name: OTUD6B-Related Neurodevelopmental Disorder
creation_date: "2026-08-01T00:00:00Z"
category: Mendelian
description: >-
  OTUD6B-related neurodevelopmental disorder (intellectual developmental disorder
  with dysmorphic facies, seizures, and distal limb anomalies; IDDFSDA, MIM 617452)
  is an ultra-rare autosomal recessive multisystem disorder caused by biallelic
  variants in OTUD6B, which encodes an ovarian-tumor (OTU) domain deubiquitinating
  enzyme. The core clinical picture is global developmental delay and intellectual
  disability with seizures, a recognizable dysmorphic facial gestalt, poor pre- and
  postnatal growth, and characteristic distal limb findings (broad distal phalanges
  of thumbs and halluces, prominent interphalangeal joints, persistent fetal
  fingertip pads). Individuals with predicted loss-of-function alleles are more
  severely affected, with microcephaly, absent speech, hypotonia, feeding
  difficulties, structural brain abnormalities, and congenital heart disease;
  individuals carrying alleles with residual function can have mild to moderate
  intellectual disability with preserved speech and ambulation. Mechanistically,
  patient cells show reduced incorporation of 19S regulatory subunits into 26S
  proteasomes, decreased chymotrypsin-like proteasome activity, and accumulation
  of ubiquitin-protein conjugates, placing the disorder among the ubiquitin-proteasome
  system disorders of development.
notes: >-
  Named-entity-confusion guardrail. This entry is anchored strictly on
  MONDO:0044319 / OMIM:617452 / OTUD6B (HGNC:24281), confirmed by the MONDO
  `RO:0004003` gene-association relation. It is deliberately NOT merged with
  three closely named or closely related entities. (1) MONDO:0060596
  "neurodevelopmental disorder with dysmorphic facies and distal limb
  anomalies" is the BPTF-related disorder (NEDDFL) and is a different gene and
  a different MONDO entity; PMID:33522091 describes that BPTF entity and is
  therefore excluded from every OTUD6B claim in this entry, appearing only as
  evidence on the BPTF differential_diagnoses record. (2) MONDO:0032855
  "neurodevelopmental disorder with dysmorphic facies and distal skeletal
  anomalies" is likewise a separate entity. (3) Other OTU-family
  deubiquitinase disorders are distinct: OTUD5 causes an X-linked
  multiple-congenital-anomaly/neurodevelopmental syndrome, OTUD7A lies in the
  15q13.3 microdeletion interval, and OTUD1/OTUB1 appear in overlapping
  ubiquitin-signalling literature without being the cause of this disorder.
  Every citation used here was checked to name OTUD6B specifically. Most
  OTUD6B PubMed hits are cancer-biology or lncRNA (OTUD6B-AS1) papers that are
  unrelated to the Mendelian disorder and were excluded.

  Frequency discipline. Frequency bands here come from exactly two denominator
  sources, both recorded per phenotype in that phenotype's `notes:`. (1) The
  HPO disease-annotation file (phenotype.hpoa, checked directly against the
  current release) carries per-phenotype `n/m` counts for OMIM:617452 curated
  from the founding cohort PMID:28343629, e.g. Seizure 12/12, Microcephaly
  9/12, Generalized hypotonia 9/12, Feeding difficulties 9/12, Intrauterine
  growth retardation 7/12, Long palpebral fissure 6/12, Broad thumb 6/12,
  Atrial septal defect 3/6. (2) PMID:41188742 supplies an explicit denominator
  for the ocular phenotype. Where neither source applies the band is omitted
  rather than guessed. Important caveat on the HPOA counts: they derive from a
  single, ascertainment-biased 2017 cohort weighted toward severe
  loss-of-function genotypes, so they likely overstate severity across the full
  allelic spectrum. HPOA records Severe intellectual disability as 12/12, which
  is directly contradicted by the later mild cases (PMID:30364145,
  PMID:34354232); this entry therefore models the broader HP:0001249
  Intellectual disability rather than adopting the severe-ID annotation, and
  bands should be read as cohort-specific rather than population estimates.

  HPOA-annotated features not separately modeled here. phenotype.hpoa lists
  additional terms for OMIM:617452 that are not given their own phenotype
  entries: macrotia 7/12, short stature 7/12, decreased body weight 6/12, thin
  upper lip vermilion 6/12, prominent nasal bridge 5/12, scoliosis 5/12,
  retrognathia 4/12, overlapping toe 3/12, autistic behavior 3/12, hypoplasia
  of the corpus callosum 3/12, short neck 3/12, highly arched eyebrow 3/12,
  down-sloping shoulders 3/12, spastic tetraplegia 2/12, chronic constipation
  2/12, sacral dimple 2/12, brachycephaly 1/12, plus unquantified terms
  including inability to walk, ventriculomegaly, failure to thrive, hearing
  impairment, cryptorchidism, and talipes equinovarus. The reason for the
  omission is that these counts derive from the PMID:28343629 full-text table
  rather than from its abstract, and this entry takes its snippets from
  abstracts. That reason must not be overstated: references_cache/PMID_41188742.md
  is cached as full text and does contain a 28-case aggregate table carrying
  several of these rows (short stature 16/28, poor weight gain 14/28, scoliosis
  8/22, cryptorchidism 7/24, abnormal cranial MRI 13/24). Those rows are
  PDF-mangled and bundle several features per line, so they were judged too
  unreliable to quote, but they do exist, and quoting the primary full text is
  the right way to close this gap in a follow-up pass. Long philtrum was
  previously listed here as unsupported by any cached abstract; that was wrong,
  and it is now modeled as its own phenotype from the PMID:34680978 abstract.

  Blended phenotypes and attribution discipline. Three reported probands carry
  a second, independent pathogenic locus that contributes to the observed
  picture: RP1L1 causing the retinal degeneration in PMID:34354232, a
  heterozygous PKD1 variant contributing renal cystic disease in PMID:35707595,
  and a ZMIZ1 splice variant in PMID:34680978. These are co-occurring
  conditions, not OTUD6B modifiers. The RP1L1 retinal degeneration and the PKD1
  renal cystic disease are therefore not attributed to OTUD6B at all. The
  PMID:34680978 proband is handled differently, because that paper's authors
  explicitly propose their facial findings as an OTUD6B phenotype expansion: the
  Williams syndrome-like features (periorbital edema, hanging cheek, long and
  smooth philtrum) and the polydactyly are curated, but every one of them
  carries supports PARTIAL and a note naming the heterozygous ZMIZ1
  c.1491 + 2T > C exon-14-skipping variant as an unresolved confounder, with a
  cross-reference to the ZMIZ1 entry in differential_diagnoses.

  Structured-source citations unavailable. ClinGen has a Definitive
  gene-disease validity assertion for OTUD6B and syndromic intellectual
  disability (assertion 3c60103c-7d9b-4dca-aa03-151130c5d6db, SOP10, AR,
  Intellectual Disability and Autism Gene Curation Expert Panel, 2024-08-22),
  and Orphanet codes this disorder as ORPHA:505237. Neither a `CGGV:` nor an
  `ORPHA:` record could be generated into references_cache in this working
  environment, and the relevant data MANIFEST pins are stale and
  un-refreshable pending #7622, so no structured-source snippet is cited. The
  gene-disease relationship is instead supported here by primary literature.

  Not cited for snippets. PMID:31147255 (first Spanish case) and PMID:32181568
  (Alkuraya, phenotypic-expansion comment) are genuine OTUD6B disorder reports
  but have no abstract text in PubMed, so no verbatim snippet could be taken
  from them; they are recorded in the top-level references block only.
disease_term:
  preferred_term: OTUD6B-related neurodevelopmental disorder
  term:
    id: MONDO:0044319
    label: intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies
parents:
- Neurodevelopmental Disorder
- Autosomal Recessive Syndromic Intellectual Disability
synonyms:
- intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies
- IDDFSDA
- OTUD6B-related syndrome
- OTUD6B-associated intellectual disability
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
    notes: >-
      The dominant clinical burden is neurodevelopmental: global developmental
      delay, intellectual disability, seizures, hypotonia, and structural brain
      abnormalities.
    evidence:
    - reference: PMID:28343629
      reference_title: "Biallelic Variants in OTUD6B Cause an Intellectual Disability Syndrome Associated with Seizures and Dysmorphic Features."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        we report biallelic pathogenic variants in OTUD6B in 12 individuals from 6
        independent families with an intellectual disability syndrome associated
        with seizures and dysmorphic features
      explanation: >-
        The defining cohort establishes intellectual disability and seizures as the
        core presenting features, supporting a neurologic chapter assignment.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      A monogenic, autosomal recessive Mendelian disorder diagnosed by exome or
      genome sequencing.
    evidence:
    - reference: PMID:35430327
      reference_title: "Novel biallelic variants affecting the OTU domain of the gene OTUD6B associate with severe intellectual disability syndrome and molecular dynamics simulations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Intellectual developmental disorder with dysmorphic facies, seizures, and
        distal limb anomalies (IDDFSDA) is an autosomal recessive multisystem
        disorder caused by compound heterozygous or homozygous variants in the gene
        OTUD6B
      explanation: >-
        States the Mendelian, autosomal recessive, single-gene basis of the disorder.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Disease requires biallelic (homozygous or compound heterozygous) OTUD6B
    variants. Reported families include consanguineous pedigrees with homozygous
    alleles and non-consanguineous pedigrees with compound heterozygous alleles.
    Heterozygous carrier parents are unaffected. Recurrence risk for siblings of an
    affected proband is 25 percent, and carrier testing plus genetic counseling are
    indicated for at-risk relatives.
  evidence:
  - reference: PMID:35430327
    reference_title: "Novel biallelic variants affecting the OTU domain of the gene OTUD6B associate with severe intellectual disability syndrome and molecular dynamics simulations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      an autosomal recessive multisystem disorder caused by compound heterozygous
      or homozygous variants in the gene OTUD6B
    explanation: >-
      Directly states the autosomal recessive, biallelic requirement, including both
      the homozygous and compound heterozygous configurations.
  - reference: PMID:30364145
    reference_title: "First Replication of the Involvement of OTUD6B in Intellectual Disability Syndrome With Seizures and Dysmorphic Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The segregation in the family was confirmed by Sanger sequencing: the father
      (I1) was carrier of the c.324+1G>C mutation whereas the mother (I2) was
      heterozygous for c.405+1G>A.
    explanation: >-
      Documents biparental transmission of two different alleles to an affected
      compound heterozygous child, with unaffected heterozygous carrier parents.
prevalence:
- population: Worldwide reported literature
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Fewer than 30 individuals had been reported worldwide as of the 2025 Chinese
    case report; that paper's own literature table enumerates 27 previously
    reported cases plus its index case. No population-based prevalence study
    exists. Orphanet assigns ORPHA:505237 a point-prevalence band of below 1 in
    1,000,000, which would correspond to the BELOW_1_IN_1000000 class and a rate
    of under 0.1 per 100,000; that band is recorded here as context only and is
    not adopted as the structured value, because no ORPHA cache record could be
    generated in this environment to carry a validated snippet (see the
    entry-level notes and #7622). The measure actually asserted is therefore the
    snippet-verifiable published case count.
  evidence:
  - reference: PMID:41188742
    reference_title: "Novel variant causing OTUD6B-related syndrome with ocular dysplasia and hypothyroidism: the first Chinese case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There have been < 30 reported cases globally without fundus and retinal
      lesions.
    explanation: >-
      Provides the published worldwide case count supporting an ultra-rare
      classification based on cases in the literature rather than a population rate.
pathophysiology:
- name: Biallelic OTUD6B Loss-of-Function Variants
  biological_scale: MOLECULAR
  description: >-
    The disorder is initiated by inheritance of two damaging OTUD6B alleles. The
    reported allelic spectrum includes nonsense alleles, canonical splice-donor
    alleles that abolish normal splicing and trigger nonsense-mediated decay,
    frameshift alleles, and rare missense alleles within the catalytic OTU domain.
  genes:
  - preferred_term: OTUD6B
    term:
      id: hgnc:24281
      label: OTUD6B
  downstream:
  - target: Loss of OTUD6B Deubiquitinase Activity
    description: >-
      Damaging biallelic alleles remove or inactivate the OTU-domain
      deubiquitinating enzyme encoded by OTUD6B.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28343629
      reference_title: "Biallelic Variants in OTUD6B Cause an Intellectual Disability Syndrome Associated with Seizures and Dysmorphic Features."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Our findings suggest a role for OTUD6B in proteasome function, establish
        that defective OTUD6B function underlies a multisystemic human disorder
      explanation: >-
        The authors frame the disease as arising from defective OTUD6B function,
        the direct consequence of the biallelic damaging alleles.
