name: USP9X Female-Restricted Syndromic Intellectual Disability
creation_date: '2026-07-31T00:00:00Z'
category: Genetic
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
parents:
- Neurodevelopmental Disorder
- X-linked Disorder
- Multiple Congenital Anomaly Syndrome
disease_term:
  preferred_term: intellectual disability, X-linked 99, syndromic, female-restricted
  term:
    id: MONDO:0010502
    label: intellectual disability, X-linked 99, syndromic, female-restricted
synonyms:
- MRXS99F
- USP9X-female syndrome
- female-restricted X-linked syndromic intellectual developmental disorder-99
- intellectual developmental disorder, X-linked 99, syndromic, female-restricted
- USP9X X-linked syndromic intellectual disability
description: >
  USP9X female-restricted syndromic intellectual disability (MRXS99F; OMIM
  300968; MONDO:0010502) is a rare, clinically recognisable
  multiple-congenital-anomaly neurodevelopmental syndrome of heterozygous
  females caused by
  de novo loss-of-function variants in USP9X at Xp11.4. USP9X encodes a large,
  substrate-specific ubiquitin-specific protease (deubiquitinase) that rescues
  many of its substrates from proteasomal degradation, thereby setting their
  steady-state abundance. Many of those substrates are themselves
  neurodevelopmental-disorder proteins or components of the TGF-beta, Wnt,
  Notch and mTOR pathways.

  The core presentation combines developmental delay and intellectual
  disability of highly variable severity, near-universal speech and language
  impairment, hypotonia and motor delay, a recognisable facial gestalt, and a
  distinctive set of extra-neural congenital malformations - choanal atresia,
  anal anomalies, postaxial polydactyly, congenital heart defects, hypomastia,
  cleft palate or bifid uvula, progressive scoliosis and hip dysplasia -
  together with structural brain abnormalities, most often agenesis or
  hypoplasia of the corpus callosum and ventriculomegaly. Pigmentary changes
  along the lines of Blaschko and body asymmetry are characteristic and reflect
  tissue-level mosaicism of USP9X dosage.

  IMPORTANT SCOPE / NAMED-ENTITY NOTE - this entry is the FEMALE-RESTRICTED
  entity only (OMIM:300968, MONDO:0010502, MRXS99F). USP9X causes a second,
  distinct MONDO entity: intellectual disability, X-linked 99 (MRX99;
  OMIM:300919, MONDO:0010487), a non-syndromic-to-mildly-syndromic disorder of
  hemizygous MALES driven by partial loss-of-function missense variants, often
  maternally inherited from unaffected mothers. The two literatures are
  routinely co-published by the same groups and must not be blended. The
  entities are separated by allele class (complete LOF/null in females versus
  hypomorphic missense in males), by sex of the affected individual, and by
  phenotype: males share the core neurological features but are largely spared
  the skeletal, cardiac and other congenital malformations that define the
  female syndrome. Male-derived data are cited here only where the paper itself
  makes a female-relevant claim, and are labelled as such.

  The disorder is "female-restricted" for a mechanistic reason rather than a
  classical dominance reason. Complete loss of USP9X is incompatible with early
  embryonic development, so a hemizygous male null is not observed; the null
  allele is therefore only seen in heterozygous females. Because USP9X escapes
  X-inactivation, the second X allele is normally expressed and cannot be
  recruited to compensate, so heterozygosity produces a genuine ~50% dosage
  reduction rather than the all-or-none mosaic seen for X-inactivated genes.
  This entry therefore models the mechanism as female haploinsufficiency of an
  X-inactivation-escape gene and deliberately avoids labelling it a
  conventional X-linked dominant or X-linked recessive disorder; the HPO
  annotation used is the neutral `X-linked inheritance` term.
references:
- reference: PMID:26833328
  title: De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific Recognizable
    Syndrome with Developmental Delay and Congenital Malformations.
  findings: []
- reference: PMID:33298948
  title: Missense variant contribution to USP9X-female syndrome.
  findings: []
- reference: PMID:31443933
  title: Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral
    Disorder Converging on Transforming Growth Factor beta Signaling.
  findings: []
- reference: CGGV:assertion_bd411e83-8373-44b7-8ad5-00894c873880-2021-11-17T110000.000Z
  title: USP9X / X-linked syndromic intellectual disability (Definitive)
  findings: []
- reference: CGDS:HGNC_12632
  title: USP9X dosage sensitivity
  findings: []
notes: >
  GENEREVIEWS BASELINE: searched PubMed on 2026-07-31 with
  `USP9X GeneReviews[All Fields]`, `USP9X[All Fields] AND GeneReviews[Book]`,
  and `USP9X-related neurodevelopmental disorder GeneReviews`. All returned
  zero results. No GeneReviews chapter exists for USP9X or for MRXS99F, so
  there is no GeneReviews phenotype baseline to cross-check and none is
  tagged in `references:`. The phenotype list here is instead anchored on the
  two largest systematic aggregations of affected females - Reijnders et al.
  2016 (PMID:26833328, the 17-female founding cohort that defined the syndrome)
  and Jolly et al. 2020 (PMID:33298948, which aggregates 35 females across
  null and missense/in-frame-deletion allele classes) - supplemented by
  individual case reports.

  FREQUENCY DISCIPLINE: the aggregated per-feature frequencies in Jolly et al.
  2020 are presented only as Sankey-plot terminal nodes in Figure 5, whose
  numeric values are not recoverable from the cached text. Frequency bands are
  therefore asserted ONLY where a quotable sentence states a proportion
  qualitatively ("in all individuals", "in almost all individuals"), and the
  band is scoped in the evidence explanation to the cohort the sentence is
  about. Where no such sentence exists the `frequency:` slot is deliberately
  omitted rather than guessed. No population prevalence estimate exists.

  NOT CURATED FOR WANT OF SOURCING: quantitative per-feature frequencies for
  the full 35-female aggregate; genotype-phenotype correlation by variant
  position (asserted as absent of striking hotspots but not quantified for
  clinical severity); natural history and adult outcomes, for which no
  longitudinal cohort exists; and any disease-modifying therapy, of which there
  is none.

  DEEP RESEARCH PROVENANCE: `just research-disorder claude_code
  USP9X_Female-Restricted_Syndromic_Intellectual_Disability` (report at
  research/USP9X_Female-Restricted_Syndromic_Intellectual_Disability-deep-research-claude_code.md;
  24m49s, 106 turns, 24 citations). Every PMID and snippet taken from that
  report was independently re-fetched with `just fetch-reference` and
  re-verified as a byte-exact substring of the cached text before use; the
  report's own "[PARAPHRASE - DO NOT USE AS SNIPPET]" items were discarded
  rather than repaired.

  TWO UPSTREAM DATA ISSUES SURFACED BY THE RESEARCH RUN (recorded, not acted on
  here): (1) MONDO appears to carry a second, un-merged term for this entity,
  MONDO:0018821 ("X-linked female restricted facial dysmorphism-short
  stature-choanal atresia-intellectual disability"), derived from the Orphanet
  branch, alongside the OMIM-derived MONDO:0010502 used here. This entry uses
  MONDO:0010502 because that is the term carrying the OMIM:300968 xref and the
  RO:0004003 USP9X gene relation. A MONDO merge request is warranted. (2)
  ClinGen's Intellectual Disability and Autism GCEP deliberately LUMPS the male
  and female USP9X disorders into one gene-disease assertion
  (CGGV:assertion_bd411e83-8373-44b7-8ad5-00894c873880-2021-11-17T110000.000Z,
  Definitive, 2021-11-17, now cited in `genetic:` and `inheritance:`) anchored
  on the broader MONDO:0020119, and additionally labels the female mode of
  inheritance "X-linked recessive", whereas OMIM/MONDO/Orphanet split the two
  entities and HPO/OMIM annotate the female entity as X-linked dominant. dismech
  follows the OMIM/MONDO split. This entry additionally declines BOTH the
  "dominant" and "recessive" labels for the reasons set out in the
  `inheritance:` block, so it is neither ClinGen's position nor OMIM's verbatim.
  The disagreement is recorded rather than silently resolved. Note that the
  ClinGen record's own evidence summary nonetheless describes exactly the
  allele-class boundary this entry uses (female null alleles versus male
  partial-loss-of-function missense), so the disagreement is administrative
  (one disease anchor versus two) rather than biological. ClinGen's separate
  dosage curation (CGDS:HGNC_12632, haploinsufficiency score 3, 2024-11-27) is
  cited on the haploinsufficiency and male-lethality pathophysiology nodes.

  OMIM NUMBER DISCREPANCY IN A CITED SOURCE: the authoritative OMIM number for
  this entity is 300968, which is the `OMIM:` xref carried by MONDO:0010502 and
  is what this entry uses. PMID:35253988 writes "MIM 300969, also known as
  MRX99F" in its abstract; 300969 is a different OMIM entry and this is an error
  in that paper. The paper is nonetheless clearly about this entity (its title
  and subject are female-specific syndromic ID caused by a truncating USP9X
  variant), so it is retained, but the OMIM digit in its abstract should not be
  propagated.

