name: Hearing Loss Autosomal Recessive 100
category: Mendelian
creation_date: "2026-09-08T00:00:00Z"
synonyms:
- DFNB100
- deafness, autosomal recessive 100
- PPIP5K2-related nonsyndromic hearing loss
description: >-
  DFNB100 is autosomal recessive nonsyndromic sensorineural hearing loss caused by
  biallelic variants in PPIP5K2, which encodes one of the two human diphosphoinositol
  pentakisphosphate kinases. It is defined by a single founder missense allele,
  c.2510G>A p.(Arg837His), homozygous in two large consanguineous Pakistani families
  (PKDF041 and PKDF751) that together delimit the DFNB100 locus on chromosome 5.
  Affected individuals have prelingual, bilateral, severe-to-profound sensorineural
  hearing loss with normal tympanometry, absent transient evoked otoacoustic
  emissions, no overt vestibular dysfunction, and no retinal degeneration.

  The mechanism is what distinguishes this entry from the other numbered DFNB loci.
  PPIP5K2 is a bifunctional enzyme that interconverts the inositol pyrophosphates
  5-InsP7 and InsP8 through mutually competing kinase and phosphatase domains. The
  Arg837His substitution sits in the phosphatase domain, and in vitro it both lowers
  IP8 phosphatase activity and raises 5-IP7 kinase activity, so the net effect is
  increased metabolic flux toward InsP8 rather than a simple loss of enzyme. The
  route to deafness therefore runs through inositol pyrophosphate signalling rather
  than through a structural, gap-junction or ion-transport lesion; the founding report
  presents it as the first demonstration that PP-IP metabolism is required for inner
  ear function at all.
disease_term:
  preferred_term: hearing loss, autosomal recessive 100
  term:
    id: MONDO:0032740
    label: hearing loss, autosomal recessive 100
parents:
- hearing loss, autosomal recessive
external_assertions:
- name: OMIM deafness, autosomal recessive 100 record
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:618422
  url: https://omim.org/entry/618422
  description: >-
    The OMIM phenotype identifier that MONDO:0032740 cross-references, confirmed
    independently against the NCBI MedGen record for concept 1682525 (which carries
    the same MIM number and the OMIM title DEAFNESS, AUTOSOMAL RECESSIVE 100).
    Recorded here rather than under `mappings` because the `DiseaseMappings` class
    carries only ICD-10-CM, ICD-11, MONDO and NCIT slots.
- name: OMIM PPIP5K2 gene record
  source: OMIM
  assertion_type: gene_record
  external_id: OMIM:611648
  url: https://omim.org/entry/611648
  description: >-
    The gene-level MIM number for PPIP5K2. Confirmed against NCBI's mim2gene_medgen
    table, which maps MIM 611648 to NCBI Gene 23262 as type `gene` and MIM 618422 to
    the same gene as type `phenotype`, so the gene and phenotype identifiers are not
    interchangeable.
references:
- reference: PMID:20301607
  title: "Genetic Hearing Loss Overview."
  tags:
  - GeneReviews
- reference: PMID:29590114
  title: "Mutations in Diphosphoinositol-Pentakisphosphate Kinase PPIP5K2 are associated with hearing loss in human and mouse."

inheritance:
- name: Autosomal recessive
  description: >-
    Both reported families are consanguineous Pakistani kindreds in which affected
    individuals are homozygous for PPIP5K2 c.2510G>A and unaffected relatives are
    not. Penetrance and expressivity are recorded as UNKNOWN rather than COMPLETE
    and CONSISTENT: only two families and a single allele have been described, which
    is too little to support a quantitative statement either way. Worth noting for
    counselling is that human heterozygotes are unaffected, whereas heterozygous
    Ppip5k2 gene-trap mice show a measurable high-frequency threshold shift and
    basal-turn outer hair cell loss - so the mouse allele behaves semi-dominantly
    while the human allele does not.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  penetrance: UNKNOWN
  expressivity: UNKNOWN
  evidence:
  - reference: PMID:29590114
    reference_title: "Mutations in Diphosphoinositol-Pentakisphosphate Kinase PPIP5K2 are associated with hearing loss in human and mouse."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exome enrichment followed by massive parallel sequencing revealed a c.2510G>A transition variant in PPIP5K2 that segregated with DFNB100-associated hearing loss in two large apparently unrelated Pakistani families."
    explanation: >-
      Records segregation of a single homozygous allele with hearing loss in two
      consanguineous families, the basis for the recessive assignment.
genetic:
- name: PPIP5K2
  gene_term:
    preferred_term: PPIP5K2
    term:
      id: hgnc:29035
      label: PPIP5K2
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    PPIP5K2 (diphosphoinositol pentakisphosphate kinase 2, 5q21.1) encodes a large
    bifunctional enzyme with an N-terminal kinase domain, a histidine acid
    phosphatase domain, and an intrinsically disordered region. Despite the
    phosphatase-family fold it is the kinase activity that defines the protein's
    role, synthesising InsP8 from 5-InsP7. Humans carry a paralogue, PPIP5K1, but
    in mouse inner ear Ppip5k1 transcript levels in hair cells, supporting cells and
    ganglion neurons are up to 100-fold below Ppip5k2, which is why loss of PPIP5K2
    function is not buffered in the cochlea. The gene also carries the aliases
    HISPPD1, VIP2, IP7K2 and CFAP160; the last is a cilia-and-flagella designation
    and is not the basis of the hearing phenotype described here.
