GJB2-GJB6 Digenic Nonsyndromic Hearing Loss

Mendelian MONDO:0009076 Pathograph 5 Show in embeddings browser Nonsyndromic Hearing Loss Inner Ear Disorder

DFNB1 is the most common cause of autosomal recessive nonsyndromic prelingual sensorineural hearing loss and maps to a complex locus on chromosome 13q12 that contains two genes encoding cochlear gap-junction beta connexins: GJB2 (connexin 26) and GJB6 (connexin 30). Most DFNB1 disease is monogenic, caused by biallelic GJB2 mutations. However, a substantial fraction of patients carry only a single GJB2 mutant allele, and in many of these the second lesion is a large deletion in GJB6, del(GJB6-D13S1830). Because connexin 26 and connexin 30 co-assemble into the same cochlear gap-junction plaques required for potassium recycling, a GJB2 mutation on one allele together with a GJB6 deletion on the other can cause hearing loss digenically - the classic textbook example of digenic inheritance in nonsyndromic deafness. The GJB6 deletion may also act in cis by removing a GJB2 regulatory element; both routes converge on loss of cochlear connexin function.

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2
Inheritance
3
Pathophys.
1
Phenotypes
5
Pathograph
2
Genes
👪

Inheritance

2
Autosomal recessive (monogenic GJB2, DFNB1A) HP:0000007
The majority of DFNB1 hearing loss is monogenic autosomal recessive disease caused by biallelic pathogenic variants in GJB2 (connexin 26), the single most common cause of hereditary nonsyndromic deafness.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:11807148 SUPPORT Human Clinical
"Up to 50 percent of all patients with autosomal recessive nonsyndromic prelingual deafness in different populations have mutations in the gene encoding the gap-junction protein connexin 26 (GJB2) at locus DFNB1 on chromosome 13q12."
Establishes GJB2 (connexin 26) biallelic mutation as the predominant, monogenic autosomal recessive cause of DFNB1 prelingual deafness.
Digenic inheritance (GJB2/GJB6) HP:0010984
A large fraction of patients carry only one GJB2 mutant allele; in many of these the second lesion is the del(GJB6-D13S1830) deletion in GJB6 (connexin 30) in trans, so that double heterozygosity for a GJB2 mutation and a GJB6 deletion causes hearing loss digenically. This is the canonical example of digenic inheritance in nonsyndromic deafness.
Digenic inheritance
Show evidence (2 references)
PMID:11807148 SUPPORT Human Clinical
"Our data suggest that mutations in the complex locus DFNB1, which contains two genes (GJB2 and GJB6), can result in a monogenic or a digenic pattern of inheritance of prelingual deafness."
Directly establishes a digenic (GJB2/GJB6) pattern of inheritance at the DFNB1 locus alongside the monogenic GJB2 form.
PMID:11807148 SUPPORT Human Clinical
"Twenty-two of the 33 subjects were heterozygous for both the GJB6 and GJB2 mutations, including all 9 with evidence of linkage to DFNB1."
Documents the double-heterozygous GJB2/GJB6 genotype in affected patients, the genetic signature of digenic DFNB1 deafness.
⚙

