Autosomal Recessive Nonsyndromic Hearing Loss 70

name: Autosomal Recessive Nonsyndromic Hearing Loss 70
category: Mendelian
creation_date: "2026-09-25T00:00:00Z"
synonyms:
- DFNB70
- deafness, autosomal recessive 70
- autosomal recessive nonsyndromic deafness 70
- PNPT1-related nonsyndromic hearing loss
disease_term:
  preferred_term: autosomal recessive nonsyndromic hearing loss 70
  term:
    id: MONDO:0013978
    label: autosomal recessive nonsyndromic hearing loss 70
parents:
- Autosomal Recessive Nonsyndromic Hearing Loss
- Hereditary Hearing Loss
description: >-
  DFNB70 (OMIM 614934) is severe-to-profound, prelingual or congenital,
  sensorineural hearing impairment caused by biallelic variants in PNPT1, the
  nuclear gene encoding the mitochondrial polynucleotide phosphorylase, PNPase.
  It is the isolated-deafness end of the recessive PNPT1 phenotype range, and
  whether it is a distinct entity or one end of a single spectrum is the central
  unresolved question about it.

  PNPase is a homotrimeric 3'-5' phosphorolytic exoribonuclease that sits mostly
  in the mitochondrial intermembrane space. Two of its jobs are relevant here: it
  is one of the very few known components of the machinery that imports a subset
  of nuclear-encoded RNAs into mitochondria, and, with the helicase SUV3, it
  degrades and processes mitochondrial transcripts. The founding DFNB70 allele,
  homozygous c.1424A>G p.(Glu475Gly) in a consanguineous Moroccan family, sits on
  a conserved residue of the second RNase-PH domain and yields a hypofunctional
  protein: the trimer is disturbed and mitochondrial RNA import is impaired.
  Later in vitro work found the same substitution strongly impaired at RNA
  degradation as well, so both PNPase activities are affected by the deafness
  allele.

  Why the ear. PNPase stains strongly in the murine cochlea, in the sensory hair
  cells and the auditory ganglion neurons, and a mouse in which PNPase is knocked
  out in inner ear hair cells develops progressive hearing loss - so hair cells do
  need the enzyme. What remains unexplained is why a hypomorphic allele expressed
  in every tissue deafens and does nothing else: that mouse is a complete knockout
  confined to one cell type, no mouse carries the human allele, and nothing has
  been measured in human inner-ear tissue.

  The published case material is four families. The Moroccan family carries
  homozygous p.(Glu475Gly); a consanguineous Tunisian family with five affected
  siblings carries the same allele; a South Indian assortative-mating family
  carries compound heterozygous p.(Ala46Gly) and p.(Asn540Ser) with prelingual
  profound hearing loss, vestibular dysfunction and unilateral progressive vision
  loss; and a fourth family's two adult siblings, ascertained as isolated severe
  congenital hearing loss, went on in their forties to develop ataxia, dystonia
  and cognitive decline, then optic atrophy, spasticity and incontinence. That
  last family is the reason the nonsyndromic designation carries a caveat rather
  than a full stop, and it is why age at assessment matters when a PNPT1
  genotype is called DFNB70.

  The gene-disease relationship has been formally graded as weak for the hearing
  phenotype: the ClinGen Hearing Loss Working Group classified PNPT1 for
  autosomal recessive nonsyndromic hearing impairment as Limited. The current
  ClinGen Gene-Disease Validity download carries only one PNPT1 assertion at all,
  for Leigh syndrome.
references:
- reference: PMID:23084290
  title: "A mutation in PNPT1, encoding mitochondrial-RNA-import protein PNPase, causes hereditary hearing loss."
- reference: PMID:34194829
  title: "Novel pathogenic mutations and further evidence for clinical relevance of genes and variants causing hearing impairment in Tunisian population."
- reference: PMID:34374074
  title: "PNPT1, MYO15A, PTPRQ, and SLC12A2-associated genetic and phenotypic heterogeneity among hearing impaired assortative mating families in Southern India."
- reference: PMID:30244537
  title: "Is PNPT1-related hearing loss ever non-syndromic? Whole exome sequencing of adult siblings expands the natural history of PNPT1-related disorders."
- reference: PMID:41255389
  title: "Pathological PNPase variants with altered RNA binding and degradation activity affect the phenotype of bacterial and human cell models."
- reference: PMID:35411967
  title: "Heterozygous PNPT1 Variants Cause Spinocerebellar Ataxia Type 25."
- reference: PMID:30024931
  title: "PNPase knockout results in mtDNA loss and an altered metabolic gene expression program."
- reference: PMID:20301607
  title: "Genetic Hearing Loss Overview."
  tags: [GeneReviews]
inheritance:
- name: Autosomal recessive
  description: >-
    Every reported DFNB70 family has two PNPT1 alleles in the affected
    individuals - homozygous p.(Glu475Gly) in the Moroccan and Tunisian
    consanguineous families, compound heterozygous p.(Ala46Gly) with
    p.(Asn540Ser) in the South Indian family. Heterozygous parents are reported
    as unaffected. The sibling recurrence risk for a couple who have had one
    affected child is 25 percent.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:23084290
    reference_title: "A mutation in PNPT1, encoding mitochondrial-RNA-import protein PNPase, causes hereditary hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By positional cloning, we identified a homozygous PNPT1 missense mutation (c.1424A>G predicting the protein substitution p.Glu475Gly) of a highly conserved PNPase residue within the second RNase-PH domain in a family affected by autosomal-recessive nonsyndromic hearing impairment."
    explanation: The founding family, its homozygous genotype and the recessive nonsyndromic
      phenotype it segregates with.
  - reference: PMID:34194829
    reference_title: Novel pathogenic mutations and further evidence for clinical relevance
      of genes and variants causing hearing impairment in Tunisian population.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The PNPT1-Glu475Gly variant identified in (Family.7_P7) segregated in 5 siblings born from consanguineous parents with ARNSHI"
    explanation: Independent recessive segregation of the same allele in a second
      consanguineous family, in five affected siblings.
  - reference: PMID:41255389
    reference_title: Pathological PNPase variants with altered RNA binding and degradation
      activity affect the phenotype of bacterial and human cell models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "In all cases, the heterozygous parents carrying a wild-type (wt)PNPT1 allele were asymptomatic."
    explanation: >-
      States that carriers across the reported PNPT1 families are unaffected, which is
      what makes this recessive rather than a dominant with reduced penetrance.
      HUMAN_CLINICAL grades the quoted sentence, which reports the clinical status of
      parents in the published families; BACKGROUND records that this in vitro paper
      is restating the clinical literature it drew its variants from rather than
      reporting its own result.
pathophysiology:
- name: PNPT1 Biallelic Hypomorphic Missense Variants
  biological_scale: MOLECULAR
  role: initiator
  mechanism_confidence: ESTABLISHED
  description: >-
    Two PNPT1 missense alleles, inherited from unaffected carrier parents. The
    founding and best-characterised allele is c.1424A>G p.(Glu475Gly), which
    changes a highly conserved residue in the second RNase-PH domain and was
    found homozygous in the Moroccan family and, independently, in a Tunisian
    family. A South Indian family carries a different pair, p.(Ala46Gly) with
    p.(Asn540Ser), in compound heterozygosity.

