⚙

Pathophysiology

3

TBC1D24 loss of function impairs synaptic vesicle cycling

TBC1D24 is a vesicle-associated protein linked to Rab/ARF6 small-GTPase regulation and synaptic vesicle trafficking. Biallelic loss-of-function impairs presynaptic endocytosis and synaptic vesicle recycling, disrupting neurotransmission. In hippocampal neurons TBC1D24 localizes to clathrin-coated vesicles and synapses, consistent with a presynaptic trafficking role underlying epilepsy and neurodevelopmental impairment.

Neuron CL:0000540

Synaptic vesicle endocytosis GO:0048488 ↓ DECREASED Synaptic vesicle cycle GO:0099504 ⚠ ABNORMAL

Clathrin-coated vesicle GO:0030136 Synapse GO:0045202

Downstream

Impaired v-ATPase activity and endolysosomal acidification TBC1D24 loss not only disrupts synaptic vesicle cycling but also mislocalizes the v-ATPase V1 sector, so the same trafficking defect feeds into impaired endolysosomal acidification and synaptic vesicle reacidification.

Intellectual disability / developmental delay Synaptic vesicle trafficking dysfunction disrupts neuronal signaling required for development and cognition.

Seizures Impaired synaptic vesicle cycling in hippocampal neurons contributes to seizures.

Epileptic encephalopathy Severe synaptic vesicle dysfunction can produce early epileptic encephalopathy in TBC1D24-related disease.

Show evidence (2 references)

PMID:32873933 SUPPORT Human Clinical

"Biallelic variants in TBC1D24, which encodes a protein that regulates vesicular transport, are frequently identified in patients with DOORS"

Establishes TBC1D24 as a regulator of vesicular transport in DOORS.

PMID:30602030 SUPPORT Model Organism

"TBC1D24 is associated with clathrin-coated vesicles and synapses of hippocampal neurons, suggesting a crucial role of TBC1D24 in vesicle trafficking important for neuronal signal transmission."

Mouse model localizes TBC1D24 to clathrin-coated vesicles/synapses, supporting the presynaptic trafficking mechanism.

Impaired v-ATPase activity and endolysosomal acidification

TBC1D24 interacts with the vacuolar ATPase (v-ATPase) in the brain and acts as a positive regulator of v-ATPase activity. Loss of TBC1D24 causes mislocalization of the V1 sector, increased pH in endo-lysosomal compartments, impaired autophagy, accumulation of lysosomes and non-degraded lipid material, and defective synaptic vesicle endocytosis and reacidification. The recurrent ATP6V1B2 p.Arg506* variant likewise impairs lysosomal acidification, defining a shared endolysosomal disease axis for DOORS syndrome.

Neuron CL:0000540

Autophagy GO:0006914 ↓ DECREASED Lysosome organization GO:0007040 ⚠ ABNORMAL

Lysosome GO:0005764

Downstream

Cochlear glia-like supporting cell vesicle trafficking dysfunction The same TBC1D24-dependent vesicle-trafficking and acidification defect manifests in cochlear glia-like supporting cells, contributing to the sensorineural deafness of DOORS syndrome.

Onychodystrophy Shared endolysosomal dysfunction contributes to the nail dystrophy component of DOORS syndrome.

Anonychia Shared endolysosomal dysfunction contributes to absent nails in the DOORS spectrum.

Hypoplasia/aplasia of the distal phalanges (osteodystrophy) Shared endolysosomal dysfunction contributes to distal phalangeal osteodystrophy.

Triphalangeal thumb Shared endolysosomal dysfunction contributes to thumb malformation in the DOORS spectrum.

Microcephaly Neuronal endolysosomal dysfunction contributes to abnormal brain growth.

Optic atrophy Neuronal endolysosomal dysfunction contributes to optic atrophy in affected individuals.

Peripheral neuropathy Neuronal endolysosomal dysfunction contributes to peripheral neuropathy.

Show evidence (3 references)

PMID:39758816 SUPPORT Model Organism

"In Tbc1d24 knockout neurons, we detected V1 mis-localization with increased pH at endo-lysosomal compartments and autophagy impairment. Furthermore, synaptic vesicles endocytosis and reacidification were impaired."

Demonstrates TBC1D24 regulates v-ATPase-dependent organellar pH, autophagy, and synaptic vesicle reacidification.

PMID:39758816 SUPPORT Model Organism

"we demonstrate that TBC1D24 is a positive regulator of v-ATPase activity in neurons"

Identifies TBC1D24 as a positive regulator of v-ATPase activity.

PMID:32849222 SUPPORT Human Clinical

"DOORS [deafness, onychodystrophy, osteodystrophy, intellectual disability (mental retardation), and seizures] syndrome can be caused by mutations in the TBC1D24 and ATP6V1B2 genes, both of which are involved in endolysosomal function."