  variants:
  - name: PPIP5K2 c.2510G>A p.(Arg837His)
    description: >-
      The only PPIP5K2 allele so far associated with human disease. It substitutes an
      arginine conserved from Drosophila to human, nine residues C-terminal to the
      histidine that is catalytically essential for IP8 phosphatase activity in the
      yeast orthologue, and it is present in all eleven annotated PPIP5K2 splice
      isoforms. It was absent from 180 ethnically matched Pakistani controls and sits
      at 0.000146 in ExAC. A shared flanking haplotype in the two families indicates a
      founder allele rather than two independent mutational events.
    gene:
      preferred_term: PPIP5K2
      term:
        id: hgnc:29035
        label: PPIP5K2
    evidence:
    - reference: PMID:29590114
      reference_title: "Mutations in Diphosphoinositol-Pentakisphosphate Kinase PPIP5K2 are associated with hearing loss in human and mouse."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "SNPs linked to PPIP5K2 were genotyped in affected individuals of the PKDF041 and PKDF751 families, and the flanking haplotype was consistent with a founder effect for c.2510G>A variant (S3 Table)."
      explanation: >-
        Establishes that the two families share a founder allele, which is why the
        entry describes a single allele rather than allelic heterogeneity.
    - reference: PMID:29590114
      reference_title: "Mutations in Diphosphoinositol-Pentakisphosphate Kinase PPIP5K2 are associated with hearing loss in human and mouse."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We did not detect this variant in 180 ethnically-matched Pakistani control samples"
      explanation: >-
        Population control data supporting pathogenicity of the allele in these families.
  evidence:
  - reference: PMID:29590114
    reference_title: "Mutations in Diphosphoinositol-Pentakisphosphate Kinase PPIP5K2 are associated with hearing loss in human and mouse."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report a severe-to-profound sensorineural hearing loss locus, DFNB100 on chromosome 5q13.2-q23.2."
    explanation: >-
      Names the DFNB100 locus that PPIP5K2 was subsequently identified within.
  - reference: PMID:29590114
    reference_title: "Mutations in Diphosphoinositol-Pentakisphosphate Kinase PPIP5K2 are associated with hearing loss in human and mouse."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Yet surprisingly, as far as we are aware, our work provides the first description of any amino acid variant in either PPIP5K1 or PPIP5K2 that is both functionally-significant and associates with a human disorder."
    explanation: >-
      The authors' own statement that no PPIP5K1 or PPIP5K2 variant had previously
      been tied to human disease. Graded OTHER because it is a claim about the state
      of the literature rather than a result from a study design.
pathophysiology:
- name: PPIP5K2 Arg837His Catalytic Imbalance
  role: trigger
  biological_scale: MOLECULAR
  description: >-
    The Arg837His substitution lies in the histidine acid phosphatase domain of
    PPIP5K2, whose kinase and phosphatase activities compete to set the 5-InsP7/InsP8
    balance. Purified recombinant PPIP5K2-R837H has 21% lower IP8 phosphatase activity
    than wild type and, rather than being self-correcting, accumulates 60% more IP8 in
    the kinase assay. The two arms therefore act in the same direction, and the authors
    attribute the disproportionate kinase effect to altered conformational coupling
    between the domains.
  molecular_functions:
  - preferred_term: PPIP5K2 IP8 phosphatase activity
    term:
      id: GO:0008486
      label: diphosphoinositol-polyphosphate diphosphatase activity
    modifier: DECREASED
  - preferred_term: PPIP5K2 5-InsP7 kinase activity
    term:
      id: GO:0000829
      label: diphosphoinositol pentakisphosphate kinase activity
    modifier: INCREASED
  genetic_context:
    gene:
      preferred_term: PPIP5K2
      term:
        id: hgnc:29035
        label: PPIP5K2
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: HYPERMORPHIC
    description: >-
      Recorded as HYPERMORPHIC on the net enzymatic output, because the allele raises
      production of the InsP8 signal. This is a judgement over a bifunctional enzyme
      and is worth stating explicitly: the phosphatase arm is partially lost while the
      kinase arm is gained, so neither PARTIAL_LOSS_OF_FUNCTION nor a plain
      GAIN_OF_FUNCTION describes the allele on its own, and the single-valued slot
      forces a choice. The paper's own framing is the increase - it calls the
      equivalent mouse allele a hyper kinase.
  downstream:
  - target: Increased Metabolic Flux from 5-InsP7 to InsP8
    causal_link_type: DIRECT
    description: >-
      Reduced dephosphorylation combined with increased phosphorylation shifts the
      steady state of the interconversion toward InsP8.
  evidence:
  - reference: PMID:29590114
    reference_title: "Mutations in Diphosphoinositol-Pentakisphosphate Kinase PPIP5K2 are associated with hearing loss in human and mouse."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The IP8 phosphatase activity of the PPIP5K2R837H protein was reduced by 21% (*p< 0.05) as compared to the WT protein (Fig 2E)."
    explanation: >-
      Direct enzymatic measurement of the phosphatase arm, on FLAG-tagged protein
      immunopurified from HEK293 cells.
  - reference: PMID:29590114
    reference_title: "Mutations in Diphosphoinositol-Pentakisphosphate Kinase PPIP5K2 are associated with hearing loss in human and mouse."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Assays that used PPIP5K2R837H accumulated 60% higher levels of IP8 compared to assays that contained WT protein (Fig 2F)."
    explanation: >-
      Direct enzymatic measurement of the kinase arm in the same system, showing the
      two arms act in the same direction rather than cancelling.
  - reference: PMID:29590114
    reference_title: "Mutations in Diphosphoinositol-Pentakisphosphate Kinase PPIP5K2 are associated with hearing loss in human and mouse."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "To the best of our knowledge, this is the first study demonstrating the necessity of PP-IP metabolism for inner ear development and hearing function."
    explanation: >-
      Supports the entry's framing that inositol pyrophosphate metabolism is a mechanism
      class newly implicated in hearing, rather than a restatement of a known cochlear
      pathway. Graded OTHER because it is a novelty claim about the literature, not a
      result of the study's own design.