    These are hypomorphic rather than null alleles. PNPase is essential in mice
    and in human cells, so a complete absence of the protein is not what DFNB70
    patients have; what they have is an enzyme that assembles and works badly.
  genes:
  - preferred_term: PNPT1
    term:
      id: hgnc:23166
      label: PNPT1
  genetic_context:
    genes:
    - preferred_term: PNPT1
      term:
        id: hgnc:23166
        label: PNPT1
    allele_type: missense
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
    notes: >-
      HOMOZYGOUS describes the two consanguineous families carrying
      p.(Glu475Gly); the South Indian family is compound heterozygous for a
      different pair of missense alleles, and the schema slot is single-valued.
      PARTIAL_LOSS_OF_FUNCTION rather than LOSS_OF_FUNCTION because
      p.(Glu475Gly) was shown to be hypofunctional rather than absent, and
      because PNPase is essential in human cells.
  downstream:
  - target: Disrupted PNPase Trimer Assembly
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:23084290
    reference_title: "A mutation in PNPT1, encoding mitochondrial-RNA-import protein PNPase, causes hereditary hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By positional cloning, we identified a homozygous PNPT1 missense mutation (c.1424A>G predicting the protein substitution p.Glu475Gly) of a highly conserved PNPase residue within the second RNase-PH domain in a family affected by autosomal-recessive nonsyndromic hearing impairment."
    explanation: The allele, its position in the protein and the phenotype it was found in.
  - reference: PMID:34374074
    reference_title: PNPT1, MYO15A, PTPRQ, and SLC12A2-associated genetic and phenotypic
      heterogeneity among hearing impaired assortative mating families in Southern India.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Compound heterozygous PNPT1 variants were associated with DFNB70 causing prelingual profound sensorineural hearing loss (SNHL), vestibular dysfunction, and unilateral progressive vision loss in one family."
    explanation: A second allele class - compound heterozygous rather than homozygous
      founder - producing the same named entity.
  - reference: PMID:34194829
    reference_title: Novel pathogenic mutations and further evidence for clinical relevance
      of genes and variants causing hearing impairment in Tunisian population.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This missense variant was not annotated in both dbSNP and gnomAD databases. It was also absent in over 400 control individuals analyzed in the published study from Germany, Morocco and Turkey"
    explanation: The population-genetic argument for p.(Glu475Gly) being a disease allele
      rather than a rare benign variant.
  - reference: PMID:41255389
    reference_title: Pathological PNPase variants with altered RNA binding and degradation
      activity affect the phenotype of bacterial and human cell models.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "The protein is essential in mice and in human cells"
    explanation: >-
      Why the DFNB70 alleles have to be hypomorphic rather than null: a complete absence
      of PNPase is not survivable. OTHER because the quoted sentence aggregates mouse
      knockout data and human cell-line data from several prior studies, so no single
      study type describes it, and BACKGROUND because it is this paper's introduction
      citing that earlier work rather than one of its own results.
- name: Disrupted PNPase Trimer Assembly
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    PNPase is catalytically active only as a homotrimer, whose protomers form a
    doughnut with the KH and S1 RNA-binding domains above a central channel
    holding the catalytic site. p.(Glu475Gly) disturbs that assembly, and the
    2025 survey of pathological PNPase variants found defective assembly common
    to every disease allele it tested. This is the step at which the two PNPase
    jobs downstream - RNA import and RNA degradation - both become impaired.
  molecular_functions:
  - preferred_term: polyribonucleotide nucleotidyltransferase activity
    modifier: DECREASED
    term:
      id: GO:0004654
      label: polyribonucleotide nucleotidyltransferase activity
  biological_processes:
  - preferred_term: PNPase homotrimer assembly
    modifier: DECREASED
    term:
      id: GO:0070207
      label: protein homotrimerization
  downstream:
  - target: Impaired Mitochondrial RNA Import
    causal_link_type: DIRECT
  - target: Impaired Mitochondrial RNA Degradation
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:23084290
    reference_title: "A mutation in PNPT1, encoding mitochondrial-RNA-import protein PNPase, causes hereditary hearing loss."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In vitro analyses in bacteria, yeast, and mammalian cells showed that the identified mutation results in a hypofunctional protein leading to disturbed PNPase trimerization and impaired mitochondrial RNA import."
    explanation: The direct demonstration that the deafness allele breaks trimer assembly,
      in three heterologous systems.
  - reference: PMID:41255389
    reference_title: Pathological PNPase variants with altered RNA binding and degradation
      activity affect the phenotype of bacterial and human cell models.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We found that all pathogenic mutations tested caused defects in protein assembly and affected the degradation and RNA binding efficiency to varying degrees."
    explanation: Assembly failure generalised across the PNPT1 disease alleles, including
      the DFNB70 allele E475G, in a single comparative study.
  - reference: PMID:41255389
    reference_title: Pathological PNPase variants with altered RNA binding and degradation
      activity affect the phenotype of bacterial and human cell models.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "Structural studies on PNPases of different organisms have shown that the protein is a homotrimer in which the protomers are assembled in a doughnut shape with the KH and S1 RNA binding domains on the top of a central channel where the catalytic site is located"
    explanation: >-
      Why trimer assembly is the functionally decisive step rather than an incidental
      structural property. BACKGROUND because the sentence is the paper's summary of
      prior structural work, not its own result.
- name: Impaired Mitochondrial RNA Import
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    A subset of nuclear-encoded RNAs has to reach the mitochondrial matrix for
    the organelle's genome to be replicated and transcribed, and PNPase is one of
    very few known components of that import route in mammals. The DFNB70 allele
    impairs it. How much of the hearing phenotype this branch carries, as against
    the degradation branch below, has not been separated experimentally.
  biological_processes:
  - preferred_term: RNA import into mitochondrion
    modifier: DECREASED
    term:
      id: GO:0035927
      label: RNA import into mitochondrion
  downstream:
  - target: Cochlear Hair Cell and Spiral Ganglion Neuron Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:23084290
    reference_title: "A mutation in PNPT1, encoding mitochondrial-RNA-import protein PNPase, causes hereditary hearing loss."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In vitro analyses in bacteria, yeast, and mammalian cells showed that the identified mutation results in a hypofunctional protein leading to disturbed PNPase trimerization and impaired mitochondrial RNA import."
    explanation: The import defect attributed specifically to the deafness allele.
  - reference: PMID:23084290
    reference_title: "A mutation in PNPT1, encoding mitochondrial-RNA-import protein PNPase, causes hereditary hearing loss."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "A subset of nuclear-encoded RNAs has to be imported into mitochondria for the proper replication and transcription of the mitochondrial genome and, hence, for proper mitochondrial function."
    explanation: >-
      Why an import defect matters downstream at all. OTHER because the quoted
      sentence states established cell biology built from many study types rather
      than any one of them, and BACKGROUND because it is the paper's opening framing
      rather than a result of this study.
- name: Impaired Mitochondrial RNA Degradation
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    PNPase is a 3'-5' phosphorolytic exonuclease and, with SUV3, forms the
    mitochondrial degradosome that clears and processes mitochondrial
    transcripts. The DFNB70 allele E475G was strongly impaired at degrading a
    model RNA substrate in vitro, alongside the COXPD13 allele Q387R. This
    branch is included because it is measured, not because it has been shown to
    be the one that deafens: the same comparative study found that catalytic
    impairment does not track disease severity across PNPT1 alleles.
  molecular_functions:
  - preferred_term: 3'-5' RNA exonuclease activity
    modifier: DECREASED
    term:
      id: GO:0000175
      label: 3'-5'-RNA exonuclease activity
  biological_processes:
  - preferred_term: mitochondrial RNA catabolism
    modifier: DECREASED
    term:
      id: GO:0000957
      label: mitochondrial RNA catabolic process
  downstream:
  - target: Cochlear Hair Cell and Spiral Ganglion Neuron Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:41255389
    reference_title: Pathological PNPase variants with altered RNA binding and degradation
      activity affect the phenotype of bacterial and human cell models.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the Q387R and E475G variants were strongly impaired in RNA20 degradation"
    explanation: The direct measurement of impaired degradation by the DFNB70 allele.
  - reference: PMID:41255389
    reference_title: Pathological PNPase variants with altered RNA binding and degradation
      activity affect the phenotype of bacterial and human cell models.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "Human PNPase (hPNPase) is an essential RNA exonuclease located in mitochondria, where it contributes to RNA import from the cytoplasm, degradation of mitochondrial RNA and R-loop homeostasis."
    explanation: >-
      The enzyme's three mitochondrial jobs, which is why an assembly defect has more
      than one downstream branch. BACKGROUND because it is the abstract's framing of
      established function rather than a finding of this work.
- name: Cochlear Hair Cell and Spiral Ganglion Neuron Dysfunction
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: >-
    The site of the lesion. PNPase stains strongly in the murine cochlea, in the
    sensory hair cells and the auditory ganglion neurons, and the original report
    concludes that the mitochondrial RNA-import machinery is specifically required
    for auditory function. The strongest evidence that this is causal rather than
    correlative is a mouse in which PNPase was knocked out in inner ear hair cells
    and which developed progressive hearing loss, an experiment its authors relate
    directly to the human PNPT1 hearing phenotype.