  MALE-DERIVED EVIDENCE: PMID:31443933 (Johnson et al. 2020) and PMID:24607389
  (Homan et al. 2014) are studies of the MALE entity (MRX99, MONDO:0010487).
  They are cited here only for (a) statements those papers make explicitly
  about the female syndrome, and (b) the differential-diagnosis contrast. They
  are never used as the sole support for a female phenotype.
pathophysiology:
- name: USP9X Loss-of-Function Allele
  biological_scale: MOLECULAR
  description: >
    The single upstream lesion from which both arms of this entity's biology
    fan out. USP9X (Xp11.4) encodes a 2570-amino-acid substrate-specific
    ubiquitin-specific protease. The gene sits in the top 5% of evolutionarily
    constrained human genes and is highly intolerant to variation
    (pLI = 1.0). Female-associated alleles are predominantly complete
    loss-of-function - whole or partial gene deletions, nonsense and early
    frameshift variants - with missense and single-amino-acid deletion variants
    in the catalytic ubiquitin-C-hydrolase domain and the N-terminal extension
    now also established as causal. The two downstream branches modelled here
    are not a chain but a fork determined by zygosity: a hemizygous male null is
    not compatible with development, whereas a heterozygous female null produces
    a viable haploinsufficient state. That fork is why the entity is
    female-restricted.
  gene:
    preferred_term: USP9X
    term:
      id: hgnc:12632
      label: USP9X
  molecular_functions:
  - preferred_term: cysteine-type deubiquitinase activity
    term:
      id: GO:0004843
      label: cysteine-type deubiquitinase activity
    modifier: DECREASED
  evidence:
  - reference: PMID:26833328
    reference_title: De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific
      Recognizable Syndrome with Developmental Delay and Congenital Malformations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report 17 females with de novo loss-of-function mutations in USP9X, encoding a highly conserved deubiquitinating enzyme."
    explanation: The founding cohort establishing de novo USP9X loss-of-function as
      the cause of this female entity.
  - reference: PMID:33298948
    reference_title: Missense variant contribution to USP9X-female syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is ranked among the top 5% of evolutionary constrained genes and is highly intolerant to variation"
    explanation: Quantifies the constraint that makes USP9X dosage-sensitive and
      supports a loss-of-function mechanism.
  - reference: PMID:33298948
    reference_title: Missense variant contribution to USP9X-female syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "While males are impacted primarily by hemizygous partial loss-of-function missense variants, in females de novo heterozygous complete loss-of-function mutations predominate, and give rise to the clinically recognisable USP9X-female syndrome."
    explanation: States the allele-class fork - complete LOF in females versus partial
      LOF missense in males - that separates this entity from MRX99.
  downstream:
  - target: Hemizygous Male Lethality of Null Alleles
  - target: Female USP9X Haploinsufficiency
- name: Hemizygous Male Lethality of Null Alleles
  biological_scale: ORGANISM
  description: >
    A complete USP9X null allele in a hemizygous male leaves no functional
    protein at all. USP9X (formerly FAM) is required for the earliest stages of
    mammalian development: antisense depletion of FAM in two-cell mouse embryos
    prevents blastocyst formation, and the gene is essential for embryonic
    viability. Consequently the null alleles that define this syndrome are
    expected never to be ascertained in a liveborn male. This node is not a
    disease mechanism in an affected patient - it is the survivorship filter
    that makes the entity female-restricted, and it is the single most important
    reason this disorder must not be modelled as ordinary X-linked dominance.
  biological_processes:
  - preferred_term: blastocyst formation
    term:
      id: GO:0001825
      label: blastocyst formation
    modifier: DECREASED
  evidence:
  - reference: PMID:33298948
    reference_title: Missense variant contribution to USP9X-female syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Such LOF alleles are likely to never be observed in a male as complete loss of USP9X, as would be the case of a hemizygous male, is known to result in early embryonic lethality in at least mouse"
    explanation: States the survivorship argument explicitly and attributes it to
      the mouse embryonic-lethality data.
  - reference: PMID:11731229
    reference_title: FAM deubiquitylating enzyme is essential for preimplantation mouse
      embryo development.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Exposure of two-cell embryos to FAM-specific antisense, but not sense, oligodeoxynucleotides resulted in depletion of the FAM protein and failure of the embryos to develop to blastocysts."
    explanation: The primary experimental basis for USP9X/FAM being essential at the
      earliest developmental stages; mouse data, hence MODEL_ORGANISM.
  - reference: PMID:33298948
    reference_title: Missense variant contribution to USP9X-female syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is essential for embryonic viability"
    explanation: Independent restatement of USP9X essentiality in the female-syndrome
      paper.
  - reference: PMID:40751225
    reference_title: 'c.7156C > T p.(Gln2386*) variant causes loss-of-function of the
      USP9X gene in a female-restricted X-linked syndromic intellectual disability:
      a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Loss-of-function variants in male individuals have never been reported"
    explanation: >
      The key human observation underpinning this node - the complete absence of
      male LOF alleles in the reported literature, which is what a survivorship
      filter predicts.
  - reference: PMID:30997057
    reference_title: Whole-exome sequencing reveals novel USP9X variant in female fetus
      with isolated agenesis of the corpus callosum.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast, loss‐of‐function variants have not been reported in affected males nor in the population database Exome Aggregation Consortium (ExAC) suggesting hemizygous loss‐of‐function variants in USP9X in males cause prenatal or neonatal demise."
    explanation: >
      Independent statement of the same inference, adding the population-database
      argument (absence from ExAC) to the clinical-literature argument.
  - reference: PMID:30997057
    reference_title: Whole-exome sequencing reveals novel USP9X variant in female fetus
      with isolated agenesis of the corpus callosum.
    supports: PARTIAL
    evidence_source: MODEL_ORGANISM
    snippet: "USP9X is required for neural development and in vivo studies reveal whole‐brain depletion of USP9X causes postnatal lethality in male mice."
    explanation: >
      Mouse corroboration of lethality on complete loss. Marked PARTIAL because
      whole-brain conditional depletion causing postnatal lethality is not the
      same claim as whole-organism embryonic lethality; it supports the direction
      but not the precise developmental stage.
  - reference: CGDS:HGNC_12632
    reference_title: ClinGen Dosage Sensitivity curation, USP9X (HGNC:12632)
    supports: PARTIAL
    evidence_source: OTHER
    snippet: "Multiple studies note the lack of observed true loss-of-function variants in males with USP9X-related intellectual disability, suggesting the possibility that loss of USP9X is male-lethal"
    explanation: >
      ClinGen's dosage-curation narrative reaches the same survivorship
      inference from the same observation (no true male LOF alleles reported).
      Marked PARTIAL because ClinGen states it as a possibility rather than an
      established fact, which matches how this node is framed. evidence_source
      is OTHER (expert-panel synthesis).
- name: Female USP9X Haploinsufficiency
  biological_scale: MOLECULAR
  description: >
    In a heterozygous female one USP9X allele is null (or functionally null) and
    the other is intact. For a gene subject to X-inactivation this would produce
    a mosaic of wild-type and mutant cells. USP9X, however, escapes
    X-inactivation, so both alleles are normally expressed and the intact allele
    cannot be up-regulated to compensate. The result is a true, cell-autonomous
    dosage reduction rather than a mosaic. This has been confirmed directly:
    mRNA and protein studies in fibroblasts from affected females show
    significantly reduced USP9X levels. Female penetrance is high but not
    complete - approximately 95% - and at least two transmitting mothers with
    minimal or no features are documented, one germline mosaic and one not,
    implying an unidentified modifier.
  biological_processes:
  - preferred_term: dosage compensation by inactivation of X chromosome
    term:
      id: GO:0009048
      label: dosage compensation by inactivation of X chromosome
    modifier: ABSENT
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  evidence:
  - reference: PMID:33298948
    reference_title: Missense variant contribution to USP9X-female syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "USP9X is an X-chromosome gene that escapes X-inactivation."
    explanation: Establishes the escape-from-X-inactivation premise on which the
      haploinsufficiency model depends.
  - reference: PMID:26833328
    reference_title: De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific
      Recognizable Syndrome with Developmental Delay and Congenital Malformations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Expression studies on both mRNA and protein level in affected-female-derived fibroblasts showed significant reduction of USP9X level, confirming the loss-of-function effect of the identified mutations."
    explanation: Direct measurement of reduced USP9X dosage in patient-derived cells,
      the core evidence for haploinsufficiency.
  - reference: CGDS:HGNC_12632
    reference_title: ClinGen Dosage Sensitivity curation, USP9X (HGNC:12632)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "USP9X | HGNC:12632 | 8239 | Xp11.4 | chrX:41085445-41236579 | 3 - Sufficient Evidence for Haploinsufficiency | 0 - No Evidence for Triplosensitivity | 2024-11-27"
    explanation: >
      ClinGen's expert-panel dosage curation scores USP9X haploinsufficiency 3
      ("Sufficient Evidence"), the strongest available structured attestation of
      the dosage mechanism this node asserts, and scores triplosensitivity 0
      (no evidence), which is why no gain-of-dosage arm is modelled.
      evidence_source is OTHER because the record is an expert-panel synthesis
      of published evidence, not a primary study.
  - reference: PMID:31443933
    reference_title: Partial Loss of USP9X Function Leads to a Male Neurodevelopmental
      and Behavioral Disorder Converging on Transforming Growth Factor beta Signaling.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "USP9X escapes X inactivation, and in female subjects de novo heterozygous copy number loss or truncating mutations cause haploinsufficiency culminating in a recognizable syndrome with intellectual disability and signature brain and congenital abnormalities."
    explanation: >
      Although this paper's own subjects are male, this sentence is an explicit
      statement about the female entity and is used only for that claim.
  - reference: PMID:35253988
    reference_title: Exome and RNA-Seq analyses of an incomplete penetrance variant
      in USP9X in female-specific syndromic intellectual disability.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "While the penetrance of pathogenic variants in USP9X in female appears to be high (95%) and the variants frequently occur de novo, incomplete penetrance should be considered."
    explanation: Qualifies the haploinsufficiency model - dosage reduction is
      necessary but not always sufficient; penetrance is ~95%, not complete.
  - reference: PMID:33298948
    reference_title: Missense variant contribution to USP9X-female syndrome.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "mechanism of USP9X-female NDD is not supported by e.g. phenotypes observed in Turner Syndrome with XO sex chromosome karyotype, which generally lack neurological manifestations"
    explanation: >
      A genuine counterargument, recorded rather than suppressed. Individuals
      with 45,X have a single USP9X allele - nominally the same dosage state as
      a heterozygous null - yet generally lack neurological manifestations. This
      is an argument against a simple, whole-body 50%-dosage model and is the
      reason this node is not asserted as a closed mechanism. See the
      corresponding entry under discussions.
  downstream:
  - target: Loss of Substrate Deubiquitination and Proteasomal Substrate Destabilization
  - target: Tissue-Level Mosaicism of USP9X Dosage
- name: Loss of Substrate Deubiquitination and Proteasomal Substrate Destabilization
  biological_scale: MOLECULAR
  description: >
    USP9X removes ubiquitin from a large, context-dependent set of substrates,
    thereby antagonising their proteasomal degradation and raising their
    steady-state abundance. Halving USP9X dose therefore lowers the abundance of
    many substrates at once. Crucially, USP9X substrates are disproportionately
    proteins encoded by neurodevelopmental-disorder genes and regulators of the
    TGF-beta, Wnt, Notch and mTOR pathways, so a single quantitative lesion in a
    deubiquitinase produces a pleiotropic developmental phenotype. This node is
    the convergence point from which the three mechanistic sub-branches below
    diverge; they are modelled as siblings because different substrate classes
    are affected in parallel rather than sequentially.
  biological_processes:
  - preferred_term: protein deubiquitination
    term:
      id: GO:0016579
      label: protein deubiquitination
    modifier: DECREASED
  - preferred_term: proteasome-mediated ubiquitin-dependent protein catabolic process
    term:
      id: GO:0043161
      label: proteasome-mediated ubiquitin-dependent protein catabolic process
    modifier: INCREASED
  evidence:
  - reference: PMID:33298948
    reference_title: Missense variant contribution to USP9X-female syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "USP9X thus protects many of its substrates from degradation, thereby increasing their abundance and hence function"
    explanation: States the substrate-stabilisation function whose loss is modelled
      at this node.
  - reference: PMID:25672900
    reference_title: 'La FAM fatale: USP9X in development and disease.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In most instances, DUBs moderate the absolute level of a substrate, its locality or activity, rather than being an \"all-or-none\" phenomenon. Yet, disruption of this quantitative regulation can produce dramatic qualitative differences."
    explanation: >
      Review framing of why a quantitative (dosage) lesion in a deubiquitinase
      yields a qualitative developmental syndrome. Classified OTHER because this
      is an expert review, not primary data.
  downstream:
  - target: Attenuated TGF-beta Signalling
  - target: Reduced RAPTOR and mTORC1 Signalling in Neural Progenitors
  - target: Dysregulated Wnt and Notch Signalling in Neural Progenitors
  - target: Destabilization of Cytoskeletal and Ankyrin-Repeat Neuronal Substrates
  - target: Disrupted Extra-Neural Organogenesis
- name: Attenuated TGF-beta Signalling
  biological_scale: CELLULAR
  description: >
    The best-characterised signalling arm, and the one with a defined molecular
    lesion. USP9X is the deubiquitinase that reverses monoubiquitination of
    SMAD4 at lysine 519 - a modification that blocks SMAD4 from partnering
    phospho-SMAD2. With USP9X dose reduced, SMAD4 remains monoubiquitinated and
    TGF-beta/BMP transcriptional output falls. USP9X additionally stabilises
    SMURF1 and PJA1, further regulators of the pathway. In the mouse, Usp9x-null
    neurons show a failure of Tgf-beta signalling that accounts in part for
    their reduced axonal length. In USP9X-variant human fibroblasts, TGF-beta
    reporter induction, TGF-beta-stimulated nuclear SMAD4 translocation and
    TGF-beta-stimulated migration are all blunted. Note the scope limit: the
    biochemistry (Dupont) is non-neural cell systems, the in vivo work is mouse,
    and the human patient-cell work is from the MALE partial-loss-of-function
    cohort. The authors flag TGF-beta as the candidate convergent mechanism
    shared with the female dosage-loss syndrome; this node is annotated at that
    confidence level rather than as a demonstrated female mechanism.
  mechanism_confidence: PROVISIONAL
  biological_processes:
  - preferred_term: transforming growth factor beta receptor signaling pathway
    term:
      id: GO:0007179
      label: transforming growth factor beta receptor signaling pathway
    modifier: DECREASED
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:19135894
    reference_title: FAM/USP9x, a deubiquitinating enzyme essential for TGFbeta signaling,
      controls Smad4 monoubiquitination.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "By means of siRNA screen we identified FAM (USP9x), a deubiquitinase acting as essential and evolutionarily conserved component in TGFbeta and bone morphogenetic protein signaling."
    explanation: Establishes USP9X as a required component of TGF-beta/BMP signalling.
  - reference: PMID:19135894
    reference_title: FAM/USP9x, a deubiquitinating enzyme essential for TGFbeta signaling,
      controls Smad4 monoubiquitination.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Smad4 is monoubiquitinated in lysine 519 in vivo, a modification that inhibits Smad4 by impeding association with phospho-Smad2. FAM reverts this negative modification, re-empowering Smad4 function."
    explanation: >
      Defines the specific molecular lesion at this node - loss of USP9X leaves
      SMAD4-K519 monoubiquitinated and unable to partner phospho-SMAD2. This is
      the mechanistic substrate for the pathway-level attenuation.
  - reference: PMID:19135894
    reference_title: FAM/USP9x, a deubiquitinating enzyme essential for TGFbeta signaling,
      controls Smad4 monoubiquitination.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "loss of FAM disables Smad4-dependent responses in several model systems"
    explanation: Directly links loss of USP9X to collapse of SMAD4-dependent
      transcriptional output.
  - reference: PMID:23861879
    reference_title: Loss of Usp9x disrupts cortical architecture, hippocampal development
      and TGFbeta-mediated axonogenesis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Usp9x absence also led to dramatic reductions in axonal length, in vivo and in vitro, which could in part be explained by a failure in Tgf-β signaling."
    explanation: Primary in vivo demonstration that loss of Usp9x dosage impairs
      TGF-beta-dependent axon growth.
  - reference: PMID:23861879
    reference_title: Loss of Usp9x disrupts cortical architecture, hippocampal development
      and TGFbeta-mediated axonogenesis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "This study establishes that Usp9x is critical for several aspects of CNS development, and suggests that its regulation of Tgf-β signaling extends to neurons."
    explanation: Generalises the TGF-beta link to neurons specifically.
  - reference: PMID:31443933
    reference_title: Partial Loss of USP9X Function Leads to a Male Neurodevelopmental
      and Behavioral Disorder Converging on Transforming Growth Factor beta Signaling.
    supports: PARTIAL
    evidence_source: IN_VITRO
    snippet: "In support of partial loss-of-function mechanisms, using patient-derived cell lines, we show loss of only specific USP9X substrates that regulate neurodevelopmental signaling pathways and a united defect in transforming growth factor β signaling."
    explanation: >
      Human patient-derived-cell evidence for the TGF-beta defect. Marked
      PARTIAL because the cell lines are from MALE partial-LOF subjects
      (MONDO:0010487), not from females with this entity; the convergence onto
      the female syndrome is the authors' inference, not a measurement.
  downstream:
  - target: Impaired Axonogenesis and Commissural Tract Formation
- name: Reduced RAPTOR and mTORC1 Signalling in Neural Progenitors
  biological_scale: CELLULAR
  description: >
    A second, mechanistically distinct signalling arm with its own named
    substrate. RAPTOR, the defining component of mTORC1, is a USP9X