Confirms that both DOORS genes converge on endolysosomal function, supporting the shared acidification axis.

Cochlear glia-like supporting cell vesicle trafficking dysfunction

Beyond auditory neurons, TBC1D24 is expressed in glia-like non-sensory (supporting) epithelial cells of the developing cochlear sensory epithelium and is virtually absent from adjacent sensory hair cells, with the distinguishing expression disappearing around the onset of hearing. This suggests that disturbed vesicle trafficking in cochlear supporting cells, rather than a hair-cell-intrinsic defect alone, may contribute to the sensorineural deafness of DOORS syndrome.

Organ of Corti supporting cell CL:0002490 Sensory hair cell CL:0000855

Cochlea UBERON:0001844

Downstream

Sensorineural hearing loss Cochlear supporting-cell vesicle trafficking dysfunction manifests as sensorineural hearing loss.

Show evidence (1 reference)

PMID:38869222 SUPPORT Model Organism

"TBC1D24 was detected in glia-like non-sensory epithelial cells during early developmental stages. In contrast, TBC1D24 was virtually absent in adjacent sensory hair cells."

Localizes developmental cochlear TBC1D24 to supporting cells, supporting a non-hair-cell-intrinsic deafness mechanism.

⬡

Pathograph

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●

Phenotypes

11

Ear 1

Sensorineural hearing loss VERY_FREQUENT Sensorineural hearing impairment HP:0000407

Show evidence (2 references)

PMID:25719194 SUPPORT Human Clinical

"DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures), with profound sensorineural hearing loss, onychodystrophy, osteodystrophy, intellectual disability / developmental delay, and seizures"

GeneReviews lists profound sensorineural hearing loss as a core DOORS feature.

PMID:32873933 SUPPORT Human Clinical

"Deafness was present in all individuals, along with onychodystrophy and abnormal fingers and/or toes."

Deafness present in all individuals of the ATP6V1B2-DOORS cohort, supporting very frequent occurrence.

Eye 1

Optic atrophy Optic atrophy HP:0000648

The only available exact-quote evidence documents strabismus (HP:0000486), a distinct ophthalmologic sign, rather than optic atrophy itself. Optic atrophy is a reported DOORS manifestation in the broader literature but lacks a directly quotable abstract among the cached references; the association is therefore retained as PARTIAL pending a more direct citation.

Show evidence (1 reference)

PMID:32969800 PARTIAL Human Clinical

"physical examination revealed left eye strabismus"

Ophthalmologic involvement (strabismus) is documented in this case; optic atrophy is a reported DOORS manifestation in the broader literature but is not directly quoted here, so the association is marked PARTIAL.

Head and Neck 1

Microcephaly Microcephaly HP:0000252

Show evidence (1 reference)

PMID:24291220 PARTIAL Human Clinical

"Deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS) syndrome is a rare autosomal recessive disorder of unknown cause."

The exome study describes the DOORS cohort in which craniofacial features including microcephaly were assessed; the abstract does not give the microcephaly frequency directly, so this is marked PARTIAL pending a quantitative source.

Integument 1

Onychodystrophy VERY_FREQUENT Nail dystrophy HP:0008404

Show evidence (2 references)

PMID:32873933 SUPPORT Human Clinical

"Deafness was present in all individuals, along with onychodystrophy and abnormal fingers and/or toes."

Onychodystrophy present in all individuals of the cohort.

PMID:32969800 SUPPORT Human Clinical

"a history of recurrent seizures and absence of all finger- and toenails since birth"

Case report documents absence of all finger- and toenails (severe onychodystrophy).

Limbs 1

Triphalangeal thumb FREQUENT Triphalangeal thumb HP:0001199

Show evidence (1 reference)

PMID:32849222 PARTIAL Human Clinical

"This Caucasian male patient, who died at the age of 72 years, presented all the typical cardinal signs of DOORS syndrome."

A genetically confirmed DOORS patient presenting the cardinal DOORS signs; the case (full text) documents a triphalangeal thumb radiographically, but the abstract only confirms the cardinal-sign constellation, so this is marked PARTIAL.

Nervous System 3

Intellectual disability / developmental delay VERY_FREQUENT Intellectual disability HP:0001249

Show evidence (2 references)

PMID:25719194 SUPPORT Human Clinical

"intellectual disability / developmental delay, and seizures"

GeneReviews lists intellectual disability/developmental delay as a core DOORS feature.

PMID:32873933 SUPPORT Human Clinical

"All families but one had developmental delay or intellectual disability and five individuals had epilepsy."

Developmental delay or intellectual disability in nearly all cohort families.

Seizures VERY_FREQUENT Seizure HP:0001250

Show evidence (2 references)

PMID:24291220 SUPPORT Human Clinical

"The seizure types in individuals with TBC1D24 mutations included generalised tonic-clonic, complex partial, focal clonic, and infantile spasms."