  - target: Allele-Dependent Residual OTUD6B Function
    description: >-
      Because different alleles leave different amounts of functional protein or
      differently destabilize the fold, the specific genotype sets the residual
      activity available to the developing organism.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35430327
      reference_title: "Novel biallelic variants affecting the OTU domain of the gene OTUD6B associate with severe intellectual disability syndrome and molecular dynamics simulations."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        Our findings suggest that compound LOF and ultrarare missense variants may
        be contribute to the underlying variability expressivity associated with
        this disorder.
      explanation: >-
        Links the specific allele combination to the residual-function and
        expressivity axis. The awkward phrasing is quoted verbatim from the
        published abstract.
  evidence:
  - reference: PMID:28343629
    reference_title: "Biallelic Variants in OTUD6B Cause an Intellectual Disability Syndrome Associated with Seizures and Dysmorphic Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we report biallelic pathogenic variants in OTUD6B in 12 individuals from 6
      independent families with an intellectual disability syndrome associated
      with seizures and dysmorphic features
    explanation: >-
      Establishes biallelic OTUD6B variants as the initiating genetic lesion in the
      original multi-family discovery cohort.
  - reference: PMID:30364145
    reference_title: "First Replication of the Involvement of OTUD6B in Intellectual Disability Syndrome With Seizures and Dysmorphic Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Data analysis highlighted the presence of two heterozygous variants affecting
      exons 2 (c.324+1G>C) and 3 (c.405+1G>A) donor splice sites of the OTUD6B gene
    explanation: >-
      An independent replication family in which two canonical splice-donor alleles
      constitute the biallelic lesion.
- name: Loss of OTUD6B Deubiquitinase Activity
  biological_scale: MOLECULAR
  description: >-
    OTUD6B encodes a member of the ovarian tumor (OTU) domain subfamily of
    deubiquitinating enzymes, which remove ubiquitin from substrate proteins and
    thereby counterbalance E1/E2/E3 ubiquitin conjugation. Loss of this activity
    removes a node of control over ubiquitin-dependent protein turnover, trafficking,
    and signaling.
  molecular_functions:
  - preferred_term: cysteine-type deubiquitinase activity
    term:
      id: GO:0004843
      label: cysteine-type deubiquitinase activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: protein deubiquitination
    term:
      id: GO:0016579
      label: protein deubiquitination
    modifier: DECREASED
  downstream:
  - target: Impaired 26S Proteasome Assembly
    description: >-
      Loss of OTUD6B activity is associated with defective incorporation of the 19S
      regulatory particle into the mature 26S proteasome in patient cells.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:28343629
      reference_title: "Biallelic Variants in OTUD6B Cause an Intellectual Disability Syndrome Associated with Seizures and Dysmorphic Features."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Analysis of peripheral blood mononuclear cells from an affected subject
        showed reduced incorporation of 19S subunits into 26S proteasomes
      explanation: >-
        Cells lacking functional OTUD6B show the 19S incorporation defect,
        establishing the edge from lost deubiquitinase activity to impaired
        proteasome assembly. The intermediate steps are not resolved.
  - target: Dysregulated mTORC1-Linked Translation Initiation
    description: >-
      OTUD6B also acts on the translation initiation machinery downstream of mTORC1,
      so its loss removes a second, proteasome-independent output.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27864334
      reference_title: "Deubiquitinase OTUD6B Isoforms Are Important Regulators of Growth and Proliferation."
      supports: PARTIAL
      evidence_source: IN_VITRO
      snippet: >-
        OTUD6B associates with the protein synthesis initiation complex and
        modifies components of the 48S preinitiation complex.
      explanation: >-
        Establishes the physical and enzymatic link from OTUD6B to translation
        initiation. PARTIAL because the work is in a cancer cell line rather than
        a developmental model.
  evidence:
  - reference: PMID:28343629
    reference_title: "Biallelic Variants in OTUD6B Cause an Intellectual Disability Syndrome Associated with Seizures and Dysmorphic Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      OTUD6B encodes a member of the ovarian tumor domain (OTU)-containing subfamily
      of deubiquitinating enzymes.
    explanation: >-
      Identifies the molecular function lost when OTUD6B is disrupted.
  - reference: PMID:33421002
    reference_title: "Studying OTUD6B-OTUB1 Protein-Protein Interaction by Low-Throughput GFP-Trap Assays and High-Throughput AlphaScreen Assays."
    supports: PARTIAL
    evidence_source: IN_VITRO
    snippet: >-
      we study the protein-protein interaction between the two deubiquitinating
      enzymes OTUB1 and OTUD6B and report for the first time that both proteins
      directly interact with each other
    explanation: >-
      Places OTUD6B within the deubiquitinase interaction network. This is
      supporting context for the enzyme's role in ubiquitin signaling, not direct
      evidence about the disease, hence PARTIAL.
- name: Allele-Dependent Residual OTUD6B Function
  biological_scale: MOLECULAR
  description: >-
    The severity of the clinical phenotype tracks the predicted functional severity
    of the specific OTUD6B alleles. Truncating and splice alleles that trigger
    nonsense-mediated decay give little or no product, whereas some missense alleles
    only locally destabilize the protein and others distort the overall fold. Molecular
    dynamics modeling of two OTU-domain missense alleles predicted localized
    destabilization for the allele found in a mildly affected individual and gross
    fold distortion for the allele found in a severely affected individual. In one
    replication family, residual wild-type splicing of under one percent, together
    with alleles that spare the short OTUD6B-2 isoform, was proposed to explain an
    unusually mild presentation.
  downstream:
  - target: Disrupted Embryonic Organogenesis and Growth
    description: >-
      The amount and quality of residual OTUD6B protein modulates how severely
      development is perturbed, producing the observed severity gradient from severe
      multisystem disease to mild intellectual disability.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:35430327
      reference_title: "Novel biallelic variants affecting the OTU domain of the gene OTUD6B associate with severe intellectual disability syndrome and molecular dynamics simulations."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        our findings support that the clinical severity could be related with the
        predicted functional severity of the variations in OTUD6B
      explanation: >-
        Ties residual protein function directly to the severity of the resulting
        developmental phenotype.
  evidence:
  - reference: PMID:35430327
    reference_title: "Novel biallelic variants affecting the OTU domain of the gene OTUD6B associate with severe intellectual disability syndrome and molecular dynamics simulations."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      it is anticipated that Tyr216Cys in the earlier reported case with less severe
      IDDFSDA will lead to localized destabilization, whereas Ile274Arg in the
      presented index case with the severe IDDFSDA phenotype will lead to significant
      distortion in the overall fold of OTUD6B
    explanation: >-
      Structural modeling and molecular dynamics link predicted protein-level damage
      to observed clinical severity for two OTU-domain missense alleles.
  - reference: PMID:35430327
    reference_title: "Novel biallelic variants affecting the OTU domain of the gene OTUD6B associate with severe intellectual disability syndrome and molecular dynamics simulations."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      our findings support that the clinical severity could be related with the
      predicted functional severity of the variations in OTUD6B
    explanation: >-
      States the genotype-severity relationship explicitly as the study's conclusion.
  - reference: PMID:30364145
    reference_title: "First Replication of the Involvement of OTUD6B in Intellectual Disability Syndrome With Seizures and Dysmorphic Features."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      we performed quantitative analysis by competitive-fluorescent RT-PCR showing
      that the proband presents less than 1% of the wild-type transcript
    explanation: >-
      Direct patient-RNA quantification of residual normal transcript, the measurable
      substrate of the residual-function idea.
- name: Impaired 26S Proteasome Assembly
  biological_scale: CELLULAR
  description: >-
    Peripheral blood mononuclear cells from an affected individual show reduced
    incorporation of 19S regulatory-particle subunits into 26S proteasomes. The
    mature 26S holoenzyme is formed by capping the 20S catalytic core with the 19S
    regulatory particle, so defective 19S incorporation reduces the pool of
    assembly-competent, ubiquitin-receptive proteasomes.
  cell_types:
  - preferred_term: peripheral blood mononuclear cell
    term:
      id: CL:2000001
      label: peripheral blood mononuclear cell
  cellular_components:
  - preferred_term: proteasome accessory complex (19S regulatory particle)
    term:
      id: GO:0022624
      label: proteasome accessory complex
  biological_processes:
  - preferred_term: proteasome assembly
    term:
      id: GO:0043248
      label: proteasome assembly
    modifier: DECREASED
  downstream:
  - target: Reduced Proteasomal Chymotrypsin-Like Activity
    description: >-
      Fewer correctly assembled 26S proteasomes yield lower measured peptidase
      activity in the same patient cells.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28343629
      reference_title: "Biallelic Variants in OTUD6B Cause an Intellectual Disability Syndrome Associated with Seizures and Dysmorphic Features."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        showed reduced incorporation of 19S subunits into 26S proteasomes,
        decreased chymotrypsin-like activity
      explanation: >-
        The same patient-cell experiment reports the assembly defect and the
        peptidase-activity deficit together, supporting the direct edge between
        them.
  evidence:
  - reference: PMID:28343629
    reference_title: "Biallelic Variants in OTUD6B Cause an Intellectual Disability Syndrome Associated with Seizures and Dysmorphic Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Analysis of peripheral blood mononuclear cells from an affected subject showed
      reduced incorporation of 19S subunits into 26S proteasomes
    explanation: >-
      Direct patient-cell measurement of the proteasome-assembly defect.
- name: Reduced Proteasomal Chymotrypsin-Like Activity
  biological_scale: MOLECULAR
  description: >-
    Chymotrypsin-like peptidase activity, the rate-limiting catalytic activity of the
    20S core, is decreased in patient peripheral blood mononuclear cells, indicating
    functionally reduced proteolytic throughput and not merely an assembly
    stoichiometry change.
  cellular_components:
  - preferred_term: proteasome complex
    term:
      id: GO:0000502
      label: proteasome complex
  biological_processes:
  - preferred_term: proteasome-mediated ubiquitin-dependent protein catabolic process
    term:
      id: GO:0043161
      label: proteasome-mediated ubiquitin-dependent protein catabolic process
    modifier: DECREASED
  downstream:
  - target: Accumulation of Ubiquitin-Protein Conjugates
    description: >-
      Reduced proteolytic throughput leaves polyubiquitinated substrates undegraded.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28343629
      reference_title: "Biallelic Variants in OTUD6B Cause an Intellectual Disability Syndrome Associated with Seizures and Dysmorphic Features."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        decreased chymotrypsin-like activity, and accumulation of
        ubiquitin-protein conjugates
      explanation: >-
        The reduced peptidase activity and the conjugate build-up are reported in
        the same patient cells, supporting the direct degradation-failure edge.
  evidence:
  - reference: PMID:28343629
    reference_title: "Biallelic Variants in OTUD6B Cause an Intellectual Disability Syndrome Associated with Seizures and Dysmorphic Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      decreased chymotrypsin-like activity
    explanation: >-
      Reports the specific reduction of proteasome chymotrypsin-like peptidase
      activity in cells from an affected individual.