    Two gaps keep this node at PROVISIONAL rather than ESTABLISHED. That mouse
    carries a complete hair-cell knockout, where DFNB70 patients carry a
    hypomorphic allele expressed in every tissue, so it isolates the cochlear
    contribution without showing that the human disease is hair-cell autonomous.
    And the spiral ganglion arm of this node rests on expression alone: no
    ganglion-restricted deletion has been reported and no patient temporal bone
    has been examined.
  cell_types:
  - preferred_term: auditory hair cell
    term:
      id: CL:0000202
      label: auditory hair cell
  - preferred_term: spiral ganglion neuron
    term:
      id: CL:0011113
      label: spiral ganglion neuron
  biological_processes:
  - preferred_term: sensory perception of sound
    modifier: DECREASED
    term:
      id: GO:0007605
      label: sensory perception of sound
  downstream:
  - target: Prelingual Severe-to-Profound Sensorineural Hearing Impairment
    causal_link_type: DIRECT
  - target: Vestibular Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:23084290
    reference_title: "A mutation in PNPT1, encoding mitochondrial-RNA-import protein PNPase, causes hereditary hearing loss."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Immunohistochemistry revealed strong PNPase staining in the murine cochlea, including the sensory hair cells and the auditory ganglion neurons."
    explanation: The localisation evidence, in mouse, that places the protein in the two
      cell types this node names.
  - reference: PMID:23084290
    reference_title: "A mutation in PNPT1, encoding mitochondrial-RNA-import protein PNPase, causes hereditary hearing loss."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "In summary, we show that a component of the mitochondrial RNA-import machinery is specifically required for auditory function."
    explanation: >-
      The authors' own conclusion that the requirement is auditory-specific. INDIRECT
      because it is an inference from a human genetic result plus mouse expression, not
      a measurement of hair cell or ganglion neuron function in the disease state.
phenotypes:
- name: Prelingual Severe-to-Profound Sensorineural Hearing Impairment
  category: Ear
  description: >-
    The defining and, in three of the four reported families, the only feature.
    The South Indian family's hearing loss is described as prelingual and
    profound; the adult siblings reported separately had severe congenital
    hearing loss; the Tunisian and Moroccan families are described as autosomal
    recessive nonsyndromic hearing impairment, severe in the Moroccan kindred.
    Bilaterality is stated for the fourth family and implied by the recessive
    nonsyndromic designation elsewhere.
  frequency: OBLIGATE
  phenotype_term:
    preferred_term: Prelingual profound sensorineural hearing impairment
    term:
      id: HP:0000399
      label: Prelingual sensorineural hearing impairment
  notes: >-
    OBLIGATE because the entity is ascertained through its hearing loss, so the
    band carries no information about penetrance.