    deubiquitination substrate: RAPTOR abundance tracks USP9X dose in both
    loss- and gain-of-function experiments, and USP9X activity opposes RAPTOR's
    proteasomal degradation. Reducing USP9X in a human neural progenitor line
    arrests cells in G0 with a matching fall in mTORC1 signalling, reproduced in
    Usp9x-null mouse neurospheres and embryonic brain. The consequence is
    impaired neural progenitor proliferation - a plausible contributor to the
    reduced size of multiple brain regions. A counter-intuitive detail worth
    preserving: loss of Usp9x simultaneously INCREASED sphere-forming capacity,
    i.e. proliferation and self-renewal move in opposite directions, so this
    node should not be simplified to "fewer neural progenitors".
  biological_processes:
  - preferred_term: TORC1 signaling
    term:
      id: GO:0038202
      label: TORC1 signaling
    modifier: DECREASED
  cell_types:
  - preferred_term: neural progenitor cell
    term:
      id: CL:0011020
      label: neural progenitor cell
  - preferred_term: neural stem cell
    term:
      id: CL:0000047
      label: neural stem cell
  evidence:
  - reference: PMID:28341829
    reference_title: USP9X deubiquitylating enzyme maintains RAPTOR protein levels,
      mTORC1 signalling and proliferation in neural progenitors.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Decreasing USP9X resulted in ReNcell VM cells arresting in G0 cell cycle phase, with a concomitant decrease in mTORC1 signalling, a major regulator of G0/G1 cell cycle progression."
    explanation: >
      Human neural progenitor line evidence linking reduced USP9X dose to
      mTORC1 loss and cell-cycle arrest.
  - reference: PMID:28341829
    reference_title: USP9X deubiquitylating enzyme maintains RAPTOR protein levels,
      mTORC1 signalling and proliferation in neural progenitors.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "RAPTOR protein level is directly proportional to USP9X, in both loss- and gain-of-function experiments in cultured cells and, (iii) USP9X deubiquitlyating activity opposes the proteasomal degradation of RAPTOR."
    explanation: >
      Identifies RAPTOR as the substrate and shows dose-proportionality, which
      is exactly the relationship a haploinsufficiency model requires.
  - reference: PMID:28341829
    reference_title: USP9X deubiquitylating enzyme maintains RAPTOR protein levels,
      mTORC1 signalling and proliferation in neural progenitors.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Interestingly, loss of Usp9x increased the number of sphere-forming cells consistent with enhanced neural stem cell self-renewal."
    explanation: The divergence between proliferation and self-renewal, recorded so the
      node is not oversimplified.
  downstream:
  - target: Disorganized Cortical and Hippocampal Neurogenesis
- name: Dysregulated Wnt and Notch Signalling in Neural Progenitors
  biological_scale: CELLULAR
  description: >
    Beyond TGF-beta, USP9X coordinates several fate-determining pathways in
    neural progenitors. Loss of Usp9x in embryonic mouse neural progenitors
    disrupts cell adhesion and apical-basal polarity, alters the beta-catenin
    destruction complex and Wnt pathway output, and lowers ITCH and NUMB with a
    reciprocal rise in Notch intracellular domain and the Notch target Hes5.
    The net effect is an increased and ectopically positioned intermediate
    progenitor pool. USP9X also maintains RAPTOR and thereby mTORC1 signalling
    in neural progenitors, an additional dosage-sensitive arm.
  biological_processes:
  - preferred_term: Wnt signaling pathway
    term:
      id: GO:0016055
      label: Wnt signaling pathway
    modifier: ABNORMAL
  - preferred_term: Notch signaling pathway
    term:
      id: GO:0007219
      label: Notch signaling pathway
    modifier: INCREASED
  cell_types:
  - preferred_term: neural progenitor cell
    term:
      id: CL:0011020
      label: neural progenitor cell
  evidence:
  - reference: PMID:28808228
    reference_title: Loss of Usp9x disrupts cell adhesion, and components of the Wnt
      and Notch signaling pathways in neural progenitors.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Nestin-cre mediated ablation of Usp9x from embryonic neural progenitors in vivo resulted in a transient disruption of cell adhesion and apical-basal polarity and, an increased number and ectopic localisation of intermediate neural progenitors."
    explanation: Establishes the progenitor-level consequence of Usp9x loss in vivo.
  - reference: PMID:28808228
    reference_title: Loss of Usp9x disrupts cell adhesion, and components of the Wnt
      and Notch signaling pathways in neural progenitors.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Loss of Usp9x led to decreased Itch and Numb levels, and a concomitant increase in levels of the Notch intracellular domain as well as, increased expression of the Notch target gene Hes5."
    explanation: Documents the Notch arm as a direct substrate-abundance consequence.
  - reference: PMID:28808228
    reference_title: Loss of Usp9x disrupts cell adhesion, and components of the Wnt
      and Notch signaling pathways in neural progenitors.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Pathway analysis of transcriptomic data identified Wnt signalling as significantly affected in Usp9x -/Y embryonic brains."
    explanation: Documents the Wnt arm.
  downstream:
  - target: Disorganized Cortical and Hippocampal Neurogenesis
- name: Destabilization of Cytoskeletal and Ankyrin-Repeat Neuronal Substrates
  biological_scale: CELLULAR
  description: >
    A third substrate class is structural rather than signalling. Unbiased
    proteomics of Usp9x-knockout neurons identifies disruption of the
    cytoskeleton as the principal consequence of Usp9x loss, and doublecortin
    (DCX), a canonical neuronal migration protein, is a USP9X interactor.
    Separately, USP9X deubiquitinates and stabilises ankyrin-G and other
    ankyrin-repeat-domain proteins at the synapse; forebrain Usp9x knockout mice
    show transient loss of these proteins but a persistent reduction in cortical
    spine density into adulthood, and human USP9X variants found in intellectual
    disability and autism abolish either catalytic activity or the ankyrin-G
    interaction.
  biological_processes:
  - preferred_term: dendritic spine development
    term:
      id: GO:0060996
      label: dendritic spine development
    modifier: DECREASED
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:24607389
    reference_title: Mutations in USP9X are associated with X-linked intellectual disability
      and disrupt neuronal cell migration and growth.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We also performed proteomics analysis of neurons from both the wild-type and Usp9x knockout embryos and identified disruption of the cytoskeleton as the main underlying consequence of the loss of Usp9x."
    explanation: >
      Unbiased identification of the cytoskeletal substrate class. This paper's
      human subjects are male (MRX99), but the cited finding is a mouse
      knockout proteomics result about USP9X dosage loss generally.
  - reference: PMID:31813652
    reference_title: Usp9X Controls Ankyrin-Repeat Domain Protein Homeostasis during
      Dendritic Spine Development.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Usp9X phosphorylation enhances their interaction, decreases ankyrin-G polyubiquitination, and stabilizes ankyrin-G to maintain dendritic spine development."
    explanation: Defines the ankyrin-repeat substrate arm and its synaptic readout.
  - reference: PMID:31813652
    reference_title: Usp9X Controls Ankyrin-Repeat Domain Protein Homeostasis during
      Dendritic Spine Development.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "However, reduced cortical spine density in knockouts persists into adulthood."
    explanation: Shows the structural deficit is persistent, not transient, which is
      what links it to a lifelong neurodevelopmental phenotype.
  downstream:
  - target: Impaired Neuronal Migration and Axon Growth
  - target: Reduced Cortical Dendritic Spine Density
- name: Impaired Axonogenesis and Commissural Tract Formation
  biological_scale: TISSUE
  description: >
    The corpus callosum is the largest commissural axon tract, and its formation
    is the developmental process most sensitive to loss of USP9X-dependent
    TGF-beta-driven axon growth. Dorsal-telencephalon-restricted deletion of
    Usp9x in mouse spares survival but produces reduction or loss of the corpus
    callosum together with a marked decrease in hippocampal size. This is the
    mechanistic route to the callosal findings that dominate neuroimaging in
    affected females.
  biological_processes:
  - preferred_term: axonogenesis
    term:
      id: GO:0007409
      label: axonogenesis
    modifier: DECREASED
  - preferred_term: corpus callosum development
    term:
      id: GO:0022038
      label: corpus callosum development
    modifier: ABNORMAL
  locations:
  - preferred_term: corpus callosum
    term:
      id: UBERON:0002336
      label: corpus callosum
  evidence:
  - reference: PMID:23861879
    reference_title: Loss of Usp9x disrupts cortical architecture, hippocampal development
      and TGFbeta-mediated axonogenesis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "resulted in reduction or loss of the corpus callosum, a dramatic decrease in hippocampal size, and disorganization of the hippocampal CA3 region"
    explanation: Direct in vivo recapitulation of the callosal phenotype from loss of
      Usp9x dosage.
  - reference: PMID:33298948
    reference_title: Missense variant contribution to USP9X-female syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "provides a strong recapitulation of the neurological phenotypes of these affected females, including hypoplastic corpus callosum, ventriculomegaly, and learning and memory problems"
    explanation: >
      The female-syndrome paper itself states that mouse Usp9x dosage loss
      recapitulates the female neurological phenotype, which is what licenses
      the mouse evidence above to be used for this human entity.
  - reference: PMID:33188399
    reference_title: Abnormal Behavior and Cortical Connectivity Deficits in Mice Lacking
      Usp9x.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Diffusion tensor magnetic resonance imaging revealed deficits in all three major forebrain commissures, as well as long-range hypoconnectivity between cortical and subcortical regions."
    explanation: >
      Extends the commissural defect beyond the corpus callosum to all three
      forebrain commissures and adds a long-range connectivity deficit, showing
      the lesion is a general failure of commissural/long-tract axonogenesis
      rather than a callosum-specific anomaly.
  downstream:
  - target: Structural Brain Malformation
- name: Disorganized Cortical and Hippocampal Neurogenesis
  biological_scale: TISSUE
  description: >
    Loss of Usp9x from the whole brain leaves gross architecture intact but
    disrupts the cellular organisation of the ventricular and sub-ventricular
    zones and of the cortical plate, and disorganises the hippocampal CA3
    region - a pattern resembling Doublecortin-knockout mice, consistent with
    DCX being a USP9X interactor. This is the lamination/organisation arm of the
    brain phenotype, distinct from the commissural-tract arm above.
  biological_processes:
  - preferred_term: cerebral cortex development
    term:
      id: GO:0021987
      label: cerebral cortex development
    modifier: ABNORMAL
  cell_types:
  - preferred_term: neural progenitor cell
    term:
      id: CL:0011020
      label: neural progenitor cell
  evidence:
  - reference: PMID:23861879
    reference_title: Loss of Usp9x disrupts cortical architecture, hippocampal development
      and TGFbeta-mediated axonogenesis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "loss of Usp9x disrupted the cellular organization of the ventricular and sub-ventricular zones, and cortical plate"
    explanation: Documents the progenitor-zone and cortical-plate disorganisation.
  - reference: PMID:23861879
    reference_title: Loss of Usp9x disrupts cortical architecture, hippocampal development
      and TGFbeta-mediated axonogenesis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "This latter phenotypic aspect resembled that observed in Doublecortin knock-out mice, which is an Usp9x interacting protein."
    explanation: Links the hippocampal disorganisation to a specific USP9X substrate,
      DCX.
  - reference: PMID:27181636
    reference_title: Usp9x-deficiency disrupts the morphological development of the
      postnatal hippocampal dentate gyrus.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Usp9x conditional knockout mice exhibit a smaller hippocampus and shortened dentate gyrus blades from as early as P7. Moreover, the analysis of cellular populations within the dentate gyrus revealed reduced stem cell, neuroblast and neuronal numbers and abnormal neuroblast morphology."
    explanation: Resolves the hippocampal arm to specific cell populations and dates
      its onset to the early postnatal period.
  downstream:
  - target: Structural Brain Malformation
- name: Impaired Neuronal Migration and Axon Growth
  biological_scale: CELLULAR
  description: >
    At the level of the individual neuron, loss of USP9X reduces both axonal
    outgrowth and migration. Overexpression of wild-type human USP9X rescues
    both defects in Usp9x-null neurons, establishing that they are USP9X-dose
    dependent rather than secondary. Disease-associated USP9X variants fail to
    rescue axonal growth and show reduced USP9X localisation in axonal growth
    cones.
  biological_processes:
  - preferred_term: neuron migration
    term:
      id: GO:0001764
      label: neuron migration
    modifier: DECREASED
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:24607389
    reference_title: Mutations in USP9X are associated with X-linked intellectual disability
      and disrupt neuronal cell migration and growth.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Loss of Usp9x causes reduction in both axonal growth and neuronal cell migration."
    explanation: The core cellular phenotype of USP9X loss in neurons.
  - reference: PMID:24607389
    reference_title: Mutations in USP9X are associated with X-linked intellectual disability
      and disrupt neuronal cell migration and growth.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Although overexpression of wild-type human USP9X rescued these defects, all three USP9X variants failed to rescue axonal growth, caused reduced USP9X protein localization in axonal growth cones, and (in 2/3 variants) failed to rescue neuronal cell migration."
    explanation: Rescue experiment establishing dose-dependence and variant
      loss-of-function.
  downstream:
  - target: Structural Brain Malformation
- name: Reduced Cortical Dendritic Spine Density
  biological_scale: CELLULAR
  description: >
    A synapse-level deficit that persists after the upstream substrate
    abundances have normalised. In forebrain-specific Usp9x knockout mice
    ankyrin-repeat-domain proteins fall transiently at 2 weeks and recover by 12
    weeks, yet cortical spine density remains reduced into adulthood and the
    animals are hyperactive. This dissociation is mechanistically important: it
    implies a critical developmental window during which USP9X dose must be
    adequate, after which restoring substrate levels does not restore the
    structural or behavioural phenotype - an argument against any simple
    substrate-replacement therapeutic strategy.
  biological_processes:
  - preferred_term: dendritic spine development
    term:
      id: GO:0060996
      label: dendritic spine development
    modifier: DECREASED
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:31813652
    reference_title: Usp9X Controls Ankyrin-Repeat Domain Protein Homeostasis during
      Dendritic Spine Development.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In forebrain-specific Usp9X knockout mice (Usp9X-/Y), ankyrin-G as well as multiple ankyrin-repeat domain (ANKRD)-containing proteins are transiently reduced at 2 but recovered at 12 weeks postnatally."
    explanation: Establishes the transient nature of the substrate deficit.
  - reference: PMID:31813652
    reference_title: Usp9X Controls Ankyrin-Repeat Domain Protein Homeostasis during
      Dendritic Spine Development.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Our data reveal a DUB-dependent mechanism of ANKRD protein homeostasis, the impairment of which only transiently affects ANKRD protein levels but leads to persistent neuronal, behavioral, and clinical abnormalities."
    explanation: States the transient-cause/persistent-effect dissociation that
      motivates the critical-window argument.
  downstream:
  - target: Neurodevelopmental Impairment
- name: Structural Brain Malformation
  biological_scale: TISSUE
  description: >
    The convergent anatomical readout of the axonogenesis, neurogenesis and
    migration arms. Brain malformation is essentially universal in affected
    females where imaging has been performed, with agenesis or hypoplasia of the
    corpus callosum and ventriculomegaly the most frequent findings; prominent
    extra-axial spaces, Dandy-Walker malformation, Blake's pouch cyst, optic
    nerve atrophy and generalised atrophy are also reported.
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:33298948
    reference_title: Missense variant contribution to USP9X-female syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All individuals presented with brain malformations, most frequently agenesis of the corpus callosum and ventriculomegaly"
    explanation: Human evidence that brain malformation is the convergent anatomical
      endpoint in affected females.
  - reference: PMID:26833328
    reference_title: De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific
      Recognizable Syndrome with Developmental Delay and Congenital Malformations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "progressive scoliosis, and structural brain abnormalities"
    explanation: Structural brain abnormality is part of the founding syndrome
      definition.
  downstream:
  - target: Neurodevelopmental Impairment
- name: Neurodevelopmental Impairment
  biological_scale: ORGANISM
  description: >
    The clinical neurological endpoint: global developmental delay and
    intellectual disability spanning borderline to severe, near-universal speech
    and language impairment ranging from mild delay to complete absence of
    speech, motor disability most often related to hypotonia, and a range of
    behavioural disturbances including autism, anxiety and aggression. The wide
    severity range within a single molecular mechanism is itself a feature of
    the disorder and is not currently predictable from variant position.
  evidence:
  - reference: PMID:33298948
    reference_title: Missense variant contribution to USP9X-female syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "was present in all individuals where assessed, but was variable, ranging from borderline to severe"
    explanation: Documents both the universality and the variability of intellectual
      disability in the female cohort.
  - reference: PMID:33298948
    reference_title: Missense variant contribution to USP9X-female syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hearing loss was a prominent feature, and individuals displayed a number of different behavioural disturbances including autism, anxiety and aggression"
    explanation: Documents the behavioural component of the neurodevelopmental
      endpoint.
- name: Tissue-Level Mosaicism of USP9X Dosage
  biological_scale: TISSUE
  description: >
    A branch that is specific to females and to escape genes. The degree to
    which an escape gene evades X-inactivation varies between cells and between
    tissues, so a heterozygous female is a patchwork of territories with
    differing residual USP9X dose. Clonal territories established early in
    development then follow the lines of Blaschko. This is the accepted
    explanation for the pigmentary streaking and body asymmetry that are
    characteristic of the syndrome, and it is a genuinely different mechanism
    from the cell-autonomous dosage reduction modelled upstream.
  biological_processes:
  - preferred_term: dosage compensation by inactivation of X chromosome
    term:
      id: GO:0009048
      label: dosage compensation by inactivation of X chromosome
    modifier: ABNORMAL
  evidence:
  - reference: PMID:26833328