- name: Accumulation of Ubiquitin-Protein Conjugates
  biological_scale: CELLULAR
  description: >-
    Polyubiquitinated proteins accumulate in patient cells, the expected consequence
    of a reduced-capacity ubiquitin-proteasome system. This is the proteostatic
    lesion that the developing organism must tolerate.
  biological_processes:
  - preferred_term: ubiquitin-dependent protein catabolic process
    term:
      id: GO:0006511
      label: ubiquitin-dependent protein catabolic process
    modifier: DECREASED
  downstream:
  - target: Impaired Cell Growth and Proliferation
    description: >-
      Failure to clear ubiquitinated regulatory proteins on schedule impairs the
      proliferative programs of developing tissues.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27864334
      reference_title: "Deubiquitinase OTUD6B Isoforms Are Important Regulators of Growth and Proliferation."
      supports: PARTIAL
      evidence_source: IN_VITRO
      snippet: >-
        Deubiquitinases (DUB) are increasingly linked to the regulation of
        fundamental processes in normal and cancer cells, including DNA
        replication and repair, programmed cell death, and oncogenes and tumor
        suppressor signaling.
      explanation: >-
        Supports the general principle that failure of deubiquitinase-dependent
        turnover perturbs replication and proliferation programs. PARTIAL because
        it is a framing statement rather than a direct measurement of this edge in
        OTUD6B-deficient developing tissue.
  evidence:
  - reference: PMID:28343629
    reference_title: "Biallelic Variants in OTUD6B Cause an Intellectual Disability Syndrome Associated with Seizures and Dysmorphic Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      accumulation of ubiquitin-protein conjugates
    explanation: >-
      Patient-cell demonstration that undegraded ubiquitin conjugates build up when
      OTUD6B is lost.
  - reference: PMID:28343629
    reference_title: "Biallelic Variants in OTUD6B Cause an Intellectual Disability Syndrome Associated with Seizures and Dysmorphic Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our findings suggest a role for OTUD6B in proteasome function, establish that
      defective OTUD6B function underlies a multisystemic human disorder
    explanation: >-
      The authors' own synthesis tying the proteasome defect to the multisystem
      human phenotype.
- name: Dysregulated mTORC1-Linked Translation Initiation
  biological_scale: CELLULAR
  description: >-
    Independently of the proteasome arm, OTUD6B regulates protein synthesis
    downstream of mTORC1. It associates with the protein synthesis initiation complex
    and modifies components of the 48S preinitiation complex, and its two main
    splicing isoforms act in opposing directions, with the long OTUD6B-1 isoform
    inhibitory and the short OTUD6B-2 isoform stimulatory. This work was performed in
    non-small cell lung cancer cell lines rather than in neural tissue, so its
    relevance to the human developmental phenotype is inferential.
  biological_processes:
  - preferred_term: regulation of translation
    term:
      id: GO:0006417
      label: regulation of translation
    modifier: ABNORMAL
  downstream:
  - target: Impaired Cell Growth and Proliferation
    description: >-
      Loss of OTUD6B-dependent control over translation initiation contributes to the
      growth and proliferation defect.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27864334
      reference_title: "Deubiquitinase OTUD6B Isoforms Are Important Regulators of Growth and Proliferation."
      supports: PARTIAL
      evidence_source: IN_VITRO
      snippet: >-
        These properties affect NSCLC cell proliferation, because OTUD6B-1
        represses DNA synthesis while OTUD6B-2 promotes it.
      explanation: >-
        Explicitly connects the translation-regulatory properties of OTUD6B to
        proliferation. PARTIAL because it is measured in a cancer cell line.
  evidence:
  - reference: PMID:27864334
    reference_title: "Deubiquitinase OTUD6B Isoforms Are Important Regulators of Growth and Proliferation."
    supports: PARTIAL
    evidence_source: IN_VITRO
    snippet: >-
      evidence is presented that the deubiquitinase OTUD6B regulates protein
      synthesis in non-small cell lung cancer (NSCLC) cells, operating downstream
      from mTORC1
    explanation: >-
      Establishes the translation-regulatory function of OTUD6B. Marked PARTIAL
      because the experiments are in a cancer cell line, not in a disease-relevant
      developmental model.
  - reference: PMID:27864334
    reference_title: "Deubiquitinase OTUD6B Isoforms Are Important Regulators of Growth and Proliferation."
    supports: PARTIAL
    evidence_source: IN_VITRO
    snippet: >-
      OTUD6B associates with the protein synthesis initiation complex and modifies
      components of the 48S preinitiation complex.
    explanation: >-
      Identifies the specific molecular target of OTUD6B in the translation
      initiation machinery.
- name: Impaired Cell Growth and Proliferation
  biological_scale: CELLULAR
  description: >-
    Both the proteostatic arm and the translational arm converge on reduced growth
    and proliferative capacity. In cell models the two OTUD6B isoforms have opposing
    effects on DNA synthesis, so loss of the balanced isoform pair perturbs
    proliferation control rather than simply slowing it.
  notes: >-
    This node previously bound GO:0030182 neuron differentiation with modifier
    ABNORMAL. That binding was removed: none of the node's evidence addresses
    neuronal differentiation, which is instead an unsupported mechanistic claim
    injected at the bridge to the neurodevelopmental output. The two processes
    now bound are the ones the cited NSCLC DNA-synthesis experiments actually
    speak to.
  biological_processes:
  - preferred_term: cell population proliferation
    term:
      id: GO:0008283
      label: cell population proliferation
    modifier: ABNORMAL
  - preferred_term: growth
    term:
      id: GO:0040007
      label: growth
    modifier: DECREASED
  downstream:
  - target: Disrupted Embryonic Organogenesis and Growth
    description: >-
      A cell-autonomous proliferation deficit during embryogenesis translates into
      reduced somatic growth and malformation of the organs with the highest
      developmental proliferative demand.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:28343629
      reference_title: "Biallelic Variants in OTUD6B Cause an Intellectual Disability Syndrome Associated with Seizures and Dysmorphic Features."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Homozygous Otud6b knockout mice were subviable, smaller in size, and had
        congenital heart defects, consistent with the severity of loss-of-function
        variants in humans.
      explanation: >-
        Complete loss of the gene in a mammalian model produces exactly the
        reduced-growth-plus-organ-malformation output this edge asserts.
  evidence:
  - reference: PMID:27864334
    reference_title: "Deubiquitinase OTUD6B Isoforms Are Important Regulators of Growth and Proliferation."
    supports: PARTIAL
    evidence_source: IN_VITRO
    snippet: >-
      These properties affect NSCLC cell proliferation, because OTUD6B-1 represses
      DNA synthesis while OTUD6B-2 promotes it.
    explanation: >-
      Demonstrates that OTUD6B isoform balance controls proliferation. PARTIAL
      because the model system is a cancer cell line.
- name: Disrupted Embryonic Organogenesis and Growth
  biological_scale: ORGANISM
  description: >-
    The organism-level convergence node. Reduced proliferative and biosynthetic
    capacity during embryogenesis produces prenatal-onset growth restriction,
    microcephaly and structural brain malformation, congenital heart defects, and
    the distal limb and craniofacial patterning anomalies that define the syndrome.
    Homozygous Otud6b knockout mice recapitulate the severe end of this spectrum,
    being subviable and small with congenital heart defects.
  biological_processes:
  - preferred_term: heart development
    term:
      id: GO:0007507
      label: heart development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:28343629
    reference_title: "Biallelic Variants in OTUD6B Cause an Intellectual Disability Syndrome Associated with Seizures and Dysmorphic Features."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Homozygous Otud6b knockout mice were subviable, smaller in size, and had
      congenital heart defects, consistent with the severity of loss-of-function
      variants in humans.
    explanation: >-
      An orthologous null mouse reproduces the growth restriction and congenital
      heart disease seen at the severe end of the human spectrum, supporting a
      developmental-organogenesis mechanism.
  - reference: PMID:28343629
    reference_title: "Biallelic Variants in OTUD6B Cause an Intellectual Disability Syndrome Associated with Seizures and Dysmorphic Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      growth retardation with prenatal onset, feeding difficulties, structural brain
      abnormalities, congenital malformations including congenital heart disease,
      and musculoskeletal features
    explanation: >-
      The human multisystem malformation and growth phenotype that this node
      represents.
phenotypes:
- name: Global Developmental Delay
  description: >-
    Delayed acquisition of motor, language, and adaptive milestones is present in
    affected individuals and is typically the presenting concern.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:28343629
    reference_title: "Biallelic Variants in OTUD6B Cause an Intellectual Disability Syndrome Associated with Seizures and Dysmorphic Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In subjects with predicted loss-of-function alleles, additional features
      include global developmental delay, microcephaly, absent speech, hypotonia
    explanation: >-
      Lists global developmental delay among the features of individuals with
      loss-of-function alleles.
- name: Intellectual Disability
  description: >-
    Intellectual disability is a defining feature. Severity spans the spectrum: the
    most severely affected individuals lack speech and independent ambulation,
    whereas individuals with alleles retaining some function can have mild
    intellectual disability with normal speech and motor development.
  frequency: VERY_FREQUENT
  notes: >-
    Frequency derivation: phenotype.hpoa annotates HP:0010864 Severe
    intellectual disability for OMIM:617452 at 12/12 (100 percent), curated from
    PMID:28343629, supporting a VERY_FREQUENT band (80-100 percent) for
    intellectual disability as such. This entry deliberately binds the broader
    HP:0001249 rather than the severe-ID term, because the 12/12 severity
    annotation reflects the ascertainment-biased 2017 cohort and is contradicted
    by later mild cases (PMID:30364145, PMID:34354232).
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:28343629
    reference_title: "Biallelic Variants in OTUD6B Cause an Intellectual Disability Syndrome Associated with Seizures and Dysmorphic Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      an intellectual disability syndrome associated with seizures and dysmorphic
      features
    explanation: >-
      Intellectual disability is the anchoring feature named in the original
      gene-disease report.
  - reference: PMID:30364145
    reference_title: "First Replication of the Involvement of OTUD6B in Intellectual Disability Syndrome With Seizures and Dysmorphic Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At the latest neurological evaluation, at 6 years of age, she has mild
      intellectual disability, mild motor difficulty, and episodic behavioral
      disorders.
    explanation: >-
      Documents the mild end of the intellectual disability spectrum in a
      replication case.
- name: Seizures
  description: >-
    Seizures are part of the core triad and are named in the disorder's canonical
    label. Reported semiologies include generalized tonic-clonic seizures, and onset
    may be in infancy or later in childhood.
  frequency: VERY_FREQUENT
  notes: >-
    Frequency derivation: phenotype.hpoa annotates HP:0001250 Seizure for
    OMIM:617452 at 12/12 (100 percent), curated from PMID:28343629. That maps to
    the VERY_FREQUENT band (80-100 percent).