    The binding takes the onset axis rather than the severity axis, because
    onset is the feature reported consistently across families while the
    severity wording is not - profound in the South Indian family, severe in the
    other reports - and HPO has no combined severe-to-profound term. HP:0000399
    Prelingual sensorineural hearing impairment carries onset, sensorineural
    character and hearing impairment together; the full severity range is carried
    in preferred_term and in the description. Checked against the live ontology on
    2026-09-25: a query of the HPO for "Prelingual sensorineural hearing
    impairment" returns HP:0000399 and nothing more specific, and a query for
    "Bilateral sensorineural hearing impairment" returns HP:0008619, HP:0011474,
    HP:0000408 and HP:0008527, none of which combines prelingual onset with
    profound severity.

    No audiogram configuration, no serial audiometry and no per-individual
    threshold data are published for any DFNB70 family, so no configuration or
    progression phenotype is curated.
  evidence:
  - reference: PMID:34374074
    reference_title: PNPT1, MYO15A, PTPRQ, and SLC12A2-associated genetic and phenotypic
      heterogeneity among hearing impaired assortative mating families in Southern India.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Compound heterozygous PNPT1 variants were associated with DFNB70 causing prelingual profound sensorineural hearing loss (SNHL), vestibular dysfunction, and unilateral progressive vision loss in one family."
    explanation: Onset, severity and sensorineural character in one sentence, attributed
      explicitly to DFNB70.
  - reference: PMID:30244537
    reference_title: "Is PNPT1-related hearing loss ever non-syndromic? Whole exome sequencing of adult siblings expands the natural history of PNPT1-related disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe adult siblings with biallelic PNPT1 variants identified through WES who presented with isolated severe congenital sensorineural hearing loss (SNHL)."
    explanation: A second, independently ascertained family presenting as isolated severe
      congenital sensorineural hearing loss.
- name: Vestibular Dysfunction
  category: Ear
  description: >-
    Reported in the South Indian family alongside the hearing loss. The
    vestibular and auditory end organs share hair cell biology and a common
    mitochondrial demand, so a shared lesion is the obvious reading, but no
    vestibular testing is reported for the other DFNB70 families and no
    vestibular tissue has been examined.

    Read the incoming edge with that in mind. It comes from the cochlear node,
    and vestibular hair cells are not cochlear: no published work places PNPase
    in the utricle, saccule or crista, and the mouse knockout that produces
    hearing loss was not assessed for balance. The edge is marked
    INDIRECT_UNKNOWN_INTERMEDIATES because it asserts a shared hair cell
    vulnerability and nothing more.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Vestibular dysfunction
    term:
      id: HP:0001751
      label: Abnormal vestibular function
  notes: >-
    Reported in one of the four published families. As a family-level fraction
    that is 25 percent, which falls in the OCCASIONAL band (5-29 percent). The
    denominator is four families, not four patients, and no other family had
    vestibular testing reported at all, so the band is a floor rather than an
    estimate.
  evidence:
  - reference: PMID:34374074
    reference_title: PNPT1, MYO15A, PTPRQ, and SLC12A2-associated genetic and phenotypic
      heterogeneity among hearing impaired assortative mating families in Southern India.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Compound heterozygous PNPT1 variants were associated with DFNB70 causing prelingual profound sensorineural hearing loss (SNHL), vestibular dysfunction, and unilateral progressive vision loss in one family."
    explanation: The only report of vestibular involvement in a DFNB70 family.
- name: Unilateral Progressive Vision Loss
  category: Eye
  description: >-
    Reported in the same South Indian family. It is recorded here because the
    source attributes it to the DFNB70 family rather than to an incidental
    comorbidity, and because it bears directly on whether this entity is truly
    nonsyndromic. No ophthalmological detail - no optic nerve findings, no
    retinal findings, no age at onset - is given, and optic atrophy is part of
    the late multisystem course seen in the adult siblings reported elsewhere.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Unilateral progressive vision loss
    term:
      id: HP:0000529
      label: Progressive visual loss
  notes: >-
    One of four published families, a family-level fraction of 25 percent, within
    the OCCASIONAL band (5-29 percent). HPO has no term combining laterality with
    progressive visual loss, so laterality is carried in preferred_term only;
    checked against the live ontology on 2026-09-25, where a query for
    "Progressive visual loss" returns HP:0000529 and HP:0200068 Nonprogressive
    visual loss and no unilateral variant.
  evidence:
  - reference: PMID:34374074
    reference_title: PNPT1, MYO15A, PTPRQ, and SLC12A2-associated genetic and phenotypic
      heterogeneity among hearing impaired assortative mating families in Southern India.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Compound heterozygous PNPT1 variants were associated with DFNB70 causing prelingual profound sensorineural hearing loss (SNHL), vestibular dysfunction, and unilateral progressive vision loss in one family."
    explanation: The visual finding, attributed to a DFNB70 family by the authors who
      made the genetic diagnosis.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No prevalence estimate exists. Four families have been published - Moroccan,
    Tunisian, South Indian, and the family of adult siblings whose hearing loss
    later proved not to stay isolated. Two of those carry the same founder-like
    allele p.(Glu475Gly) in North African consanguineous kindreds. There is no
    population denominator of any kind, so no rate is recorded, and DFNB70 does
    not appear as a recurring cause in any of the hearing-loss cohorts that
    reported it: the South Indian family came out of a cohort of 113 hearing
    impaired probands.
  evidence:
  - reference: PMID:34374074
    reference_title: PNPT1, MYO15A, PTPRQ, and SLC12A2-associated genetic and phenotypic
      heterogeneity among hearing impaired assortative mating families in Southern India.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "From a cohort of 113 hearing impaired (HI), five non-DFNB12 probands identified with heterozygous CDH23 variants were subjected to exome analysis."
    explanation: The size of the screened cohort from which a single DFNB70 family emerged,
      which is the nearest thing to a denominator in the literature.
progression:
- phase: Isolated hearing loss in childhood and early adult life
  notes: >-
    The hearing loss is prelingual or congenital and no report describes it
    worsening. Three of the four families were reported without neurological
    follow-up, so a stable course is what was observed rather than what was
    demonstrated.
- phase: Late multisystem neurodegeneration in at least one family
  notes: >-
    Two adult siblings ascertained as isolated severe congenital sensorineural
    hearing loss developed ataxia, dystonia and cognitive decline in their
    forties, then optic nerve atrophy, spasticity and incontinence in their
    fifties and sixties. Whether this is the natural history of DFNB70 or the
    natural history of one genotype is unknown; it is the single most important
    open question about this entity, and it is what the surveillance
    recommendation under diagnosis rests on.
  evidence:
  - reference: PMID:30244537
    reference_title: "Is PNPT1-related hearing loss ever non-syndromic? Whole exome sequencing of adult siblings expands the natural history of PNPT1-related disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In their 40s, they each developed and then followed a nearly identical neurodegenerative course with ataxia, dystonia, and cognitive decline. Now in their 50s and 60s, all have developed the additional features of optic nerve atrophy, spasticity, and incontinence."
    explanation: The late course in full, in the one family followed long enough to see it.
genetic:
- name: PNPT1
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: PNPT1
    term:
      id: hgnc:23166
      label: PNPT1
  features: >-
    PNPT1 encodes the mitochondrial polynucleotide phosphorylase, PNPase: a
    homotrimeric 3'-5' phosphorolytic exoribonuclease with two RNase-PH domains,
    an all-alpha-helical domain and KH and S1 RNA-binding domains. DFNB70
    alleles are missense: homozygous c.1424A>G p.(Glu475Gly) in the second
    RNase-PH domain in two North African families, and compound heterozygous
    p.(Ala46Gly) with p.(Asn540Ser) in a South Indian family.
  variants:
  - name: "PNPT1 c.1424A>G (p.Glu475Gly)"
    description: >-
      The founding DFNB70 allele, homozygous in a consanguineous Moroccan family
      and again in a consanguineous Tunisian family with five affected siblings.
      It was absent from dbSNP and gnomAD at the time of the Tunisian report and
      absent from over 400 controls from Germany, Morocco and Turkey in the
      original study. It disturbs PNPase trimerization and impairs mitochondrial
      RNA import, and in later in vitro work it is also strongly impaired at RNA
      degradation.
    clinical_significance: PATHOGENIC
  - name: "PNPT1 p.(Ala46Gly) and p.(Asn540Ser)"
    description: >-
      The compound heterozygous pair reported in a South Indian assortative
      mating family with DFNB70. No functional assay of either allele has been
      published.
    clinical_significance: PATHOGENIC
  notes: >-
    The gene-disease relationship for the hearing phenotype is weakly supported
    and has been graded as such. The ClinGen Hearing Loss Working Group
    classified PNPT1 for autosomal recessive nonsyndromic hearing impairment as
    Limited, as reported in the Tunisian study; the ClinGen Gene-Disease Validity
    download retrieved on 2026-09-25 contains exactly one PNPT1 row, PNPT1 -
    Leigh syndrome (MONDO:0009723), autosomal recessive, Moderate, Mitochondrial
    Diseases Gene Curation Expert Panel, so no separate hearing-loss assertion is
    currently published and none is cited here.