Documents the seizure types in TBC1D24-related DOORS syndrome.

PMID:32969800 SUPPORT Human Clinical

"an abnormal diffuse epileptiform pattern was found on electroencephalography"

EEG documents epileptiform activity in a DOORS case with recurrent seizures.

Peripheral neuropathy Peripheral neuropathy HP:0009830

Show evidence (1 reference)

PMID:25719194 PARTIAL Human Clinical

"standard treatment for tremors, dystonic attacks, or other neurologic manifestations"

GeneReviews notes additional neurologic manifestations requiring management; peripheral neuropathy is reported in the DOORS literature but is not named in the abstract, so the association is marked PARTIAL.

Other 3

Anonychia Anonychia HP:0001798

Show evidence (1 reference)

PMID:32969800 SUPPORT Human Clinical

"absence of all finger- and toenails since birth"

Documents complete absence of all nails (anonychia).

Hypoplasia/aplasia of the distal phalanges (osteodystrophy) VERY_FREQUENT Aplasia/Hypoplasia of the distal phalanges of the hand HP:0009835

Show evidence (2 references)

PMID:32969800 SUPPORT Human Clinical

"X-rays of the hands and feet showed absence of the distal phalanx of her right and left fingers II-V and the distal phalanx of her right and left toes I-V"

Radiographs document absence of the distal phalanges of fingers and toes.

PMID:32969800 SUPPORT Human Clinical

"mainly characterized by sensorineural deafness, shortened terminal phalanges with small nails of hands and feet, intellectual deficit, and seizures"

Review states shortened terminal phalanges as a core characteristic.

Epileptic encephalopathy Epileptic encephalopathy HP:0200134

Show evidence (1 reference)

PMID:30602030 SUPPORT Model Organism

"a recessive mutation of TBC1D24 associated with early infantile epileptic encephalopathy (EIEE)"

Links a recessive TBC1D24 mutation to early infantile epileptic encephalopathy.

🧬

Genetic Associations

2

Biallelic TBC1D24 pathogenic variants (Causative)

Gene: TBC1D24 hgnc:29203 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal recessive inheritance

Show evidence (3 references)

PMID:24291220 SUPPORT Human Clinical

"We identified TBC1D24 mutations in 11 individuals from nine families (by exome sequencing in seven families, and Sanger sequencing in two families)."

Landmark exome study identifying TBC1D24 as the major cause of DOORS syndrome.

PMID:32873933 SUPPORT Human Clinical

"Biallelic variants in TBC1D24, which encodes a protein that regulates vesicular transport, are frequently identified in patients with DOORS"

Confirms biallelic TBC1D24 vesicular-transport gene as the frequent cause of DOORS.

PMID:32969800 SUPPORT Human Clinical

"The disease is caused by homozygous or compound heterozygous mutation in the TBC1 domain family member 24 (TBC1D24) gene (gene locus/MIM 613577) on chromosome 16p13."

States the biallelic TBC1D24 etiology and locus.

Recurrent truncating ATP6V1B2 variant (p.Arg506*) (Causative)

Gene: ATP6V1B2 hgnc:854 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal dominant inheritance

Show evidence (2 references)

PMID:32873933 SUPPORT Human Clinical

"We identified the same truncating variant in ATP6V1B2 (NM_001693.4:c.1516C>T; p.Arg506*) in nine individuals from eight unrelated families with DOORS syndrome."

Identifies the recurrent ATP6V1B2 p.Arg506* variant as a cause of DOORS syndrome.

PMID:32849222 SUPPORT Human Clinical

"DOORS [deafness, onychodystrophy, osteodystrophy, intellectual disability (mental retardation), and seizures] syndrome can be caused by mutations in the TBC1D24 and ATP6V1B2 genes, both of which are involved in endolysosomal function."

Confirms ATP6V1B2 as a DOORS gene and the shared endolysosomal basis.

💊

Medical Actions

7

Antiseizure pharmacotherapy

Action: anticonvulsant agent therapy MAXO:0000167

Symptomatic pharmacologic management of seizures. No single regimen is established; seizures may be drug-resistant.

Show evidence (1 reference)

PMID:25719194 SUPPORT Human Clinical

"symptomatic pharmacologic management for seizures"

GeneReviews recommends symptomatic pharmacologic seizure management.

Hearing aids

Action: hearing aid usage MAXO:0009030

Hearing aids are used as needed for hearing loss; annual audiologic evaluation assesses progression and efficacy.

Show evidence (1 reference)

PMID:25719194 SUPPORT Human Clinical

"Hearing aids or cochlear implants as needed for hearing loss"

GeneReviews recommends hearing aids or cochlear implants for hearing loss.

Cochlear implantation

Action: cochlear device implantation MAXO:0009025

Cochlear implantation may benefit selected individuals with profound sensorineural hearing loss.