- name: Increased Metabolic Flux from 5-InsP7 to InsP8
  role: amplifier
  biological_scale: MOLECULAR
  description: >-
    The catalytic imbalance is expected to raise cellular InsP8 relative to 5-InsP7.
    This is the step the founding study could measure only indirectly: PP-IP levels in
    the inner ear are at sub- to low-micromolar concentrations and were not assayed in
    vivo, so the flux claim rests on radiolabelled HEK293 cells lacking both PPIP5Ks
    and on the enzymology above.
  biological_processes:
  - preferred_term: inositol pyrophosphate (PP-IP) turnover
    term:
      id: GO:0071543
      label: diphosphoinositol polyphosphate metabolic process
    modifier: DYSREGULATED
  chemical_entities:
  - preferred_term: diphosphoinositol polyphosphate
    term:
      id: CHEBI:64604
      label: diphosphoinositol polyphosphate
    modifier: INCREASED
  downstream:
  - target: Disrupted Inositol Pyrophosphate Homeostasis in the Cochlear Sensory Epithelium
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      How a raised InsP8 signal is transduced into hair-cell injury is not established;
      the founding report offers pro-apoptotic PP-IP signalling and bioenergetic
      imbalance as competing possibilities without testing either.
  evidence:
  - reference: PMID:29590114
    reference_title: "Mutations in Diphosphoinositol-Pentakisphosphate Kinase PPIP5K2 are associated with hearing loss in human and mouse."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Biochemical analyses revealed that, compared to WT human PPIP5K2, the PPIP5K2R837H variant exhibited lower phosphatase activity and higher kinase activity, indicating it promotes increased metabolic flux from 5-IP7 to IP8 in vivo."
    explanation: >-
      The authors' interpretation of their enzymology as a directional flux change. The
      in vivo extension is their inference; the measurements are cell-free and cell-line.
- name: Disrupted Inositol Pyrophosphate Homeostasis in the Cochlear Sensory Epithelium
  role: central_effector
  biological_scale: CELLULAR
  conforms_to: "sensorineural_hair_cell_loss#Cochlear Sensory Epithelium Insult"
  description: >-
    PPIP5K2 is the dominant PPIP5K expressed in the organ of Corti, and it is present
    in cochlear and vestibular hair cells, supporting cells, spiral ganglion neurons
    and all three layers of the stria vascularis. Because Ppip5k1 runs up to 100-fold
    lower in these same cells, there is no paralogous buffer, and the cochlear sensory
    epithelium bears a hereditary metabolic lesion from birth. This is the module's
    generic cochlear insult with a PP-IP metabolic defect substituted for the usual
    stereociliary or connexin lesion.
  cell_types:
  - preferred_term: cochlear hair cell
    term:
      id: CL:0000855
      label: sensory hair cell
  biological_processes:
  - preferred_term: sensory perception of sound
    term:
      id: GO:0007605
      label: sensory perception of sound
    modifier: ABNORMAL
  downstream:
  - target: Outer Hair Cell Dysfunction and Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Selective vulnerability of outer hair cells is observed, but why outer rather
      than inner hair cells is unexplained.
  evidence:
  - reference: PMID:29590114
    reference_title: "Mutations in Diphosphoinositol-Pentakisphosphate Kinase PPIP5K2 are associated with hearing loss in human and mouse."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We found that in mouse inner ear, PPIP5K2 is expressed in the cochlear and vestibular sensory hair cells, supporting cells and spiral ganglion neurons."
    explanation: >-
      Places the enzyme in the cochlear cell types the module's insult node names.
      Mouse immunolocalisation; human inner-ear tissue was not examined.
  - reference: PMID:29590114
    reference_title: "Mutations in Diphosphoinositol-Pentakisphosphate Kinase PPIP5K2 are associated with hearing loss in human and mouse."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Transcriptome analysis indicates that Ppip5k2 is the major Ppip5k gene to be expressed in the mouse cochlear and vestibular sensory hair cells, supporting cells as well as in ganglion neurons, while levels of Ppip5k1 expression in these cells are up to 100-fold lower (gEAR, SHIELD) [28]."
    explanation: >-
      Supports the absence of paralogous redundancy in the cochlea, which is why a
      PPIP5K2 defect is not compensated there.
- name: Outer Hair Cell Dysfunction and Degeneration
  role: effector
  biological_scale: CELLULAR
  description: >-
    Outer hair cells are the cell type that fails. In affected humans this is shown
    functionally: transient evoked otoacoustic emissions are absent, which localises
    the defect to outer hair cells while the middle ear is normal on tympanometry. In
    the Ppip5k2 gene-trap mouse it is shown histologically: outer hair cells are
    significantly reduced in the basal turn at P150 while inner hair cell counts are
    unchanged. No human temporal-bone histology exists, so the cellular lesion in
    humans is inferred from the emissions test.
  cell_types:
  - preferred_term: cochlear outer hair cell
    term:
      id: CL:0000601
      label: cochlear outer hair cell
  downstream:
  - target: Loss of Cochlear Amplification
    causal_link_type: DIRECT
    description: >-
      Outer hair cells generate the cochlear amplifier, so their dysfunction and loss
      removes it.
  evidence:
  - reference: PMID:29590114
    reference_title: "Mutations in Diphosphoinositol-Pentakisphosphate Kinase PPIP5K2 are associated with hearing loss in human and mouse."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Humans who are homozygous for the c.2510G>A variant failed transient evoked otoacoustic emission tests, indicating an outer hair cell functional defect."
    explanation: >-
      The human evidence that the lesion is at the outer hair cell.