    The same gene carries two other inherited phenotypes on different allele
    classes: biallelic hypomorphic missense alleles cause combined oxidative
    phosphorylation defect type 13 (OMIM 614932, curated separately), and
    heterozygous truncating and splice alleles in the S1 domain cause
    spinocerebellar ataxia type 25. Zygosity and allele class therefore have to
    be established before a PNPT1 genotype is called DFNB70.
  evidence:
  - reference: PMID:34194829
    reference_title: Novel pathogenic mutations and further evidence for clinical relevance
      of genes and variants causing hearing impairment in Tunisian population.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Even though the genetic data reported the functional importance of this residue (Glu475) suggesting the implication of this missense variation in HI, the PNPT1-ARNSHI relationship was classified as limited, when reviewed by the ClinGen Hearing Loss Working Group."
    explanation: The formal gene-disease validity grading for the hearing phenotype, which
      is the honest summary of how much replication exists.
  - reference: PMID:30244537
    reference_title: "Is PNPT1-related hearing loss ever non-syndromic? Whole exome sequencing of adult siblings expands the natural history of PNPT1-related disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PNPT1 is a mitochondrial RNA transport protein that has been linked to two discrete phenotypes, namely isolated sensorineural hearing loss (OMIM 614934) and combined oxidative phosphorylation deficiency (OMIM 614932)."
    explanation: The two recessive PNPT1 entities and the OMIM numbers that separate them,
      which is what makes this a separate entry from the COXPD13 one.
diagnosis:
- name: Exome or hearing-loss panel sequencing including PNPT1
  description: >-
    Every DFNB70 family on record was solved by exome sequencing or by a
    targeted hearing-loss panel that happened to include PNPT1, after more common
    causes had been excluded. The South Indian family reached exome sequencing
    only after heterozygous CDH23 variants failed to explain the phenotype; the
    Tunisian family was found on a custom hearing-impairment panel in which PNPT1
    was one of the targeted genes. The practical point is that PNPT1 is a
    mitochondrial-disease gene that also sits on hearing-loss panels, and a
    laboratory filtering a deafness exome by a nonsyndromic gene list may not
    carry it.
  evidence:
  - reference: PMID:34374074
    reference_title: PNPT1, MYO15A, PTPRQ, and SLC12A2-associated genetic and phenotypic
      heterogeneity among hearing impaired assortative mating families in Southern India.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "From a cohort of 113 hearing impaired (HI), five non-DFNB12 probands identified with heterozygous CDH23 variants were subjected to exome analysis. This resolved the etiology of hearing loss (HL) in four South Indian assortative mating families."
    explanation: The diagnostic route - exome sequencing after a candidate-gene result
      failed to explain the phenotype - that identified a DFNB70 family.
- name: Neurological surveillance after a PNPT1 diagnosis
  description: >-
    Because two adult siblings with biallelic PNPT1 variants and apparently
    isolated congenital hearing loss developed a progressive neurodegenerative
    course in their forties, a PNPT1 genotype found in a child with isolated
    deafness does not settle the prognosis. The authors of that report state the
    implication directly. What surveillance should consist of, and at what
    interval, has not been established by anyone; this records the risk, not a
    protocol.
  evidence:
  - reference: PMID:30244537
    reference_title: "Is PNPT1-related hearing loss ever non-syndromic? Whole exome sequencing of adult siblings expands the natural history of PNPT1-related disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The natural history of the condition in this family may suggest that the individuals previously reported as having isolated SNHL may be at risk of developing multisystem disease in late adulthood, and that PNPT1-related disorders may constitute a spectrum rather than distinct phenotypes."
    explanation: The statement that makes late neurological surveillance a defensible
      recommendation rather than an extrapolation.
treatments:
- name: Genetic Counselling and Cascade Testing
  description: >-
    Counselling for an autosomal recessive condition, most often in a
    consanguineous family: a 25 percent sibling recurrence risk once one affected
    child is born, carrier testing for at-risk relatives, and a discussion of the
    uncertain long-term neurological prognosis raised by the adult siblings
    reported with late multisystem disease. Counselling does not act on the
    mechanism; it is curated because it is the intervention the genotype itself
    indicates.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:34194829
    reference_title: Novel pathogenic mutations and further evidence for clinical relevance
      of genes and variants causing hearing impairment in Tunisian population.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The PNPT1-Glu475Gly variant identified in (Family.7_P7) segregated in 5 siblings born from consanguineous parents with ARNSHI"
    explanation: The consanguineous recessive pedigree structure that carrier testing and
      recurrence counselling act on.
  notes: >-
    No audiological or surgical management is reported for any DFNB70 patient.
    Cochlear implantation is standard care for bilateral prelingual
    severe-to-profound sensorineural hearing loss and would be expected here, but
    no published DFNB70 family records an implant, a hearing aid, or an
    audiological outcome, so nothing is curated for it: attributing implantation
    to these patients would import an indication recorded only in other people.
    There is no disease-modifying therapy, no trial and no gene-directed approach
    for PNPT1 of any kind.
animal_models:
- name: Pnpt1 hair-cell knockout mouse
  species: Mouse
  genotype: PNPase knockout restricted to inner ear hair cells
  publication: PMID:30024931
  description: >-
    The only reported mammalian model with an auditory phenotype. The study's
    main system is a constitutive PNPase knockout in mouse embryonic fibroblasts,
    which is viable only after the cells are adapted to respiratory deficiency
    and which loses its mitochondrial DNA entirely - a lesion DFNB70 patients do
    not have. The arm relevant here is the separate hair-cell-restricted knockout,
    which develops progressive hearing loss.
  modeled_mechanisms:
  - target: Cochlear Hair Cell and Spiral Ganglion Neuron Dysfunction
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Removing PNPase from inner ear hair cells is sufficient to cause progressive
      hearing loss in a mammal, which is the step neither the human genetics nor
      the heterologous functional work can supply.
    limitations: >-
      A complete knockout confined to one cell type, against a hypomorphic allele
      expressed everywhere in patients - so the model shows that hair cells need
      PNPase, not that the human hearing loss is hair-cell autonomous. The hearing
      loss is progressive in the mouse where DFNB70 is prelingual and reported as
      stable, and the model says nothing about the spiral ganglion neurons this
      node also names.
    readouts:
    - name: Progressive hearing loss after hair-cell PNPase knockout
      target: Cochlear Hair Cell and Spiral Ganglion Neuron Dysfunction
      direction: DECREASED
      interpretation: >-
        Auditory function declines over time in the hair-cell knockout, the animal
        counterpart of the human sensorineural loss.