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:28343629
    reference_title: "Biallelic Variants in OTUD6B Cause an Intellectual Disability Syndrome Associated with Seizures and Dysmorphic Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      an intellectual disability syndrome associated with seizures and dysmorphic
      features
    explanation: >-
      Seizures are named as a core feature of the syndrome in the discovery cohort.
  - reference: PMID:30364145
    reference_title: "First Replication of the Involvement of OTUD6B in Intellectual Disability Syndrome With Seizures and Dysmorphic Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At 5 years, tonic-clonic seizures occurred, thus valproate treatment was
      started.
    explanation: >-
      Documents generalized tonic-clonic semiology and childhood onset in an
      individual with biallelic OTUD6B splice variants.
- name: Dysmorphic Facial Features
  description: >-
    A recognizable dysmorphic facial gestalt accompanies the neurodevelopmental
    phenotype. Reported components include long palpebral fissures and prominent,
    cupped ears; the resemblance to Kabuki syndrome has led to initial misdiagnosis.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:38389298
    reference_title: "Biallelic OTUD6B variants associated with a Kabuki syndrome-like disorder in three siblings: A clinical report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Physical differences described for affected individuals suggest that the
      disorder may be clinically recognizable, but previous publications have
      reported an initial clinical suspicion for Kabuki syndrome (KS) in some
      affected individuals.
    explanation: >-
      Establishes a recognizable dysmorphic facial phenotype and documents the
      clinically important Kabuki syndrome overlap.
- name: Long Palpebral Fissures
  description: >-
    Horizontally elongated palpebral fissures contribute to the Kabuki-like facial
    impression in affected individuals.
  frequency: FREQUENT
  notes: >-
    Frequency derivation: phenotype.hpoa annotates HP:0000637 Long palpebral
    fissure for OMIM:617452 at 6/12 (50 percent), curated from PMID:28343629.
    That maps to the FREQUENT band (30-79 percent).
  phenotype_term:
    preferred_term: Long palpebral fissure
    term:
      id: HP:0000637
      label: Long palpebral fissure
  evidence:
  - reference: PMID:38389298
    reference_title: "Biallelic OTUD6B variants associated with a Kabuki syndrome-like disorder in three siblings: A clinical report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      clinical manifestations such as long palpebral fissures, prominent and cupped
      ears, developmental delay, growth deficiency, persistent fetal fingertip pads,
      vertebral anomaly, and seizures in the proband
    explanation: >-
      Names long palpebral fissures in three siblings with biallelic OTUD6B variants.
- name: Cupped Ears
  description: >-
    Prominent, cupped auricles are part of the reported craniofacial phenotype.
  phenotype_term:
    preferred_term: Cupped ear
    term:
      id: HP:0000378
      label: Cupped ear
  evidence:
  - reference: PMID:38389298
    reference_title: "Biallelic OTUD6B variants associated with a Kabuki syndrome-like disorder in three siblings: A clinical report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      long palpebral fissures, prominent and cupped ears
    explanation: >-
      Directly reports prominent and cupped ears in affected siblings.
- name: Periorbital Edema
  description: >-
    Puffiness of the periorbital region was one of three facial features that led
    the reporting authors to describe the gestalt as Williams syndrome-like and to
    propose it as an expansion of the OTUD6B facial phenotype.
  notes: >-
    Attribution caveat. This observation comes from the single proband of
    PMID:34680978, who carries both a hemizygous OTUD6B c.873delA allele in trans
    with a paternally inherited 0.118 Mb 8q21.3 whole-gene deletion AND a
    heterozygous ZMIZ1 splice variant, c.1491 + 2T > C, shown by mRNA study to
    skip exon 14. ZMIZ1 causes its own autosomal dominant neurodevelopmental
    disorder with dysmorphic facies (MONDO:0032855), which is recorded in this
    entry's differential_diagnoses, so the facial gestalt in this proband cannot
    be attributed to OTUD6B alone. The authors themselves only "suggest" the
    expansion. Curated with supports PARTIAL for that reason. No frequency band
    is given: this is a single case with no denominator.
  phenotype_term:
    preferred_term: Periorbital edema
    term:
      id: HP:0100539
      label: Periorbital edema
  evidence:
  - reference: PMID:34680978
    reference_title: "Compound Heterozygote of Point Mutation and Chromosomal Microdeletion Involving OTUD6B Coinciding with ZMIZ1 Variant in Syndromic Intellectual Disability."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We suggest that Williams syndrome-like phenotypes, namely, periorbital
      edema, hanging cheek, and long and smooth philtrum represent expanded
      phenotypes of OTUD6B-related ID.
    explanation: >-
      Author-asserted phenotypic expansion naming periorbital edema. PARTIAL
      because the proband also carries a ZMIZ1 exon-14-skipping splice variant
      and the authors frame the attribution as a suggestion rather than an
      established finding.
- name: Hanging Cheek
  description: >-
    A drooping, hanging appearance of the cheeks was the second of the three
    Williams syndrome-like facial features proposed as an OTUD6B phenotype
    expansion.
  notes: >-
    Ontology gap. HPO has no term for "hanging cheek". HP:0034273 Premature
    sagging cheeks is defined as sagging beyond that expected for age and
    HP:0000293 Full cheeks describes increased fullness, neither of which is what
    the authors describe, so this is bound to the immediate parent HP:0004426
    Abnormal cheek morphology with the published wording kept in preferred_term.
    Same attribution caveat as Periorbital Edema: the single PMID:34680978
    proband also carries a heterozygous ZMIZ1 c.1491 + 2T > C splice variant that
    skips exon 14, and ZMIZ1-related disorder (MONDO:0032855, in this entry's
    differential_diagnoses) itself causes dysmorphic facies, so attribution to
    OTUD6B alone is not secure.
  phenotype_term:
    preferred_term: Hanging cheek
    term:
      id: HP:0004426
      label: Abnormal cheek morphology
  evidence:
  - reference: PMID:34680978
    reference_title: "Compound Heterozygote of Point Mutation and Chromosomal Microdeletion Involving OTUD6B Coinciding with ZMIZ1 Variant in Syndromic Intellectual Disability."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We suggest that Williams syndrome-like phenotypes, namely, periorbital
      edema, hanging cheek, and long and smooth philtrum represent expanded
      phenotypes of OTUD6B-related ID.
    explanation: >-
      Author-asserted phenotypic expansion naming hanging cheek. PARTIAL because
      of the co-occurring ZMIZ1 splice variant in the same proband and the
      authors' own hedged framing.
- name: Long Philtrum
  description: >-
    An increased distance between the nasal base and the upper lip vermilion
    border was the third Williams syndrome-like facial feature proposed as an
    OTUD6B phenotype expansion. It is independently annotated in phenotype.hpoa
    for OMIM:617452 at 7/12 from the founding cohort, which corroborates the
    feature even though this entry's snippet comes from PMID:34680978.
  notes: >-
    No frequency band is asserted. phenotype.hpoa does carry long philtrum at
    7/12 for OMIM:617452 from PMID:28343629, which would map to FREQUENT, but the
    snippet cited here is the single-proband PMID:34680978 sentence rather than
    the cohort count, so the band is omitted rather than attributed to a source
    this entry does not quote. Same ZMIZ1 attribution caveat as Periorbital Edema
    applies to the PMID:34680978 observation itself.
  phenotype_term:
    preferred_term: Long philtrum
    term:
      id: HP:0000343
      label: Long philtrum
  evidence:
  - reference: PMID:34680978
    reference_title: "Compound Heterozygote of Point Mutation and Chromosomal Microdeletion Involving OTUD6B Coinciding with ZMIZ1 Variant in Syndromic Intellectual Disability."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We suggest that Williams syndrome-like phenotypes, namely, periorbital
      edema, hanging cheek, and long and smooth philtrum represent expanded
      phenotypes of OTUD6B-related ID.
    explanation: >-
      Author-asserted phenotypic expansion naming a long philtrum. PARTIAL
      because the proband also carries a ZMIZ1 splice variant, though the
      independent HPOA annotation of long philtrum at 7/12 for OMIM:617452 makes
      this the best-corroborated member of the Williams-like triad.
- name: Smooth Philtrum
  description: >-
    Flattening of the philtral ridges accompanied the long philtrum in the same
    proband and was reported as part of the Williams syndrome-like gestalt.
  notes: >-
    Curated separately from Long Philtrum because HPO codes philtral length
    (HP:0000343) and philtral depth (HP:0000319) as distinct terms, and the
    source sentence asserts both. Unlike long philtrum, smooth philtrum has no
    corroborating HPOA annotation for OMIM:617452, so it rests entirely on this
    one proband, who also carries the heterozygous ZMIZ1 c.1491 + 2T > C variant.
  phenotype_term:
    preferred_term: Smooth philtrum
    term:
      id: HP:0000319
      label: Smooth philtrum
  evidence:
  - reference: PMID:34680978
    reference_title: "Compound Heterozygote of Point Mutation and Chromosomal Microdeletion Involving OTUD6B Coinciding with ZMIZ1 Variant in Syndromic Intellectual Disability."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We suggest that Williams syndrome-like phenotypes, namely, periorbital
      edema, hanging cheek, and long and smooth philtrum represent expanded
      phenotypes of OTUD6B-related ID.
    explanation: >-
      Author-asserted phenotypic expansion naming a smooth philtrum. PARTIAL
      because it is a single-proband observation confounded by a co-occurring
      ZMIZ1 exon-14-skipping variant.
- name: Microcephaly
  description: >-
    Reduced occipitofrontal head circumference is reported in individuals with
    predicted loss-of-function alleles, consistent with the impaired-proliferation
    mechanism.
  frequency: FREQUENT
  notes: >-
    Frequency derivation: phenotype.hpoa annotates HP:0000252 Microcephaly for
    OMIM:617452 at 9/12 (75 percent), curated from PMID:28343629. That maps to
    the FREQUENT band (30-79 percent).
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:28343629
    reference_title: "Biallelic Variants in OTUD6B Cause an Intellectual Disability Syndrome Associated with Seizures and Dysmorphic Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In subjects with predicted loss-of-function alleles, additional features
      include global developmental delay, microcephaly, absent speech, hypotonia
    explanation: >-
      Microcephaly is listed among the features of the loss-of-function subgroup.
- name: Absent Speech
  description: >-
    Failure to develop expressive speech occurs at the severe end of the spectrum,
    in individuals with predicted loss-of-function alleles.
  phenotype_term:
    preferred_term: Absent speech
    term:
      id: HP:0001344
      label: Absent speech
  evidence:
  - reference: PMID:28343629
    reference_title: "Biallelic Variants in OTUD6B Cause an Intellectual Disability Syndrome Associated with Seizures and Dysmorphic Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      additional features include global developmental delay, microcephaly, absent
      speech, hypotonia
    explanation: >-
      Absent speech is reported in the loss-of-function subgroup.
- name: Hypotonia
  description: >-
    Diminished muscle tone contributes to feeding difficulty and to delayed gross
    motor milestones.
  frequency: FREQUENT
  notes: >-
    Frequency derivation: phenotype.hpoa annotates HP:0001290 Generalized
    hypotonia for OMIM:617452 at 9/12 (75 percent), curated from PMID:28343629.
