defects and behavioral seizures, while heterozygous counterparts displayed behavioral phenotypes relevant to neuropsychiatric disorders, despite normal motor activity. Notably, both heterozygous and homozygous Supt6 cKO PV mice showed a significant reduction in parvalbumin-expressing neurons compared to wild-type controls. These findings establish a direct link between Supt6 loss-of-function and neurodevelopmental phenotypes, highlighting its critical role in maintaining interneuron populations and neural circuit integrity. Altogether, our results suggest that deleterious SUPT6H variants may contribute to the etiology of NDDs, providing valuable insights into its function and potential as a therapeutic target. • Data mining of SUPT6H variants associated with human developmental disorders • In silico molecular modeling suggests loss-of-function effects of SUPT6H variants. • Generation of the first mouse model of Supt6 KO in a specific neuronal type • Supt6 KO in parvalbumin interneurons leads to neuronal loss and postnatal mortality. • Supt6 KO mice exhibit phenotypes linked to neurological and psychiatric disorders.