Show evidence (1 reference)

PMID:25719194 SUPPORT Human Clinical

"Hearing aids or cochlear implants as needed for hearing loss"

GeneReviews lists cochlear implants as an option for hearing loss.

Physical therapy

Action: physical therapy MAXO:0000011

Physical therapy as part of early intervention for developmental delay.

Show evidence (1 reference)

PMID:25719194 SUPPORT Human Clinical

"early educational intervention and physical, occupational, and speech therapy for developmental delay"

GeneReviews recommends physical therapy for developmental delay.

Occupational therapy

Action: occupational therapy MAXO:0001351

Occupational therapy as part of early intervention for developmental delay.

Show evidence (1 reference)

PMID:25719194 SUPPORT Human Clinical

"early educational intervention and physical, occupational, and speech therapy for developmental delay"

GeneReviews recommends occupational therapy for developmental delay.

Speech therapy

Action: speech therapy MAXO:0000930

Speech therapy and augmentative communication support for developmental delay and communication impairment.

Show evidence (1 reference)

PMID:25719194 SUPPORT Human Clinical

"early educational intervention and physical, occupational, and speech therapy for developmental delay"

GeneReviews recommends speech therapy for developmental delay.

Genetic counseling

Action: Genetic Counseling NCIT:C15240

Genetic counseling for the autosomal recessive recurrence risk; once familial pathogenic variants are known, prenatal and preimplantation genetic testing are possible.

Show evidence (1 reference)

PMID:25719194 SUPPORT Human Clinical

"Once the TBC1D24 pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible."

GeneReviews describes genetic counseling and reproductive testing options.