  - reference: PMID:29590114
    reference_title: "Mutations in Diphosphoinositol-Pentakisphosphate Kinase PPIP5K2 are associated with hearing loss in human and mouse."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Although no difference was observed in the number of IHCs, a statistically significant (p<0.01) reduction in OHCs was observed in the basal turn (Fig 5B)."
    explanation: >-
      The histological counterpart in mouse, and the source of the claim that the loss
      is selective for outer over inner hair cells.
- name: Loss of Cochlear Amplification
  role: consequence
  biological_scale: TISSUE
  description: >-
    Without functioning outer hair cells the cochlea loses its active amplifier, and
    the sensitivity and frequency selectivity it provides. In humans the endpoint is
    prelingual severe-to-profound loss across the audiometric range; in the mouse it
    is a late-onset, progressive, high-frequency threshold elevation with reduced ABR
    wave I amplitude. The two do not match, and the human phenotype is the more severe.
  downstream:
  - target: Prelingual bilateral severe-to-profound sensorineural hearing loss
    causal_link_type: DIRECT
    description: >-
      Loss of cochlear amplification is the proximate cause of the audiometric deficit.
  evidence:
  - reference: PMID:29590114
    reference_title: "Mutations in Diphosphoinositol-Pentakisphosphate Kinase PPIP5K2 are associated with hearing loss in human and mouse."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, these affected individuals (V:2, V:3, V:5) failed a transient evoked otoacoustic emission test, which is indicative of defective outer hair cell function."
    explanation: >-
      Absent evoked emissions are the direct clinical readout of a failed cochlear
      amplifier in these patients.
  - reference: PMID:29590114
    reference_title: "Mutations in Diphosphoinositol-Pentakisphosphate Kinase PPIP5K2 are associated with hearing loss in human and mouse."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mice homozygous for a targeted deletion of the Ppip5k2 phosphatase domain exhibit degeneration of cochlear outer hair cells and elevated hearing thresholds."
    explanation: >-
      Links outer hair cell degeneration to a measured threshold elevation, in the
      mouse. Graded MODEL_ORGANISM; the mouse deficit is milder and later than the
      human one, which is recorded as a discussion.
phenotypes:
- category: Clinical
  name: Prelingual bilateral severe-to-profound sensorineural hearing loss
  description: >-
    Present in all affected individuals of both families. Pure-tone air and bone
    conduction audiometry from 250 to 8,000 Hz showed profound bilateral loss; family
    history recorded no hearing from birth. Tympanometry was normal in the three
    affected individuals of PKDF751 who were tested, excluding a conductive component;
    that result is reported in the source but is not separately quotable here, so it is
    carried as description rather than as its own phenotype row.
  phenotype_term:
    preferred_term: Prelingual bilateral severe-to-profound sensorineural hearing loss
    term:
      id: HP:0000399
      label: Prelingual sensorineural hearing impairment
  evidence:
  - reference: PMID:29590114
    reference_title: "Mutations in Diphosphoinositol-Pentakisphosphate Kinase PPIP5K2 are associated with hearing loss in human and mouse."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected individuals of both families have prelingual bilateral severe to profound sensorineural hearing loss (Fig 1C and 1D)."
    explanation: >-
      States the defining phenotype, its laterality, severity and prelingual onset.
  - reference: PMID:29590114
    reference_title: "Mutations in Diphosphoinositol-Pentakisphosphate Kinase PPIP5K2 are associated with hearing loss in human and mouse."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "According to family history no hearing was noted since birth in all of the affected individuals."
    explanation: >-
      Supports congenital rather than acquired or postlingual onset. This is family
      report, not newborn screening, and is graded accordingly in the notes.
- category: Clinical
  name: Absent transient evoked otoacoustic emissions
  description: >-
    Three affected individuals of family PKDF751 tested at 19, 23 and 26 years failed
    transient evoked otoacoustic emission testing while a normal-hearing relative did
    not, localising the lesion to the outer hair cells rather than the middle ear.
  phenotype_term:
    preferred_term: Absent transient evoked otoacoustic emissions
    term:
      id: HP:6000182
      label: Absent otoacoustic emissions
  diagnostic: true
  evidence:
  - reference: PMID:29590114
    reference_title: "Mutations in Diphosphoinositol-Pentakisphosphate Kinase PPIP5K2 are associated with hearing loss in human and mouse."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, these affected individuals (V:2, V:3, V:5) failed a transient evoked otoacoustic emission test, which is indicative of defective outer hair cell function."
    explanation: >-
      Direct report of the finding in named affected individuals.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Only two consanguineous Pakistani families, PKDF041 and PKDF751, sharing one
    founder allele, have been reported. No population-based prevalence estimate exists
    for DFNB100, and no numeric rate is recorded here because none has been measured.
    The ULTRA_RARE band is a qualitative tier used with CASES_IN_LITERATURE, which is
    permitted precisely because it presupposes no numeric estimate.
  evidence:
  - reference: PMID:29590114
    reference_title: "Mutations in Diphosphoinositol-Pentakisphosphate Kinase PPIP5K2 are associated with hearing loss in human and mouse."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exome enrichment followed by massive parallel sequencing revealed a c.2510G>A transition variant in PPIP5K2 that segregated with DFNB100-associated hearing loss in two large apparently unrelated Pakistani families."
    explanation: >-
      Establishes that the reported case material is two families, which is the basis
      for the CASES_IN_LITERATURE measure.