      evidence:
      - reference: PMID:30024931
        reference_title: PNPase knockout results in mtDNA loss and an altered metabolic
          gene expression program.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "PKO in mouse inner ear hair cells caused progressive hearing loss that parallels human familial hearing loss previously linked to mutations in PNPase."
        explanation: The auditory phenotype of the model and the authors' own mapping
          of it onto the human disease.
    evidence:
    - reference: PMID:30024931
      reference_title: PNPase knockout results in mtDNA loss and an altered metabolic
        gene expression program.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "PKO in mouse inner ear hair cells caused progressive hearing loss that parallels human familial hearing loss previously linked to mutations in PNPase."
      explanation: Why this model is treated as informative for the cochlear node -
        it is the only mammalian experiment that produces a hearing phenotype from
        loss of PNPase.
  evidence:
  - reference: PMID:30024931
    reference_title: PNPase knockout results in mtDNA loss and an altered metabolic
      gene expression program.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we established PNPase knockout (PKO) systems by first shifting culture conditions to enable cell growth with defective respiration"
    explanation: How the fibroblast arm of the model was built, and the constraint
      that shapes it - in culture, complete PNPase loss is tolerated only after the
      cells are adapted to respiratory deficiency. IN_VITRO because the sentence
      describes cultured mouse embryonic fibroblasts, not an animal.
  - reference: PMID:30024931
    reference_title: PNPase knockout results in mtDNA loss and an altered metabolic
      gene expression program.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: BACKGROUND
    snippet: "Constitutive PNPase knockout (PKO) in mice is lethal at embryonic day 8"
    explanation: >-
      Why the mouse work has to be conditional, and a second reason the DFNB70
      alleles must be hypomorphic rather than null. BACKGROUND because the paper is
      citing earlier mouse work here rather than reporting its own result.
  notes: >-
    This model is also curated on the allelic
    Combined_Oxidative_Phosphorylation_Defect_Type_13 entry, whose own note on it
    observes that the relevant human comparator for the hearing arm is DFNB70
    rather than COXPD13. It is curated here for that reason, not duplicated by
    oversight.
differential_diagnoses:
- name: Combined oxidative phosphorylation defect type 13 (COXPD13)
  description: >-
    The allelic recessive multisystem disease, OMIM 614932, curated separately as
    Combined_Oxidative_Phosphorylation_Defect_Type_13. Biallelic hypomorphic
    PNPT1 missense alleles cause an infantile encephalomyopathy with hypotonia, a
    hyperkinetic movement disorder, developmental delay or regression, seizures,
    sensorineural hearing loss and visual impairment, usually with basal ganglia
    lesions in a Leigh pattern. The hearing loss is shared; everything else is
    not.
  distinguishing_features:
  - >-
    Neurological and developmental involvement from infancy, against isolated
    hearing loss with normal development in DFNB70.
  - >-
    Bilateral basal ganglia lesions or other abnormal neuroimaging, against no
    reported imaging abnormality in DFNB70.
  - >-
    A different set of PNPT1 missense alleles, although both entities are
    biallelic missense and neither allele class is diagnostic on its own.
  - >-
    The separation may be a matter of age at assessment rather than of entity -
    see the discussion attached to this entry.
  evidence:
  - reference: PMID:30244537
    reference_title: "Is PNPT1-related hearing loss ever non-syndromic? Whole exome sequencing of adult siblings expands the natural history of PNPT1-related disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PNPT1 is a mitochondrial RNA transport protein that has been linked to two discrete phenotypes, namely isolated sensorineural hearing loss (OMIM 614934) and combined oxidative phosphorylation deficiency (OMIM 614932)."
    explanation: The two entities and the OMIM numbers that distinguish them.
- name: Spinocerebellar ataxia type 25 (heterozygous PNPT1)
  description: >-
    The third PNPT1 phenotype, and the one most cleanly separated from this
    entity. It is dominant, caused by heterozygous truncating and splice variants
    affecting the S1 domain, and presents as ataxia with sensory neuropathy
    rather than as congenital deafness. A PNPT1 variant found in the
    heterozygous state in a person with hearing loss is not DFNB70.
  distinguishing_features:
  - Heterozygous rather than biallelic
  - Truncating and splice alleles in the S1 domain rather than missense alleles
  - Dominant transmission
  - Ataxia and sensory neuropathy rather than prelingual deafness
  evidence:
  - reference: PMID:41255389
    reference_title: Pathological PNPase variants with altered RNA binding and degradation
      activity affect the phenotype of bacterial and human cell models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Several missense PNPT1 mutations cause genetic diseases with different symptoms and severity ranging from hereditary hearing loss to multisystem oxidative phosphorylation (OXPHOS) deficiency disorders, Leigh syndrome, spinocerebellar ataxia type 25 and Aicardi-Goutiéres syndrome."
    explanation: >-
      The full published range of PNPT1 disease, which is the reason a PNPT1 result
      needs zygosity and allele class read before it is called DFNB70. HUMAN_CLINICAL
      grades the quoted sentence, which summarises clinical entities; BACKGROUND
      records that this in vitro paper is restating that literature in its
      introduction rather than reporting it.
  - reference: PMID:35411967
    reference_title: "Heterozygous PNPT1 Variants Cause Spinocerebellar Ataxia Type 25."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both nonsense and splice heterozygous variants result in premature stop codons, all located in the S1-domain of PNPase."
    explanation: The zygosity, allele class and protein domain that distinguish SCA25
      from the biallelic missense alleles of DFNB70.
  - reference: PMID:35411967
    reference_title: "Heterozygous PNPT1 Variants Cause Spinocerebellar Ataxia Type 25."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The SCA25 phenotype spans a slowly evolving sensory and cerebellar ataxia, in most cases attributed to ganglionopathy."
    explanation: The clinical picture of SCA25, which shares no feature with prelingual
      deafness.
discussions:
- discussion_id: dfnb70_distinct_entity_or_one_spectrum
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - "pathophysiology#PNPT1 Biallelic Hypomorphic Missense Variants"
  - "genetic#PNPT1"
  - "progression#Late multisystem neurodegeneration in at least one family"
  prompt: >-
    Is DFNB70 a distinct disease, or is it the early, isolated stage of a single
    biallelic PNPT1 disorder whose later stages are the COXPD13 picture?
  rationale: >-
    OMIM separates the two, 614934 and 614932, and this KB curates them as two
    entries. The separation has one substantial piece of evidence against it: two
    adult siblings diagnosed with isolated severe congenital sensorineural
    hearing loss developed ataxia, dystonia and cognitive decline in their
    forties, and optic atrophy, spasticity and incontinence thereafter. Their
    reporting authors ask in their title whether PNPT1-related hearing loss is
    ever non-syndromic, and conclude that PNPT1-related disorders may be a
    spectrum rather than distinct phenotypes.

