USP9X

Chr XXLRXLD

ubiquitin specific peptidase 9 X-linked

Also known as: DFFRX, FAF, FAF-X, FAM, MRX99, MRXS99F, XLID99, hFAM

NCBI Gene: 8239 ENSG00000124486 UniProt: Q93008 OMIM: 300072

The protein is a ubiquitin-specific protease that removes ubiquitin from target proteins in the cytoplasm. Loss-of-function mutations cause X-linked intellectual developmental disorder 99, which can present as either a syndromic female-restricted form or a non-syndromic form affecting both males and females. The inheritance pattern can be either X-linked recessive or X-linked dominant depending on the specific mutation and clinical presentation.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene is a member of the peptidase C19 family and encodes a protein that is similar to ubiquitin-specific proteases. Though this gene is located on the X chromosome, it escapes X-inactivation. Mutations in this gene have been associated with Turner syndrome. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismXLR/XLDLOEUF 0.052 OMIM phenotypes

Clinical Summary— USP9X

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Gene-Disease Validity (ClinGen)

X-linked syndromic intellectual disability · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.05LOEUF

pLI 1.000

Z-score 8.86

OE 0.01 (0.00–0.05)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

6.41Z-score

OE missense 0.41 (0.37–0.44)

378 obs / 927.4 exp

Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios?

LoF OE?0.01 (0.00–0.05)

0≤0.351.4

Missense OE?0.41 (0.37–0.44)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 1 / 93.5Missense obs/exp: 378 / 927.4Syn Z: 0.41

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveUSP9X-related intellectual developmental disorder (hemizygous)LOFXLR

strongUSP9X-related intellectual developmental disorder (heterozygous)LOFmonoallelic_X_heterozygous

This gene — mechanism propensity

0.3594th %ile

GOF

0.5562th %ile

LOF

0.68top 25%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.05 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.