Pathophysiology

3
Loss of Cochlear Connexin Gap-Junction Coupling
Connexin 26 (GJB2) and connexin 30 (GJB6) co-assemble into the gap-junction plaques of the non-sensory epithelial supporting cells and the spiral ligament fibrocytes of the cochlea. A GJB2 loss-of-function mutation combined with a GJB6 deletion (or biallelic GJB2 mutation) disrupts this shared connexin network and abolishes intercellular coupling.
Cochlear supporting cell CL:0000630 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cochlear supporting cell, annotated with supporting cell (CL:0000630). CL:0000630 is a cell type from the Cell Ontology.
GJB2 hgnc:4284 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves GJB2 (hgnc:4284). hgnc:4284 is a gene from the HUGO Gene Nomenclature Committee. GJB6 hgnc:4288 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves GJB6 (hgnc:4288). hgnc:4288 is a gene from the HUGO Gene Nomenclature Committee.
Gap junction assembly GO:0016264 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Gap junction assembly (GO:0016264). GO:0016264 is a biological process from the Gene Ontology.
Downstream
Impaired Endocochlear Potassium Recycling
Show evidence (1 reference)
PMID:9139825 SUPPORT In Vitro
"Immunohistochemical staining of human cochlear cells for Cx26 demonstrated high levels of expression."
Demonstrates high connexin 26 expression in human cochlear cells, the substrate whose loss disrupts cochlear gap-junction coupling.
Impaired Endocochlear Potassium Recycling
The cochlear connexin gap-junction networks form the route by which potassium ions entering sensory hair cells during mechanotransduction are recycled back to the endolymph. Loss of connexin 26/30 coupling interrupts this potassium recycling pathway, disturbing endolymph homeostasis.
Cochlear supporting cell CL:0000630 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cochlear supporting cell, annotated with supporting cell (CL:0000630). CL:0000630 is a cell type from the Cell Ontology.
Potassium ion recycling GO:0006813 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Potassium ion recycling, annotated with potassium ion transport (GO:0006813). GO:0006813 is a biological process from the Gene Ontology.
Downstream
Prelingual Sensorineural Hearing Loss
Show evidence (1 reference)
PMID:11810458 SUPPORT Other
"The two networks of gap junctions form the route by which K+ ions that pass through the sensory cells during mechanosensory transduction can be recycled back to the endolymphatic space, from which they reenter the sensory cells."
Describes the cochlear gap-junction potassium recycling pathway whose interruption by connexin loss underlies DFNB1 deafness.
Prelingual Sensorineural Hearing Loss
Disruption of cochlear potassium recycling causes sensorineural hearing loss that is typically prelingual (congenital), bilateral, and ranges from mild to profound.
Show evidence (1 reference)
PMID:9139825 SUPPORT Human Clinical
"identified a mutation in the gene encoding the gap-junction protein connexin 26 (Cx26) that segregates with the profound deafness in the family."
Links connexin 26 mutation to profound sensorineural deafness segregating in an affected family.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for GJB2-GJB6 Digenic Nonsyndromic Hearing Loss Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

1
Congenital Sensorineural Hearing Loss Clinical HP:0008527 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital sensorineural hearing impairment (HP:0008527). HP:0008527 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:11807148 SUPPORT Human Clinical
"Up to 50 percent of all patients with autosomal recessive nonsyndromic prelingual deafness in different populations have mutations in the gene encoding the gap-junction protein connexin 26 (GJB2) at locus DFNB1 on chromosome 13q12."
Documents the prelingual nonsyndromic sensorineural deafness phenotype of DFNB1.
🧬

Genetic Associations

2
GJB2 (Causative (connexin 26); biallelic in monogenic DFNB1A or monoallelic in trans with a GJB6 deletion in digenic disease)
Gene: GJB2 hgnc:4284 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is GJB2 (hgnc:4284). hgnc:4284 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (1 reference)
PMID:9139825 SUPPORT Human Clinical
"identified a mutation in the gene encoding the gap-junction protein connexin 26 (Cx26) that segregates with the profound deafness in the family."
Establishes GJB2 (connexin 26) as causative for nonsyndromic sensorineural deafness.
GJB6 (Causative (connexin 30) via the del(GJB6-D13S1830) deletion; digenic with GJB2 or homozygous)
Gene: GJB6 hgnc:4288 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is GJB6 (hgnc:4288). hgnc:4288 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (1 reference)
PMID:11807148 SUPPORT Human Clinical
"Twenty-two of the 33 subjects were heterozygous for both the GJB6 and GJB2 mutations, including all 9 with evidence of linkage to DFNB1."
Establishes the GJB6 deletion as a DFNB1 disease lesion acting digenically with GJB2.
🔬