    reference_title: De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific
      Recognizable Syndrome with Developmental Delay and Congenital Malformations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In several females, pigment changes along Blaschko lines and body asymmetry were observed, which is probably related to differential (escape from) X-inactivation between tissues."
    explanation: Directly asserts the tissue-differential-escape mechanism for the
      mosaic features.
  - reference: PMID:29022598
    reference_title: Landscape of X chromosome inactivation across human tissues.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "XCI is, however, incomplete in humans: up to one-third of X-chromosomal genes are expressed from both the active and inactive X chromosomes (Xa and Xi, respectively) in female cells, with the degree of 'escape' from inactivation varying between genes and individuals."
    explanation: >
      The population-scale transcriptomic basis for the premise this node
      depends on - that escape is partial and varies between individuals (and,
      per the same survey, between tissues), which is what makes a heterozygous
      female a patchwork of residual-dosage territories. Classified COMPUTATIONAL
      because it is a large-scale integrative transcriptome/genome analysis.
  - reference: PMID:29022598
    reference_title: Landscape of X chromosome inactivation across human tissues.
    supports: PARTIAL
    evidence_source: COMPUTATIONAL
    snippet: "We show that XCI at 683 X-chromosomal genes is generally uniform across human tissues, but identify examples of heterogeneity between tissues, individuals and cells."
    explanation: >
      An important qualifier rather than plain support - escape is mostly
      uniform across tissues, with heterogeneity the exception. The mosaic
      features of this syndrome therefore require USP9X to be one of the
      heterogeneous cases, which this survey does not establish for USP9X
      specifically.
  downstream:
  - target: Blaschko-Linear Pigmentary Mosaicism and Body Asymmetry
- name: Blaschko-Linear Pigmentary Mosaicism and Body Asymmetry
  biological_scale: ORGANISM
  description: >
    Streaky hyper- and hypopigmentation following the lines of Blaschko, and
    asymmetry of the body, brain, breasts and limbs. Clinically this is a useful
    handle: in a girl with developmental delay and congenital anomalies,
    Blaschko-linear pigmentation should raise USP9X specifically, and it was one
    of the features that allowed several probands in the founding cohort to be
    diagnosed by targeted testing rather than untargeted exome sequencing.
  evidence:
  - reference: PMID:31666975
    reference_title: Novel USP9X variants in two patients with X-linked intellectual
      disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report two female patients with intellectual disability and pigment abnormalities along Blaschko lines."
    explanation: Independent replication of the Blaschko-linear pigmentary phenotype
      in USP9X-variant females.
  - reference: PMID:26833328
    reference_title: De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific
      Recognizable Syndrome with Developmental Delay and Congenital Malformations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Four females from our cohort were identified by targeted genetic testing because their phenotype was suggestive for USP9X mutations."
    explanation: Supports the claim that the gestalt, including the mosaic skin
      findings, is recognisable enough to drive targeted testing.
- name: Disrupted Extra-Neural Organogenesis
  biological_scale: ORGANISM
  description: >
    The feature that most sharply separates this entity from the male USP9X
    disorder. Reduced USP9X dosage during organogenesis produces a
    characteristic constellation of structural birth defects outside the CNS:
    choanal atresia, anal anomalies, postaxial polydactyly, congenital heart
    defects, hypomastia, cleft palate or bifid uvula, progressive scoliosis, and
    hip dysplasia or dislocation. Males with partial-loss-of-function USP9X
    missense variants share the neurological features but are largely spared
    these congenital malformations, which is direct clinical evidence that this
    branch is dosage-threshold dependent. The specific substrate(s) mediating
    each malformation are not established; because several of the features
    overlap known ciliopathies, a ciliary contribution has been proposed but not
    demonstrated (see discussions).
  mechanism_confidence: HYPOTHETICAL
  evidence:
  - reference: PMID:26833328
    reference_title: De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific
      Recognizable Syndrome with Developmental Delay and Congenital Malformations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The females in our study have a specific phenotype that includes ID/developmental delay (DD), characteristic facial features, short stature, and distinct congenital malformations comprising choanal atresia, anal abnormalities, post-axial polydactyly, heart defects, hypomastia, cleft palate/bifid uvula, progressive scoliosis, and structural brain abnormalities."
    explanation: Defines the extra-neural malformation constellation modelled at this
      node.
  - reference: PMID:33298948
    reference_title: Missense variant contribution to USP9X-female syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "were similar between males and females, males were unlikely to have congenital presentations including skeletal and heart defects, among others"
    explanation: The male-female contrast that establishes this branch as
      female-entity-defining rather than shared USP9X biology.
phenotypes:
- name: Intellectual Disability
  category: Neurologic
  description: >
    Intellectual disability is present in essentially every assessed affected
    female, but severity spans the full range from borderline to severe, and
    the disorder cannot be excluded on the basis of mild impairment.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:33298948
    reference_title: Missense variant contribution to USP9X-female syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "was present in all individuals where assessed, but was variable, ranging from borderline to severe"
    explanation: >
      Supports both the association and the VERY_FREQUENT band ("in all
      individuals where assessed"); the band is set to VERY_FREQUENT rather than
      OBLIGATE because the statement is qualified by "where assessed" and refers
      to the 12-individual missense/in-frame-deletion sub-cohort.
  - reference: PMID:40751225
    reference_title: 'c.7156C > T p.(Gln2386*) variant causes loss-of-function of the
      USP9X gene in a female-restricted X-linked syndromic intellectual disability:
      a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is characterized by developmental delays, behavioral alterations, and moderate-to-severe intellectual disability."
    explanation: Independent characterisation of intellectual disability as a core
      feature of the named entity.
- name: Global Developmental Delay
  category: Neurologic
  description: >
    Psychomotor developmental delay is the presenting complaint that leads to
    ascertainment in essentially all cases, and is the feature on which the
    founding cohorts were assembled.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:33298948
    reference_title: Missense variant contribution to USP9X-female syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All females in our missense and single amino acid deletion cohort (n = 12) were ascertained primarily on the basis of psychomotor developmental delay"
    explanation: >
      Supports the association and, for that cohort, universality; VERY_FREQUENT
      is used because ascertainment on delay makes 100% partly circular.
  - reference: PMID:30828969
    reference_title: Female-restricted syndromic intellectual disability in a patient
      from Thailand.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Female-restricted syndromic intellectual disability (ID) is a neurodevelopmental disorder with developmental delay (DD)/ID, facial dysmorphism, and diverse congenital anomalies comprising heart defects, anal anomalies, choanal atresia, postaxial polydactyly, scoliosis, and brain abnormalities."
    explanation: Independent statement placing developmental delay in the core
      definition of the entity.
- name: Delayed Speech and Language Development
  category: Neurologic
  description: >
    Speech and language impairment is universal in reported cohorts and ranges
    from mild expressive delay to complete absence of speech. It is often
    disproportionate to the overall cognitive level and is a primary target for
    early intervention.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:33298948
    reference_title: Missense variant contribution to USP9X-female syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All individuals displayed problems with speech and language, the severity of which was also across a wide spectrum, ranging from somewhat innocuous delay through to complete absence."
    explanation: Supports the association and the VERY_FREQUENT band ("All
      individuals") within the 12-individual cohort described.
- name: Hypotonia
  category: Neurologic
  description: >
    Generalised hypotonia is the usual substrate of the motor disability, which
    ranges from unreported to a need for standing supports or a wheelchair.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  frequency: FREQUENT
  evidence:
  - reference: PMID:40751225
    reference_title: 'c.7156C > T p.(Gln2386*) variant causes loss-of-function of the
      USP9X gene in a female-restricted X-linked syndromic intellectual disability:
      a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "short stature (53%), hip dysplasia (47%), hypotonia (47%), and leg length discrepancy (41%)"
    explanation: Hypotonia in 47% of the Reijnders cohort, which maps to FREQUENT (30-79%).
  - reference: PMID:33298948
    reference_title: Missense variant contribution to USP9X-female syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There was also variable effects on the development of motor function, ranging from unreported to severe disability, which in two individuals required standing supports or wheel chairs. Motor disability was most frequently related to hypotonia"
    explanation: Attributes the motor disability specifically to hypotonia. Frequency
      omitted - "most frequently related to" quantifies the attribution, not the
      prevalence of hypotonia itself.
- name: Motor Delay
  category: Neurologic
  description: >
    Delayed acquisition of gross and fine motor milestones, variable in degree
    and frequently accompanied by hypotonia.
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
  evidence:
  - reference: PMID:41240171
    reference_title: A rare variant of USP9X associated with female-restricted X-linked
      syndromic intellectual disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Loss-of-function mutations in USP9X gene is primarily characterized by development delay, speech and motor disorders, special facial features and multiple congenital malformations."
    explanation: Places motor impairment in the core characterisation of MRXS99F.
- name: Agenesis of the Corpus Callosum
  category: Neurologic
  description: >
    Complete agenesis or hypoplasia of the corpus callosum is the single most
    characteristic structural brain finding and is the anatomical correlate of
    the impaired TGF-beta-dependent commissural axonogenesis modelled in the
    pathophysiology.
  phenotype_term:
    preferred_term: Agenesis of corpus callosum
    term:
      id: HP:0001274
      label: Agenesis of corpus callosum
  evidence:
  - reference: PMID:33298948
    reference_title: Missense variant contribution to USP9X-female syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All individuals presented with brain malformations, most frequently agenesis of the corpus callosum and ventriculomegaly"
    explanation: Identifies callosal agenesis as the most frequent brain malformation
      in the cohort.
  - reference: PMID:40751225
    reference_title: 'c.7156C > T p.(Gln2386*) variant causes loss-of-function of the
      USP9X gene in a female-restricted X-linked syndromic intellectual disability:
      a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional tests revealed structural anomalies, such as corpus callosum agenesis and congenital hip dysplasia."
    explanation: Independent case-level confirmation.
- name: Hypoplasia of the Corpus Callosum
  category: Neurologic
  description: >
    A partial form of the same commissural defect; thin or hypoplastic corpus
    callosum is reported both in affected females and in Usp9x-deficient mice.
  phenotype_term:
    preferred_term: Hypoplasia of the corpus callosum
    term:
      id: HP:0002079
      label: Hypoplasia of the corpus callosum
  frequency: FREQUENT
  evidence:
  - reference: PMID:40751225
    reference_title: 'c.7156C > T p.(Gln2386*) variant causes loss-of-function of the
      USP9X gene in a female-restricted X-linked syndromic intellectual disability:
      a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "enlarged ventricles (73%), dental abnormalities (71%), scoliosis (65%), pigmentary abnormalities along Blaschko’s lines (65%), hypoplastic corpus callosum (62%)"
    explanation: Hypoplastic corpus callosum in 62% of the Reijnders cohort, which maps
      to FREQUENT (30-79%).
  - reference: PMID:30997057
    reference_title: Whole-exome sequencing reveals novel USP9X variant in female fetus
      with isolated agenesis of the corpus callosum.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additionally, over half of described females with loss‐of‐function variants in USP9X have a hypoplastic corpus callosum."
    explanation: Independent corroboration that the callosal anomaly affects more than
      half of reported females, consistent with the FREQUENT band.
  - reference: PMID:33298948
    reference_title: Missense variant contribution to USP9X-female syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "provides a strong recapitulation of the neurological phenotypes of these affected females, including hypoplastic corpus callosum, ventriculomegaly, and learning and memory problems"
    explanation: Names hypoplastic corpus callosum among the neurological phenotypes
      of affected females.
- name: Ventriculomegaly
  category: Neurologic
  description: >
    Enlargement of the cerebral ventricles, frequently accompanying the callosal
    anomaly, and reported together with prominent extra-axial spaces.
  phenotype_term:
    preferred_term: Ventriculomegaly
    term:
      id: HP:0002119
      label: Ventriculomegaly
  frequency: FREQUENT
  evidence:
  - reference: PMID:40751225
    reference_title: 'c.7156C > T p.(Gln2386*) variant causes loss-of-function of the
      USP9X gene in a female-restricted X-linked syndromic intellectual disability:
      a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "enlarged ventricles (73%), dental abnormalities (71%), scoliosis (65%), pigmentary abnormalities along Blaschko’s lines (65%), hypoplastic corpus callosum (62%)"
    explanation: >
      Restates the Reijnders 17-female cohort frequencies numerically: enlarged
      ventricles in 73%, which maps to FREQUENT (30-79%).
  - reference: PMID:33298948
    reference_title: Missense variant contribution to USP9X-female syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All individuals presented with brain malformations, most frequently agenesis of the corpus callosum and ventriculomegaly"
    explanation: Names ventriculomegaly as one of the two most frequent brain
      malformations.
- name: Dandy-Walker Malformation
  category: Neurologic
  description: >
    A posterior-fossa malformation reported in a subset of affected females,
    alongside Blake's pouch cyst; part of the broader spectrum of structural
    brain abnormality rather than a constant feature.
  phenotype_term:
    preferred_term: Dandy-Walker malformation
    term:
      id: HP:0001305
      label: Dandy-Walker malformation
  evidence:
  - reference: PMID:33298948
    reference_title: Missense variant contribution to USP9X-female syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dandy Walker malformation and Blake's pouch cyst in Female 26"
    explanation: Documents Dandy-Walker malformation in a specific affected female;
      frequency omitted because this is a single-individual observation.
- name: Optic Atrophy
  category: Ophthalmologic
  description: >
    Optic nerve atrophy reported on neuroimaging in an affected female; part of
    the visual-system involvement of the syndrome.
  phenotype_term:
    preferred_term: Optic atrophy
    term:
      id: HP:0000648
      label: Optic atrophy
  evidence:
  - reference: PMID:33298948
    reference_title: Missense variant contribution to USP9X-female syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "optic nerve atrophy and in Female 25"
    explanation: Documents optic nerve atrophy in a specific affected female;
      frequency omitted as a single-individual observation.
- name: Abnormal Facial Shape
  category: Craniofacial
  description: >
    A recognisable facial gestalt is present in almost all affected females and
    is consistent enough that it has prompted targeted USP9X testing. Reported
    components include deep-set eyes, telecanthus, blepharophimosis, a broad
    nasal tip with wide alae and short columella, low-set and dysplastic ears, a
    small mouth and micrognathia.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:33298948
    reference_title: Missense variant contribution to USP9X-female syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Facial dysmorphisms were prevalent in almost all individuals, and was in close alignment with previously reported individuals with USP9X-female syndrome, with common features including deep-set eyes, telecanthus, blepharophimosis, broad nasal tip with wide alae and short collumnella, low set and dysplastic ears, small mouth and micrognathia"
    explanation: '"prevalent in almost all individuals" maps to VERY_FREQUENT
      (80-99%) under the project frequency-mapping table, and the sentence also
      enumerates the constituent features.'
- name: Deeply Set Eye
  category: Craniofacial
  description: Deep-set eyes, one of the recurrent components of the facial gestalt.
  phenotype_term:
    preferred_term: Deeply set eye
    term:
      id: HP:0000490
      label: Deeply set eye
  evidence:
  - reference: PMID:33298948
    reference_title: Missense variant contribution to USP9X-female syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with common features including deep-set eyes, telecanthus, blepharophimosis"
    explanation: Lists deep-set eyes among the common facial features.
- name: Telecanthus
  category: Craniofacial
  description: Increased distance between the inner canthi, a recurrent component of
    the facial gestalt.
  phenotype_term:
    preferred_term: Telecanthus
    term:
      id: HP:0000506
      label: Telecanthus
  evidence:
  - reference: PMID:33298948
    reference_title: Missense variant contribution to USP9X-female syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with common features including deep-set eyes, telecanthus, blepharophimosis"
    explanation: Lists telecanthus among the common facial features.
- name: Blepharophimosis
  category: Craniofacial
  description: Horizontally narrowed palpebral fissures, a recurrent component of the
    facial gestalt.
  phenotype_term:
    preferred_term: Blepharophimosis
    term:
      id: HP:0000581
      label: Blepharophimosis
  evidence:
  - reference: PMID:33298948
    reference_title: Missense variant contribution to USP9X-female syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with common features including deep-set eyes, telecanthus, blepharophimosis"
    explanation: Lists blepharophimosis among the common facial features.
- name: Micrognathia
  category: Craniofacial
  description: Small mandible, reported together with a small mouth as part of the
    facial gestalt.
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  evidence:
  - reference: PMID:33298948
    reference_title: Missense variant contribution to USP9X-female syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "low set and dysplastic ears, small mouth and micrognathia"
    explanation: Lists micrognathia among the common facial features.
- name: Low-Set Ears
  category: Craniofacial
  description: Low-set and dysplastic ears, part of the recurrent facial gestalt.