🔬

Biochemical Markers

1

Elevated urinary 2-oxoglutarate

{ }

Source YAML

click to show

name: DOORS Syndrome
creation_date: "2026-06-03T12:00:00Z"
category: Mendelian
synonyms:
- DOORS syndrome
- deafness-onychodystrophy-osteodystrophy-intellectual disability-seizures syndrome
- deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures syndrome
- DOOR syndrome
description: >-
  DOORS syndrome is a rare autosomal recessive multisystem neurodevelopmental
  disorder characterized by Deafness (profound sensorineural hearing loss),
  Onychodystrophy (small or absent nails), Osteodystrophy (hypoplastic or absent
  terminal phalanges), intellectual disability/developmental delay (the historical
  "Retardation"), and Seizures. It is most commonly caused by biallelic
  loss-of-function variants in TBC1D24, which encodes a vesicle-associated protein
  that regulates synaptic vesicle trafficking and intraorganellar pH; a recurrent
  truncating ATP6V1B2 variant (p.Arg506*) accounts for a substantial additional
  fraction of cases, placing DOORS within a TBC1D24/v-ATPase endolysosomal disease
  spectrum. Many affected individuals also have triphalangeal thumb, microcephaly,
  optic atrophy, peripheral neuropathy, and frequently elevated urinary
  2-oxoglutarate. Seizures usually begin in the first year of life and may be
  drug-resistant, with status epilepticus and early death reported.
disease_term:
  preferred_term: DOORS syndrome
  term:
    id: MONDO:0009079
    label: DOORS syndrome
parents:
- autosomal recessive disease
- syndromic intellectual disability
references:
- reference: PMID:25719194
  title: "TBC1D24-Related Disorders."
  tags:
  - GeneReviews
genetic:
- name: Biallelic TBC1D24 pathogenic variants
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: TBC1D24
    term:
      id: hgnc:29203
      label: TBC1D24
  notes: >
    TBC1D24 (gene MIM 613577, chromosome 16p13) encodes a TBC-domain
    vesicle-associated protein that regulates vesicular transport. Biallelic
    (homozygous or compound heterozygous) pathogenic variants are the most
    frequently identified cause of DOORS syndrome. Variants are distributed
    across the gene and include missense and loss-of-function alleles, with
    limited genotype-phenotype predictability; some variants act by reducing
    TBC1D24 mRNA stability.
  inheritance:
  - name: Autosomal recessive inheritance
  evidence:
  - reference: PMID:24291220
    reference_title: "The genetic basis of DOORS syndrome: an exome-sequencing study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified TBC1D24 mutations in 11 individuals from nine \nfamilies (by exome sequencing in seven families, and Sanger sequencing in two \nfamilies)."
    explanation: Landmark exome study identifying TBC1D24 as the major cause of DOORS syndrome.
  - reference: PMID:32873933
    reference_title: "DOORS syndrome and a recurrent truncating ATP6V1B2 variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Biallelic variants in TBC1D24, which encodes a protein that regulates \nvesicular transport, are frequently identified in patients with DOORS"
    explanation: Confirms biallelic TBC1D24 vesicular-transport gene as the frequent cause of DOORS.
  - reference: PMID:32969800
    reference_title: "Deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS) syndrome: a new case report from Indonesia and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The disease is caused by homozygous or compound heterozygous mutation in the TBC1 \ndomain family member 24 (TBC1D24) gene (gene locus/MIM 613577) on chromosome \n16p13."
    explanation: States the biallelic TBC1D24 etiology and locus.
- name: Recurrent truncating ATP6V1B2 variant (p.Arg506*)
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: ATP6V1B2
    term:
      id: hgnc:854
      label: ATP6V1B2
  notes: >
    ATP6V1B2 encodes the B2 subunit of the vacuolar (V1) ATPase. A recurrent
    truncating variant NM_001693.4:c.1516C>T (p.Arg506*) was identified in
    DOORS-syndrome individuals without TBC1D24 variants; the same variant was
    previously reported in dominant deafness-onychodystrophy (DDOD) syndrome,
    suggesting DDOD and DOORS lie on a clinically and molecularly related
    spectrum. Both TBC1D24 and ATP6V1B2 converge on endolysosomal function.
    In contrast to the biallelic TBC1D24 mechanism, the recurrent ATP6V1B2
    p.Arg506* allele acts in an autosomal dominant / de novo manner.
  inheritance:
  - name: Autosomal dominant inheritance
  variants:
  - name: ATP6V1B2 p.Arg506*
    description: "NM_001693.4:c.1516C>T; p.Arg506* recurrent truncating variant."
  evidence:
  - reference: PMID:32873933
    reference_title: "DOORS syndrome and a recurrent truncating ATP6V1B2 variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified the same truncating variant in ATP6V1B2 \n(NM_001693.4:c.1516C>T; p.Arg506*) in nine individuals from eight unrelated \nfamilies with DOORS syndrome."
    explanation: Identifies the recurrent ATP6V1B2 p.Arg506* variant as a cause of DOORS syndrome.
  - reference: PMID:32849222
    reference_title: "Clinicopathological Relationships in an Aged Case of DOORS Syndrome With a p.Arg506X Mutation in the ATP6V1B2 Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DOORS [deafness, onychodystrophy, osteodystrophy, intellectual disability \n(mental retardation), and seizures] syndrome can be caused by mutations in the \nTBC1D24 and ATP6V1B2 genes, both of which are involved in endolysosomal \nfunction."
    explanation: Confirms ATP6V1B2 as a DOORS gene and the shared endolysosomal basis.
pathophysiology:
- name: TBC1D24 loss of function impairs synaptic vesicle cycling
  description: >
    TBC1D24 is a vesicle-associated protein linked to Rab/ARF6 small-GTPase
    regulation and synaptic vesicle trafficking. Biallelic loss-of-function
    impairs presynaptic endocytosis and synaptic vesicle recycling, disrupting
    neurotransmission. In hippocampal neurons TBC1D24 localizes to clathrin-coated
    vesicles and synapses, consistent with a presynaptic trafficking role
    underlying epilepsy and neurodevelopmental impairment.
  cell_types:
  - preferred_term: Neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: Synaptic vesicle endocytosis
    term:
      id: GO:0048488
      label: synaptic vesicle endocytosis
