Leber Congenital Amaurosis with Early-Onset Deafness

name: Leber Congenital Amaurosis with Early-Onset Deafness
creation_date: "2026-06-21T00:00:00Z"
category: Mendelian
description: >-
  Leber congenital amaurosis with early-onset deafness (LCAEOD) is a rare
  autosomal dominant sensorineural disorder caused by heterozygous variants in
  TUBB4B, which encodes the beta-tubulin 4B isotype. It is defined by the
  atypical co-occurrence of Leber congenital amaurosis - a severe, early
  neurodegeneration of retinal photoreceptors that causes blindness within the
  first year of life - with early-onset sensorineural hearing loss. The
  causative variants recurrently affect the Arg391 residue of beta-tubulin and
  act in a dominant-negative manner on microtubule behavior. The delineating
  study attributed the disease to altered microtubule dynamics rather than overt
  ciliary dysfunction, but subsequent structure-function work established that
  TUBB4B variants perturb centriole and cilium biogenesis and stratify patients
  across a spectrum of ciliopathic diseases, placing LCAEOD within the
  sensory-cilium ciliopathies and linking the tubulinopathies to the
  ciliopathies. The non-redundant role of the cilia-enriched TUBB4B isotype in
  photoreceptor connecting cilia and cochlear sensory cells accounts for the
  combined retinal and auditory phenotype.
disease_term:
  preferred_term: Leber congenital amaurosis with early-onset deafness
  term:
    id: MONDO:0060650
    label: Leber congenital amaurosis with early-onset deafness
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
  mechanistic_category:
  - classification_value: ciliopathy
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0060650
      label: Leber congenital amaurosis with early-onset deafness
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: Primary MONDO disease identifier for Leber congenital amaurosis with early-onset deafness.
parents:
- Ciliopathy
synonyms:
- LCAEOD
- TUBB4B-related Leber congenital amaurosis with deafness
notes: >-
  External cross-references: OMIM:617879 (LEBER CONGENITAL AMAUROSIS WITH
  EARLY-ONSET DEAFNESS; LCAEOD). MONDO classifies this disorder as a retinal
  ciliopathy and a TUBB4B-related ciliopathy (is-a descendant of ciliopathy,
  MONDO:0005308). Mechanistic nuance worth preserving: the gene-identification
  study (Luscan et al., 2017) concluded that the recurrent Arg391 TUBB4B
  mutations cause a syndromic LCA via altered microtubule dynamics and described
  it as "unrelated to ciliary dysfunction"; the later structure-function study
  (Dodd, Mechaussier, et al., 2024) showed that distinct TUBB4B variants perturb
  centriole and cilium biogenesis in a dominant-negative manner and stratify
  patients into classes of ciliopathic disease, reconciling LCAEOD with the
  ciliopathy framework now reflected in MONDO. The same Arg391 residue recurs
  across reported LCAEOD families, and broader TUBB4B allelic series include
  primary-ciliary-dyskinesia-like motile ciliopathy, illustrating
  isotype-specific, organelle-specific tubulin functions.
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    LCAEOD is inherited in an autosomal dominant pattern; heterozygous TUBB4B
    variants recurrently affecting Arg391 act in a dominant-negative manner.
  evidence:
  - reference: PMID:29198720
    reference_title: "Mutations in TUBB4B Cause a Distinctive Sensorineural Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we identified two heterozygous mutations affecting Arg391 in β-tubulin
      4B isotype-encoding (TUBB4B)
    explanation: >-
      Documents heterozygous (autosomal dominant) TUBB4B Arg391 variants in
      affected families and simplex cases.
  - reference: PMID:38662826
    reference_title: "Ciliopathy patient variants reveal organelle-specific functions for TUBB4B in axonemal microtubules."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Distinct TUBB4B variants differentially affected microtubule dynamics and
      cilia formation in a dominant-negative manner.
    explanation: >-
      Confirms the dominant-negative mechanism of TUBB4B variants on microtubule
      and cilia function, consistent with dominant inheritance.
genetic:
- name: TUBB4B
  association: Pathogenic heterozygous (dominant-negative) variants, recurrently at Arg391
  gene_term:
    preferred_term: TUBB4B
    term:
      id: hgnc:20771
      label: TUBB4B
  notes: >-
    TUBB4B encodes a cilia-enriched beta-tubulin isotype. The Arg391 residue
    contributes to the longitudinal alpha/beta-tubulin binding interface within
    the microtubule protofilament; recurrent Arg391 substitutions dampen
    microtubule growth dynamics and, through dominant-negative incorporation into
    the microtubule lattice, perturb centriole and cilium biogenesis.
  evidence:
  - reference: PMID:29198720
    reference_title: "Mutations in TUBB4B Cause a Distinctive Sensorineural Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Using exome sequencing in a multiplex family and three simplex case
      subjects with an atypical association of LCA with early-onset hearing loss,
      we identified two heterozygous mutations affecting Arg391 in β-tubulin
      4B isotype-encoding (TUBB4B).
    explanation: >-
      Establishes TUBB4B Arg391 variants as the cause of the LCA-plus-deafness
      syndrome.