    That maps to the FREQUENT band (30-79 percent). The generalized term is used
    here to match the HPO disease annotation.
  phenotype_term:
    preferred_term: Generalized hypotonia
    term:
      id: HP:0001290
      label: Generalized hypotonia
  evidence:
  - reference: PMID:28343629
    reference_title: "Biallelic Variants in OTUD6B Cause an Intellectual Disability Syndrome Associated with Seizures and Dysmorphic Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      global developmental delay, microcephaly, absent speech, hypotonia, growth
      retardation with prenatal onset
    explanation: >-
      Hypotonia is listed among the features of individuals with loss-of-function
      alleles.
- name: Prenatal-Onset Growth Restriction
  description: >-
    Growth failure begins in utero and persists postnatally, giving short stature and
    low weight in addition to microcephaly.
  frequency: FREQUENT
  notes: >-
    Frequency derivation: phenotype.hpoa annotates HP:0001511 Intrauterine
    growth retardation for OMIM:617452 at 7/12 (58 percent), curated from
    PMID:28343629. That maps to the FREQUENT band (30-79 percent).
  phenotype_term:
    preferred_term: Intrauterine growth retardation
    term:
      id: HP:0001511
      label: Intrauterine growth retardation
  evidence:
  - reference: PMID:28343629
    reference_title: "Biallelic Variants in OTUD6B Cause an Intellectual Disability Syndrome Associated with Seizures and Dysmorphic Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hypotonia, growth retardation with prenatal onset, feeding difficulties
    explanation: >-
      Explicitly reports growth retardation with prenatal onset.
  - reference: PMID:38389298
    reference_title: "Biallelic OTUD6B variants associated with a Kabuki syndrome-like disorder in three siblings: A clinical report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      developmental delay, growth deficiency, persistent fetal fingertip pads
    explanation: >-
      Independent confirmation of growth deficiency in a second family.
- name: Feeding Difficulties
  description: >-
    Poor feeding is common and, at the severe end of the spectrum, can require
    gastrostomy or other enteral feeding support.
  frequency: FREQUENT
  notes: >-
    Frequency derivation: phenotype.hpoa annotates HP:0011968 Feeding
    difficulties for OMIM:617452 at 9/12 (75 percent), curated from
    PMID:28343629. That maps to the FREQUENT band (30-79 percent).
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:28343629
    reference_title: "Biallelic Variants in OTUD6B Cause an Intellectual Disability Syndrome Associated with Seizures and Dysmorphic Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      growth retardation with prenatal onset, feeding difficulties, structural brain
      abnormalities
    explanation: >-
      Feeding difficulties are reported in the loss-of-function subgroup.
- name: Structural Brain Abnormalities
  description: >-
    Nonspecific structural brain abnormalities are seen on neuroimaging in a subset
    of affected individuals, with inter- and intrafamilial variability in the imaging
    findings.
  phenotype_term:
    preferred_term: Abnormal brain morphology
    term:
      id: HP:0012443
      label: Abnormal brain morphology
  evidence:
  - reference: PMID:28343629
    reference_title: "Biallelic Variants in OTUD6B Cause an Intellectual Disability Syndrome Associated with Seizures and Dysmorphic Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      feeding difficulties, structural brain abnormalities, congenital malformations
      including congenital heart disease
    explanation: >-
      Reports structural brain abnormalities as part of the multisystem phenotype.
  - reference: PMID:34354232
    reference_title: "OTUD6B-associated intellectual disability: novel variants and genetic exclusion of retinal degeneration as part of a refined phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      our patients showed inter- and intrafamilial differences with regard to the
      clinical and brain imaging findings
    explanation: >-
      Documents variability of the brain imaging phenotype within and between
      OTUD6B families.
- name: Congenital Heart Disease
  description: >-
    Congenital cardiac malformations occur in a subset of affected individuals and
    are recapitulated in the Otud6b null mouse, making cardiac evaluation part of
    initial assessment. Septal defects predominate, but conotruncal malformation
    also occurs: one proband was ascertained through antenatal diagnosis of
    Tetralogy of Fallot, and a preceding pregnancy in the same family was
    terminated for the same finding.
  frequency: FREQUENT
  notes: >-
    Frequency derivation: phenotype.hpoa annotates the specific cardiac lesions
    for OMIM:617452 against a cardiac-evaluated denominator of 6, giving atrial
    septal defect 3/6 (50 percent) and ventricular septal defect 2/6 (33
    percent), both curated from PMID:28343629. Either maps to the FREQUENT band
    (30-79 percent), so FREQUENT is applied to the parent cardiac term. Note the
    denominator is 6, not the 12 used for the neurological terms, because only a
    subset of the founding cohort had cardiac assessment reported.
  phenotype_term:
    preferred_term: Abnormal heart morphology
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:28343629
    reference_title: "Biallelic Variants in OTUD6B Cause an Intellectual Disability Syndrome Associated with Seizures and Dysmorphic Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      congenital malformations including congenital heart disease, and
      musculoskeletal features
    explanation: >-
      Reports congenital heart disease among the malformations in affected humans.
  - reference: PMID:28343629
    reference_title: "Biallelic Variants in OTUD6B Cause an Intellectual Disability Syndrome Associated with Seizures and Dysmorphic Features."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Homozygous Otud6b knockout mice were subviable, smaller in size, and had
      congenital heart defects
    explanation: >-
      The orthologous null mouse independently supports a causal role for OTUD6B loss
      in congenital heart defects.
  - reference: PMID:35707595
    reference_title: "A New Family with a Novel OTUD6B Mutation: Practicing Whole Exome Sequencing for Antenatal Diagnosis of Tetralogy of Fallot."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we report one additional case with Tetralogy of Fallot (ToF), who has
      microcephaly and dysmorphic features along with renal parenchymal disease
      with simple cortical cysts
    explanation: >-
      Extends the cardiac phenotype beyond septal defects to a conotruncal
      malformation in a genetically confirmed individual. The renal cystic disease
      in the same proband is attributed by the authors to a separate PKD1 variant
      and is therefore not curated as an OTUD6B feature here.
- name: Persistent Fetal Fingertip Pads
  description: >-
    Persistence of the fetal fingertip pads is one of the recognizable distal limb
    findings and, together with broad distal phalanges and prominent interphalangeal
    joints, has been proposed as a diagnostic handle.
  phenotype_term:
    preferred_term: Prominent fingertip pads
    term:
      id: HP:0001212
      label: Prominent fingertip pads
  evidence:
  - reference: PMID:38389298
    reference_title: "Biallelic OTUD6B variants associated with a Kabuki syndrome-like disorder in three siblings: A clinical report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      growth deficiency, persistent fetal fingertip pads, vertebral anomaly, and
      seizures in the proband
    explanation: >-
      Directly reports persistent fetal fingertip pads in affected siblings.
  - reference: PMID:34354232
    reference_title: "OTUD6B-associated intellectual disability: novel variants and genetic exclusion of retinal degeneration as part of a refined phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Broad distal phalanges (especially the thumbs and halluces) with prominent
      interphalangeal joints and fetal pads were recognized in all patients and
      hence considered pathognomonic.
    explanation: >-
      Independent report of fetal pads in all five patients of two Egyptian families.
- name: Broad Distal Phalanges
  description: >-
    Broadening of the distal phalanges, most conspicuous in the thumbs and halluces,
    is one of the distal limb anomalies named in the disorder's canonical label. In
    one series this finding was present in all five affected individuals and was
    considered pathognomonic by the authors.
  frequency: FREQUENT
  notes: >-
    Frequency derivation: phenotype.hpoa annotates HP:0011304 Broad thumb for
    OMIM:617452 at 6/12 (50 percent), curated from PMID:28343629. That maps to
    the FREQUENT band (30-79 percent). The HPO disease annotation uses the thumb
    term, which is also the digit the primary reports single out, so that term is
    bound here; the halluces are affected in parallel but are not separately
    annotated in HPOA.
  phenotype_term:
    preferred_term: Broad distal phalanges of the thumbs and halluces
    term:
      id: HP:0011304
      label: Broad thumb
  evidence:
  - reference: PMID:34354232
    reference_title: "OTUD6B-associated intellectual disability: novel variants and genetic exclusion of retinal degeneration as part of a refined phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Broad distal phalanges (especially the thumbs and halluces) with prominent
      interphalangeal joints and fetal pads were recognized in all patients and
      hence considered pathognomonic.
    explanation: >-
      Reports broad distal phalanges of thumbs and halluces in all patients studied.
- name: Prominent Interphalangeal Joints
  description: >-
    Prominence of the interphalangeal joints accompanies the broad distal phalanges
    in the characteristic hand and foot phenotype.
  phenotype_term:
    preferred_term: Prominent interphalangeal joints
    term:
      id: HP:0006237
      label: Prominent interphalangeal joints
  evidence:
  - reference: PMID:34354232
    reference_title: "OTUD6B-associated intellectual disability: novel variants and genetic exclusion of retinal degeneration as part of a refined phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Broad distal phalanges (especially the thumbs and halluces) with prominent
      interphalangeal joints and fetal pads
    explanation: >-
      Directly reports prominent interphalangeal joints as part of the distal limb
      phenotype.
- name: Polydactyly
  description: >-
    Supernumerary digits were reported in one affected girl alongside terminal
    broadening of the fingers, extending the distal limb phenotype beyond
    broadening and joint prominence. This is a single-case observation and is not
    part of the HPO disease annotation for OMIM:617452.
  phenotype_term:
    preferred_term: Polydactyly
    term:
      id: HP:0010442
      label: Polydactyly
  evidence:
  - reference: PMID:34680978
    reference_title: "Compound Heterozygote of Point Mutation and Chromosomal Microdeletion Involving OTUD6B Coinciding with ZMIZ1 Variant in Syndromic Intellectual Disability."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient also had terminal broadening of the fingers and polydactyly.
    explanation: >-
      Reports polydactyly with terminal digital broadening. Marked PARTIAL because
      this proband also carries a heterozygous ZMIZ1 c.1491 + 2T > C splice variant
      that skips exon 14, so attribution of the limb finding to OTUD6B alone is not
      secure. See the ZMIZ1 entry (MONDO:0032855) in differential_diagnoses.
- name: Macrodontia
  description: >-
    Abnormally large teeth are part of a distinctive orodental phenotype that also
    includes dental crowding, abnormally shaped teeth, and thick alveolar ridges.
  phenotype_term:
    preferred_term: Macrodontia
    term:
      id: HP:0001572
      label: Macrodontia
  evidence:
  - reference: PMID:34354232
    reference_title: "OTUD6B-associated intellectual disability: novel variants and genetic exclusion of retinal degeneration as part of a refined phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      various orodental features were present including macrodontia, dental
      crowding, abnormally shaped teeth, and thick alveolar ridges
    explanation: >-
      Directly reports macrodontia in the Egyptian OTUD6B cohort.
- name: Dental Crowding
  description: >-
    Crowding of the dental arch accompanies macrodontia in the orodental phenotype.
  phenotype_term:
    preferred_term: Dental crowding
    term:
      id: HP:0000678
      label: Dental crowding
  evidence:
  - reference: PMID:34354232
    reference_title: "OTUD6B-associated intellectual disability: novel variants and genetic exclusion of retinal degeneration as part of a refined phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      including macrodontia, dental crowding, abnormally shaped teeth, and thick
      alveolar ridges
    explanation: >-
      Directly reports dental crowding.
