USP34 Haploinsufficiency as a Cause of Neurodevelopmental Phenotypes

The 2p15p16.1 microdeletion syndrome is a rare neurodevelopmental disorder caused by heterozygous deletions of variable size involving multiple dosage-sensitive genes. Within the narrowed critical interval, USP34 has emerged as a particularly strong candidate for the core phenotype, supported by reports of smaller deletions involving only USP34 and XPO1, and by the fact that USP34 encodes a deubiquitinating enzyme that stabilizes Axin and thereby regulates canonical Wnt/β-catenin signaling, a pathway critical for neurodevelopment, craniofacial morphogenesis, and limb patterning. We report six individuals with heterozygous loss-of-function variants in USP34, including five with confirmed de novo variants, associated with global developmental delay, craniofacial dysmorphism, marked speech impairment, variable autism spectrum disorder, and distal limb anomalies. The phenotype associated with isolated loss of USP34 overlaps substantially with that reported in 2p15p16.1 microdeletion syndrome, while suggesting that some features seen in larger deletions may reflect the contribution of additional genes within the interval. These findings support haploinsufficiency of USP34 as sufficient to cause a distinct neurodevelopmental disorder, establish USP34 as a major contributor to the neurodevelopmental and dysmorphic phenotype associated with the 2p15p16.1 locus, and refine gene-specific contributions within this microdeletion syndrome.