Diagnosis

1
Pure-tone audiometry
Pure-tone audiometry, together with auditory brainstem response testing, establishes the degree of the sensorineural hearing loss in children screened for GJB2 (connexin 26) and GJB6 (connexin 30) lesions.
audiometric test NCIT:C38036 NCI Thesaurus (NCIT)
pure-tone threshold audiometry LOINC:89015-2 Logical Observation Identifiers Names and Codes (LOINC) hearing threshold, left ear, 500 Hz LOINC:89024-4 Logical Observation Identifiers Names and Codes (LOINC) hearing threshold, right ear, 500 Hz LOINC:89025-1 Logical Observation Identifiers Names and Codes (LOINC) hearing threshold, left ear, 1000 Hz LOINC:89016-0 Logical Observation Identifiers Names and Codes (LOINC) hearing threshold, right ear, 1000 Hz LOINC:89017-8 Logical Observation Identifiers Names and Codes (LOINC) hearing threshold, left ear, 2000 Hz LOINC:89018-6 Logical Observation Identifiers Names and Codes (LOINC) hearing threshold, right ear, 2000 Hz LOINC:89019-4 Logical Observation Identifiers Names and Codes (LOINC) hearing threshold, left ear, 4000 Hz LOINC:89022-8 Logical Observation Identifiers Names and Codes (LOINC) hearing threshold, right ear, 4000 Hz LOINC:89023-6 Logical Observation Identifiers Names and Codes (LOINC)
Reference Ranges
(Grades recommended by the Global Burden of Disease Expert Group on Hearing Loss, better-ear average of 500, 1000, 2000 and 4000 Hz, as tabulated by Olusanya, Davis and Hoffman (WHO Bulletin))
Normal hearing (< 20 dB) Mild hearing loss (20–35 dB) Moderate hearing loss (35–50 dB) Moderately severe hearing loss (50–65 dB) Severe hearing loss (65–80 dB) Profound hearing loss (80–95 dB) Complete or total hearing loss (≥ 95 dB)
Values are dB hearing level (HL). The source gives each grade as a closed range to one decimal place (Mild hearing loss 20.0 to 34.9 dB hearing level, and so on up to Complete or total hearing loss 95.0 dB hearing level or greater); the half-open bands here are the same partition. The source splits normal hearing into -10.0 to 4.9 and 5.0 to 19.9 dB hearing level; both are folded into one Normal hearing band. Its Unilateral category (below 20.0 dB in the better ear, 35.0 dB or greater in the worse ear) needs both ears and is not representable as a band. Severity is set only where the grade name is mild, moderate or severe. Bonetti (PMID:41718341) applies the same boundaries, up to moderately severe, as the WHO-defined hearing loss categories; the WHO report itself is not PubMed-indexed, so the grades are quoted from these restatements. No LOINC code was found for the better-ear four-frequency pure-tone average these grades read: Monarch KG searches for pure tone average, threshold average, average hearing, PTA and hearing level returned none. The range therefore names no loinc_term. A numeric band on the panel LOINC:89015-2 would put a number on an instrument, and on any one frequency code would misstate what is graded; the average is computed from the eight per-frequency codes bound above. LOINC:98422-9 (Hearing loss degree Ear - left) and LOINC:98427-8 (Hearing loss degree Ear - right) exist but carry the category, not the dB value, so they are not bound. The grading is generic to hearing loss of any cause, not specific to this disease. The severity words this entry uses come from its cited clinical sources, which do not necessarily use these boundaries.
Show evidence (5 references)
PMID:31656340 SUPPORT REVIEW SYNTHESIS Other
"Mild hearing loss | 20.0 to 34.9 dB hearing level"
Table 2 row giving the lower boundary of hearing loss and the mild grade in the Global Burden of Disease Expert Group scheme.
PMID:31656340 SUPPORT REVIEW SYNTHESIS Other
"Profound hearing loss | 80.0 to 94.9 dB hearing level"
Table 2 row giving the profound grade.
PMID:31656340 SUPPORT REVIEW SYNTHESIS Other
"Complete or total hearing loss | 95.0 dB hearing level or greater"
Table 2 row giving the top, open-ended grade.
+ 2 more references
(Earlier WHO grades of hearing impairment (based on the 1991 version), better-ear average of 500, 1000, 2000 and 4000 Hz, as tabulated by Olusanya, Davis and Hoffman (WHO Bulletin))
Grade 0: no impairment (< 26 dB) Grade 1: slight impairment (26–41 dB) Grade 2: moderate impairment (41–61 dB) Grade 3: severe impairment (61–81 dB) Grade 4: profound impairment including deafness (≥ 81 dB)
Superseded scheme, recorded because older clinical literature reports severity on it and its boundaries differ from the Global Burden of Disease grades above. The source states whole-decibel ranges (25 dB or better, 26-40 dB, 41-60 dB, 61-80 dB, 81 dB or greater); an average falling between two stated ranges, such as 25.5 dB, is not assigned by the source and falls in the upper grade under the half-open convention used here. The same source records that only adults with a permanent unaided impairment above 40 dB hearing level in the better ear, and children with more than 30 dB, were regarded as having a disabling hearing impairment. Severity is set only where the grade name is moderate or severe. The grading is generic to hearing loss of any cause.
Show evidence (3 references)
PMID:31656340 SUPPORT REVIEW SYNTHESIS Other
"1: slight impairment | 26-40 dB | Able to hear and repeat words spoken in normal voice at 1 m"
Table 1 row giving the slight grade in the earlier WHO scheme.
PMID:31656340 SUPPORT REVIEW SYNTHESIS Other
"4: profound impairment including deafness | 81 dB or greater"
Table 1 row giving the top grade in the earlier WHO scheme.
PMID:31656340 SUPPORT REVIEW SYNTHESIS Other
"currently only adults (≥ 15 years) with a permanent unaided hearing impairment above 40 dB hearing level in the better ear and children (from birth to 14 years of age) with > 30 dB hearing level are regarded as having a disabling hearing impairment"
Places the earlier scheme's disabling-impairment cut-offs in the better ear.
Show evidence (1 reference)
PMID:15064611 SUPPORT Human Clinical
"Audiometric testing, including pure-tone audiometry and auditory evoked brainstem response, was also performed to determine the degree of hearing loss."
In a cohort of children with nonsyndromic sensorineural hearing loss screened for Cx26 mutations and the del(GJB6-D13S1830) Cx30 deletion, pure-tone audiometry and auditory brainstem response testing were the measurements used to grade the degree of hearing loss.
📊