- name: Abnormally Shaped Teeth
  description: >-
    Abnormal crown morphology is reported alongside macrodontia and crowding.
  phenotype_term:
    preferred_term: Abnormal dental morphology
    term:
      id: HP:0006482
      label: Abnormal dental morphology
  evidence:
  - reference: PMID:34354232
    reference_title: "OTUD6B-associated intellectual disability: novel variants and genetic exclusion of retinal degeneration as part of a refined phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      macrodontia, dental crowding, abnormally shaped teeth, and thick alveolar
      ridges
    explanation: >-
      Directly reports abnormally shaped teeth.
- name: Delayed Eruption of Primary Teeth
  description: >-
    Delayed eruption of the primary dentition was reported as a novel feature in a
    three-sibling family, extending the orodental phenotype.
  phenotype_term:
    preferred_term: Delayed eruption of primary teeth
    term:
      id: HP:0000680
      label: Delayed eruption of primary teeth
  evidence:
  - reference: PMID:38389298
    reference_title: "Biallelic OTUD6B variants associated with a Kabuki syndrome-like disorder in three siblings: A clinical report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      previously unreported clinical manifestations such as delayed eruption of
      primary dentition, soft doughy skin with reduced sweating, and mirror movements
      present in our patients suggest an expansion of the phenotype
    explanation: >-
      Reports delayed eruption of primary dentition as a phenotype-expanding finding.
- name: Vertebral Anomalies
  description: >-
    Vertebral segmentation or morphology anomalies are reported among the
    musculoskeletal features.
  phenotype_term:
    preferred_term: Abnormal vertebral morphology
    term:
      id: HP:0003468
      label: Abnormal vertebral morphology
  evidence:
  - reference: PMID:38389298
    reference_title: "Biallelic OTUD6B variants associated with a Kabuki syndrome-like disorder in three siblings: A clinical report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      persistent fetal fingertip pads, vertebral anomaly, and seizures in the proband
    explanation: >-
      Reports a vertebral anomaly in the proband of the three-sibling family.
- name: Mirror Movements
  description: >-
    Involuntary mirrored movements of the contralateral hand were reported as a novel
    neurological finding, suggesting abnormal development or decussation of
    corticospinal projections.
  phenotype_term:
    preferred_term: Mirror movements
    term:
      id: HP:0001335
      label: Bimanual synkinesia
  evidence:
  - reference: PMID:38389298
    reference_title: "Biallelic OTUD6B variants associated with a Kabuki syndrome-like disorder in three siblings: A clinical report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      delayed eruption of primary dentition, soft doughy skin with reduced sweating,
      and mirror movements present in our patients suggest an expansion of the
      phenotype
    explanation: >-
      Reports mirror movements as a newly described feature in OTUD6B-related disease.
- name: Soft Doughy Skin
  description: >-
    Soft, doughy skin texture was described as part of the phenotype expansion in a
    three-sibling family.
  phenotype_term:
    preferred_term: Soft skin
    term:
      id: HP:0000977
      label: Soft skin
  evidence:
  - reference: PMID:38389298
    reference_title: "Biallelic OTUD6B variants associated with a Kabuki syndrome-like disorder in three siblings: A clinical report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      soft doughy skin with reduced sweating
    explanation: >-
      Directly reports soft doughy skin.
- name: Reduced Sweating
  description: >-
    Reduced sweating was reported together with the soft doughy skin texture,
    suggesting an ectodermal component to the phenotype.
  phenotype_term:
    preferred_term: Hypohidrosis
    term:
      id: HP:0000966
      label: Hypohidrosis
  evidence:
  - reference: PMID:38389298
    reference_title: "Biallelic OTUD6B variants associated with a Kabuki syndrome-like disorder in three siblings: A clinical report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      soft doughy skin with reduced sweating, and mirror movements
    explanation: >-
      Directly reports reduced sweating.
- name: Hypothyroidism
  description: >-
    Hypothyroidism has been reported in multiple unrelated affected individuals and
    is a treatable comorbidity, making thyroid function testing worthwhile at
    diagnosis.
  phenotype_term:
    preferred_term: Hypothyroidism
    term:
      id: HP:0000821
      label: Hypothyroidism
  evidence:
  - reference: PMID:32924626
    reference_title: "Comparison of Genetic Variants and Manifestations of OTUD6B-Related Disorder: The First Mexican Case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      this is the third patient with associated hypothyroidism and
      hypogammaglobulinemia, underscoring the value of screening for these
      conditions in other patients
    explanation: >-
      Identifies hypothyroidism recurring across at least three unrelated affected
      individuals.
  - reference: PMID:41188742
    reference_title: "Novel variant causing OTUD6B-related syndrome with ocular dysplasia and hypothyroidism: the first Chinese case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A 6-month-old girl presented with nystagmus and hypothyroidism.
    explanation: >-
      A further independent case of hypothyroidism in a genetically confirmed
      individual.
- name: Hypogammaglobulinemia
  description: >-
    Reduced circulating immunoglobulin has been reported alongside hypothyroidism in
    a minority of affected individuals, prompting recommendations for immunologic
    screening.
  phenotype_term:
    preferred_term: Hypogammaglobulinemia
    term:
      id: HP:0004313
      label: Decreased circulating immunoglobulin concentration
  evidence:
  - reference: PMID:32924626
    reference_title: "Comparison of Genetic Variants and Manifestations of OTUD6B-Related Disorder: The First Mexican Case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the third patient with associated hypothyroidism and hypogammaglobulinemia
    explanation: >-
      Reports hypogammaglobulinemia recurring in a third unrelated affected
      individual.
- name: Nystagmus
  description: >-
    Nystagmus was the presenting sign in a 6-month-old girl who also had optic disc
    hypoplasia and retinal abnormalities.
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: PMID:41188742
    reference_title: "Novel variant causing OTUD6B-related syndrome with ocular dysplasia and hypothyroidism: the first Chinese case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A 6-month-old girl presented with nystagmus and hypothyroidism.
    explanation: >-
      Reports nystagmus as the presenting ocular sign in a genetically confirmed case.
- name: Optic Disc Hypoplasia and Ocular Developmental Anomalies
  description: >-
    Optic disc hypoplasia with retinal abnormalities was described in a single
    reported individual. The authors emphasize that this was the first such report
    and call for further investigation before accepting ocular developmental anomaly
    as an established part of the phenotype.
  frequency: VERY_RARE
  notes: >-
    Frequency derivation: PMID:41188742 states that none of the 27 previously
    reported IDDFSDA cases exhibited ocular developmental abnormalities, and reports
    one new case with them. That gives 1 of 28 reported individuals (approximately
    3.6 percent), which maps to the VERY_RARE band (1-4 percent). This is the only
    phenotype in this entry with a published denominator; all others omit a
    frequency band deliberately.
  phenotype_term:
    preferred_term: Optic disc hypoplasia
    term:
      id: HP:0007766
      label: Optic disc hypoplasia
  evidence:
  - reference: PMID:41188742
    reference_title: "Novel variant causing OTUD6B-related syndrome with ocular dysplasia and hypothyroidism: the first Chinese case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      On admission, optic disc hypoplasia and retinal abnormalities were detected
      with a typical phenotype of IDDFSDA.
    explanation: >-
      Reports optic disc hypoplasia and retinal abnormalities in a genetically
      confirmed individual.
  - reference: PMID:41188742
    reference_title: "Novel variant causing OTUD6B-related syndrome with ocular dysplasia and hypothyroidism: the first Chinese case."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Significantly, none of the 27 previously reported IDDFSDA cases exhibited
      ocular developmental abnormalities.
    explanation: >-
      Supplies the denominator for the VERY_RARE band and simultaneously flags that
      the association rests on a single observation.
- name: Retinal Degeneration
  description: >-
    Retinal degeneration was initially observed in two brothers with homozygous
    OTUD6B variants, but exome reanalysis showed it was caused by a co-segregating
    homozygous RP1L1 nonsense variant causing autosomal recessive retinitis
    pigmentosa 88, not by OTUD6B. This entry records retinal degeneration as
    explicitly excluded from the OTUD6B phenotype. It is distinct from the optic
    disc hypoplasia and retinal abnormalities reported separately in PMID:41188742,
    which remain a single unreplicated observation.
  phenotype_term:
    preferred_term: Retinal degeneration
    term:
      id: HP:0000546
      label: Retinal degeneration
  evidence:
  - reference: PMID:34354232
    reference_title: "OTUD6B-associated intellectual disability: novel variants and genetic exclusion of retinal degeneration as part of a refined phenotype."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Retinal degeneration, albeit present in both patients from Family I, was shown
      to be unrelated to OTUD6B, demonstrating the need for in-depth analysis of WES
      data in consanguineous families to uncover simultaneous autosomal recessive
      disorders.
    explanation: >-
      Explicitly refutes retinal degeneration as part of the OTUD6B phenotype and
      attributes it to a second, independent recessive disorder in the same family.
  - reference: PMID:34354232
    reference_title: "OTUD6B-associated intellectual disability: novel variants and genetic exclusion of retinal degeneration as part of a refined phenotype."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biallelic pathogenic variants in RP1L1 cause autosomal recessive retinitis
      pigmentosa type 88 (RP88). Thus, RP1L1 dysfunction likely accounts for the
      visual phenotype in this family
    explanation: >-
      Names the alternative causal gene, closing the loop on the exclusion.
genetic:
- name: OTUD6B biallelic pathogenic variants
  gene_term:
    preferred_term: OTUD6B
    term:
      id: hgnc:24281
      label: OTUD6B
  association: Biallelic pathogenic variants are causative for IDDFSDA
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: PMID:35430327
      reference_title: "Novel biallelic variants affecting the OTU domain of the gene OTUD6B associate with severe intellectual disability syndrome and molecular dynamics simulations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        an autosomal recessive multisystem disorder caused by compound heterozygous
        or homozygous variants in the gene OTUD6B
      explanation: >-
        States the recessive, biallelic disease model for OTUD6B.
  notes: >-
    Reported disease alleles span several classes. Nonsense: c.271C>T p.(Gln91Ter)
    (Egyptian family) and c.433C>T p.(Arg145*) (Mexican case). Canonical splice
    donor: c.324+1G>C and c.405+1G>A (Italian replication case), functionally shown
    to cause exon 2 and exon 3 skipping with nonsense-mediated decay. Missense in the
    OTU domain: c.767G>T p.(Gly256Val), c.815T>G p.(Ile272Arg), plus Tyr216Cys and
    Ile274Arg analyzed by molecular dynamics. Compound heterozygous
    frameshift-plus-missense genotypes have also been reported, and in one proband
    the second hit was a 0.118 Mb paternally inherited 8q21.3 deletion spanning
    OTUD6B in trans with a maternal frameshift, so chromosomal microarray as well as
    sequencing can be needed to establish biallelic status. Reported missense alleles
    cluster in or immediately adjacent to the OTU catalytic domain. Transcript
    numbering follows NM_016023.5 and the 293-residue UniProt Q8N6M0 protein; note
    that the original 2017 paper's full text uses a longer isoform numbering, so
    residue positions quoted across papers are not directly comparable without
    checking the isoform. ClinGen classifies the OTUD6B-syndromic intellectual
    disability relationship as Definitive (AR, SOP10, Intellectual Disability and
    Autism Gene Curation Expert Panel, 2024-08-22); that structured assertion could
    not be cached as a CGGV reference here (see the entry-level notes), so it is
    recorded descriptively rather than as a validated snippet.
  evidence:
  - reference: PMID:28343629
    reference_title: "Biallelic Variants in OTUD6B Cause an Intellectual Disability Syndrome Associated with Seizures and Dysmorphic Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we report biallelic pathogenic variants in OTUD6B in 12 individuals from 6
      independent families with an intellectual disability syndrome associated with
      seizures and dysmorphic features
    explanation: >-
      The gene-disease-establishing multi-family cohort.
