USP9X – Non-syndromic X-linked Intellectual Disability

In a systematic X-chromosome resequencing study of 208 unrelated families with nonsyndromic X-linked intellectual disability, three unique USP9X variants were identified in three male probands, all presenting with moderate to severe intellectual disability and infantile hypotonia ([PMID:24607389]). Detailed clinical assessment confirmed hypotonia (HP:0001252) and global developmental delay with characteristic behavioral features in each kindred. All variants segregated with affected males in their respective families and were absent in unaffected relatives and population controls, supporting a pathogenic role in an X-linked recessive inheritance pattern.

The genetic spectrum comprised two missense substitutions (c.6254G>A (p.Arg2085His) and c.5683A>G (p.Asn1895Asp)) and one protein-truncating deletion (c.7526del (p.Gln2509fs)), indicating both loss-of-function and missense mechanisms. We highlight the missense variant c.6254G>A (p.Arg2085His) as representative of these findings.

Experimental studies leveraged a Usp9x knockout mouse model to interrogate variant impact on neuronal development. Homozygous loss of Usp9x caused marked reductions in axonal growth and neuronal migration. Overexpression of wild-type human USP9X fully rescued these deficits, whereas all three patient-derived variants failed to restore axonal extension, showed decreased localization to growth cones, and (in two of three) did not complement migration abnormalities ([PMID:24607389]).

Proteomic profiling of Usp9x-null neurons revealed disrupted cytoskeletal pathways, aligning with impaired neuronal morphology and supporting a loss-of-function mechanism. These convergent data provide strong functional concordance with the human phenotype.

Overall, the accumulated genetic and experimental evidence reaches a Moderate level of clinical validity per ClinGen criteria, with robust functional demonstration of pathogenicity. USP9X germline variants should be considered in the diagnostic evaluation of males with nonsyndromic X-linked intellectual disability. Key Take-home: USP9X loss-of-function causes X-linked intellectual disability through impaired neuronal migration and axonal growth, supporting its inclusion in gene panels for male neurodevelopmental disorders.

References

• American journal of human genetics • 2014 • Mutations in USP9X are associated with X-linked intellectual disability and disrupt neuronal cell migration and growth. PMID:24607389

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