  phenotype_term:
    preferred_term: Low-set ears
    term:
      id: HP:0000369
      label: Low-set ears
  evidence:
  - reference: PMID:33298948
    reference_title: Missense variant contribution to USP9X-female syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "low set and dysplastic ears, small mouth and micrognathia"
    explanation: Lists low-set, dysplastic ears among the common facial features.
- name: Hypertelorism
  category: Craniofacial
  description: >
    Increased interpupillary distance, listed among the craniofacial
    dysmorphisms typical of the syndrome in the infant-onset literature.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: PMID:41240171
    reference_title: A rare variant of USP9X associated with female-restricted X-linked
      syndromic intellectual disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected individuals typically exhibit a spectrum of congenital anomalies, including craniofacial dysmorphisms (such as hypertelorism, flat nasal bridge, and cleft palate)"
    explanation: Lists hypertelorism among the typical craniofacial dysmorphisms.
- name: Cleft Palate
  category: Craniofacial
  description: >
    Cleft palate, or its microform bifid uvula, is one of the defining
    congenital malformations of the syndrome.
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  evidence:
  - reference: PMID:26833328
    reference_title: De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific
      Recognizable Syndrome with Developmental Delay and Congenital Malformations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "post-axial polydactyly, heart defects, hypomastia, cleft palate/bifid uvula, progressive scoliosis"
    explanation: Cleft palate is named in the founding syndrome definition.
- name: Bifid Uvula
  category: Craniofacial
  description: A submucous-cleft microform of the palatal defect.
  phenotype_term:
    preferred_term: Bifid uvula
    term:
      id: HP:0000193
      label: Bifid uvula
  evidence:
  - reference: PMID:26833328
    reference_title: De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific
      Recognizable Syndrome with Developmental Delay and Congenital Malformations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cleft palate/bifid uvula, progressive scoliosis"
    explanation: Bifid uvula is named in the founding syndrome definition.
- name: Choanal Atresia
  category: Craniofacial
  description: >
    Bony or membranous occlusion of the posterior nasal aperture. One of the
    most distinctive malformations of this syndrome; when bilateral it is a
    neonatal airway emergency, which makes it the single most clinically urgent
    feature to recognise.
  phenotype_term:
    preferred_term: Choanal atresia
    term:
      id: HP:0000453
      label: Choanal atresia
  evidence:
  - reference: PMID:26833328
    reference_title: De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific
      Recognizable Syndrome with Developmental Delay and Congenital Malformations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "distinct congenital malformations comprising choanal atresia, anal abnormalities, post-axial polydactyly, heart defects"
    explanation: Choanal atresia heads the list of defining congenital malformations.
  - reference: PMID:30828969
    reference_title: Female-restricted syndromic intellectual disability in a patient
      from Thailand.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "diverse congenital anomalies comprising heart defects, anal anomalies, choanal atresia, postaxial polydactyly, scoliosis, and brain abnormalities"
    explanation: Independent restatement of the malformation constellation including
      choanal atresia.
- name: Abnormality of the Anus
  category: Gastrointestinal
  description: >
    Anal anomalies, including anteriorly placed or imperforate anus, are part of
    the defining malformation set and require examination at birth.
  phenotype_term:
    preferred_term: Abnormality of the anus
    term:
      id: HP:0004378
      label: Abnormality of the anus
  evidence:
  - reference: PMID:26833328
    reference_title: De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific
      Recognizable Syndrome with Developmental Delay and Congenital Malformations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "choanal atresia, anal abnormalities, post-axial polydactyly"
    explanation: Anal abnormality is named in the founding syndrome definition; the
      generic HPO anus term is used because the source says "anal abnormalities"
      without specifying atresia.
- name: Postaxial Polydactyly
  category: Skeletal
  description: >
    Extra digit(s) on the ulnar or fibular side of the limb, one of the defining
    congenital malformations and part of the reason the syndrome was initially
    compared with ciliopathies.
  phenotype_term:
    preferred_term: Postaxial polydactyly
    term:
      id: HP:0100259
      label: Postaxial polydactyly
  evidence:
  - reference: PMID:26833328
    reference_title: De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific
      Recognizable Syndrome with Developmental Delay and Congenital Malformations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "anal abnormalities, post-axial polydactyly, heart defects, hypomastia"
    explanation: Postaxial polydactyly is named in the founding syndrome definition.
- name: Abnormal Heart Morphology
  category: Cardiovascular
  description: >
    Structural congenital heart defects occur in a substantial minority and are
    not trivial - a cardiac defect caused neonatal death in one reported
    individual. Echocardiography is therefore warranted at diagnosis.
  phenotype_term:
    preferred_term: Abnormal heart morphology
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:26833328
    reference_title: De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific
      Recognizable Syndrome with Developmental Delay and Congenital Malformations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "post-axial polydactyly, heart defects, hypomastia, cleft palate/bifid uvula"
    explanation: Heart defects are named in the founding syndrome definition.
  - reference: PMID:33298948
    reference_title: Missense variant contribution to USP9X-female syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "and heart defects, the latter of which resulted in neonatal lethality in one case"
    explanation: Establishes that the cardiac involvement can be lethal, which is what
      makes cardiac screening actionable.
- name: Scoliosis
  category: Skeletal
  description: >
    Scoliosis is characteristically progressive, which distinguishes it from
    incidental curvature and mandates serial spinal monitoring through growth.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
    clinical_course: PROGRESSIVE
  frequency: FREQUENT
  evidence:
  - reference: PMID:40751225
    reference_title: 'c.7156C > T p.(Gln2386*) variant causes loss-of-function of the
      USP9X gene in a female-restricted X-linked syndromic intellectual disability:
      a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "enlarged ventricles (73%), dental abnormalities (71%), scoliosis (65%), pigmentary abnormalities along Blaschko’s lines (65%), hypoplastic corpus callosum (62%)"
    explanation: Scoliosis in 65% of the Reijnders cohort, which maps to FREQUENT (30-79%).
  - reference: PMID:26833328
    reference_title: De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific
      Recognizable Syndrome with Developmental Delay and Congenital Malformations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cleft palate/bifid uvula, progressive scoliosis, and structural brain abnormalities"
    explanation: The founding cohort describes the scoliosis specifically as
      progressive.
  - reference: PMID:30828969
    reference_title: Female-restricted syndromic intellectual disability in a patient
      from Thailand.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "congenital malformations including s-shaped thoracolumbar scoliosis, hip dislocation, and generalized brain atrophy"
    explanation: Independent case-level confirmation of scoliosis and hip involvement.
- name: Congenital Hip Dislocation
  category: Skeletal
  description: >
    Hip dysplasia or frank dislocation is recurrent and, like scoliosis, is a
    reason for orthopaedic surveillance from infancy.
  phenotype_term:
    preferred_term: Congenital hip dislocation
    term:
      id: HP:0001374
      label: Congenital hip dislocation
  frequency: FREQUENT
  evidence:
  - reference: PMID:40751225
    reference_title: 'c.7156C > T p.(Gln2386*) variant causes loss-of-function of the
      USP9X gene in a female-restricted X-linked syndromic intellectual disability:
      a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "short stature (53%), hip dysplasia (47%), hypotonia (47%), and leg length discrepancy (41%)"
    explanation: Hip dysplasia in 47% of the Reijnders cohort, which maps to FREQUENT
      (30-79%).
  - reference: PMID:30828969
    reference_title: Female-restricted syndromic intellectual disability in a patient
      from Thailand.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "s-shaped thoracolumbar scoliosis, hip dislocation, and generalized brain atrophy"
    explanation: Documents hip dislocation in an affected female.
  - reference: PMID:40751225
    reference_title: 'c.7156C > T p.(Gln2386*) variant causes loss-of-function of the
      USP9X gene in a female-restricted X-linked syndromic intellectual disability:
      a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "structural anomalies, such as corpus callosum agenesis and congenital hip dysplasia"
    explanation: Independent case-level confirmation of congenital hip dysplasia.
- name: Short Stature
  category: Growth
  description: >
    Short stature is part of the founding syndrome definition. Notably it was
    the single feature that did NOT overlap cleanly between the null-allele and
    missense/in-frame-deletion female cohorts, so it should not be treated as a
    required feature.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  frequency: FREQUENT
  evidence:
  - reference: PMID:40751225
    reference_title: 'c.7156C > T p.(Gln2386*) variant causes loss-of-function of the
      USP9X gene in a female-restricted X-linked syndromic intellectual disability:
      a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "short stature (53%), hip dysplasia (47%), hypotonia (47%), and leg length discrepancy (41%)"
    explanation: Short stature in 53% of the Reijnders cohort, which maps to FREQUENT
      (30-79%).
  - reference: PMID:26833328
    reference_title: De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific
      Recognizable Syndrome with Developmental Delay and Congenital Malformations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characteristic facial features, short stature, and distinct congenital malformations"
    explanation: Short stature is named in the founding syndrome definition.
  - reference: PMID:33298948
    reference_title: Missense variant contribution to USP9X-female syndrome.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Sankey plot highlights overlap across all features except short stature."
    explanation: >
      Qualifies the feature - short stature is the one feature that did not
      overlap between the two female allele-class cohorts, so the FREQUENT band
      above is asserted for the null-allele (Reijnders) cohort only and should
      not be generalised across allele classes.
- name: Breast Hypoplasia
  category: Endocrine
  description: >
    Hypomastia is an unusual and therefore diagnostically useful feature of this
    syndrome. Asymmetric breast development is also reported and is attributed
    to the same tissue-level mosaicism of USP9X dosage that produces the
    Blaschko-linear pigmentation.
  phenotype_term:
    preferred_term: Breast hypoplasia
    term:
      id: HP:0003187
      label: Breast hypoplasia
  evidence:
  - reference: PMID:26833328
    reference_title: De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific
      Recognizable Syndrome with Developmental Delay and Congenital Malformations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "heart defects, hypomastia, cleft palate/bifid uvula"
    explanation: Hypomastia is named in the founding syndrome definition.
- name: Abnormality of Skin Pigmentation
  category: Dermatologic
  description: >
    Streaky pigmentary change following the lines of Blaschko. Combined with
    developmental delay and congenital anomalies in a girl, this is a strong
    pointer to USP9X and can justify targeted testing.
  phenotype_term:
    preferred_term: Abnormality of skin pigmentation
    term:
      id: HP:0001000
      label: Abnormality of skin pigmentation
  frequency: FREQUENT
  evidence:
  - reference: PMID:40751225
    reference_title: 'c.7156C > T p.(Gln2386*) variant causes loss-of-function of the
      USP9X gene in a female-restricted X-linked syndromic intellectual disability:
      a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "enlarged ventricles (73%), dental abnormalities (71%), scoliosis (65%), pigmentary abnormalities along Blaschko’s lines (65%), hypoplastic corpus callosum (62%)"
    explanation: Pigmentary abnormalities along Blaschko's lines in 65% of the Reijnders
      cohort, which maps to FREQUENT (30-79%).
  - reference: PMID:26833328
    reference_title: De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific
      Recognizable Syndrome with Developmental Delay and Congenital Malformations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In several females, pigment changes along Blaschko lines and body asymmetry were observed"
    explanation: Documents the Blaschko-linear pigmentary phenotype in the founding
      cohort.
  - reference: PMID:31666975
    reference_title: Novel USP9X variants in two patients with X-linked intellectual
      disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we report two female patients with intellectual disability and pigment abnormalities along Blaschko lines"
    explanation: Independent replication in two further USP9X-variant females.
- name: Hearing Impairment
  category: Otologic
  description: >
    Hearing loss was described as a prominent feature of the female cohort and
    is an actionable one, because uncorrected hearing loss compounds the
    speech-language impairment that is already near-universal.
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:33298948
    reference_title: Missense variant contribution to USP9X-female syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hearing loss was a prominent feature"
    explanation: >
      Establishes the association. Frequency omitted - "prominent feature" is not
      mappable to a FrequencyEnum band under the project mapping table.
- name: Autistic Behavior
  category: Behavioral
  description: >
    Autism spectrum behaviour is one of several behavioural disturbances
    reported, alongside anxiety and aggression.
  phenotype_term:
    preferred_term: Autistic behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  evidence:
  - reference: PMID:33298948
    reference_title: Missense variant contribution to USP9X-female syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "individuals displayed a number of different behavioural disturbances including autism, anxiety and aggression"
    explanation: Names autism among the behavioural features of affected females.
- name: Anxiety
  category: Behavioral
  description: Anxiety reported among the behavioural disturbances of affected females.
  phenotype_term:
    preferred_term: Anxiety
    term:
      id: HP:0000739
      label: Anxiety
  evidence:
  - reference: PMID:33298948
    reference_title: Missense variant contribution to USP9X-female syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "behavioural disturbances including autism, anxiety and aggression"
    explanation: Names anxiety among the behavioural features.
- name: Aggressive Behavior
  category: Behavioral
  description: Aggression reported among the behavioural disturbances of affected females.
  phenotype_term:
    preferred_term: Aggressive behavior
    term:
      id: HP:0000718
      label: Aggressive behavior
  evidence:
  - reference: PMID:33298948
    reference_title: Missense variant contribution to USP9X-female syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "behavioural disturbances including autism, anxiety and aggression"
    explanation: Names aggression among the behavioural features.
- name: Abnormality of the Dentition
  category: Craniofacial
  description: >
    Dental anomalies - hypodontia and severe crowding in particular - are among
    the most frequent features of the syndrome, reported in 71% of the founding
    cohort, yet are easy to overlook because they are not life-threatening.
    Their frequency justifies routine dental and orthodontic review.
  phenotype_term:
    preferred_term: Abnormality of the dentition
    term:
      id: HP:0000164
      label: Abnormality of the dentition
  frequency: FREQUENT
  evidence:
  - reference: PMID:40751225
    reference_title: 'c.7156C > T p.(Gln2386*) variant causes loss-of-function of the
      USP9X gene in a female-restricted X-linked syndromic intellectual disability:
      a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "enlarged ventricles (73%), dental abnormalities (71%), scoliosis (65%), pigmentary abnormalities along Blaschko’s lines (65%), hypoplastic corpus callosum (62%)"
    explanation: Dental abnormalities in 71% of the Reijnders cohort, which maps to
      FREQUENT (30-79%).
  - reference: PMID:30828969
    reference_title: Female-restricted syndromic intellectual disability in a patient
      from Thailand.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We have observed severely malformed oro-dental organs and a choledochal cyst, which have never been reported."
    explanation: Case-level documentation of severe oro-dental malformation.
- name: Lower Limb Asymmetry
  category: Skeletal
  description: >
    Leg-length discrepancy and lower-limb asymmetry, reported in 41% of the
    founding cohort. Mechanistically this belongs with the Blaschko-linear
    pigmentation and breast asymmetry as a manifestation of tissue-level
    mosaicism in USP9X dosage, rather than with the bilateral midline
    malformations.
  phenotype_term:
    preferred_term: Lower limb asymmetry
    term:
      id: HP:0100559
      label: Lower limb asymmetry
  frequency: FREQUENT
  evidence:
  - reference: PMID:40751225
    reference_title: 'c.7156C > T p.(Gln2386*) variant causes loss-of-function of the
      USP9X gene in a female-restricted X-linked syndromic intellectual disability:
      a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "short stature (53%), hip dysplasia (47%), hypotonia (47%), and leg length discrepancy (41%)"
    explanation: Leg-length discrepancy in 41% of the Reijnders cohort, which maps to
      FREQUENT (30-79%).
  - reference: PMID:26833328
    reference_title: De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific
      Recognizable Syndrome with Developmental Delay and Congenital Malformations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "pigment changes along Blaschko lines and body asymmetry were observed, which is probably related to differential (escape from) X-inactivation between tissues"
    explanation: Places body asymmetry, of which limb asymmetry is an instance, in the
      mosaic-X-inactivation-escape category.
- name: Seizure
  category: Neurologic
  description: >
    Epilepsy is described in the infant-presentation literature as part of the
    neurological deficit spectrum of MRXS99F. It is not a constant feature and
    no frequency estimate is available for the female cohort.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:41240171
    reference_title: A rare variant of USP9X associated with female-restricted X-linked
      syndromic intellectual disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "neurological deficits (including severe intellectual disability, epilepsy, and motor delay)"
    explanation: Places epilepsy in the reported spectrum of MRXS99F; frequency
      omitted for want of a quantitative source.
genetic:
- name: USP9X
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: USP9X
    term:
      id: hgnc:12632
      label: USP9X
  notes: >
    USP9X (Xp11.4; ubiquitin specific peptidase 9 X-linked; formerly FAM, DFFRX)
    encodes a 2570-amino-acid substrate-specific deubiquitinase with a central
    ubiquitin-C-hydrolase (UCH) catalytic domain flanked by long N- and
    C-terminal substrate-recognition extensions. Reference transcript
    NM_001039590.2 / NP_001034679.2.