  - reference: PMID:34354232
    reference_title: "OTUD6B-associated intellectual disability: novel variants and genetic exclusion of retinal degeneration as part of a refined phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole-exome sequencing (WES) identified a novel nonsense variant in OTUD6B
      (c.271C>T, p.(Gln91Ter))
    explanation: >-
      Documents a specific nonsense allele identified by exome sequencing.
  - reference: PMID:34354232
    reference_title: "OTUD6B-associated intellectual disability: novel variants and genetic exclusion of retinal degeneration as part of a refined phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In Family II, targeted sequencing revealed a novel homozygous missense variant
      (c.767G>T, p.(Gly256Val)), confirming the clinically suspected OTUD6B-related ID.
    explanation: >-
      Documents a homozygous OTU-domain missense allele.
  - reference: PMID:32924626
    reference_title: "Comparison of Genetic Variants and Manifestations of OTUD6B-Related Disorder: The First Mexican Case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The homozygous c.433C>T (p.Arg145*) variant of the OTUD6B gene confirmed this
      intellectual disability syndrome.
    explanation: >-
      Documents a homozygous nonsense allele in an independent case.
  - reference: PMID:30364145
    reference_title: "First Replication of the Involvement of OTUD6B in Intellectual Disability Syndrome With Seizures and Dysmorphic Features."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      both variants affect OTUD6B splicing and lead to the production of aberrant
      transcripts
    explanation: >-
      Patient-RNA functional validation that the two canonical splice-donor alleles
      are indeed loss-of-function.
  - reference: PMID:35707595
    reference_title: "A New Family with a Novel OTUD6B Mutation: Practicing Whole Exome Sequencing for Antenatal Diagnosis of Tetralogy of Fallot."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      was revealed by whole exome sequencing (WES) along with a previously
      reported heterozygous PKD1 variant, unraveling the blended phenotype
      observed in the proband.
    explanation: >-
      Documents a further homozygous OTU-domain missense allele, c.815T>G
      p.(Ile272Arg), and is an explicit
      worked example of a blended two-locus phenotype, which matters for attribution
      discipline in this disorder.
  - reference: PMID:34680978
    reference_title: "Compound Heterozygote of Point Mutation and Chromosomal Microdeletion Involving OTUD6B Coinciding with ZMIZ1 Variant in Syndromic Intellectual Disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The CMA showed a paternally inherited 0.118 Mb deletion of 8q21.3,
      chr8:92084087-92202189, with OTUD6B involved.
    explanation: >-
      Documents the allelic class of a whole-gene copy-number deletion supplying
      the second hit in trans with a point mutation. The diagnostic-workup
      consequence of this allelic class is modeled in the diagnosis section
      rather than here.
diagnosis:
- name: Trio Exome Sequencing
  description: >-
    There are no formal clinical diagnostic criteria; the diagnosis is molecular.
    Trio-based exome sequencing is the appropriate first-line test for a child
    with global developmental delay, seizures, the distal limb findings, and a
    dysmorphic facial gestalt, and it is how the reported cases were ascertained.
    The trio design matters specifically because the disorder is autosomal
    recessive: phasing the two candidate alleles across the parents is what
    establishes that they are in trans, and it is also what identifies each
    parent as a carrier for counseling.
  diagnosis_term:
    preferred_term: trio exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  results: >-
    Biallelic OTUD6B variants in trans; reported alleles include splice-donor,
    frameshift, nonsense, and OTU-domain missense changes
  markers: OTUD6B (hgnc:24281)
  evidence:
  - reference: PMID:41188742
    reference_title: "Novel variant causing OTUD6B-related syndrome with ocular dysplasia and hypothyroidism: the first Chinese case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pathogenic gene variants were identified using whole exome trio sequencing
      (trioWES) and confirmed using Sanger sequencing.
    explanation: >-
      States the trio exome plus Sanger confirmation pathway that produced the
      molecular diagnosis in a genetically confirmed case.
  - reference: PMID:30364145
    reference_title: "First Replication of the Involvement of OTUD6B in Intellectual Disability Syndrome With Seizures and Dysmorphic Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sanger sequencing confirmed the segregation of the variants in the family,
      showing that both parents are carriers of one mutation.
    explanation: >-
      Documents the parental segregation step that establishes the two alleles
      are in trans, which is the reason the trio design is specified here.
- name: Chromosomal Microarray
  description: >-
    Chromosomal microarray is required alongside sequencing rather than being
    superseded by it. One reported proband is a compound heterozygote for an
    OTUD6B point mutation and a paternally inherited 0.118 Mb whole-gene deletion
    of 8q21.3; exome sequencing alone reports that individual as a single
    heterozygote and the diagnosis is missed. A single apparently heterozygous
    OTUD6B variant in a clinically compatible child should therefore prompt
    copy-number analysis of the locus.
  diagnosis_term:
    preferred_term: chromosomal microarray testing
    term:
      id: NCIT:C18477
      label: Microarray Analysis
  results: >-
    May reveal a whole-gene or partial-gene 8q21.3 deletion supplying the second
    hit in trans with a sequence variant
  markers: 8q21.3
  evidence:
  - reference: PMID:34680978
    reference_title: "Compound Heterozygote of Point Mutation and Chromosomal Microdeletion Involving OTUD6B Coinciding with ZMIZ1 Variant in Syndromic Intellectual Disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cytogenomic microarray (CMA), whole exome sequencing (WES), and mRNA
      analysis were performed.
    explanation: >-
      Records the combined assay panel used to reach this diagnosis, with CMA run
      in parallel with sequencing rather than as a superseded first-tier test.
  - reference: PMID:34680978
    reference_title: "Compound Heterozygote of Point Mutation and Chromosomal Microdeletion Involving OTUD6B Coinciding with ZMIZ1 Variant in Syndromic Intellectual Disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The CMA showed a paternally inherited 0.118 Mb deletion of 8q21.3,
      chr8:92084087-92202189, with OTUD6B involved.
    explanation: >-
      The specific copy-number second hit that only microarray detected, which is
      what makes CMA non-optional in this disorder's workup.
- name: Reflex OTUD6B Testing in Suspected Rubinstein-Taybi or Kabuki Syndrome
  description: >-
    The facial gestalt overlaps two better-known syndromes, so affected children
    are commonly worked up for those first. The authors of the first replication
    report explicitly recommend screening OTUD6B in a child suspected of having
    Rubinstein-Taybi syndrome once CREBBP and EP300 are negative. An initial
    clinical suspicion of Kabuki syndrome has likewise been recorded in several
    affected individuals. This is actionable reflex testing rather than an
    academic differential.
  diagnosis_term:
    preferred_term: reflex OTUD6B genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  results: >-
    Biallelic OTUD6B variants in a child previously worked up, negatively, for
    Rubinstein-Taybi or Kabuki syndrome
  evidence:
  - reference: PMID:30364145
    reference_title: "First Replication of the Involvement of OTUD6B in Intellectual Disability Syndrome With Seizures and Dysmorphic Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      appropriateness of screening OTUD6B in suspected Rubinstein-Taybi syndrome
      patients with negative results after the screening of the major genes
    explanation: >-
      The authors' own explicit reflex-testing recommendation, which is a
      diagnostic-pathway claim rather than a phenotype claim.
  - reference: PMID:38389298
    reference_title: "Biallelic OTUD6B variants associated with a Kabuki syndrome-like disorder in three siblings: A clinical report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      previous publications have reported an initial clinical suspicion for
      Kabuki syndrome (KS) in some affected individuals
    explanation: >-
      Documents that the Kabuki misdirection has actually occurred in practice,
      supporting the second half of the reflex-testing recommendation.
treatments:
- name: Antiseizure Pharmacotherapy
  description: >-
    Seizures are managed with standard antiseizure medication. Valproate was used to
    treat generalized tonic-clonic seizures in a reported individual with biallelic
    OTUD6B splice variants. There is no disorder-specific antiseizure protocol and no
    evidence that any particular agent is preferred in OTUD6B-related disease; drug
    choice follows general pediatric epilepsy practice and seizure semiology.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: valproic acid
      term:
        id: CHEBI:39867
        label: valproic acid
  evidence:
  - reference: PMID:30364145
    reference_title: "First Replication of the Involvement of OTUD6B in Intellectual Disability Syndrome With Seizures and Dysmorphic Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At 5 years, tonic-clonic seizures occurred, thus valproate treatment was
      started.
    explanation: >-
      Documents actual antiseizure pharmacotherapy in a genetically confirmed
      individual.
- name: Levothyroxine Replacement for Hypothyroidism
  description: >-
    Hypothyroidism recurs in unrelated affected individuals and is the one
    genuinely treatable manifestation of this disorder, which is why endocrine
    surveillance is recommended in the first place. Standard thyroid hormone
    replacement is used; nothing about the OTUD6B genotype changes the drug or
    the monitoring. In the reported Chinese case, levothyroxine was started in
    the week the newborn metabolic screen returned, and by 3 years 6 months the
    dose had been titrated down with thyroid function in the normal range on
    every check, so this is a treatment with a documented biochemical response
    in a genetically confirmed individual.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: levothyroxine
      term:
        id: CHEBI:18332
        label: L-thyroxine
  evidence:
  - reference: PMID:41188742
    reference_title: "Novel variant causing OTUD6B-related syndrome with ocular dysplasia and hypothyroidism: the first Chinese case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She started levothyroxine sodium tablets that same week.
    explanation: >-
      Documents actual levothyroxine therapy in a genetically confirmed
      individual with OTUD6B-related hypothyroidism.
  - reference: PMID:41188742
    reference_title: "Novel variant causing OTUD6B-related syndrome with ocular dysplasia and hypothyroidism: the first Chinese case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At her last visit, age 3 years 6 months, the dose was down
      to 12.5  µg daily, with every thyroid check since 3monts
      age within the normal range.
    explanation: >-
      Records the biochemical response and dose titration on follow-up. Quoted
      verbatim from the cached full text including its typographic artifacts
      ("3monts"), per the never-retype rule.
- name: Endocrine and Immunologic Surveillance
  description: >-
    Because hypothyroidism and hypogammaglobulinemia have recurred in unrelated
    affected individuals and both are treatable, thyroid function testing and
    immunoglobulin quantification are recommended at diagnosis and on follow-up.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:32924626
    reference_title: "Comparison of Genetic Variants and Manifestations of OTUD6B-Related Disorder: The First Mexican Case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the third patient with associated hypothyroidism and hypogammaglobulinemia,
      underscoring the value of screening for these conditions in other patients
    explanation: >-
      The authors explicitly recommend screening for these two treatable
      comorbidities in other affected individuals.
- name: Multidisciplinary Supportive Care
  description: >-
    Management is supportive and symptom-directed: seizure control, nutritional and
    feeding support for poor growth and feeding difficulty, developmental and
    rehabilitative therapies, cardiac evaluation for congenital heart disease, and
    dental care for the orodental phenotype. There is no disease-modifying therapy.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:32924626
    reference_title: "Comparison of Genetic Variants and Manifestations of OTUD6B-Related Disorder: The First Mexican Case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The current challenge with this patient is to ensure medical management of his
      seizures and provide him with a better quality of life.
    explanation: >-
      Characterizes present-day management as symptomatic and quality-of-life
      focused rather than disease-modifying.