- population: ExAC aggregate exome cohort
  measure_type: CARRIER_FREQUENCY
  rate_per_100000: 14.6
  rate_denominator: POPULATION
  notes: >-
    Allele frequency of c.2510G>A in ExAC was 0.000146, normalised here to 14.6 per
    100,000. This is an allele frequency for one variant in an aggregate exome
    reference set, not a measured carrier rate in any defined population, and it is
    not a disease prevalence. No `prevalence_class` is set because a qualitative tier
    must not be combined with a populated numeric rate.
  evidence:
  - reference: PMID:29590114
    reference_title: "Mutations in Diphosphoinositol-Pentakisphosphate Kinase PPIP5K2 are associated with hearing loss in human and mouse."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the c.2510G>A variant of PPIP5K2 is at a low frequency (0.000146) in the ExAC database"
    explanation: >-
      Source of the frequency figure and of the authors' reading that the allele is not
      a common polymorphism.
diagnosis:
- name: Pure-tone audiometry
  description: >-
    Air and bone conduction thresholds from 250 to 8,000 Hz establish the severity,
    laterality and sensorineural character of the loss. In reported affected
    individuals this shows profound bilateral loss.
  diagnosis_term:
    preferred_term: pure-tone audiometry
    term:
      id: NCIT:C38036
      label: Audiometric Test
  markers: Bilateral severe-to-profound air and bone conduction thresholds, 250-8,000 Hz
  evidence:
  - reference: PMID:29590114
    reference_title: "Mutations in Diphosphoinositol-Pentakisphosphate Kinase PPIP5K2 are associated with hearing loss in human and mouse."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pure tone audiometry tests for air and bone conduction were performed at frequencies from 250 to 8,000 Hz."
    explanation: >-
      The audiometric protocol used to characterise affected individuals in the
      founding study.
  notes: >-
    NCIT has no term for pure-tone audiometry specifically; NCIT:C38036 Audiometric
    Test is the closest clinical action reachable from NCIT:C25218, and the specificity
    is carried by `preferred_term`.
- name: Transient evoked otoacoustic emission testing
  description: >-
    Absent transient evoked emissions with a normal tympanogram localises the lesion to
    the outer hair cells and is the finding that ties this disease's clinical picture
    to its outer-hair-cell mechanism.
  diagnosis_term:
    preferred_term: transient evoked otoacoustic emission testing
    term:
      id: NCIT:C184946
      label: Transient Evoked Otoacoustic Emissions
  markers: Absent transient evoked otoacoustic emissions
  evidence:
  - reference: PMID:29590114
    reference_title: "Mutations in Diphosphoinositol-Pentakisphosphate Kinase PPIP5K2 are associated with hearing loss in human and mouse."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Humans who are homozygous for the c.2510G>A variant failed transient evoked otoacoustic emission tests, indicating an outer hair cell functional defect."
    explanation: >-
      Establishes the test result expected in affected individuals and its
      interpretation.
- name: Tympanometry
  description: >-
    Performed to exclude a conductive or mixed component. Normal in the tested affected
    individuals.
  diagnosis_term:
    preferred_term: tympanometry
    term:
      id: NCIT:C88505
      label: Tympanometry Assessment
  markers: Normal tympanic membrane compliance and middle ear pressure
  evidence:
  - reference: PMID:29590114
    reference_title: "Mutations in Diphosphoinositol-Pentakisphosphate Kinase PPIP5K2 are associated with hearing loss in human and mouse."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Tympanometry and otoacoustic emission tests were performed to assess middle ear and cochlear function."
    explanation: >-
      Establishes tympanometry as part of the diagnostic assessment used to separate
      middle ear from cochlear causes in these families. The sentence reporting the
      normal result itself could not be quoted: it embeds a bracketed list of subject
      identifiers that the reference validator strips before matching, and every
      bracket-free fragment of it attributes the normal finding to the unaffected
      relative alone, which would misstate the result.
- name: Exome or gene-panel sequencing of PPIP5K2
  description: >-
    DFNB100 has no clinical feature that distinguishes it from the other numbered
    autosomal recessive nonsyndromic hearing losses, so molecular diagnosis is the only
    route to the specific diagnosis. In the founding families, candidate-gene
    sequencing of the six genes then favoured in the linkage interval was negative and
    exome sequencing was required.
  diagnosis_term:
    preferred_term: whole exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  markers: Biallelic PPIP5K2 variants; in reported families homozygous c.2510G>A p.(Arg837His)
  evidence:
  - reference: PMID:29590114
    reference_title: "Mutations in Diphosphoinositol-Pentakisphosphate Kinase PPIP5K2 are associated with hearing loss in human and mouse."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exome enrichment followed by massive parallel sequencing revealed a c.2510G>A transition variant in PPIP5K2 that segregated with DFNB100-associated hearing loss in two large apparently unrelated Pakistani families."
    explanation: >-
      Exome sequencing is the method that produced the molecular diagnosis in both
      reported families.
- name: Funduscopy and electroretinography to exclude Usher syndrome
  description: >-
    Prelingual severe-to-profound recessive sensorineural hearing loss in a
    consanguineous family raises Usher syndrome, in which retinitis pigmentosa may not
    yet be apparent in childhood. Retinal examination was normal in affected DFNB100
    individuals up to age 42, with normal ERG a- and b-wave amplitudes.
  diagnosis_term:
    preferred_term: funduscopic examination
    term:
      id: NCIT:C38060
      label: Eye Examination
  markers: Normal fundus, no retinitis pigmentosa; normal ERG a- and b-wave amplitudes
  evidence:
  - reference: PMID:29590114
    reference_title: "Mutations in Diphosphoinositol-Pentakisphosphate Kinase PPIP5K2 are associated with hearing loss in human and mouse."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Funduscopy examinations of affected individuals of PKDF041, V:5 (42 years), VI:3 (16 years), VI:4 (10 years) and VI:5 (20 years) revealed no evidence of retinitis pigmentosa."
    explanation: >-
      The retinal examination result that excluded a retinal degeneration phenotype in
      these families, including in an individual examined at 42 years.
differential_diagnoses:
- name: Usher syndrome type 1
  description: >-
    The principal differential for prelingual profound recessive sensorineural hearing
    loss in a consanguineous family. Usher type 1 adds vestibular areflexia and
    retinitis pigmentosa, both of which were specifically looked for and not found in
    the DFNB100 families.
  distinguishing_features:
  - >-
    In DFNB100, Romberg and tandem gait testing showed no overt vestibular dysfunction,
    whereas Usher type 1 has congenital vestibular areflexia.