    modifier: DECREASED
  - preferred_term: Synaptic vesicle cycle
    term:
      id: GO:0099504
      label: synaptic vesicle cycle
    modifier: ABNORMAL
  cellular_components:
  - preferred_term: Clathrin-coated vesicle
    term:
      id: GO:0030136
      label: clathrin-coated vesicle
  - preferred_term: Synapse
    term:
      id: GO:0045202
      label: synapse
  evidence:
  - reference: PMID:32873933
    reference_title: "DOORS syndrome and a recurrent truncating ATP6V1B2 variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Biallelic variants in TBC1D24, which encodes a protein that regulates \nvesicular transport, are frequently identified in patients with DOORS"
    explanation: Establishes TBC1D24 as a regulator of vesicular transport in DOORS.
  - reference: PMID:30602030
    reference_title: "The phenotypic landscape of a Tbc1d24 mutant mouse includes convulsive seizures resembling human early infantile epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "TBC1D24 is associated with \nclathrin-coated vesicles and synapses of hippocampal neurons, suggesting a \ncrucial role of TBC1D24 in vesicle trafficking important for neuronal signal \ntransmission."
    explanation: Mouse model localizes TBC1D24 to clathrin-coated vesicles/synapses, supporting the presynaptic trafficking mechanism.
  downstream:
  - target: Impaired v-ATPase activity and endolysosomal acidification
    description: >-
      TBC1D24 loss not only disrupts synaptic vesicle cycling but also
      mislocalizes the v-ATPase V1 sector, so the same trafficking defect feeds
      into impaired endolysosomal acidification and synaptic vesicle
      reacidification.
  - target: Intellectual disability / developmental delay
    description: Synaptic vesicle trafficking dysfunction disrupts neuronal signaling required for development and cognition.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Seizures
    description: Impaired synaptic vesicle cycling in hippocampal neurons contributes to seizures.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Epileptic encephalopathy
    description: Severe synaptic vesicle dysfunction can produce early epileptic encephalopathy in TBC1D24-related disease.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Impaired v-ATPase activity and endolysosomal acidification
  description: >
    TBC1D24 interacts with the vacuolar ATPase (v-ATPase) in the brain and acts
    as a positive regulator of v-ATPase activity. Loss of TBC1D24 causes
    mislocalization of the V1 sector, increased pH in endo-lysosomal compartments,
    impaired autophagy, accumulation of lysosomes and non-degraded lipid material,
    and defective synaptic vesicle endocytosis and reacidification. The recurrent
    ATP6V1B2 p.Arg506* variant likewise impairs lysosomal acidification, defining
    a shared endolysosomal disease axis for DOORS syndrome.
  cell_types:
  - preferred_term: Neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: Autophagy
    term:
      id: GO:0006914
      label: autophagy
    modifier: DECREASED
  - preferred_term: Lysosome organization
    term:
      id: GO:0007040
      label: lysosome organization
    modifier: ABNORMAL
  cellular_components:
  - preferred_term: Lysosome
    term:
      id: GO:0005764
      label: lysosome
  evidence:
  - reference: PMID:39758816
    reference_title: "TBC1D24 interacts with the v-ATPase and regulates intraorganellar pH in neurons."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In Tbc1d24 knockout neurons, we detected V1 mis-localization with increased pH \nat endo-lysosomal compartments and autophagy impairment. Furthermore, synaptic \nvesicles endocytosis and reacidification were impaired."
    explanation: Demonstrates TBC1D24 regulates v-ATPase-dependent organellar pH, autophagy, and synaptic vesicle reacidification.
  - reference: PMID:39758816
    reference_title: "TBC1D24 interacts with the v-ATPase and regulates intraorganellar pH in neurons."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "we demonstrate \nthat TBC1D24 is a positive regulator of v-ATPase activity in neurons"
    explanation: Identifies TBC1D24 as a positive regulator of v-ATPase activity.
  - reference: PMID:32849222
    reference_title: "Clinicopathological Relationships in an Aged Case of DOORS Syndrome With a p.Arg506X Mutation in the ATP6V1B2 Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DOORS [deafness, onychodystrophy, osteodystrophy, intellectual disability \n(mental retardation), and seizures] syndrome can be caused by mutations in the \nTBC1D24 and ATP6V1B2 genes, both of which are involved in endolysosomal \nfunction."
    explanation: Confirms that both DOORS genes converge on endolysosomal function, supporting the shared acidification axis.
  downstream:
  - target: Cochlear glia-like supporting cell vesicle trafficking dysfunction
    description: >-
      The same TBC1D24-dependent vesicle-trafficking and acidification defect
      manifests in cochlear glia-like supporting cells, contributing to the
      sensorineural deafness of DOORS syndrome.
  - target: Onychodystrophy
    description: Shared endolysosomal dysfunction contributes to the nail dystrophy component of DOORS syndrome.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Anonychia
    description: Shared endolysosomal dysfunction contributes to absent nails in the DOORS spectrum.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hypoplasia/aplasia of the distal phalanges (osteodystrophy)
    description: Shared endolysosomal dysfunction contributes to distal phalangeal osteodystrophy.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Triphalangeal thumb
    description: Shared endolysosomal dysfunction contributes to thumb malformation in the DOORS spectrum.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Microcephaly
    description: Neuronal endolysosomal dysfunction contributes to abnormal brain growth.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Optic atrophy
    description: Neuronal endolysosomal dysfunction contributes to optic atrophy in affected individuals.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Peripheral neuropathy
    description: Neuronal endolysosomal dysfunction contributes to peripheral neuropathy.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Cochlear glia-like supporting cell vesicle trafficking dysfunction