    Nothing settles it either way. The Moroccan and Tunisian families have not
    been reported in late adulthood. The South Indian family already has
    vestibular dysfunction and unilateral progressive vision loss alongside the
    deafness, so even at first report it is not quite isolated. And on the
    mechanistic side, the 2025 comparative study of pathological PNPase variants
    found that catalytic impairment does not track disease severity across PNPT1
    alleles, which removes the most obvious way of predicting which phenotype an
    allele will give.

    It matters clinically and it matters pediatrically: a child diagnosed with
    DFNB70 is being given a prognosis of isolated deafness on the strength of
    families who had not yet reached the age at which the other outcome
    appeared.
  proposed_experiments:
  - experiment_id: dfnb70_long_term_followup_of_reported_families
    name: Longitudinal neurological assessment of the reported DFNB70 families
    description: >-
      Re-contact and examine the Moroccan, Tunisian and South Indian families,
      with neurological examination, brain MRI and ophthalmology, reported
      whether normal or abnormal, and related to age and to genotype.
    readouts:
    - name: Neurological examination and brain MRI in adult DFNB70 patients
      target: "progression#Late multisystem neurodegeneration in at least one family"
      interpretation: >-
        Normal neurology and imaging in adults carrying p.(Glu475Gly) well past the
        fifth decade would support DFNB70 as a genuinely distinct entity. Finding
        subclinical involvement would collapse the two OMIM entities into one
        age-dependent spectrum and change what a family is told at diagnosis.
- discussion_id: dfnb70_why_the_ear_alone
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - "pathophysiology#Cochlear Hair Cell and Spiral Ganglion Neuron Dysfunction"
  prompt: >-
    Does the DFNB70 allele impair hearing through the cochlear hair cells and
    spiral ganglion neurons where PNPase is expressed, and why is the
    mitochondrial defect not manifest elsewhere?
  rationale: >-
    The tissue claim in this entry rests on immunohistochemistry: PNPase stains
    strongly in the murine cochlea, in the sensory hair cells and the auditory
    ganglion neurons, and a mouse with PNPase knocked out in inner ear hair cells
    develops progressive hearing loss. That establishes a requirement for the
    protein in hair cells; it does not establish that the DFNB70 allele acts
    there. The mouse is a complete knockout confined to one cell type, where
    patients carry a hypomorph expressed everywhere, and no mouse carrying the
    human deafness allele has been reported. The functional work on
    p.(Glu475Gly) itself was done in bacteria, yeast, mammalian cell lines and,
    most recently, CRISPR-edited 293T cells - none of which has a cochlea.