  - >-
    In DFNB100, funduscopy showed no retinitis pigmentosa up to age 42 and ERG a- and
    b-wave amplitudes were normal, whereas Usher type 1 has progressive retinal
    degeneration.
  evidence:
  - reference: PMID:29590114
    reference_title: "Mutations in Diphosphoinositol-Pentakisphosphate Kinase PPIP5K2 are associated with hearing loss in human and mouse."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Romberg and tandem gait tests did not reveal any overt vestibular dysfunction in affected individuals of both families."
    explanation: >-
      The vestibular assessment that argues against Usher type 1 in these families.
      Romberg and tandem gait are bedside tests, not caloric or VEMP testing, so this
      excludes overt dysfunction rather than subclinical vestibular involvement.
- name: DFNB49 (TRIC/MARVELD2-related hearing loss)
  description: >-
    Family PKDF041 originally mapped to the DFNB49 locus, which overlaps DFNB100 on
    chromosome 5, and DFNB49 is caused by variants in TRIC. Full sequencing of TRIC was
    negative in both families, which is what established DFNB100 as a separate locus.
  distinguishing_features:
  - >-
    DFNB49 is caused by TRIC variants and DFNB100 by PPIP5K2. The two loci overlap on
    chromosome 5, so linkage alone does not separate them and sequencing is required.
  - >-
    Mechanistically DFNB49 is a tight-junction disorder, whereas DFNB100 acts through
    inositol pyrophosphate metabolism.
  evidence:
  - reference: PMID:29590114
    reference_title: "Mutations in Diphosphoinositol-Pentakisphosphate Kinase PPIP5K2 are associated with hearing loss in human and mouse."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Similar to family PKDF041, mutation in the protein coding exons, non-coding exons or in the splice junctions of TRIC were not detected in the affected individuals of family PKDF751."
    explanation: >-
      Exclusion of the overlapping DFNB49 gene in both families, the step that
      justified a separate DFNB100 designation.
treatments:
- name: Cochlear Implantation
  description: >-
    Standard rehabilitation for prelingual severe-to-profound sensorineural hearing
    loss, and the intervention DFNB100 patients would be offered on the basis of their
    audiometric phenotype. No DFNB100-specific outcome data have been published; this
    row records standard-of-care practice for the phenotype, not a result in this
    disease.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: cochlear device implantation
    term:
      id: NCIT:C15329
      label: Surgical Procedure
    qualifiers:
    - predicate:
        preferred_term: medical device
        term:
          id: NCIT:C16830
          label: Medical Device
      value:
        preferred_term: cochlear implant
        term:
          id: NCIT:C157820
          label: Cochlear Implant
  notes: >-
    Deliberately carries no `evidence` block and no `target_mechanisms`. The founding
    report describes no treatment of any kind, and there is no DFNB100 publication to
    quote; attaching a general cochlear-implant citation here would be evidence about
    the class of prelingual profound hearing loss presented as evidence about this
    disease. The treatment term is the generic surgical action, with the device
    attached as a qualifier, because NCIT:C157820 denotes the device and is not
    reachable from NCIT:C25218, so it cannot itself be the term of a TreatmentTerm.
- name: Genetic counselling and family testing
  description: >-
    Autosomal recessive inheritance with a 25% recurrence risk for siblings, in
    families that are consanguineous and share a founder allele. Testing at-risk
    relatives for c.2510G>A is straightforward once the familial variant is known.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  notes: >-
    No evidence block: the recurrence risk follows from the inheritance pattern
    recorded above rather than from a separate published finding about DFNB100.
animal_models:
- name: Ppip5k2 gene-trap mouse (Ppip5k2K^)
  species: Mouse
  genotype: B6N(Cg)-Ppip5k2tm1a(EUCOMM)Wtsi/J gene trap between exons 13 and 14; homozygous and heterozygous
  background: C57BL/6N
  publication: PMID:29590114
  description: >-
    A KOMP gene-trap allele that truncates the phosphatase domain to 84 residues while
    leaving the kinase domain intact. The equivalent truncated human protein converts
    5-InsP7 to InsP8 at 23-fold the rate of full-length enzyme, so the allele models
    elevated kinase output rather than loss of the protein. Homozygotes develop
    late-onset, progressive, high-frequency threshold elevation with basal-turn outer
    hair cell loss; heterozygotes show a milder version of the same.
  modeled_mechanisms:
  - target: Outer Hair Cell Dysfunction and Degeneration
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Reproduces selective outer hair cell degeneration with inner hair cells spared,
      the cellular lesion inferred in humans from absent otoacoustic emissions.
    limitations: >-
      The allele is a phosphatase-domain truncation, not the human p.Arg837His missense
      substitution, and it produces a far larger kinase gain (23-fold in the equivalent
      human construct) than the missense allele does (60% more IP8). Degeneration is
      confined to the basal turn at P150 and is late-onset and progressive, whereas the
      human phenotype is prelingual and profound across the audiometric range. The
      C57BL/6 background is itself susceptible to age-related hearing loss, and wild-type
      controls also showed elevated 32 kHz thresholds at P120 and P150. Ppip5k1 message
      is upregulated nearly 3-fold in the mutant inner ear, a compensatory change with no
      human counterpart described.