  description: >
    Beyond auditory neurons, TBC1D24 is expressed in glia-like non-sensory
    (supporting) epithelial cells of the developing cochlear sensory epithelium
    and is virtually absent from adjacent sensory hair cells, with the
    distinguishing expression disappearing around the onset of hearing. This
    suggests that disturbed vesicle trafficking in cochlear supporting cells,
    rather than a hair-cell-intrinsic defect alone, may contribute to the
    sensorineural deafness of DOORS syndrome.
  cell_types:
  - preferred_term: Organ of Corti supporting cell
    term:
      id: CL:0002490
      label: organ of Corti supporting cell
  - preferred_term: Sensory hair cell
    term:
      id: CL:0000855
      label: sensory hair cell
  locations:
  - preferred_term: Cochlea
    term:
      id: UBERON:0001844
      label: cochlea
  evidence:
  - reference: PMID:38869222
    reference_title: "TBC1D24 is likely to regulate vesicle trafficking in glia-like non-sensory epithelial cells of the cochlea."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "TBC1D24 was detected in glia-like \nnon-sensory epithelial cells during early developmental stages. In contrast, \nTBC1D24 was virtually absent in adjacent sensory hair cells."
    explanation: Localizes developmental cochlear TBC1D24 to supporting cells, supporting a non-hair-cell-intrinsic deafness mechanism.
  downstream:
  - target: Sensorineural hearing loss
    description: Cochlear supporting-cell vesicle trafficking dysfunction manifests as sensorineural hearing loss.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
phenotypes:
- name: Sensorineural hearing loss
  category: Neurologic
  description: >
    Profound, typically prelingual sensorineural deafness is a cardinal feature,
    present in essentially all affected individuals.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:25719194
    reference_title: "TBC1D24-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, \nand seizures), with profound sensorineural hearing loss, onychodystrophy, \nosteodystrophy, intellectual disability / developmental delay, and seizures"
    explanation: GeneReviews lists profound sensorineural hearing loss as a core DOORS feature.
  - reference: PMID:32873933
    reference_title: "DOORS syndrome and a recurrent truncating ATP6V1B2 variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Deafness was present in all individuals, along with onychodystrophy and abnormal fingers and/or toes."
    explanation: Deafness present in all individuals of the ATP6V1B2-DOORS cohort, supporting very frequent occurrence.
- name: Onychodystrophy
  category: Skin/Integument
  description: >
    Dystrophic, small, or absent nails of the fingers and toes (onychodystrophy /
    anonychia), one of the defining DOORS features.
  phenotype_term:
    preferred_term: Nail dystrophy
    term:
      id: HP:0008404
      label: Nail dystrophy
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:32873933
    reference_title: "DOORS syndrome and a recurrent truncating ATP6V1B2 variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Deafness was present in all individuals, along with onychodystrophy and abnormal fingers and/or toes."
    explanation: Onychodystrophy present in all individuals of the cohort.
  - reference: PMID:32969800
    reference_title: "Deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS) syndrome: a new case report from Indonesia and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a history of recurrent \nseizures and absence of all finger- and toenails since birth"
    explanation: Case report documents absence of all finger- and toenails (severe onychodystrophy).
- name: Anonychia
  category: Skin/Integument
  description: >
    Complete absence of nails can occur, representing the severe end of the
    onychodystrophy spectrum.
  phenotype_term:
    preferred_term: Anonychia
    term:
      id: HP:0001798
      label: Anonychia
  evidence:
  - reference: PMID:32969800
    reference_title: "Deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS) syndrome: a new case report from Indonesia and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "absence of all finger- and toenails since birth"
    explanation: Documents complete absence of all nails (anonychia).
- name: Hypoplasia/aplasia of the distal phalanges (osteodystrophy)
  category: Musculoskeletal
  description: >
    Shortened or absent terminal (distal) phalanges of the hands and feet
    constitute the osteodystrophy component of DOORS.
  phenotype_term:
    preferred_term: Aplasia/Hypoplasia of the distal phalanges of the hand
    term:
      id: HP:0009835
      label: Aplasia/Hypoplasia of the distal phalanges of the hand
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:32969800
    reference_title: "Deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS) syndrome: a new case report from Indonesia and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "X-rays of the hands and feet showed absence of the distal \nphalanx of her right and left fingers II-V and the distal phalanx of her right \nand left toes I-V"
    explanation: Radiographs document absence of the distal phalanges of fingers and toes.
  - reference: PMID:32969800
    reference_title: "Deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS) syndrome: a new case report from Indonesia and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mainly characterized by sensorineural deafness, shortened terminal phalanges \nwith small nails of hands and feet, intellectual deficit, and seizures"
    explanation: Review states shortened terminal phalanges as a core characteristic.
- name: Triphalangeal thumb
  category: Musculoskeletal
  description: >
    Triphalangeal thumb is reported in roughly one third of affected individuals
    and was documented radiographically in a genetically confirmed DOORS case.
  phenotype_term:
    preferred_term: Triphalangeal thumb
    term:
      id: HP:0001199
      label: Triphalangeal thumb
  frequency: FREQUENT
  evidence:
  - reference: PMID:32849222