  - reference: PMID:32924626
    reference_title: "Comparison of Genetic Variants and Manifestations of OTUD6B-Related Disorder: The First Mexican Case."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The possibilities of additional therapeutic approaches may increase by
      understanding the physiopathology of the involved pathways.
    explanation: >-
      States that mechanism-targeted therapy does not yet exist and remains
      aspirational.
- name: Genetic Counseling and Carrier Testing
  description: >-
    Autosomal recessive inheritance gives a 25 percent sibling recurrence risk.
    Counseling should cover the recessive model, carrier testing of parents and
    at-risk relatives, and the option of prenatal or preimplantation testing once the
    familial variants are known. Consanguinity is common in reported families, and
    the RP1L1 experience in PMID:34354232 shows that a second independent recessive
    disorder can co-segregate and confound the phenotype, so exome or genome data
    should be reanalyzed in depth in consanguineous pedigrees.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:34354232
    reference_title: "OTUD6B-associated intellectual disability: novel variants and genetic exclusion of retinal degeneration as part of a refined phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      demonstrating the need for in-depth analysis of WES data in consanguineous
      families to uncover simultaneous autosomal recessive disorders
    explanation: >-
      Directly supports the counseling and reanalysis recommendation for
      consanguineous families.
differential_diagnoses:
- name: BPTF-related neurodevelopmental disorder with dysmorphic facies and distal limb anomalies
  disease_term:
    preferred_term: BPTF-related neurodevelopmental disorder (NEDDFL)
    term:
      id: MONDO:0060596
      label: neurodevelopmental disorder with dysmorphic facies and distal limb anomalies
  description: >-
    A distinct autosomal dominant entity (MONDO:0060596, OMIM:617755) caused by
    heterozygous variants in BPTF (hgnc:3581). Its MONDO label differs from this
    disorder's by two words, which makes it the single most likely entity to be
    conflated with OTUD6B disease in a text or label-based search.
  distinguishing_features:
  - >-
    Molecular: BPTF (hgnc:3581) heterozygous, autosomal dominant and typically de
    novo, versus OTUD6B (hgnc:24281) biallelic and autosomal recessive. The
    inheritance mode alone separates them in almost every family.
  - >-
    Nomenclature: the near-identical MONDO labels are the hazard, not the
    phenotypes. Confirm the causative gene before importing any cohort data
    published under the "dysmorphic facies and distal limb anomalies" phrasing.
  notes: >-
    PMID:33522091 is cited here, and only here. It is a 25-individual NEDDFL
    cohort and it is exactly the kind of paper a label-based search would sweep
    into this entry by mistake; recording it against the differential is the
    honest place for it, and none of its phenotype data is used anywhere in the
    OTUD6B sections.
  evidence:
  - reference: PMID:33522091
    reference_title: "Phenotypic expansion of the BPTF-related neurodevelopmental disorder with dysmorphic facies and distal limb anomalies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neurodevelopmental disorder with dysmorphic facies and distal limb
      anomalies (NEDDFL), defined primarily by developmental delay/intellectual
      disability, speech delay, postnatal microcephaly, and dysmorphic features,
      is a syndrome resulting from heterozygous variants in the dosage-sensitive
      bromodomain PHD finger chromatin remodeler transcription factor BPTF gene.
    explanation: >-
      Establishes in the source's own words that the near-identically labelled
      NEDDFL entity is caused by heterozygous BPTF variants, which is the
      molecular discriminator this differential turns on.
- name: ZMIZ1-related neurodevelopmental disorder with dysmorphic facies and distal skeletal anomalies
  disease_term:
    preferred_term: ZMIZ1-related neurodevelopmental disorder (NEDDFSA)
    term:
      id: MONDO:0032855
      label: neurodevelopmental disorder with dysmorphic facies and distal skeletal anomalies
  description: >-
    A distinct autosomal dominant entity (MONDO:0032855, OMIM:618659) caused by
    heterozygous variants in ZMIZ1 (hgnc:16493). Its label differs from this
    disorder's only in "skeletal" versus "limb". This is not only a label
    hazard: PMID:34680978 reports a proband who genuinely carries variants in
    both genes, so the two entities can co-occur in one patient.
  distinguishing_features:
  - >-
    Molecular: ZMIZ1 (hgnc:16493) heterozygous and autosomal dominant, versus
    biallelic recessive OTUD6B. ZMIZ1 is a transcriptional coregulator, not a
    deubiquitinase, so there is no shared mechanism to justify pooling evidence.
  - >-
    Co-occurrence, not just confusion: in PMID:34680978 the same 5-year-old girl
    carries a hemizygous OTUD6B c.873delA over a paternal 8q21.3 whole-gene
    deletion AND a heterozygous ZMIZ1 c.1491 + 2T > C splice variant confirmed by
    mRNA study to skip exon 14. Her Williams syndrome-like facial features
    (periorbital edema, hanging cheek, long and smooth philtrum) and her
    polydactyly are curated in this entry with supports PARTIAL for exactly this
    reason. Finding a ZMIZ1 variant therefore does not exclude OTUD6B disease,
    and vice versa.
  notes: >-
    Cross-reference: the phenotypes Periorbital Edema, Hanging Cheek, Long
    Philtrum, Smooth Philtrum, and Polydactyly in this entry all derive from the
    dual-locus PMID:34680978 proband and all name this differential in their
    attribution notes.
  evidence:
  - reference: PMID:34680978
    reference_title: "Compound Heterozygote of Point Mutation and Chromosomal Microdeletion Involving OTUD6B Coinciding with ZMIZ1 Variant in Syndromic Intellectual Disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The OTUD6B and ZMIZ1 genes were recently identified as causes of syndromic
      intellectual disability (ID) with shared phenotypes of facial dysmorphism,
      distal limb anomalies, and seizure disorders.
    explanation: >-
      States the phenotypic overlap that makes ZMIZ1 a differential for this
      disorder, in the authors' own words.
  - reference: PMID:34680978
    reference_title: "Compound Heterozygote of Point Mutation and Chromosomal Microdeletion Involving OTUD6B Coinciding with ZMIZ1 Variant in Syndromic Intellectual Disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      OTUD6B- and ZMIZ1-related ID are inherited in autosomal recessive and
      autosomal dominant patterns, respectively.
    explanation: >-
      Sources the inheritance-mode discriminator that separates the two entities
      in nearly every family.
  - reference: PMID:34680978
    reference_title: "Compound Heterozygote of Point Mutation and Chromosomal Microdeletion Involving OTUD6B Coinciding with ZMIZ1 Variant in Syndromic Intellectual Disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This ZMIZ1 variant yielded exon 14 skipping, as evidenced by mRNA study.
    explanation: >-
      Functional confirmation that the second-locus ZMIZ1 allele in this proband
      is real and consequential, which is what makes it a genuine confounder for
      the facial phenotypes rather than an incidental finding.
- name: OTUD5-related multiple congenital anomalies syndrome
  disease_term:
    preferred_term: OTUD5-related multiple congenital anomalies-neurodevelopmental syndrome (MCAND)
    term:
      id: MONDO:0025351
      label: multiple congenital anomalies-neurodevelopmental syndrome, X-linked
  description: >-
    An X-linked disorder (MONDO:0025351, OMIM:301056) caused by hemizygous
    variants in OTUD5 (hgnc:25402), confirmed against the MONDO
    `RO:0004003` gene-association relation. OTUD5 is a member
    of the same OTU deubiquitinase family as OTUD6B, so the two share
    ubiquitin-signalling mechanism language and are frequently co-discussed in
    reviews of OTU-family disease.
  distinguishing_features:
  - >-
    Molecular: X-linked hemizygous OTUD5 in males, versus autosomal recessive
    biallelic OTUD6B in either sex.
  - >-
    Literature hazard: papers about "OTU deubiquitinase deficiency" may describe
    either gene. Check which gene the reported cohort actually carries variants
    in before citing it here.
- name: OTUD7A-related phenotypes and the 15q13.3 microdeletion syndrome
  disease_term:
    preferred_term: 15q13.3 microdeletion syndrome (the OTUD7A-containing interval)
    term:
      id: MONDO:0012774
      label: chromosome 15q13.3 microdeletion syndrome
  notes: >-
    The bound term is the contiguous-gene deletion syndrome (MONDO:0012774,
    OMIM:612001), not an OTUD7A gene-disease entity. MONDO carries no
    `RO:0004003` OTUD7A association on this term, and there is no separate clean
    MONDO entity for OTUD7A-related disease, so the deletion syndrome is the
    correct and only bindable target. The OTUD7A framing is retained in the
    description because the literature hazard is the gene-family adjacency, not
    the deletion syndrome's clinical picture.
  description: >-
    OTUD7A lies within the 15q13.3 microdeletion critical region and is another
    OTU-family gene implicated in neurodevelopmental disease, so it appears
    alongside OTUD6B in family-level reviews.
  distinguishing_features:
  - >-
    Molecular: a recurrent copy-number loss at 15q13.3 detected by
    chromosomal microarray, versus biallelic OTUD6B sequence variants detected
    by exome or gene-panel sequencing. Different assay, different mechanism.
references:
- reference: PMID:28343629
  title: "Biallelic Variants in OTUD6B Cause an Intellectual Disability Syndrome Associated with Seizures and Dysmorphic Features."
- reference: PMID:30364145
  title: "First Replication of the Involvement of OTUD6B in Intellectual Disability Syndrome With Seizures and Dysmorphic Features."
- reference: PMID:31147255
  title: "[First Spanish case of syndromic intellectual disability with dysmorphic facies, seizures, and distal limb anomalies caused by balletic mutations in the OTUD6B gene]."
- reference: PMID:32181568
  title: Phenotypic expansion of OTUD6B-related syndrome.
- reference: PMID:32924626
  title: "Comparison of Genetic Variants and Manifestations of OTUD6B-Related Disorder: The First Mexican Case."
- reference: PMID:34354232
  title: "OTUD6B-associated intellectual disability: novel variants and genetic exclusion of retinal degeneration as part of a refined phenotype."
- reference: PMID:34680978
  title: "Compound Heterozygote of Point Mutation and Chromosomal Microdeletion Involving OTUD6B Coinciding with ZMIZ1 Variant in Syndromic Intellectual Disability."
- reference: PMID:35707595
  title: "A New Family with a Novel OTUD6B Mutation: Practicing Whole Exome Sequencing for Antenatal Diagnosis of Tetralogy of Fallot."
- reference: PMID:35430327
  title: "Novel biallelic variants affecting the OTU domain of the gene OTUD6B associate with severe intellectual disability syndrome and molecular dynamics simulations."
- reference: PMID:38389298
  title: "Biallelic OTUD6B variants associated with a Kabuki syndrome-like disorder in three siblings: A clinical report and literature review."
- reference: PMID:41188742
  title: "Novel variant causing OTUD6B-related syndrome with ocular dysplasia and hypothyroidism: the first Chinese case."
- reference: PMID:27864334
  title: Deubiquitinase OTUD6B Isoforms Are Important Regulators of Growth and Proliferation.
- reference: PMID:33421002
  title: Studying OTUD6B-OTUB1 Protein-Protein Interaction by Low-Throughput GFP-Trap Assays and High-Throughput AlphaScreen Assays.
- reference: PMID:33522091
  title: "Phenotypic expansion of the BPTF-related neurodevelopmental disorder with dysmorphic facies and distal limb anomalies."