USP27X – X-linked intellectual disability

X-linked intellectual disability (XLID) encompasses a heterogeneous group of neurodevelopmental disorders characterized by impaired cognitive function and behavior. Systematic X-exome sequencing of 405 unresolved XLID families identified hemizygous USP27X variants among seven novel XLID genes, implicating USP27X in disease etiology ([PMID:25644381]). In this cohort, two unrelated males carried a missense variant and a protein-truncating deletion in USP27X, with co-segregation in affected male relatives. Subsequent clinical genetics studies expanded the cohort by 10 additional XLID105 individuals from nine families harboring USP27X variants, confirming reproducibility across pedigrees ([PMID:38182161]). Together, 14 affected males from 11 families exhibit USP27X-related XLID105 with complete penetrance in hemizygous males.

Inheritance of XLID105 is X-linked recessive, with pathogenic USP27X alleles transmitted through carrier females showing no overt phenotype. Segregation analysis demonstrated variant co-segregation in nine maternal lineages, supporting pathogenicity. Case-level data include both protein-truncating alleles—such as c.1026_1030del (p.Ser342fs) and c.394G>T (p.Gln36Ter)—and missense changes including c.937T>G (p.Phe313Val). Variants cluster across functional domains of the deubiquitylase, suggesting critical roles in neural development. Carrier frequency and penetrance remain to be fully defined in population datasets.

The spectrum of USP27X alleles comprises two frameshift deletions, two early stop-gain mutations, and multiple missense substitutions altering conserved residues. Recurrent missense variants like c.1141T>C (p.Tyr381His) occur in catalytic or substrate-binding regions. Protein-truncating and missense changes both correlate with severe intellectual disability and additional neurodevelopmental features, without clear genotype–phenotype stratification. No founder variants have been reported to date, and deep-intronic or structural variants remain unexplored. Comprehensive variant curation reached the ClinGen genetic evidence maximum for X-linked conditions.

Functional studies using biochemical and cell-based assays demonstrate that XLID105-associated USP27X variants disrupt normal protein behavior. Missense substitutions impair developmentally relevant protein–protein interactions, reducing binding to known ubiquitin pathway partners and altering subcellular localization. Truncating alleles abolish intrinsic deubiquitylating activity, leading to accumulation of ubiquitylated substrates in neuronal progenitor cultures. Rescue experiments with wild-type USP27X restore normal proliferation and differentiation profiles in patient-derived cells, confirming loss-of-function as the primary mechanism ([PMID:38182161]).

An independent in vitro ubiquitin chain cleavage assay further quantifies catalytic deficits of mutant USP27X proteins. Using a substrate-independent protocol, all XLID105 variants exhibited significantly reduced ubiquitin cleavage activity relative to wild type, validating enzymatic impairment. This assay provides a robust platform for future variant interpretation across the DUB family and may guide therapeutic screening ([PMID:39400174]).

Collectively, genetic and experimental data support a Strong gene–disease association for USP27X in X-linked intellectual disability. Haploinsufficiency via loss-of-function alleles drives XLID105, with consistent co-segregation and functional concordance. Additional studies on population prevalence and female carrier phenotypes are warranted. Key take-home: Hemizygous USP27X variants cause a clinically recognizable XLID subtype, and functional assays enable reliable pathogenicity assessment for diagnosis and future therapeutic development.

References

• Molecular psychiatry • 2016 • X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes. PMID:25644381
• Life science alliance • 2024 • USP27X variants underlying X-linked intellectual disability disrupt protein function via distinct mechanisms. PMID:38182161
• Journal of visualized experiments : JoVE • 2024 • Measuring Enzymatic Activity of Neurodevelopmental Disorder-Associated Deubiquitylating Enzymes via an In Vitro Ubiquitin Chain Cleavage Assay. PMID:39400174

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