    Allelic spectrum in FEMALES with this entity: predominantly de novo complete
    loss-of-function - whole and partial gene deletions, nonsense, and early
    frameshift alleles - with missense and single-amino-acid in-frame deletions
    also established as pathogenic. Five of the eleven missense/in-frame
    variants characterised by Jolly et al. lay in the UCH catalytic domain, with
    structural modelling predicting disrupted catalysis and/or ubiquitin
    binding; the remainder lay in the N-terminal extension of largely unknown
    function. Mechanism is haploinsufficiency (loss of dosage). No
    gain-of-function mechanism is established; whether N-terminal female
    missense alleles retain residual function or act as dominant negatives is
    explicitly unresolved.

    Inheritance is de novo in the large majority. Two exceptions are documented
    and matter for counselling: transmission from a germline-mosaic mother, and
    transmission of a catalytic-domain missense allele from a non-mosaic,
    clinically unaffected mother - implying an unidentified penetrance modifier.
    Maternal testing is therefore indicated for recurrence-risk estimation even
    when a variant appears de novo.

    ENTITY BOUNDARY: the SAME gene causes MONDO:0010487 / OMIM:300919 (MRX99) in
    hemizygous males via partial-loss-of-function missense alleles. That is a
    different disease entry and is not curated here.
  evidence:
  - reference: PMID:26833328
    reference_title: De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific
      Recognizable Syndrome with Developmental Delay and Congenital Malformations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report 17 females with de novo loss-of-function mutations in USP9X, encoding a highly conserved deubiquitinating enzyme."
    explanation: Gene-discovery cohort establishing the gene-disease relationship for
      the female entity.
  - reference: PMID:33298948
    reference_title: Missense variant contribution to USP9X-female syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we provide evidence of the contribution of USP9X missense and small in-frame deletion variants in USP9X-female syndrome also."
    explanation: Extends the causal allelic spectrum beyond null alleles to missense
      and in-frame deletions.
  - reference: PMID:33298948
    reference_title: Missense variant contribution to USP9X-female syndrome.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "Combined application of variant prediction algorithms, protein structure modelling, and assessment under clinically relevant guidelines universally support their pathogenicity."
    explanation: >
      In-silico and structural support for the missense allele class. Classified
      COMPUTATIONAL because the pathogenicity assessment reported here is
      predictive/structural modelling, not a functional assay.
  - reference: PMID:33638286
    reference_title: 'Novel USP9X variant associated with syndromic intellectual disability
      in a female: A case study and review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heterozygous variants in USP9X are associated with female-restricted X-linked mental retardation (MRXS99F), a rare syndrome characterized by neurodevelopmental delay, intellectual disability (ID), and a wide variety of additional congenital anomalies."
    explanation: Independent statement binding USP9X to the MRXS99F entity curated
      here.
  - reference: CGGV:assertion_bd411e83-8373-44b7-8ad5-00894c873880-2021-11-17T110000.000Z
    reference_title: ClinGen Gene-Disease Validity assertion, USP9X - X-linked syndromic
      intellectual disability (Definitive, 2021-11-17)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "USP9X | HGNC:12632 | X-linked syndromic intellectual disability | MONDO:0020119 | XL | Definitive | SOP8 | Intellectual Disability and Autism Gene Curation Expert Panel"
    explanation: >
      ClinGen classifies the USP9X gene-disease relationship as Definitive. Cited
      for the gene-disease relationship ONLY: the assertion's disease anchor is
      the broader MONDO:0020119, because ClinGen's Intellectual Disability and
      Autism GCEP deliberately lumps the male and female USP9X disorders into a
      single curation, whereas this entry follows the OMIM/MONDO split
      (MONDO:0010502 female / MONDO:0010487 male). Its "XL" MOI label is
      likewise not adopted here - see the inheritance block. evidence_source is
      OTHER because the record is an expert-panel synthesis, not a primary study.
  - reference: CGGV:assertion_bd411e83-8373-44b7-8ad5-00894c873880-2021-11-17T110000.000Z
    reference_title: ClinGen Gene-Disease Validity assertion, USP9X - X-linked syndromic
      intellectual disability (Definitive, 2021-11-17)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The USP9X variants in females are predominantly null alleles leading to haploinsufficiency and causing a recognizable syndrome with intellectual disability and characteristic brain and congenital abnormalities"
    explanation: >
      ClinGen's own evidence summary states the female allelic spectrum and
      mechanism curated here (null alleles, haploinsufficiency), and - in the
      sentence immediately following - contrasts it with the predominantly
      missense, partial-loss-of-function male spectrum. Even while lumping the
      two presentations administratively, ClinGen describes the same
      allele-class boundary this entry uses to separate the entities.
variants:
- name: USP9X p.Trp380Ter
  description: >
    A de novo nonsense allele at the severe end of the female spectrum -
    severe intellectual disability, absent speech and severe motor disability.
    Paired below with p.Ile535Asnfs*11 to show that allele class alone does not
    predict severity.
  gene:
    preferred_term: USP9X
    term:
      id: hgnc:12632
      label: USP9X
  type: NONSENSE
  evidence:
  - reference: PMID:33298948
    reference_title: Missense variant contribution to USP9X-female syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Female 30 had a de novo nonsense variant (p.Trp380Ter) and presented with severe ID, absent speech and severe motor disability."
    explanation: Documents the severe end of the phenotypic range for a bona fide null
      allele.
- name: USP9X p.Ile535Asnfs*11
  description: >
    A de novo frameshift allele - the same "complete loss-of-function" class as
    p.Trp380Ter - in an individual with only slight delays who is now largely
    meeting developmental milestones. The direct counterexample to any
    assumption that a null allele predicts a severe outcome.
  gene:
    preferred_term: USP9X
    term:
      id: hgnc:12632
      label: USP9X
  type: FRAMESHIFT
  evidence:
  - reference: PMID:33298948
    reference_title: Missense variant contribution to USP9X-female syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Female 32 with a de novo frameshift variant (p.Ile535Asnfs*11) had only slight delays in speech, language and motor skills, and is now largely meeting developmental milestones."
    explanation: Documents the mild end of the range within the same allele class.
- name: USP9X p.Arg215Ter
  description: >
    A maternally inherited nonsense allele identified on genetic autopsy of a
    terminated fetus with brain malformation and heart and skeletal defects. The
    transmitting mother had only a history of scoliosis and partial hearing
    impairment. This allele documents both the lethal-fetal end of the spectrum
    and reduced penetrance in a transmitting heterozygote.
  gene:
    preferred_term: USP9X
    term:
      id: hgnc:12632
      label: USP9X
  type: NONSENSE
  evidence:
  - reference: PMID:33298948
    reference_title: Missense variant contribution to USP9X-female syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "inherited nonsense variant (p.Arg215Ter) was found"
    explanation: >
      Names the allele itself and its inherited (not de novo) origin. Quoted as
      a separate fragment because the source sentence is hyphenated across a
      line break at "follow-ing", which the reference validator does not join,
      so a single continuous quote covering both the allele name and the fetal
      autopsy is not available; the item below supplies the rest of the
      sentence.
  - reference: PMID:33298948
    reference_title: Missense variant contribution to USP9X-female syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the genetic autopsy of Female 31, a terminated foetus with brain malformation, heart and skeletal defects"
    explanation: Documents the fetal-lethal presentation and, with the item above,
      the maternal transmission of a null allele.
- name: USP9X p.Glu1764Lys
  description: >
    A catalytic-domain missense allele inherited from a clinically unaffected,
    non-mosaic mother. Because the daughter has a clear USP9X-female phenotype
    and the mother does not, this is the principal evidence for an unidentified
    penetrance modifier; X-inactivation studies in the daughter showed no
    skewing.
  gene:
    preferred_term: USP9X
    term:
      id: hgnc:12632
      label: USP9X
  type: MISSENSE
  evidence:
  - reference: PMID:33298948
    reference_title: Missense variant contribution to USP9X-female syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A second inherited variant in Female 33 (p.Glu1764Lys) was also passed on from the mother, but intriguingly with no evidence of mosaicism, at least in blood"
    explanation: Documents transmission from a non-mosaic unaffected mother, the basis
      for the penetrance-modifier hypothesis.
- name: USP9X p.Lys296Serfs*4
  description: >
    A truncating allele (c.885_889delAAAAG) segregating in two non-twin female
    siblings with phenotypic resemblance to the syndrome, reported explicitly as
    an incomplete-penetrance observation. X-inactivation, RNA-Seq and quad exome
    analysis failed to identify a modifier.
  gene:
    preferred_term: USP9X
    term:
      id: hgnc:12632
      label: USP9X
  type: FRAMESHIFT
  evidence:
  - reference: PMID:35253988
    reference_title: Exome and RNA-Seq analyses of an incomplete penetrance variant
      in USP9X in female-specific syndromic intellectual disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report a truncating variant, c.885_889delAAAAG, p.(Lys296Serfs*4), in the USP9X gene with incomplete penetrance in two nontwin female siblings with phenotypic resemblance to female-specific syndromic ID"
    explanation: Documents the incomplete-penetrance allele and the failed modifier
      search.
inheritance:
- name: X-linked inheritance with female-restricted expression
  inheritance_term:
    preferred_term: X-linked inheritance
    term:
      id: HP:0001417
      label: X-linked inheritance
  penetrance: INCOMPLETE
  expressivity: VARIABLE
  description: >
    The neutral HPO X-linked term is used deliberately. OMIM annotates this
    entry as "X-linked dominant" and some case reports repeat that label, but
    neither classical X-linked dominant nor X-linked recessive describes the
    biology here.

