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

PURA

5q31 duplication encompassing PURA, the only gene in the 215-kb minimal region of overlap, with mRNA and protein overexpression and impaired neuronal morphology: dysregulation of PURA dosage

Heterozygous microdeletions and pathogenic variants of PURA have been associated with neurodevelopmental disorders (NDDs) grouped as PURA-NDDs, characterised by severe neonatal hypotonia, feeding difficulties, developmental delay, intellectual disability, epilepsy and distinctive facial features. The authors 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 share developmental delay and mild to moderate intellectual disability, and the 215-kb minimal region of overlap contains only PURA, suggesting it as the candidate gene. In cultured lymphocytes from one patient, the duplication causes a significant upregulation of PURA mRNA and PURA protein, RNA sequencing reveals dysregulated expression of genes involved in human pathology, especially in NDDs with intellectual disability, and in primary hippocampal neuronal cultures from mouse embryos, PURA overexpression impairs neuronal morphology in vitro, with reduced dendritic arborisation and dendritic spine density. The authors conclude that 5q31 duplications encompassing PURA represent a novel genomic disorder with a milder phenotype than the reciprocal deletion syndrome, and implicate PURA dosage dysregulation as a key contributor to the associated clinical features.

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The strongest argument is the convergence between a 215-kb minimal region of overlap containing only PURA, an overexpression of mRNA and protein in one patient, and an effect of overexpression on dendritic arborisation in mouse neuron cultures. For interpretation, a duplication encompassing PURA in a child with developmental delay and mild to moderate intellectual disability becomes a plausible candidate rather than a CNV of uncertain significance, with a milder phenotype than that of the reciprocal deletion to be relayed to families. Causality nevertheless rests on the overlap region alone: the expression evidence comes from a single patient, ten cases in total of which five come from DECIPHER and one from the literature, and in vitro overexpression in mouse neurons does not by itself demonstrate the human phenotype.

Analysis by Dr Thibaut Benquey