USP34 Haploinsufficiency as a Cause of Neurodevelopmental Phenotypes
Helena Wigoda1, Amjad Khan2, Bryce A Mendelsohn3
1Department of Pediatrics, Center for Precision Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
Clinical Genetics
|June 18, 2026
Summary
Haploinsufficiency of USP34 causes a distinct neurodevelopmental disorder. This finding establishes USP34 as a key gene in 2p15p16.1 microdeletion syndrome, impacting development and facial features.
Area of Science:
- Genetics
- Neurodevelopmental Disorders
- Molecular Biology
Background:
- 2p15p16.1 microdeletion syndrome is a rare neurodevelopmental disorder.
- USP34 is a strong candidate gene within the critical interval.
- USP34 encodes a deubiquitinating enzyme regulating Wnt/β-catenin signaling, crucial for development.
Purpose of the Study:
- To investigate the role of USP34 in neurodevelopmental disorders.
- To characterize the phenotype associated with USP34 loss-of-function variants.
- To refine gene-specific contributions within the 2p15p16.1 microdeletion syndrome.
Main Methods:
- Clinical evaluation of six individuals with USP34 variants.
- Genetic analysis to confirm heterozygous loss-of-function variants.
- Phenotypic correlation with existing 2p15p16.1 microdeletion syndrome data.
Main Results:
- Six individuals presented with heterozygous USP34 loss-of-function variants (five de novo).
- Associated phenotypes include global developmental delay, craniofacial dysmorphism, speech impairment, autism spectrum disorder, and limb anomalies.
- The phenotype of isolated USP34 loss overlaps with 2p15p16.1 microdeletion syndrome.
Conclusions:
- Haploinsufficiency of USP34 is sufficient to cause a distinct neurodevelopmental disorder.
- USP34 is a major contributor to the phenotype of 2p15p16.1 microdeletion syndrome.
- This study refines the understanding of gene-specific contributions within this microdeletion syndrome.
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