    readouts:
    - name: Outer hair cell count in the basal cochlear turn at P150
      target: Outer Hair Cell Dysfunction and Degeneration
      direction: DECREASED
      interpretation: >-
        Histological quantification of the cellular lesion, with inner hair cell counts
        as an internal negative control.
      evidence:
      - reference: PMID:29590114
        reference_title: "Mutations in Diphosphoinositol-Pentakisphosphate Kinase PPIP5K2 are associated with hearing loss in human and mouse."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Although no difference was observed in the number of IHCs, a statistically significant (p<0.01) reduction in OHCs was observed in the basal turn (Fig 5B)."
        explanation: >-
          Reports the measurement and its direction, and the preserved inner hair cell
          count that makes the loss selective.
    evidence:
    - reference: PMID:29590114
      reference_title: "Mutations in Diphosphoinositol-Pentakisphosphate Kinase PPIP5K2 are associated with hearing loss in human and mouse."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Mice homozygous for a targeted deletion of the Ppip5k2 phosphatase domain exhibit degeneration of cochlear outer hair cells and elevated hearing thresholds."
      explanation: >-
        Supports treating this mouse as informative for outer hair cell degeneration in
        this disease.
  - target: Prelingual bilateral severe-to-profound sensorineural hearing loss
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    model_scale: ORGANISM
    description: >-
      The mouse does not reproduce the human audiometric phenotype. Its hearing is
      normal at P60 and deteriorates from high frequencies with age; the human phenotype
      is severe-to-profound from birth across the range.
    limitations: >-
      Recorded as a failure rather than a partial recapitulation because the two
      phenotypes differ in onset, severity and audiometric shape, and the authors say so
      themselves. They suggest greater functional redundancy of PPIP5K2 in mouse, or
      genetic and environmental modifiers, as possible reasons; none has been tested.
      The allele difference (truncation versus missense) is a further confound, so the
      mismatch cannot be attributed to species alone.
    evidence:
    - reference: PMID:29590114
      reference_title: "Mutations in Diphosphoinositol-Pentakisphosphate Kinase PPIP5K2 are associated with hearing loss in human and mouse."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "It is intriguing that the hearing deficit in the Ppip5k2K^/K^ mice is less severe than that observed in humans homozygous for the p.(Arg837His) variant."
      explanation: >-
        The authors' explicit statement that the model is milder than the human disease,
        which is the basis for the FAILS_TO_RECAPITULATE grade on this node.
  evidence:
  - reference: PMID:29590114
    reference_title: "Mutations in Diphosphoinositol-Pentakisphosphate Kinase PPIP5K2 are associated with hearing loss in human and mouse."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Based on these findings, we conclude that the Ppip5k2 mutant mice likely expresses a “hyper kinase” activity."
    explanation: >-
      Establishes what the allele does biochemically, and therefore what the mouse is a
      model of: elevated kinase output, not absence of the protein.
discussions:
- discussion_id: dfnb100_mouse_human_severity_mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Why is the Ppip5k2 mouse phenotype late-onset, high-frequency and mild when the
    human p.(Arg837His) phenotype is prelingual and profound, and does the mouse
    therefore support the human causal chain at all?
  attaches_to:
  - pathophysiology#Loss of Cochlear Amplification
  - animal_models#Mouse
  rationale: >-
    The mouse is the only in vivo evidence that PPIP5K2 dysfunction causes hearing
    loss, and it disagrees with the human disease on every clinical axis: onset (P60
    normal versus deaf from birth), severity (threshold shift versus profound loss),
    audiometric shape (basal/high-frequency first versus flat profound), and course
    (progressive versus prelingual and static). It also differs in allele - a
    phosphatase-domain truncation with a 23-fold kinase gain versus a missense
    substitution with a 60% gain - so species and allele are confounded. Two further
    features have no human counterpart: heterozygous mice are measurably affected, and
    mutant inner ear upregulates Ppip5k1 nearly 3-fold. Resolving this matters because
    the strength of the whole causal chain below the enzymology rests on this model.
  evidence:
  - reference: PMID:29590114
    reference_title: "Mutations in Diphosphoinositol-Pentakisphosphate Kinase PPIP5K2 are associated with hearing loss in human and mouse."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Also, Ppip5k2+/K^ mice exhibited elevated hearing thresholds loss at higher frequencies [24 kHz (*p<0.05) and 32 kHz]."
    explanation: >-
      Documents the heterozygous mouse effect that has no counterpart in the unaffected
      human heterozygotes, one of the specific mismatches this discussion records.
- discussion_id: dfnb100_insp8_to_hair_cell_death_gap
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    By what mechanism does an increased InsP8 signal kill outer hair cells, and why are
    outer hair cells selectively vulnerable when PPIP5K2 is expressed throughout the
    cochlear duct?
  attaches_to:
  - pathophysiology#Increased Metabolic Flux from 5-InsP7 to InsP8
  - pathophysiology#Outer Hair Cell Dysfunction and Degeneration
  rationale: >-
    The step from raised InsP8 to hair cell injury is unmeasured. The founding report
    offers two untested possibilities - that PP-IP synthesis is pro-apoptotic, and that
    outer hair cell loss follows bioenergetic imbalance - and neither apoptosis nor
    cochlear bioenergetics was assayed in this disease. Nor is the selectivity
    explained: PPIP5K2 protein is present in inner as well as outer hair cells,
    supporting cells, spiral ganglion neurons and all three layers of the stria
    vascularis, yet only outer hair cells degenerate, with stria and ganglion
    histologically normal at P150. This is the reason the entry does not conform to the
    module's oxidative-stress or apoptotic effector nodes.