    The harder half of the question is the tissue restriction. PNPase is
    essential in mice and in human cells and its loss produces multisystem
    disease on other alleles, so a hypomorph that deafens and does nothing else
    implies that the cochlea is the tissue with the lowest tolerance for reduced
    PNPase, or that a second factor is involved. Neither has been tested. This is
    filed as a human-model mismatch rather than a plain knowledge gap because the
    functional experiments were done - in systems whose fidelity to the cochlea
    is the open question.
  proposed_experiments:
  - experiment_id: dfnb70_knockin_mouse_auditory_phenotyping
    name: Pnpt1 p.Glu475Gly knock-in mouse with auditory and systemic phenotyping
    description: >-
      A knock-in mouse carrying the orthologous p.Glu475Gly substitution,
      phenotyped with auditory brainstem response and distortion-product
      otoacoustic emission thresholds, endocochlear potential, hair bundle and
      spiral ganglion morphology, and a systemic screen covering the neurological
      and metabolic features of the allelic multisystem disease.
    readouts:
    - name: Auditory brainstem response threshold
      target: "pathophysiology#Cochlear Hair Cell and Spiral Ganglion Neuron Dysfunction"
      direction: INCREASED
      interpretation: >-
        Raised thresholds in a homozygous knock-in would establish that this allele is
        sufficient to deafen a mammal, which no current evidence shows.
    - name: Spiral ganglion neuron count
      target: "pathophysiology#Cochlear Hair Cell and Spiral Ganglion Neuron Dysfunction"
      direction: DECREASED
      interpretation: >-
        Neuronal loss would place the lesion in the ganglion rather than the hair cell,
        which matters for whether cochlear implantation would be expected to work.
external_assertions:
- name: OMIM deafness, autosomal recessive 70 record
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:614934
  url: https://omim.org/entry/614934
  description: >-
    The OMIM phenotype record for DFNB70, distinct from OMIM:614932 for the
    allelic combined oxidative phosphorylation deficiency. Recorded here rather
    than under mappings because the DiseaseMappings class carries only
    ICD-10-CM, ICD-11, MONDO and NCIT slots.
  evidence:
  - reference: PMID:30244537
    reference_title: "Is PNPT1-related hearing loss ever non-syndromic? Whole exome sequencing of adult siblings expands the natural history of PNPT1-related disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PNPT1 is a mitochondrial RNA transport protein that has been linked to two discrete phenotypes, namely isolated sensorineural hearing loss (OMIM 614934) and combined oxidative phosphorylation deficiency (OMIM 614932)."
    explanation: Cites the OMIM number this assertion records and the entity it names.
notes: >-
  Scope decision: curated as a standalone DISEASE, not as a subtype of the
  already-curated Combined_Oxidative_Phosphorylation_Defect_Type_13 and not
  merged into it. Three reasons. OMIM assigns separate phenotype numbers, 614934
  and 614932, and the reference that anchors this entry states the separation
  explicitly. The already-curated COXPD13 entry deliberately excludes DFNB70 and
  carries it as an allelic differential, so a standalone entry is what keeps the
  two consistent. And this KB curates the numbered DFNB series one entry per
  locus. The decision is recorded with its caveat rather than as a settled fact:
  the boundary is soft, one family's isolated deafness became multisystem
  neurodegeneration in the fifth decade, and that is curated as an open
  discussion and as a progression phase rather than resolved by merging.

  The nonsyndromic designation is weaker than the name suggests. Of four
  published families, one has vestibular dysfunction and unilateral progressive
  vision loss at first report and one developed a full neurodegenerative
  syndrome decades after diagnosis. Those features are curated where they were
  reported rather than filtered out to protect the label.

  Gene-disease validity is Limited for the hearing phenotype and this entry says
  so rather than reading the four families as replication. ClinGen's Hearing Loss
  Working Group graded PNPT1 for autosomal recessive nonsyndromic hearing
  impairment as Limited; the ClinGen Gene-Disease Validity download retrieved on
  2026-09-25 carries a single PNPT1 row, for Leigh syndrome at Moderate, so there
  is no published CGGV assertion for the hearing phenotype to cite and none is
  cited.

  What is not curated, and why. No cochlear implantation or hearing aid
  treatment: no DFNB70 report describes any audiological management or outcome,
  and the standard-of-care indication belongs to the phenotype in general rather
  than to these patients. No mouse carrying a DFNB70 allele: the one
  mammalian model with an auditory phenotype is a complete PNPase knockout
  restricted to hair cells, curated with its limitations rather than read as a
  model of the human hypomorph, and the 2025 models are Escherichia coli and
  CRISPR-edited 293T cells, neither of which is an organism-level model of this
  disease. No
  audiogram configuration, onset age distribution or serial audiometry: none is
  published for any family. No JAK-inhibitor treatment block: the 2026 report of
  a PNPT1 patient treated for a type I interferonopathy describes the
  multisystem interferon arm of PNPT1 disease, which belongs to the allelic
  entity curated as Combined_Oxidative_Phosphorylation_Defect_Type_13 and not to
  DFNB70.

  GeneReviews baseline: none exists for this entity. The committed Bookshelf
  index (snapshot 2026-09-10, 958 GeneReviews chapters) contains no PNPT1 or
  DFNB70 chapter - a case-insensitive search of cache/bookshelf/genereviews.csv
  for PNPT1 or DFNB70 returns no row. The nearest chapter by subject, the
  Genetic Hearing Loss Overview, is listed in references for the baseline check
  but carries no evidence item: its cached record is abstract-only, 472
  characters, and does not mention PNPT1 anywhere, so there is nothing in it to
  quote about this entity.

  Mechanism grading. The allele and trimer-assembly nodes are graded ESTABLISHED:
  both are measured directly, if in heterologous systems. The RNA-import and
  RNA-degradation nodes are PROVISIONAL, because each is measured but neither has
  been shown to be the branch that deafens. The cochlear node is PROVISIONAL
  rather than ESTABLISHED because its support is mouse immunohistochemistry plus
  a complete hair-cell knockout, neither of which carries the human allele, and
  because its spiral ganglion arm rests on expression alone. The
  2025 comparative study's finding that catalytic impairment does not track
  disease severity across PNPT1 alleles is recorded because it undercuts the
  simplest reading of the whole chain.

  The entry name follows the repository's Autosomal Recessive Nonsyndromic
  Hearing Loss NNN convention, and MONDO:0013978 happens to use the same wording,
  so preferred_term and the bound label agree here.