Prevalence

1
Spanish nonsyndromic prelingual deafness probands with a single GJB2 mutant allele
Among probands with only one GJB2 mutant allele, the del(GJB6-D13S1830) deletion was the second most frequent DFNB1 mutation, most often found in trans with a GJB2 mutation (digenic genotype).
Show evidence (1 reference)
PMID:11807148 SUPPORT Human Clinical
"A 342-kb deletion in GJB6 is the second most frequent mutation causing prelingual deafness in the Spanish population."
Quantifies the GJB6 deletion as the second most common DFNB1 lesion, supporting the epidemiological relevance of the digenic genotype.
{ }

Source YAML

click to show 
name: GJB2-GJB6 Digenic Nonsyndromic Hearing Loss
creation_date: '2026-07-03T00:00:00Z'
category: Mendelian
description: >
  DFNB1 is the most common cause of autosomal recessive nonsyndromic prelingual
  sensorineural hearing loss and maps to a complex locus on chromosome 13q12 that
  contains two genes encoding cochlear gap-junction beta connexins: GJB2 (connexin
  26) and GJB6 (connexin 30). Most DFNB1 disease is monogenic, caused by biallelic
  GJB2 mutations. However, a substantial fraction of patients carry only a single
  GJB2 mutant allele, and in many of these the second lesion is a large deletion
  in GJB6, del(GJB6-D13S1830). Because connexin 26 and connexin 30 co-assemble
  into the same cochlear gap-junction plaques required for potassium recycling,
  a GJB2 mutation on one allele together with a GJB6 deletion on the other can
  cause hearing loss digenically - the classic textbook example of digenic
  inheritance in nonsyndromic deafness. The GJB6 deletion may also act in cis by
  removing a GJB2 regulatory element; both routes converge on loss of cochlear
  connexin function.
disease_term:
  preferred_term: DFNB1 nonsyndromic hearing loss (GJB2/GJB6, digenic)
  term:
    id: MONDO:0009076
    label: autosomal recessive nonsyndromic hearing loss 1A
parents:
- Nonsyndromic Hearing Loss
- Inner Ear Disorder
inheritance:
- name: Autosomal recessive (monogenic GJB2, DFNB1A)
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >
    The majority of DFNB1 hearing loss is monogenic autosomal recessive disease
    caused by biallelic pathogenic variants in GJB2 (connexin 26), the single most
    common cause of hereditary nonsyndromic deafness.
  evidence:
  - reference: PMID:11807148
    reference_title: "A deletion involving the connexin 30 gene in nonsyndromic hearing impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Up to 50 percent of all patients with autosomal recessive nonsyndromic
      prelingual deafness in different populations have mutations in the gene
      encoding the gap-junction protein connexin 26 (GJB2) at locus DFNB1 on
      chromosome 13q12.
    explanation: >-
      Establishes GJB2 (connexin 26) biallelic mutation as the predominant,
      monogenic autosomal recessive cause of DFNB1 prelingual deafness.
- name: Digenic inheritance (GJB2/GJB6)
  inheritance_term:
    preferred_term: Digenic inheritance
    term:
      id: HP:0010984
      label: Digenic inheritance
  description: >
    A large fraction of patients carry only one GJB2 mutant allele; in many of
    these the second lesion is the del(GJB6-D13S1830) deletion in GJB6 (connexin
    30) in trans, so that double heterozygosity for a GJB2 mutation and a GJB6
    deletion causes hearing loss digenically. This is the canonical example of
    digenic inheritance in nonsyndromic deafness.
  evidence:
  - reference: PMID:11807148
    reference_title: "A deletion involving the connexin 30 gene in nonsyndromic hearing impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our data suggest that mutations in the complex locus DFNB1, which contains
      two genes (GJB2 and GJB6), can result in a monogenic or a digenic pattern
      of inheritance of prelingual deafness.
    explanation: >-
      Directly establishes a digenic (GJB2/GJB6) pattern of inheritance at the
      DFNB1 locus alongside the monogenic GJB2 form.
  - reference: PMID:11807148
    reference_title: "A deletion involving the connexin 30 gene in nonsyndromic hearing impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Twenty-two of the 33 subjects were heterozygous for both the GJB6 and GJB2
      mutations, including all 9 with evidence of linkage to DFNB1.