    It is not conventional X-linked dominance because a hemizygous male is not
    a more severely affected patient but a non-viable conceptus - complete USP9X
    loss is incompatible with early development - so the disorder is restricted
    to heterozygous females by a survivorship filter rather than by a dominance
    relationship between alleles.

    It is not X-linked recessive with manifesting carriers either, because
    USP9X escapes X-inactivation: both alleles are normally expressed, so a
    heterozygous female sustains a true ~50% dosage reduction in every cell
    rather than a mosaic of wild-type and null cells. The residual mosaicism
    that IS observed (Blaschko-linear pigmentation, body asymmetry) reflects
    tissue-variable degree of escape, not classical Lyonisation.

    Penetrance in females is high but incomplete, estimated at approximately
    95%. Variants are de novo in the large majority; documented exceptions
    include a germline-mosaic mother and a non-mosaic clinically unaffected
    transmitting mother, so maternal testing is warranted for recurrence-risk
    counselling. Expressivity is wide, from a terminated fetus with multiple
    malformations to an individual largely meeting milestones, and is not
    predicted by allele class.
  evidence:
  - reference: PMID:33298948
    reference_title: Missense variant contribution to USP9X-female syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "USP9X is an X-chromosome gene that escapes X-inactivation."
    explanation: The escape-from-X-inactivation fact that rules out a standard
      X-linked recessive/manifesting-carrier framing.
  - reference: PMID:33298948
    reference_title: Missense variant contribution to USP9X-female syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One possible candidate is skewing of X-inactivation, but USP9X is known to escape X-inactivation."
    explanation: The authors themselves reject skewed X-inactivation as the
      explanation for variable female expression.
  - reference: PMID:33298948
    reference_title: Missense variant contribution to USP9X-female syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Such LOF alleles are likely to never be observed in a male as complete loss of USP9X, as would be the case of a hemizygous male, is known to result in early embryonic lethality in at least mouse"
    explanation: The survivorship argument that makes the entity female-restricted
      rather than X-linked dominant.
  - reference: PMID:35253988
    reference_title: Exome and RNA-Seq analyses of an incomplete penetrance variant
      in USP9X in female-specific syndromic intellectual disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the penetrance of pathogenic variants in USP9X in female appears to be high (95%) and the variants frequently occur de novo, incomplete penetrance should be considered"
    explanation: Sources both the ~95% penetrance estimate and the predominantly de
      novo origin.
  - reference: CGGV:assertion_bd411e83-8373-44b7-8ad5-00894c873880-2021-11-17T110000.000Z
    reference_title: ClinGen Gene-Disease Validity assertion, USP9X - X-linked syndromic
      intellectual disability (Definitive, 2021-11-17)
    supports: PARTIAL
    evidence_source: OTHER
    snippet: "The gene is located on chromosome X, but it escapes X-chromosome inactivation. Therefore, pathogenic variants in USP9X have been associated with X-linked syndromic intellectual disability in both females and males."
    explanation: >
      Independent expert-panel statement of the escape-from-X-inactivation
      premise underlying this inheritance model. Marked PARTIAL because the same
      record labels the mode of inheritance simply "XL" and lumps the male and
      female presentations, which this entry does not adopt; only the
      XCI-escape clause is used.
prevalence:
- population: Worldwide
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  rate_per_100000: 0.1
  notes: >
    A single quoted estimate of approximately 1 in 1,000,000 live births. This
    is an estimate stated in the introduction of a case report, not the output
    of a population study, and should be treated as an order-of-magnitude figure
    only. It is very likely an underestimate: the entity was delineated only in
    2016, ascertainment depends entirely on exome or genome sequencing, and the
    mild end of the spectrum (an individual largely meeting developmental
    milestones is documented) is systematically under-diagnosed.
  evidence:
  - reference: PMID:40751225
    reference_title: 'c.7156C > T p.(Gln2386*) variant causes loss-of-function of the
      USP9X gene in a female-restricted X-linked syndromic intellectual disability:
      a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "is an ultrarare neurodevelopmental disorder, with an estimated incidence of 1:1,000,000 live births"
    explanation: The only quantitative occurrence estimate available for this disorder.
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >
    No population-based prevalence or incidence estimate exists. The literature
    quantifies the disorder only by cumulative case count: 17 females in the
    founding cohort (2016), rising to an aggregate of 35 females with predicted
    pathogenic USP9X variation by 2020, with individual case reports since from
    Thailand, Japan, Brazil, China and elsewhere. Reported cases show no founder
    effect or geographic clustering; the apparent distribution tracks access to
    trio exome sequencing. The 2025 case-report literature describes the
    disorder as ultrarare.
  evidence:
  - reference: PMID:33298948
    reference_title: Missense variant contribution to USP9X-female syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Aggregate phenotypic information of 35 currently known females with predicted pathogenic variation in USP9X reaffirms the clinically recognisable USP9X-female syndrome"
    explanation: Gives the cumulative case count as of 2020, the only quantification
      available.
  - reference: PMID:40751225
    reference_title: 'c.7156C > T p.(Gln2386*) variant causes loss-of-function of the
      USP9X gene in a female-restricted X-linked syndromic intellectual disability:
      a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Female-restricted X-linked syndromic intellectual developmental disorder-99 is an ultrarare neurodevelopmental disorder linked to X"
    explanation: Contemporary characterisation of the disorder as ultrarare.
diagnosis:
- name: Trio Exome or Genome Sequencing
  description: >
    Molecular testing is definitive; there are no formal clinical diagnostic
    criteria. Trio-based exome or genome sequencing is the appropriate
    first-line test for a girl with unexplained developmental delay plus
    congenital anomalies, and the trio design matters because the large
    majority of variants are de novo. Chromosomal microarray covers the whole-
    and partial-gene deletion fraction, which sequencing may miss. Maternal
    testing should follow even an apparently de novo result, because germline
    mosaicism and non-penetrant maternal transmission are both documented.
  evidence:
  - reference: PMID:40751225
    reference_title: 'c.7156C > T p.(Gln2386*) variant causes loss-of-function of the
      USP9X gene in a female-restricted X-linked syndromic intellectual disability:
      a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Various genetic tests were performed, but only whole exome sequencing revealed a pathogenic variant in the USP9X gene"
    explanation: Demonstrates that exome sequencing succeeded where other genetic
      tests failed in a real diagnostic pathway.
  - reference: PMID:40751225
    reference_title: 'c.7156C > T p.(Gln2386*) variant causes loss-of-function of the
      USP9X gene in a female-restricted X-linked syndromic intellectual disability:
      a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Despite the de novo nature of most loss-of-function variants, maternal testing is crucial for estimating recurrence risk."
    explanation: Sources the maternal-testing recommendation.
  - reference: PMID:41240171
    reference_title: A rare variant of USP9X associated with female-restricted X-linked
      syndromic intellectual disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "reinforces the utility of whole-genome sequencing in early diagnosis and genetic counseling"
    explanation: Supports genome sequencing as a diagnostic route, including in the
      neonatal period.
- name: Phenotype-Directed Targeted USP9X Testing
  description: >
    The gestalt is distinctive enough to be recognised prospectively. In the
    founding cohort four of seventeen females were ascertained by targeted USP9X
    testing because the clinician recognised the phenotype. The combination that
    should trigger this is a girl with developmental delay, the characteristic
    facial features, Blaschko-linear pigmentary change or body asymmetry, and
    one or more of choanal atresia, anal anomaly, postaxial polydactyly or
    hypomastia.
  evidence:
  - reference: PMID:26833328
    reference_title: De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific
      Recognizable Syndrome with Developmental Delay and Congenital Malformations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Four females from our cohort were identified by targeted genetic testing because their phenotype was suggestive for USP9X mutations."
    explanation: Direct evidence that the phenotype is recognisable enough to drive
      targeted testing.
- name: Prenatal Exome Sequencing After Anomalous Ultrasound
  description: >
    Prenatal diagnosis is achievable and has changed management. A USP9X variant
    was identified by whole-exome sequencing in a female fetus whose only
    ultrasound finding was isolated agenesis of the corpus callosum, following a
    normal chromosomal microarray. Because the callosal anomaly affects more
    than half of reported females and is detectable on fetal imaging, USP9X
    belongs on the gene list for prenatal exome sequencing performed for fetal
    corpus callosum anomalies, ventriculomegaly, polydactyly or a cardiac
    defect. Note the ascertainment caveat that follows from this: a fetus
    identified on an isolated imaging finding may lie anywhere on a very wide
    severity spectrum, and the finding does not predict outcome.
  evidence:
  - reference: PMID:30997057
    reference_title: Whole-exome sequencing reveals novel USP9X variant in female fetus
      with isolated agenesis of the corpus callosum.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-exome sequencing in a female fetus detected a USP9X variant. This X-linked gene was recently associated with intellectual disability and distinct pattern of malformation in females."
    explanation: Documents prenatal molecular ascertainment of this entity.
  - reference: PMID:30997057
    reference_title: Whole-exome sequencing reveals novel USP9X variant in female fetus
      with isolated agenesis of the corpus callosum.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Isolated agenesis of the corpus callosum has not been reported in association with USP9X. Identifying this variant impacted management of the subsequent pregnancy."
    explanation: >
      Establishes both the expansion of the prenatal phenotype to isolated
      callosal agenesis and the clinical actionability of the prenatal result.
  - reference: PMID:30997057
    reference_title: Whole-exome sequencing reveals novel USP9X variant in female fetus
      with isolated agenesis of the corpus callosum.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "this report highlights an emerging role of whole‐exome sequencing in cases of ultrasound anomalies following normal chromosomal microarray"
    explanation: States the diagnostic-pathway position of prenatal exome sequencing
      relative to microarray.
differential_diagnoses:
- name: Intellectual disability, X-linked 99 (MRX99, USP9X male entity)
  disease_term:
    preferred_term: intellectual disability, X-linked 99
    term:
      id: MONDO:0010487
      label: intellectual disability, X-linked 99
  description: >
    THE critical distinction for this entry, and the reason the entry carries an
    explicit scope note. Same gene (USP9X), different MONDO entity, different
    OMIM number (300919 versus 300968), different sex, different allele class,
    and a materially different phenotype. Affected males carry hypomorphic
    partial-loss-of-function missense alleles, frequently inherited from
    unaffected mothers; affected females carry de novo complete
    loss-of-function alleles. The two share the core neurological picture -
    global delay, speech and language impairment, hypotonia, thin corpus
    callosum, widened ventricles - but males are largely spared the skeletal,
    cardiac and other congenital malformations that define the female syndrome.
    Because the two literatures are co-published by overlapping author groups
    and routinely cited together, a curation or a clinical summary that blends
    them will silently import male phenotype frequencies and male functional
    data into the female entity. They must be kept separate.
  distinguishing_features:
  - Affects hemizygous males; this entity affects heterozygous females
  - OMIM:300919 / MONDO:0010487 versus OMIM:300968 / MONDO:0010502
  - Hypomorphic missense (partial loss of function) versus complete loss of function
  - Frequently maternally inherited from an unaffected mother versus predominantly de
    novo
  - Congenital skeletal, cardiac, choanal and anal malformations are rare or absent
    in males but definitional in females
  - Blaschko-linear pigmentary mosaicism and body asymmetry are female-specific, being
    a consequence of tissue-variable X-inactivation escape
  evidence:
  - reference: PMID:31443933
    reference_title: Partial Loss of USP9X Function Leads to a Male Neurodevelopmental
      and Behavioral Disorder Converging on Transforming Growth Factor beta Signaling.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our data demonstrate the involvement of USP9X variants in a distinctive neurodevelopmental and behavioral syndrome in male subjects"
    explanation: Establishes the male disorder as a distinct entity in its own right.
  - reference: PMID:33298948
    reference_title: Missense variant contribution to USP9X-female syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "were similar between males and females, males were unlikely to have congenital presentations including skeletal and heart defects, among others"
    explanation: The direct male-versus-female phenotype comparison that separates the
      two entities clinically.
  - reference: PMID:24607389
    reference_title: Mutations in USP9X are associated with X-linked intellectual disability
      and disrupt neuronal cell migration and growth.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Previously, as part of a large systematic resequencing of the X chromosome in 208 unrelated families with nonsyndromic X-linked intellectual disability, we identified three unique variants (two missense and one protein truncating) in USP9X."
    explanation: The original MRX99 ascertainment - nonsyndromic X-linked ID families,
      i.e. an entirely different ascertainment frame from the female syndrome.
  - reference: CGGV:assertion_bd411e83-8373-44b7-8ad5-00894c873880-2021-11-17T110000.000Z
    reference_title: ClinGen Gene-Disease Validity assertion, USP9X - X-linked syndromic
      intellectual disability (Definitive, 2021-11-17)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In contrast, the majority of the reported variants in males are missense variants with partial loss of function, resulting in a distinctive neurodevelopmental and behavioral syndrome"
    explanation: >
      ClinGen states the same male-versus-female allele-class and phenotype
      contrast that this differential rests on, even though its own curation
      administratively lumps the two under one disease anchor
      (MONDO:0020119). Recording it here keeps the lump-versus-split
      disagreement visible at the point where it matters.
- name: CHARGE syndrome
  disease_term:
    preferred_term: CHARGE syndrome
    term:
      id: MONDO:0008965
      label: CHARGE syndrome
  description: >
    The most important non-USP9X differential, because choanal atresia plus
    congenital heart defect plus developmental delay is the classic CHARGE
    triad and is also a common presentation of this syndrome. CHD7 sequencing
    will typically have been sent first. Blaschko-linear pigmentation, body
    asymmetry, hypomastia and postaxial polydactyly point away from CHARGE and
    towards USP9X.
  distinguishing_features:
  - Caused by CHD7 variants, autosomal dominant, not X-linked
  - Coloboma and semicircular canal hypoplasia are cardinal in CHARGE and not features
    of this syndrome
  - Affects both sexes, unlike the female restriction of this entity
  - Lacks Blaschko-linear pigmentary mosaicism and body asymmetry
  evidence:
  - reference: PMID:20301296
    reference_title: CHD7 Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mnemonic CHARGE syndrome, introduced in the premolecular era, stands for coloboma, heart defect, choanal atresia, retarded growth and development, genital hypoplasia, ear anomalies (including deafness)."
    explanation: >
      The GeneReviews CHD7 Disorder chapter establishes the CHARGE feature set.
      Choanal atresia, heart defect and growth/developmental delay are shared
      with this USP9X entity, which is why CHARGE is the leading non-USP9X
      differential; coloboma and genital hypoplasia are the discriminators.
  - reference: PMID:20301296
    reference_title: CHD7 Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CHD7 disorder is an autosomal dominant disorder typically caused by a de novo pathogenic variant."
    explanation: Confirms the autosomal dominant, both-sexes inheritance that separates
      CHARGE from this female-restricted X-linked entity.
- name: Ciliopathy spectrum disorders
  description: >
    Included as a differential precisely because the founding cohort raised it:
    postaxial polydactyly, structural brain malformation and congenital heart
    defect are shared with recognised ciliopathy syndromes, and USP9X was shown
    to localise along the ciliary axoneme. However, ciliary parameters were NOT
    dysregulated in affected-female fibroblasts, so a ciliary mechanism is
    unproven and this remains a phenotypic overlap rather than an established
    mechanistic relationship. Listed here so that a clinician who has excluded
    Bardet-Biedl or Joubert syndrome does not stop the differential there.
  distinguishing_features:
  - Retinal dystrophy and cystic kidney disease, cardinal in many ciliopathies, are
    not features of this syndrome
  - Ciliary parameters are not dysregulated in fibroblasts from affected females
  - Female restriction and Blaschko-linear pigmentation are not ciliopathy features
  evidence:
  - reference: PMID:26833328
    reference_title: De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific
      Recognizable Syndrome with Developmental Delay and Congenital Malformations.
    supports: PARTIAL
    evidence_source: IN_VITRO
    snippet: "Absence of dysregulated ciliary parameters in affected female-derived fibroblasts, however, points toward spatiotemporal specificity of ciliary USP9X (dys-)function."
    explanation: The negative functional result that keeps the ciliopathy relationship
      at the level of phenotypic overlap rather than shared mechanism.
treatments:
- name: Multidisciplinary Supportive and Developmental Care
  description: >
    There is no disease-modifying therapy, no approved drug, no gene therapy and
    no interventional clinical trial for this disorder. Management is entirely
    symptomatic. A mechanistic caution applies to any future substrate- or
    dosage-restoration strategy: in the forebrain Usp9x knockout mouse the
    substrate deficit is transient and normalises by 12 weeks, yet the reduced
    spine density and behavioural phenotype persist into adulthood, implying a
    developmental critical window after which restoring USP9X-dependent
    substrate levels would not be expected to reverse the phenotype.
  treatment_term:
    preferred_term: Supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  therapeutic_modality: OTHER
  evidence:
  - reference: PMID:31813652
    reference_title: Usp9X Controls Ankyrin-Repeat Domain Protein Homeostasis during
      Dendritic Spine Development.
    supports: PARTIAL
    evidence_source: MODEL_ORGANISM
    snippet: "the impairment of which only transiently affects ANKRD protein levels but leads to persistent neuronal, behavioral, and clinical abnormalities"
    explanation: >
      Supports the critical-window caution stated in the description. It does not
      evidence supportive care itself, for which no disorder-specific trial
      exists; hence PARTIAL.
- name: Speech and Language Therapy
  description: >
    Speech and language impairment is universal and can extend to complete
    absence of speech, so early speech therapy with augmentative and alternative
    communication where required is a core intervention. There is no
    disorder-specific trial evidence; the rationale is the near-universality and
    severity of the target impairment.
  treatment_term:
    preferred_term: Speech and language therapy
    term:
      id: NCIT:C159273
      label: Speech Language Therapy
  therapeutic_modality: BEHAVIORAL
  target_phenotypes:
  - preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:33298948
    reference_title: Missense variant contribution to USP9X-female syndrome.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "All individuals displayed problems with speech and language, the severity of which was also across a wide spectrum, ranging from somewhat innocuous delay through to complete absence."
    explanation: Documents the target impairment and its severity range; the
      intervention itself has no disorder-specific evidence base.
- name: Physical and Occupational Therapy
  description: >
    Physiotherapy and occupational therapy address the hypotonia-related motor
    disability, which in some individuals is severe enough to require standing
    supports or a wheelchair. Aims are gait preservation, contracture
    prevention and functional independence.
  treatment_term:
    preferred_term: Physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  therapeutic_modality: BEHAVIORAL
  target_phenotypes:
  - preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:33298948
    reference_title: Missense variant contribution to USP9X-female syndrome.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "ranging from unreported to severe disability, which in two individuals required standing supports or wheel chairs"
    explanation: Documents the severity of the motor target; no disorder-specific
      intervention trial exists.
- name: Neonatal Airway Assessment and Choanal Atresia Repair
  description: >
    Bilateral choanal atresia is a neonatal airway emergency because newborns
    are obligate nasal breathers; it requires urgent recognition and surgical
    repair. Because choanal atresia heads the list of malformations in this
    syndrome, any neonate with the phenotype warrants explicit nasal patency
    assessment. This is the most time-critical intervention in the disorder.
  treatment_term:
    preferred_term: Surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  therapeutic_modality: SURGERY
  target_phenotypes:
  - preferred_term: Choanal atresia
    term:
      id: HP:0000453
      label: Choanal atresia
  evidence:
  - reference: PMID:26833328
    reference_title: De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific
      Recognizable Syndrome with Developmental Delay and Congenital Malformations.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "distinct congenital malformations comprising choanal atresia, anal abnormalities, post-axial polydactyly, heart defects"
    explanation: >
      Establishes choanal atresia as a defining feature requiring assessment.
      The surgical management itself is general paediatric-otolaryngology
      practice with no disorder-specific evidence, hence PARTIAL.
- name: Anorectal Malformation Repair
  description: >
    Anal anomaly is one of the six malformations named in every published
    definition of this syndrome, so the newborn examination must include
    inspection of the anus and assessment of patency and position. An
    imperforate or ectopic anus requires paediatric-surgical correction, with
    the operative approach (anoplasty, or staged repair with a covering
    stoma) determined by the specific anatomy. No USP9X-specific surgical
    series exists; this is standard paediatric-surgical practice applied to a
    malformation whose disorder-specific significance is that it is
    definitional rather than incidental. Note that the published sources say
    "anal abnormalities" without consistently specifying atresia, so this entry
    is scoped to the malformation set as reported rather than to anal atresia
    specifically.
  treatment_term:
    preferred_term: Surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  therapeutic_modality: SURGERY
  target_phenotypes:
  - preferred_term: Abnormality of the anus
    term:
      id: HP:0004378
      label: Abnormality of the anus
  evidence:
  - reference: PMID:26833328
    reference_title: De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific
      Recognizable Syndrome with Developmental Delay and Congenital Malformations.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "distinct congenital malformations comprising choanal atresia, anal abnormalities, post-axial polydactyly, heart defects"
    explanation: >
      Establishes the anal anomaly as a defining feature that must be looked for
      at birth. PARTIAL because the source evidences the malformation, not the
      operative management, for which no disorder-specific evidence exists.
  - reference: PMID:30828969
    reference_title: Female-restricted syndromic intellectual disability in a patient