  - reference: PMID:29198720
    reference_title: "Mutations in TUBB4B Cause a Distinctive Sensorineural Disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      the β-tubulin Arg391 residue contributes to a binding pocket that
      interacts with α-tubulin contained in the longitudinally adjacent
      αβ-heterodimer, consistent with a role in maintaining MT stability
    explanation: >-
      Provides the structural rationale for how Arg391 variants impair
      microtubule stability.
pathophysiology:
- name: TUBB4B Variant Microtubule and Axonemal Dysfunction
  conforms_to: "ciliopathy_dysfunction#Basal Body and Transition Zone Dysfunction"
  role: trigger
  description: >-
    Heterozygous TUBB4B variants at Arg391 produce a beta-tubulin that still
    folds and co-assembles into the microtubule lattice but dampens microtubule
    growth dynamics. Because TUBB4B is a cilia-enriched isotype required for
    centriole and axoneme formation, the dominant-negative variants perturb
    centriole and cilium biogenesis, the shared upstream lesion of the
    ciliopathies. The original delineation favored a pure microtubule-dynamics
    defect; later structure-function work reframed the lesion as an
    organelle-specific ciliary one.
  cell_types:
  - preferred_term: ciliated cell
    term:
      id: CL:0000064
      label: ciliated cell
  biological_processes:
  - preferred_term: axoneme assembly
    term:
      id: GO:0035082
      label: axoneme assembly
    modifier: ABNORMAL
  - preferred_term: cilium assembly
    term:
      id: GO:0060271
      label: cilium assembly
    modifier: DECREASED
  - preferred_term: microtubule cytoskeleton organization
    term:
      id: GO:0000226
      label: microtubule cytoskeleton organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:29198720
    reference_title: "Mutations in TUBB4B Cause a Distinctive Sensorineural Disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      the dynamics of growing MTs were consistently altered, showing that the
      mutations have a significant dampening impact on normal MT growth
    explanation: >-
      Demonstrates that the Arg391 variants dampen microtubule growth dynamics,
      the proximate molecular defect.
  - reference: PMID:38662826
    reference_title: "Ciliopathy patient variants reveal organelle-specific functions for TUBB4B in axonemal microtubules."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      we identified and characterized variants in the TUBB4B isotype that
      specifically perturbed centriole and cilium biogenesis
    explanation: >-
      Establishes that TUBB4B variants perturb centriole and cilium biogenesis,
      anchoring the ciliary trigger lesion (patient cohort plus mouse mutants).
  - reference: PMID:38662826
    reference_title: "Ciliopathy patient variants reveal organelle-specific functions for TUBB4B in axonemal microtubules."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      establish a link between tubulinopathies and ciliopathies
    explanation: >-
      Positions TUBB4B disease at the interface of tubulinopathy and ciliopathy,
      justifying ciliopathy conformance for this entry.
  downstream:
  - target: Photoreceptor Connecting Cilium Degeneration
    description: >-
      Defective TUBB4B-dependent ciliary microtubules impair the photoreceptor
      connecting cilium and outer segment, driving retinal degeneration.
  - target: Cochlear Sensory Cell Ciliary Dysfunction
    description: >-
      The same isotype-specific ciliary defect impairs cochlear sensory cells,
      producing early-onset sensorineural hearing loss.
- name: Photoreceptor Connecting Cilium Degeneration
  conforms_to: "ciliopathy_dysfunction#Photoreceptor Connecting Cilium Degeneration"
  role: consequence
  description: >-
    The photoreceptor outer segment is a specialized non-motile sensory cilium
    connected to the cell body by a connecting cilium through which all
    phototransduction cargo is trafficked. TUBB4B-dependent ciliary microtubule
    defects impair outer-segment morphogenesis and maintenance, causing the
    severe, early photoreceptor degeneration of Leber congenital amaurosis.