    explanation: >-
      Documents the double-heterozygous GJB2/GJB6 genotype in affected patients,
      the genetic signature of digenic DFNB1 deafness.
prevalence:
- population: Spanish nonsyndromic prelingual deafness probands with a single GJB2 mutant allele
  notes: >-
    Among probands with only one GJB2 mutant allele, the del(GJB6-D13S1830)
    deletion was the second most frequent DFNB1 mutation, most often found in
    trans with a GJB2 mutation (digenic genotype).
  evidence:
  - reference: PMID:11807148
    reference_title: "A deletion involving the connexin 30 gene in nonsyndromic hearing impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A 342-kb deletion in GJB6 is the second most frequent mutation causing
      prelingual deafness in the Spanish population.
    explanation: >-
      Quantifies the GJB6 deletion as the second most common DFNB1 lesion,
      supporting the epidemiological relevance of the digenic genotype.
pathophysiology:
- name: Loss of Cochlear Connexin Gap-Junction Coupling
  description: >
    Connexin 26 (GJB2) and connexin 30 (GJB6) co-assemble into the gap-junction
    plaques of the non-sensory epithelial supporting cells and the spiral ligament
    fibrocytes of the cochlea. A GJB2 loss-of-function mutation combined with a
    GJB6 deletion (or biallelic GJB2 mutation) disrupts this shared connexin
    network and abolishes intercellular coupling.
  genes:
  - preferred_term: GJB2
    term:
      id: hgnc:4284
      label: GJB2
  - preferred_term: GJB6
    term:
      id: hgnc:4288
      label: GJB6
  cell_types:
  - preferred_term: Cochlear supporting cell
    term:
      id: CL:0000630
      label: supporting cell
  biological_processes:
  - preferred_term: Gap junction assembly
    modifier: DECREASED
    term:
      id: GO:0016264
      label: gap junction assembly
  evidence:
  - reference: PMID:9139825
    reference_title: "Connexin 26 mutations in hereditary non-syndromic sensorineural deafness."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Immunohistochemical staining of human cochlear cells for Cx26 demonstrated
      high levels of expression.
    explanation: >-
      Demonstrates high connexin 26 expression in human cochlear cells, the
      substrate whose loss disrupts cochlear gap-junction coupling.
  downstream:
  - target: Impaired Endocochlear Potassium Recycling
- name: Impaired Endocochlear Potassium Recycling
  description: >
    The cochlear connexin gap-junction networks form the route by which potassium
    ions entering sensory hair cells during mechanotransduction are recycled back
    to the endolymph. Loss of connexin 26/30 coupling interrupts this potassium
    recycling pathway, disturbing endolymph homeostasis.
  cell_types:
  - preferred_term: Cochlear supporting cell
    term:
      id: CL:0000630
      label: supporting cell
  biological_processes:
  - preferred_term: Potassium ion recycling
    modifier: DECREASED
    term:
      id: GO:0006813
      label: potassium ion transport
  evidence:
  - reference: PMID:11810458
    reference_title: "Potassium ion recycling pathway via gap junction systems in the mammalian cochlea and its interruption in hereditary nonsyndromic deafness."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The two networks of gap junctions form the route by which K+ ions that
      pass through the sensory cells during mechanosensory transduction can be
      recycled back to the endolymphatic space, from which they reenter the
      sensory cells.
    explanation: >-
      Describes the cochlear gap-junction potassium recycling pathway whose
      interruption by connexin loss underlies DFNB1 deafness.
  downstream:
  - target: Prelingual Sensorineural Hearing Loss
- name: Prelingual Sensorineural Hearing Loss
  description: >
    Disruption of cochlear potassium recycling causes sensorineural hearing loss
    that is typically prelingual (congenital), bilateral, and ranges from mild to
    profound.
  evidence:
  - reference: PMID:9139825
    reference_title: "Connexin 26 mutations in hereditary non-syndromic sensorineural deafness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      identified a mutation in the gene encoding the gap-junction protein