  evidence:
  - reference: PMID:29590114
    reference_title: "Mutations in Diphosphoinositol-Pentakisphosphate Kinase PPIP5K2 are associated with hearing loss in human and mouse."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "No obvious indications of stria vascularis atrophy or spiral ganglion neuron degeneration were found in Ppip5k2K^/ K^ mice at P150 (S6 Fig)."
    explanation: >-
      The negative result showing the lesion is restricted to outer hair cells despite
      broad PPIP5K2 expression, which is the selectivity puzzle this gap names.
notes: >-
  Module conformance. One node conforms: `Disrupted Inositol Pyrophosphate Homeostasis
  in the Cochlear Sensory Epithelium` declares
  `sensorineural_hair_cell_loss#Cochlear Sensory Epithelium Insult`, substituting a
  hereditary PP-IP metabolic lesion for the module's usual stereociliary or connexin
  trigger. The other four module nodes were considered and declined, each for a stated
  reason.

  `Cochlear Ionic Homeostasis Disruption and Oxidative Stress` is declined because
  neither half is evidenced here. Endocochlear potential was not measured, no potassium
  recycling defect is proposed, and no oxidative stress assay was performed. The stria
  vascularis, which the module makes central to that node, was histologically normal in
  the mutant mouse.

  `Hair Cell Mechanotransduction Failure and Death` is declined. The death half is
  supported, but the node bundles it with mechanotransduction failure, which was never
  tested - absent evoked otoacoustic emissions report outer hair cell electromotility
  and cochlear amplification, not mechanotransduction - and the node carries
  `apoptotic process` INCREASED, which in this disease is explicitly a hypothesis
  offered by the authors rather than a finding. Conforming would have imported an
  untested process assertion.

  `Cochlear Amplification Loss and Spiral Ganglion Neuron Degeneration` is declined
  because half of it is contradicted rather than merely unknown: spiral ganglion neuron
  degeneration was specifically looked for in the mutant mouse at P150 and not found.
  The amplification half is curated as its own node, `Loss of Cochlear Amplification`.

  `Progressive Sensorineural Hearing Loss` is declined because the human disease is not
  progressive. Affected individuals are described as having had no hearing since birth,
  and the phenotype is prelingual and severe-to-profound. Progression is a property of
  the mouse model, not of DFNB100, and conforming to that node would let the mouse
  describe the human disease.

  Scope and lump/split. DFNB100 is kept as a standalone entry rather than a subtype of
  another hearing-loss entry: MONDO:0032740 is a leaf term under MONDO:0019588, not a
  grouping, and it carries its own phenotype MIM (618422), its own causal gene
  (hgnc:29035) and a mechanism class - inositol pyrophosphate turnover - separate from
  the structural, connexin and ion-transport lesions that characterise the DFNB loci it
  sits beside. Distinctions are recorded here against identifiers rather than against
  which diseases happen to be curated, so that they stay true as the corpus changes.
  The mechanism is what makes it worth an entry; the audiogram alone would not.

  Named entity confusion. The wider inositol pyrophosphate literature covers the
  paralogue PPIP5K1, the IP6K family, phosphate export via XPR1, insulin secretion,
  bone and cancer. None of it is about this disease, and none is cited here. Nothing in
  this entry is sourced from a paper about the class of autosomal recessive
  nonsyndromic hearing loss in general. Two PPIP5K2 SNPs (rs35671301, rs17155147) have
  been reported as enriched in autism spectrum disorder cohorts; the founding report
  states there is no evidence that either alters protein function, and they are not
  curated here. The gene alias CFAP160 belongs to a cilia-and-flagella naming scheme and
  is not the basis of this phenotype.

  Evidence base. Every evidence item in this entry cites PMID:29590114, because that is
  the only publication on this disease. Searched on 2026-09-08, PubMed returned exactly
  one record for PPIP5K2 combined with hearing or deafness, and the same single record
  for DFNB100. That is a real limitation of the entry, not an omission: the alternative
  would be citing papers about the pathway or about hearing loss in general as though
  they were about DFNB100. If a second family is reported, the penetrance and
  expressivity slots and the prevalence record are the first things to revisit.

  Deep research. A claude_code deep-research run
  (research/Hearing_Loss_Autosomal_Recessive_100-deep-research-claude_code.md) was used
  as a lead source only; `just preflight-dr` returned PASS and its OMIM number agreed
  with MONDO's. It converged on the same single PMID. Three of its outputs were not
  followed. It suggested CL:0002095 for the outer hair cell, which is `hilus cell of
  ovary`; the entry uses CL:0000601 `cochlear outer hair cell`, checked directly against
  the local Cell Ontology build. It reported HP:0000998 with a hearing-loss label, which
  is `Hypertrichosis`, and the run's own term validation caught this; the entry uses
  HP:0000399, likewise checked directly. And it stated that a founder effect was not
  established and that haplotype sharing had not been tested, which the source
  contradicts - PMID:29590114 reports the flanking haplotype as consistent with a
  founder effect, and that sentence is quoted in the variant record above.

  GeneReviews PMID:20301607 is carried in the top-level references: block as a
  bibliographic tag only. No PPIP5K2- or DFNB100-specific GeneReviews chapter
  exists; this is the applicable overview, and ten other hearing-loss entries
  carry it the same way. Its cached abstract is a statement of the chapter's
  purpose and does not mention PPIP5K2 or diphosphoinositol-pentakisphosphate
  kinase at all, so nothing in it is quotable and no evidence item cites it.