  cell_types:
  - preferred_term: photoreceptor cell
    term:
      id: CL:0000210
      label: photoreceptor cell
  - preferred_term: retinal rod cell
    term:
      id: CL:0000604
      label: retinal rod cell
  locations:
  - preferred_term: retina
    term:
      id: UBERON:0000966
      label: retina
  biological_processes:
  - preferred_term: photoreceptor cell maintenance
    term:
      id: GO:0045494
      label: photoreceptor cell maintenance
    modifier: DECREASED
  evidence:
  - reference: PMID:29198720
    reference_title: "Mutations in TUBB4B Cause a Distinctive Sensorineural Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Leber congenital amaurosis (LCA) is a neurodegenerative disease of
      photoreceptor cells that causes blindness within the first year of life.
    explanation: >-
      Defines the retinal arm: photoreceptor neurodegeneration causing
      early-life blindness.
  downstream:
  - target: Multisystem Sensory Phenotype
    description: >-
      Photoreceptor degeneration produces the visual (LCA) component of the
      combined sensory phenotype.
- name: Cochlear Sensory Cell Ciliary Dysfunction
  role: consequence
  description: >-
    Cochlear hair cells depend on a microtubule- and cilium-based apparatus
    (including the kinocilium during development) for mechanotransduction and
    survival. The TUBB4B isotype defect that injures photoreceptor cilia also
    impairs cochlear sensory cells, producing the early-onset sensorineural
    hearing loss that distinguishes this disorder from isolated Leber congenital
    amaurosis.
  cell_types:
  - preferred_term: auditory hair cell
    term:
      id: CL:0000202
      label: auditory hair cell
  evidence:
  - reference: PMID:29198720
    reference_title: "Mutations in TUBB4B Cause a Distinctive Sensorineural Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      an atypical association of LCA with early-onset hearing loss
    explanation: >-
      Documents the early-onset sensorineural hearing loss that co-occurs with
      LCA in this TUBB4B disorder.
  downstream:
  - target: Multisystem Sensory Phenotype
    description: >-
      Cochlear sensory cell dysfunction produces the auditory (deafness)
      component of the combined sensory phenotype.
- name: Multisystem Sensory Phenotype
  conforms_to: "ciliopathy_dysfunction#Multisystem Pleiotropic Ciliopathy Phenotype"
  role: consequence
  description: >-
    LCAEOD converges on a combined sensorineural phenotype - congenital blindness
    from photoreceptor degeneration plus early-onset sensorineural hearing loss -
    reflecting the non-redundant role of the cilia-enriched TUBB4B isotype across
    sensory ciliated tissues.
  evidence:
  - reference: PMID:29198720
    reference_title: "Mutations in TUBB4B Cause a Distinctive Sensorineural Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our findings provide a link between sensorineural disease and anomalies in
      MT behavior
    explanation: >-
      Frames the disorder as a sensorineural disease arising from microtubule
      (and downstream ciliary) anomalies.
phenotypes:
- name: Blindness
  description: Severe early visual loss (Leber congenital amaurosis) within the first year of life.
  phenotype_term:
    preferred_term: Blindness
    term:
      id: HP:0000618
      label: Blindness
  evidence:
  - reference: PMID:29198720
    reference_title: "Mutations in TUBB4B Cause a Distinctive Sensorineural Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Leber congenital amaurosis (LCA) is a neurodegenerative disease of
      photoreceptor cells that causes blindness within the first year of life.
    explanation: >-
      LCA causes blindness within the first year of life in affected individuals.
- name: Rod-cone dystrophy
  description: Leber congenital amaurosis is a severe early retinal photoreceptor dystrophy.
  phenotype_term:
    preferred_term: Photoreceptor (rod-cone) degeneration
    term:
      id: HP:0000510
      label: Rod-cone dystrophy
  evidence:
  - reference: PMID:29198720
    reference_title: "Mutations in TUBB4B Cause a Distinctive Sensorineural Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Leber congenital amaurosis (LCA) is a neurodegenerative disease of
      photoreceptor cells
    explanation: >-
      LCA is a neurodegenerative photoreceptor dystrophy.
- name: Sensorineural hearing impairment
  description: Early-onset sensorineural hearing loss co-occurring with LCA.
  phenotype_term:
    preferred_term: Early-onset sensorineural hearing loss
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:29198720
    reference_title: "Mutations in TUBB4B Cause a Distinctive Sensorineural Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      an atypical association of LCA with early-onset hearing loss
    explanation: >-
      Early-onset hearing loss is the defining second sensory feature.
references:
- reference: PMID:29198720
  title: "Mutations in TUBB4B Cause a Distinctive Sensorineural Disease."
- reference: PMID:38662826
  title: "Ciliopathy patient variants reveal organelle-specific functions for TUBB4B in axonemal microtubules."