      connexin 26 (Cx26) that segregates with the profound deafness in the
      family.
    explanation: >-
      Links connexin 26 mutation to profound sensorineural deafness segregating
      in an affected family.
phenotypes:
- category: Clinical
  name: Congenital Sensorineural Hearing Loss
  description: >
    Bilateral prelingual (congenital) sensorineural hearing loss ranging from mild
    to profound, the defining clinical feature of DFNB1.
  phenotype_term:
    preferred_term: Congenital sensorineural hearing impairment
    term:
      id: HP:0008527
      label: Congenital sensorineural hearing impairment
  evidence:
  - reference: PMID:11807148
    reference_title: "A deletion involving the connexin 30 gene in nonsyndromic hearing impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Up to 50 percent of all patients with autosomal recessive nonsyndromic
      prelingual deafness in different populations have mutations in the gene
      encoding the gap-junction protein connexin 26 (GJB2) at locus DFNB1 on
      chromosome 13q12.
    explanation: >-
      Documents the prelingual nonsyndromic sensorineural deafness phenotype of
      DFNB1.
genetic:
- name: GJB2
  gene_term:
    preferred_term: GJB2
    term:
      id: hgnc:4284
      label: GJB2
  association: Causative (connexin 26); biallelic in monogenic DFNB1A or monoallelic in trans with a GJB6 deletion in digenic disease
  relationship_type: CAUSATIVE
  evidence:
  - reference: PMID:9139825
    reference_title: "Connexin 26 mutations in hereditary non-syndromic sensorineural deafness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      identified a mutation in the gene encoding the gap-junction protein
      connexin 26 (Cx26) that segregates with the profound deafness in the
      family.
    explanation: >-
      Establishes GJB2 (connexin 26) as causative for nonsyndromic sensorineural
      deafness.
- name: GJB6
  gene_term:
    preferred_term: GJB6
    term:
      id: hgnc:4288
      label: GJB6
  association: Causative (connexin 30) via the del(GJB6-D13S1830) deletion; digenic with GJB2 or homozygous
  relationship_type: CAUSATIVE
  evidence:
  - reference: PMID:11807148
    reference_title: "A deletion involving the connexin 30 gene in nonsyndromic hearing impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Twenty-two of the 33 subjects were heterozygous for both the GJB6 and GJB2
      mutations, including all 9 with evidence of linkage to DFNB1.
    explanation: >-
      Establishes the GJB6 deletion as a DFNB1 disease lesion acting digenically
      with GJB2.
diagnosis:
- name: Pure-tone audiometry
  description: >-
    Pure-tone audiometry, together with auditory brainstem response testing, establishes the degree of
    the sensorineural hearing loss in children screened for GJB2 (connexin 26) and GJB6 (connexin 30)
    lesions.
  diagnosis_term:
    preferred_term: audiometric test
    term:
      id: NCIT:C38036
      label: Audiometric Test
  measurements:
  - preferred_term: pure-tone threshold audiometry
    term:
      id: LOINC:89015-2
      label: Pure tone threshold audiometry panel
  - preferred_term: hearing threshold, left ear, 500 Hz
    term:
      id: LOINC:89024-4
      label: Hearing threshold Ear - left --500 Hz
  - preferred_term: hearing threshold, right ear, 500 Hz
    term:
      id: LOINC:89025-1
      label: Hearing threshold Ear - right --500 Hz
  - preferred_term: hearing threshold, left ear, 1000 Hz
    term:
      id: LOINC:89016-0
      label: Hearing threshold Ear - left --1000 Hz
  - preferred_term: hearing threshold, right ear, 1000 Hz
    term:
      id: LOINC:89017-8
      label: Hearing threshold Ear - right --1000 Hz
  - preferred_term: hearing threshold, left ear, 2000 Hz
    term:
      id: LOINC:89018-6
      label: Hearing threshold Ear - left --2000 Hz
  - preferred_term: hearing threshold, right ear, 2000 Hz
    term:
      id: LOINC:89019-4
      label: Hearing threshold Ear - right --2000 Hz
  - preferred_term: hearing threshold, left ear, 4000 Hz
    term:
      id: LOINC:89022-8
      label: Hearing threshold Ear - left --4000 Hz
  - preferred_term: hearing threshold, right ear, 4000 Hz
    term:
      id: LOINC:89023-6
      label: Hearing threshold Ear - right --4000 Hz
  reference_ranges:
  - unit: dB
