5q31 duplications encompassing PURA are associated with a neurodevelopmental disorder.

Abstract

PURA heterozygous microdeletions and pathogenic variants have been previously associated with neurodevelopmental disorders (NDDs), grouped into PURA-NDDs, characterized by severe neonatal hypotonia, feeding difficulties, developmental delay, intellectual disability, epilepsy, and distinctive facial features. Here we report four individuals carrying overlapping 5q31 duplications encompassing PURA, in addition to five cases from the DECIPHER database and one previously described in the literature. All patients share common features including developmental delay and mild to moderate intellectual disability. The minimal region of overlap spans 215 kb and contains only the PURA gene, suggesting PURA as the candidate gene underlying the observed phenotype. Using transcriptomic and biochemical analyses on cultured lymphocytes from one patient, we found that 5q31 duplication causes a significant upregulation of PURA mRNA and PURA protein, respectively. RNA Sequencing also revealed dysregulated expression of various genes involved in human pathology, especially in neurodevelopmental disorders characterized by intellectual disability. Using primary hippocampal neuronal cultures from mouse embryos, we demonstrated that PURA overexpression impairs neuronal morphology in vitro, inducing a reduction in dendritic arborization and in dendritic spine density. Our findings support that 5q31 duplications encompassing PURA represent a novel genomic disorder presenting with a milder phenotype than the reciprocal deletion syndrome and implicate PURA dosage dysregulation as a key contributor to the associated clinical features.