      from Thailand.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "diverse congenital anomalies comprising heart defects, anal anomalies, choanal atresia, postaxial polydactyly, scoliosis, and brain abnormalities"
    explanation: Independent restatement confirming anal anomaly as part of the
      recurrent malformation set, not a one-off report.
- name: Cleft Palate Repair
  description: >
    Cleft palate, and its submucous microform bifid uvula, is one of the
    defining malformations. Surgical repair follows standard cleft-team
    protocols and is relevant here beyond the palate itself because an unrepaired
    or late-repaired cleft compounds the speech and language impairment that is
    the principal functional disability of this syndrome. Palatal inspection
    including the uvula therefore belongs in the initial evaluation even when
    the cleft is not overt.
  treatment_term:
    preferred_term: Surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  therapeutic_modality: SURGERY
  target_phenotypes:
  - preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  - preferred_term: Bifid uvula
    term:
      id: HP:0000193
      label: Bifid uvula
  evidence:
  - reference: PMID:26833328
    reference_title: De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific
      Recognizable Syndrome with Developmental Delay and Congenital Malformations.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "post-axial polydactyly, heart defects, hypomastia, cleft palate/bifid uvula, progressive scoliosis"
    explanation: >
      Names cleft palate and bifid uvula in the founding syndrome definition.
      PARTIAL because the repair itself is general cleft-team practice with no
      disorder-specific outcome data.
- name: Postaxial Polydactyly Excision
  description: >
    Excision of the supernumerary postaxial digit is the usual management where
    the extra digit is functionless, performed for function and appearance. It
    is included here because postaxial polydactyly is one of the defining
    malformations and, together with the anal and choanal anomalies, is the part
    of the phenotype most likely to be surgically addressed in infancy before
    the syndrome is recognised. No disorder-specific surgical evidence exists.
  treatment_term:
    preferred_term: Orthopedic surgical procedure
    term:
      id: NCIT:C16186
      label: Orthopedic Surgical Procedure
  therapeutic_modality: SURGERY
  target_phenotypes:
  - preferred_term: Postaxial polydactyly
    term:
      id: HP:0100259
      label: Postaxial polydactyly
  evidence:
  - reference: PMID:26833328
    reference_title: De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific
      Recognizable Syndrome with Developmental Delay and Congenital Malformations.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "anal abnormalities, post-axial polydactyly, heart defects, hypomastia"
    explanation: >
      Establishes postaxial polydactyly as a defining feature. PARTIAL because
      the excision itself is general practice with no disorder-specific evidence.
- name: Antiseizure Pharmacotherapy
  description: >
    Epilepsy is reported within the neurological spectrum of this syndrome, so
    seizures should be asked about at every review and investigated with EEG
    when suspected. Treatment is conventional antiseizure medication chosen on
    seizure type: there is no USP9X-specific pharmacological guidance, no
    reported drug of choice and no reported drug to avoid, and no specific agent
    is therefore named here. The mechanistic literature offers no basis for
    extrapolation either: the one report in which manipulating USP9X improves
    seizures used a small-molecule USP9X INHIBITOR in prickle-mutant flies -
    the opposite dosage direction from this haploinsufficiency disorder - so it
    must not be read as a therapeutic suggestion for MRXS99F.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  therapeutic_modality: SMALL_MOLECULE
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:41240171
    reference_title: A rare variant of USP9X associated with female-restricted X-linked
      syndromic intellectual disability.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "neurological deficits (including severe intellectual disability, epilepsy, and motor delay)"
    explanation: >
      Documents epilepsy as a target within the reported spectrum. PARTIAL
      because no disorder-specific antiseizure evidence exists; no
      `therapeutic_agent` is asserted for the same reason.
  - reference: PMID:25763846
    reference_title: Seizures are regulated by ubiquitin-specific peptidase 9 X-linked
      (USP9X), a de-ubiquitinase.
    supports: NO_EVIDENCE
    evidence_source: MODEL_ORGANISM
    snippet: "The seizure phenotype was suppressed in prickle mutant flies by the small-molecule USP9X inhibitor, Degrasyn/WP1130, or by reducing the dose of fat facets a USP9X orthologue."
    explanation: >
      Recorded as a direction-of-effect caution, NOT as support. This is the
      only report linking USP9X manipulation to seizure control, and it works
      by INHIBITING USP9X in a prickle-mutant fly - the opposite dosage
      direction from a haploinsufficiency disorder. Marked NO_EVIDENCE because
      it supplies no evidence for or against antiseizure treatment of MRXS99F
      and must not be extrapolated into one.
- name: Behavioural Intervention for Autism, Anxiety and Aggression
  description: >
    Autism spectrum behaviour, anxiety and aggression are all reported in
    affected females and are managed with standard behavioural and educational
    approaches, adapted to the individual's communication ability. The
    disorder-specific point is that behavioural presentation must be interpreted
    against the near-universal speech and language impairment and the frequent
    hearing loss: apparent behavioural escalation may be an unmet communication
    need, so behavioural intervention should follow, not precede, audiological
    assessment and provision of augmentative communication. No pharmacological
    or behavioural trial data exist for this disorder.
  treatment_term:
    preferred_term: Behavioral counseling
    term:
      id: NCIT:C181743
      label: Behavioral Counseling
  therapeutic_modality: BEHAVIORAL
  target_phenotypes:
  - preferred_term: Autistic behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  - preferred_term: Anxiety
    term:
      id: HP:0000739
      label: Anxiety
  - preferred_term: Aggressive behavior
    term:
      id: HP:0000718
      label: Aggressive behavior
  evidence:
  - reference: PMID:33298948
    reference_title: Missense variant contribution to USP9X-female syndrome.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "individuals displayed a number of different behavioural disturbances including autism, anxiety and aggression"
    explanation: >
      Documents the three behavioural targets in the female cohort. PARTIAL
      because no intervention evidence specific to this disorder exists.
- name: Ophthalmological Assessment and Surveillance
  description: >
    Formal ophthalmological assessment at diagnosis with periodic review. The
    ocular findings reported in affected females span optic nerve atrophy and
    the periorbital dysmorphic features (deeply set eyes, telecanthus,
    blepharophimosis, hypertelorism) that can themselves obstruct visual
    development, and ophthalmology was one of the specialties involved in the
    only published account of real-world multidisciplinary management. As with
    hearing, uncorrected visual impairment compounds a developmental disability
    that is already the dominant functional problem, which is the argument for
    scheduled rather than symptom-driven review. No disorder-specific
    surveillance interval has been studied.
  treatment_term:
    preferred_term: Ophthalmological examination
    term:
      id: NCIT:C38060
      label: Eye Examination
  target_phenotypes:
  - preferred_term: Optic atrophy
    term:
      id: HP:0000648
      label: Optic atrophy
  evidence:
  - reference: PMID:33298948
    reference_title: Missense variant contribution to USP9X-female syndrome.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "optic nerve atrophy and in Female 25"
    explanation: >
      Documents the ocular target in an affected female. PARTIAL - a
      single-individual observation, and no surveillance study exists.
  - reference: PMID:40751225
    reference_title: 'c.7156C > T p.(Gln2386*) variant causes loss-of-function of the
      USP9X gene in a female-restricted X-linked syndromic intellectual disability:
      a case report.'
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "otolaryngologist, ophthalmologist, neurologist"
    explanation: >
      Ophthalmology is named among the specialties in the only published
      description of the multidisciplinary team actually assembled for an
      affected child. PARTIAL - it evidences real-world practice, not outcome.
- name: Cardiac Evaluation and Management
  description: >
    Echocardiography at diagnosis, with cardiology follow-up and surgical repair
    as indicated. Congenital heart disease in this syndrome is not always minor:
    a cardiac defect caused neonatal death in one reported individual, which is
    the specific justification for systematic cardiac screening rather than
    symptom-driven assessment. The treatment term below names the
    echocardiographic assessment that is the actionable, disorder-specific
    component; surgical or catheter repair of an identified lesion follows
    standard paediatric-cardiology indications for that lesion rather than
    anything specific to this syndrome.
  treatment_term:
    preferred_term: Echocardiographic cardiac assessment
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  target_phenotypes:
  - preferred_term: Abnormal heart morphology
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:33298948
    reference_title: Missense variant contribution to USP9X-female syndrome.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "and heart defects, the latter of which resulted in neonatal lethality in one case"
    explanation: Documents the lethal potential of the cardiac involvement that
      justifies systematic screening.
- name: Orthopaedic Surveillance for Scoliosis and Hip Dysplasia
  description: >
    Scoliosis in this syndrome is described as progressive, and hip dysplasia or
    dislocation is recurrent. Serial spinal examination through growth with
    imaging as indicated, plus hip assessment in infancy, with bracing or
    surgery as required.
  treatment_term:
    preferred_term: Orthopedic surgical procedure
    term:
      id: NCIT:C16186
      label: Orthopedic Surgical Procedure
  therapeutic_modality: SURGERY
  target_phenotypes:
  - preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  - preferred_term: Congenital hip dislocation
    term:
      id: HP:0001374
      label: Congenital hip dislocation
  evidence:
  - reference: PMID:26833328
    reference_title: De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific
      Recognizable Syndrome with Developmental Delay and Congenital Malformations.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "cleft palate/bifid uvula, progressive scoliosis, and structural brain abnormalities"
    explanation: The word "progressive" is the specific justification for serial
      rather than one-off spinal assessment.
- name: Audiological Assessment and Hearing Support
  description: >
    Hearing loss was described as a prominent feature of the female cohort.
    Because speech and language impairment is already near-universal,
    uncorrected hearing loss compounds the principal functional disability, so
    formal audiology at diagnosis and periodically thereafter is warranted. The
    treatment term below names the audiometric assessment, which is the
    disorder-specific action; amplification or other hearing support then
    follows standard audiological practice for the deficit identified.
  treatment_term:
    preferred_term: Audiometric assessment
    term:
      id: NCIT:C38036
      label: Audiometric Test
  target_phenotypes:
  - preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:33298948
    reference_title: Missense variant contribution to USP9X-female syndrome.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Hearing loss was a prominent feature"
    explanation: Documents the target; the surveillance recommendation is inferred
      standard practice, not trial evidence.
- name: Genetic Counselling Including Maternal Testing
  description: >
    Counselling must cover three points specific to this disorder. First, most
    variants are de novo, so empiric sibling recurrence risk is low. Second,
    that low risk is not zero: germline mosaicism in a clinically normal mother
    is documented, and one mother of five miscarriages who transmitted a
    pathogenic allele was found to be mosaic. Third, a heterozygous female
    relative cannot be reassured as an unaffected carrier - penetrance is about
    95% - although at least one non-penetrant transmitting mother is on record.
  treatment_term:
    preferred_term: Genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  therapeutic_modality: BEHAVIORAL
  evidence:
  - reference: PMID:35253988
    reference_title: Exome and RNA-Seq analyses of an incomplete penetrance variant
      in USP9X in female-specific syndromic intellectual disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the penetrance of pathogenic variants in USP9X in female appears to be high (95%) and the variants frequently occur de novo, incomplete penetrance should be considered"
    explanation: Sources both the penetrance figure and the de novo predominance that
      the counselling message rests on.
  - reference: PMID:33298948
    reference_title: Missense variant contribution to USP9X-female syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In Female 26, this variant was inherited from a mosaic mother (de novo in mother)."
    explanation: Documents maternal germline mosaicism, the reason recurrence risk is
      not zero.
  - reference: PMID:40751225
    reference_title: 'c.7156C > T p.(Gln2386*) variant causes loss-of-function of the
      USP9X gene in a female-restricted X-linked syndromic intellectual disability:
      a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Despite the de novo nature of most loss-of-function variants, maternal testing is crucial for estimating recurrence risk."
    explanation: Explicit recommendation for maternal testing.
clinical_trials:
- name: NCT01238250
  status: RECRUITING
  description: >
    Simons Searchlight - an observational, online, international natural-history
    registry for families with rare genetic variants causing neurodevelopmental
    disorders, which includes USP9X. This is the ONLY prospective individual-level
    data collection covering this disorder, and it is observational: there is no
    interventional trial of any therapy for MRXS99F, so `phase` is not
    applicable. Its relevance to this entry is that essentially every open
    question recorded here - quantified per-feature frequencies, adult natural
    history, quality-of-life measurement, and the unquantified childhood-cancer
    signal - is answerable from a registry of this design and from no other
    currently existing resource.
  evidence:
  - reference: clinicaltrials:NCT01238250
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Simons Searchlight is an observational, online, international research program for families with rare genetic variants that cause neurodevelopmental disorders and may be associated with autism."
    explanation: Confirms the registry's observational design and its scope covering
      rare neurodevelopmental-disorder variants such as USP9X.
  - reference: clinicaltrials:NCT01238250
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Simons Searchlight collects medical, behavioral, learning, and developmental information from people who have these rare genetic changes."
    explanation: Describes the phenotypic data collection that would populate the
      natural-history gaps noted in this entry.
discussions:
- discussion_id: usp9x_female_penetrance_modifier
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: What modifies penetrance in a heterozygous USP9X female, given that skewed
    X-inactivation has been excluded as the explanation?
  attaches_to:
  - pathophysiology#Female USP9X Haploinsufficiency
  rationale: >
    Two transmitting mothers are documented with pathogenic USP9X alleles and
    little or no phenotype - one germline mosaic, one non-mosaic - and two
    non-twin female siblings share a truncating allele with incomplete
    penetrance. The default explanation for variable female expression in
    X-linked disease, skewed X-inactivation, is explicitly ruled out by the
    authors because USP9X escapes X-inactivation, and X-inactivation studies in
    the informative case showed no skewing. RNA-Seq and quad exome analysis in
    the sibling pair failed to identify a candidate modifier. Without a
    mechanism, a heterozygous female relative or fetus cannot be counselled
    beyond a population-level ~95% penetrance figure.
  proposed_experiments:
  - experiment_id: allele_specific_usp9x_expression
    name: Allele-specific USP9X expression versus phenotype in heterozygous females
    description: >
      Quantify allele-specific USP9X expression and total USP9X protein in
      accessible tissues from affected versus unaffected heterozygous females
      carrying the same or comparable alleles, paired with quantitative
      X-inactivation assay and with tissue-specific escape measurement, to test
      whether residual USP9X dose rather than XCI ratio predicts phenotype.
    decision_criterion: >
      Residual USP9X dose separates affected from unaffected heterozygotes more
      cleanly than the X-inactivation ratio does.
    would_support:
    - Female manifestation is governed by quantitative residual USP9X dose, with
      tissue-variable escape as the source of variability.
    would_refute:
    - Penetrance is governed by an independent trans-acting modifier locus rather than
      by USP9X dose.
- discussion_id: usp9x_turner_dosage_paradox
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: If USP9X-female syndrome is caused by a simple 50% reduction in USP9X dosage,
    why do individuals with 45,X (Turner syndrome), who also carry a single USP9X allele,
    generally lack neurological manifestations?
  attaches_to:
  - pathophysiology#Female USP9X Haploinsufficiency
  rationale: >
    This is the strongest published challenge to the haploinsufficiency model
    and it comes from the same authors who advance that model. A 45,X individual
    has one USP9X allele, which on a naive dosage account should reproduce the
    neurological phenotype; it does not. Candidate reconciliations, none tested:
    (i) 45,X individuals up-regulate the single allele in a way a
    heterozygous-null female cannot, (ii) the relevant lesion is not steady-state
    dosage but allelic imbalance or timing during a narrow developmental window,
    (iii) 45,X and heterozygous-null differ in the co-inherited X content, or
    (iv) some female alleles are not clean nulls and exert a dominant-negative
    effect. Resolving this determines whether "haploinsufficiency" is the right
    label for the entry at all, so it is recorded here rather than glossed over.
  proposed_experiments:
  - experiment_id: usp9x_dosage_45x_vs_heterozygous_null
    name: USP9X protein and transcript dosage in 45,X versus heterozygous-null females
    description: >
      Measure total USP9X transcript and protein in matched accessible tissues
      from 45,X individuals, USP9X heterozygous-null females, and 46,XX controls,
      to test whether 45,X individuals in fact sustain a smaller dosage
      reduction than heterozygous-null females do.
    decision_criterion: >
      45,X individuals show USP9X protein levels significantly closer to 46,XX
      controls than heterozygous-null females do.
    would_support:
    - The paradox is apparent only, and 45,X does not in fact produce the same USP9X
      dosage state as a heterozygous null.
    would_refute:
    - USP9X dosage is equivalent in the two states, so steady-state dosage cannot be
      the operative variable and a dominant-negative or timing-based mechanism must be
      invoked.
- discussion_id: usp9x_childhood_malignancy_risk
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: Do individuals with USP9X-female syndrome carry an increased risk of childhood
    malignancy, and if so does it warrant a surveillance protocol?
  attaches_to:
  - pathophysiology#Female USP9X Haploinsufficiency
  rationale: >
    Two females with USP9X-female syndrome have been reported with childhood
    malignancy, and the authors raise the possibility that this is part of the
    natural course. The biological prior is not weak: USP9X is an established
    tumour suppressor, loss-of-function USP9X variants are enriched in somatic
    cancer catalogues, and the female germline alleles cluster in the same
    catalytic-domain positions as predicted-deleterious cancer variants. Against
    that, two cases in a literature of roughly 35 individuals is not an incidence
    estimate, and no cohort has been followed for cancer outcomes. The clinical
    stakes are asymmetric: if a real excess exists it is actionable through
    surveillance, and if it does not, families are being exposed to avoidable
    anxiety. No surveillance protocol exists and the risk is unquantified.
  proposed_experiments:
  - experiment_id: usp9x_registry_cancer_incidence
    name: Registry-based cancer incidence in USP9X-related neurodevelopmental disorder
    description: >
      Use a prospective registry cohort (Simons Searchlight includes USP9X) with
      cancer-registry linkage to estimate observed-versus-expected childhood
      cancer incidence in individuals with pathogenic USP9X variants, stratified
      by sex and allele class.
    decision_criterion: >
      Observed childhood cancer incidence significantly exceeds age- and
      sex-matched population expectation.
    would_support:
    - A germline tumour-predisposition component justifying a formal surveillance
      recommendation.
    would_refute:
    - The two reported malignancies are coincidental and no surveillance is warranted.
- discussion_id: usp9x_ciliary_contribution
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: Does loss of ciliary USP9X function contribute to the extra-neural congenital
    malformations of this syndrome?
  attaches_to:
  - pathophysiology#Disrupted Extra-Neural Organogenesis
  rationale: >
    Several defining malformations - postaxial polydactyly, structural brain
    malformation, congenital heart defect - are shared with recognised
    ciliopathies, and endogenous USP9X was shown to localise along the length of
    the ciliary axoneme. Yet ciliary parameters were not dysregulated in
    fibroblasts derived from affected females, and the authors attribute this to
    spatiotemporal specificity of ciliary USP9X function rather than to absence
    of a ciliary role. The question matters because it is currently the only
    proposed mechanism for the extra-neural malformation branch, which is
    otherwise modelled with HYPOTHETICAL mechanism confidence and no identified
    substrate.
  proposed_experiments:
  - experiment_id: usp9x_cilia_developmental_tissue
    name: Ciliary phenotyping of USP9X-deficient cells in developmentally relevant lineages
    description: >
      Assay ciliogenesis, ciliary length and Hedgehog signal transduction in
      USP9X-haploinsufficient cells of lineages relevant to the affected organs
      (limb bud mesenchyme, cardiac progenitors, cranial neural crest) rather
      than in dermal fibroblasts, and at developmental rather than adult
      timepoints.
    decision_criterion: >
      A ciliary or Hedgehog-signalling defect is detectable in a
      malformation-relevant lineage despite being absent in adult fibroblasts.
    would_support:
    - A spatiotemporally restricted ciliary role for USP9X underlies the ciliopathy-like
      malformations.
    would_refute:
    - The extra-neural malformations arise from non-ciliary USP9X substrates and the
      ciliary localisation is incidental.
- discussion_id: usp9x_female_tgfbeta_direct_evidence
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: Is the TGF-beta signalling defect that has been demonstrated in male
    partial-loss-of-function USP9X cells and in Usp9x-null mice actually present in
    cells from females with this entity?
  attaches_to:
  - pathophysiology#Attenuated TGF-beta Signalling
  rationale: >
    The TGF-beta arm is the best-developed mechanistic account of the
    neurological phenotype, but its human functional evidence comes entirely
    from MALE partial-loss-of-function patient fibroblasts (MONDO:0010487) and
    its in vivo evidence from Usp9x-knockout mice. The authors state the
    convergence onto the female syndrome as an explicit speculation, not a
    measurement. This is precisely the named-entity risk this entry guards
    against: importing male functional data as if it were female mechanism.
    Female-derived cells exist - the founding cohort performed expression and
    ciliary studies on them - so the experiment is tractable.
  proposed_experiments:
  - experiment_id: tgfbeta_response_female_fibroblasts
    name: TGF-beta pathway response in fibroblasts from females with USP9X null alleles
    description: >
      Repeat the TGF-beta luciferase reporter, nuclear SMAD4 translocation and
      scratch-migration assays used in the male cohort, on fibroblasts from
      females carrying bona fide USP9X null alleles, with matched female
      controls.
    decision_criterion: >
      Female USP9X-haploinsufficient fibroblasts show blunted TGF-beta reporter
      induction and reduced nuclear SMAD4 translocation comparable to the male
      partial-loss-of-function lines.
    would_support:
    - TGF-beta attenuation is a shared convergent mechanism across both USP9X entities
      and can be asserted for the female entity directly.
    would_refute:
    - TGF-beta attenuation is specific to particular missense alleles in males and is
      not the mechanism of the female dosage-loss syndrome.