    population: >-
      Grades recommended by the Global Burden of Disease Expert Group on Hearing Loss, better-ear average
      of 500, 1000, 2000 and 4000 Hz, as tabulated by Olusanya, Davis and Hoffman (WHO Bulletin)
    interpretation_bands:
    - name: Normal hearing
      upper_bound: 20
      unit: dB
      abnormal_flag: NORMAL
    - name: Mild hearing loss
      lower_bound: 20
      upper_bound: 35
      unit: dB
      abnormal_flag: HIGH
      severity: MILD
    - name: Moderate hearing loss
      lower_bound: 35
      upper_bound: 50
      unit: dB
      abnormal_flag: HIGH
      severity: MODERATE
    - name: Moderately severe hearing loss
      lower_bound: 50
      upper_bound: 65
      unit: dB
      abnormal_flag: HIGH
    - name: Severe hearing loss
      lower_bound: 65
      upper_bound: 80
      unit: dB
      abnormal_flag: HIGH
      severity: SEVERE
    - name: Profound hearing loss
      lower_bound: 80
      upper_bound: 95
      unit: dB
      abnormal_flag: HIGH
    - name: Complete or total hearing loss
      lower_bound: 95
      unit: dB
      abnormal_flag: HIGH
    notes: >-
      Values are dB hearing level (HL). The source gives each grade as a closed range to one decimal place
      (Mild hearing loss 20.0 to 34.9 dB hearing level, and so on up to Complete or total hearing loss 95.0
      dB hearing level or greater); the half-open bands here are the same partition. The source splits
      normal hearing into -10.0 to 4.9 and 5.0 to 19.9 dB hearing level; both are folded into one Normal
      hearing band. Its Unilateral category (below 20.0 dB in the better ear, 35.0 dB or greater in the
      worse ear) needs both ears and is not representable as a band. Severity is set only where the grade
      name is mild, moderate or severe. Bonetti (PMID:41718341) applies the same boundaries, up to
      moderately severe, as the WHO-defined hearing loss categories; the WHO report itself is not
      PubMed-indexed, so the grades are quoted from these restatements. No LOINC code was found for the better-ear four-frequency pure-tone average these grades read: Monarch KG searches for pure tone average, threshold average, average hearing, PTA and hearing level returned none. The range therefore names no loinc_term. A numeric band on the panel LOINC:89015-2 would put a number on an instrument, and on any one frequency code would misstate what is graded; the average is computed from the eight per-frequency codes bound above. LOINC:98422-9 (Hearing loss degree Ear - left) and LOINC:98427-8 (Hearing loss degree Ear - right) exist but carry the category, not the dB value, so they are not bound. The grading is generic to hearing loss of any cause, not specific to this disease. The severity words this entry uses come from its cited clinical sources, which do not necessarily use these boundaries.
    evidence:
    - reference: PMID:31656340
      reference_title: 'Hearing loss grades and the International classification of functioning, disability and health.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Mild hearing loss | 20.0 to 34.9 dB hearing level"
      explanation: >-
        Table 2 row giving the lower boundary of hearing loss and the mild grade in the Global Burden of
        Disease Expert Group scheme.
    - reference: PMID:31656340
      reference_title: 'Hearing loss grades and the International classification of functioning, disability and health.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Profound hearing loss | 80.0 to 94.9 dB hearing level"
      explanation: Table 2 row giving the profound grade.
    - reference: PMID:31656340
      reference_title: 'Hearing loss grades and the International classification of functioning, disability and health.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Complete or total hearing loss | 95.0 dB hearing level or greater"
      explanation: Table 2 row giving the top, open-ended grade.
    - reference: PMID:31656340
      reference_title: 'Hearing loss grades and the International classification of functioning, disability and health.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "b Average of 500, 1000, 2000 and 4000 Hz. Source: Global Burden of Disease Expert Group on Hearing Loss."
      explanation: >-
        Table 2 footnote naming the four frequencies averaged and the body that set the grades; footnote a
        places the measurement in the better ear.
    - reference: PMID:41718341
      reference_title: 'Self-Perceived Hearing Handicap and Audiometric Severity in Age-Related Hearing Loss: Associations with Age and Sex.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Moderate hearing loss (BE PTA-4 35 to <50 dB HL)"
      explanation: >-
        A clinical study stratifying patients by WHO hearing loss categories uses the same 35 to below 50 dB
        moderate band on the better-ear four-frequency average.
  - unit: dB
    population: >-
      Earlier WHO grades of hearing impairment (based on the 1991 version), better-ear average of 500, 1000,
      2000 and 4000 Hz, as tabulated by Olusanya, Davis and Hoffman (WHO Bulletin)
    interpretation_bands:
    - name: 'Grade 0: no impairment'
      upper_bound: 26
      unit: dB
      abnormal_flag: NORMAL
    - name: 'Grade 1: slight impairment'
      lower_bound: 26
      upper_bound: 41
      unit: dB
      abnormal_flag: HIGH
    - name: 'Grade 2: moderate impairment'
      lower_bound: 41
      upper_bound: 61
      unit: dB
      abnormal_flag: HIGH
      severity: MODERATE
    - name: 'Grade 3: severe impairment'
      lower_bound: 61
      upper_bound: 81
      unit: dB
      abnormal_flag: HIGH
      severity: SEVERE
    - name: 'Grade 4: profound impairment including deafness'
      lower_bound: 81
      unit: dB
      abnormal_flag: HIGH
    notes: >-
      Superseded scheme, recorded because older clinical literature reports severity on it and its
      boundaries differ from the Global Burden of Disease grades above. The source states whole-decibel
      ranges (25 dB or better, 26-40 dB, 41-60 dB, 61-80 dB, 81 dB or greater); an average falling between
      two stated ranges, such as 25.5 dB, is not assigned by the source and falls in the upper grade under
      the half-open convention used here. The same source records that only adults with a permanent
      unaided impairment above 40 dB hearing level in the better ear, and children with more than 30 dB,
      were regarded as having a disabling hearing impairment. Severity is set only where the grade name is
      moderate or severe. The grading is generic to hearing loss of any cause.
    evidence:
    - reference: PMID:31656340
      reference_title: 'Hearing loss grades and the International classification of functioning, disability and health.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "1: slight impairment | 26-40 dB | Able to hear and repeat words spoken in normal voice at 1 m"
      explanation: Table 1 row giving the slight grade in the earlier WHO scheme.
    - reference: PMID:31656340
      reference_title: 'Hearing loss grades and the International classification of functioning, disability and health.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "4: profound impairment including deafness | 81 dB or greater"
      explanation: Table 1 row giving the top grade in the earlier WHO scheme.
    - reference: PMID:31656340
      reference_title: 'Hearing loss grades and the International classification of functioning, disability and health.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        currently only adults (≥ 15 years) with a permanent unaided hearing impairment above 40 dB hearing
        level in the better ear and children (from birth to 14 years of age) with > 30 dB hearing level are
        regarded as having a disabling hearing impairment
      explanation: Places the earlier scheme's disabling-impairment cut-offs in the better ear.
  evidence:
  - reference: PMID:15064611
    reference_title: 'Connexin 26 and connexin 30 mutations in children with nonsyndromic hearing loss.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Audiometric testing, including pure-tone audiometry and auditory evoked brainstem response, was also
      performed to determine the degree of hearing loss.
    explanation: >-
      In a cohort of children with nonsyndromic sensorineural hearing loss screened for Cx26 mutations
      and the del(GJB6-D13S1830) Cx30 deletion, pure-tone audiometry and auditory brainstem response
      testing were the measurements used to grade the degree of hearing loss.