    reference_title: "Clinicopathological Relationships in an Aged Case of DOORS Syndrome With a p.Arg506X Mutation in the ATP6V1B2 Gene."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "This \nCaucasian male patient, who died at the age of 72 years, presented all the \ntypical cardinal signs of DOORS syndrome."
    explanation: >
      A genetically confirmed DOORS patient presenting the cardinal DOORS signs;
      the case (full text) documents a triphalangeal thumb radiographically, but
      the abstract only confirms the cardinal-sign constellation, so this is
      marked PARTIAL.
- name: Intellectual disability / developmental delay
  category: Neurologic
  description: >
    Intellectual disability or developmental delay (historically the "R" for
    mental retardation) is a core feature, frequently severe.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:25719194
    reference_title: "TBC1D24-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "intellectual disability / developmental delay, and seizures"
    explanation: GeneReviews lists intellectual disability/developmental delay as a core DOORS feature.
  - reference: PMID:32873933
    reference_title: "DOORS syndrome and a recurrent truncating ATP6V1B2 variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All families but one had developmental delay or intellectual disability and five \nindividuals had epilepsy."
    explanation: Developmental delay or intellectual disability in nearly all cohort families.
- name: Seizures
  category: Neurologic
  description: >
    Seizures occur in most affected individuals and usually start in the first
    year of life. Seizure types include generalized tonic-clonic, complex
    partial, focal clonic, and infantile spasms; some cases are drug-resistant.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:24291220
    reference_title: "The genetic basis of DOORS syndrome: an exome-sequencing study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The \nseizure types in individuals with TBC1D24 mutations included generalised \ntonic-clonic, complex partial, focal clonic, and infantile spasms."
    explanation: Documents the seizure types in TBC1D24-related DOORS syndrome.
  - reference: PMID:32969800
    reference_title: "Deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS) syndrome: a new case report from Indonesia and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "an abnormal diffuse epileptiform pattern \nwas found on electroencephalography"
    explanation: EEG documents epileptiform activity in a DOORS case with recurrent seizures.
- name: Epileptic encephalopathy
  category: Neurologic
  description: >
    A subset of TBC1D24-related DOORS individuals manifest a developmental and
    epileptic encephalopathy, including early infantile epileptic encephalopathy,
    which can be drug-resistant.
  phenotype_term:
    preferred_term: Epileptic encephalopathy
    term:
      id: HP:0200134
      label: Epileptic encephalopathy
  evidence:
  - reference: PMID:30602030
    reference_title: "The phenotypic landscape of a Tbc1d24 mutant mouse includes convulsive seizures resembling human early infantile epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "a recessive \nmutation of TBC1D24 associated with early infantile epileptic encephalopathy \n(EIEE)"
    explanation: Links a recessive TBC1D24 mutation to early infantile epileptic encephalopathy.
- name: Microcephaly
  category: Neurologic
  description: >
    Microcephaly is reported in approximately one third of affected individuals.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:24291220
    reference_title: "The genetic basis of DOORS syndrome: an exome-sequencing study."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Deafness, onychodystrophy, osteodystrophy, mental retardation, and \nseizures (DOORS) syndrome is a rare autosomal recessive disorder of unknown \ncause."
    explanation: >
      The exome study describes the DOORS cohort in which craniofacial features
      including microcephaly were assessed; the abstract does not give the
      microcephaly frequency directly, so this is marked PARTIAL pending a
      quantitative source.
- name: Optic atrophy
  category: HEENT
  description: >
    Visual impairment with optic atrophy/optic neuropathy is reported among the
    variable additional manifestations of DOORS syndrome; ophthalmologic
    involvement such as strabismus is also documented.
  phenotype_term:
    preferred_term: Optic atrophy
    term:
      id: HP:0000648
      label: Optic atrophy
  notes: >
    The only available exact-quote evidence documents strabismus (HP:0000486),
    a distinct ophthalmologic sign, rather than optic atrophy itself. Optic
    atrophy is a reported DOORS manifestation in the broader literature but
    lacks a directly quotable abstract among the cached references; the
    association is therefore retained as PARTIAL pending a more direct citation.
  evidence:
  - reference: PMID:32969800
    reference_title: "Deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS) syndrome: a new case report from Indonesia and review of the literature."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "physical examination revealed left eye strabismus"
    explanation: >
      Ophthalmologic involvement (strabismus) is documented in this case; optic
      atrophy is a reported DOORS manifestation in the broader literature but is
      not directly quoted here, so the association is marked PARTIAL.
- name: Peripheral neuropathy
  category: Neurologic
  description: >
    Peripheral neuropathy is among the additional reported neurologic
    manifestations of DOORS syndrome.
  phenotype_term:
    preferred_term: Peripheral neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
  evidence:
  - reference: PMID:25719194
    reference_title: "TBC1D24-Related Disorders."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "standard treatment for tremors, dystonic \nattacks, or other neurologic manifestations"
    explanation: >
      GeneReviews notes additional neurologic manifestations requiring management;
      peripheral neuropathy is reported in the DOORS literature but is not named
      in the abstract, so the association is marked PARTIAL.
biochemical:
- name: Elevated urinary 2-oxoglutarate
  notes: >
    Many individuals with DOORS syndrome have elevated urinary 2-oxoglutarate
    (alpha-ketoglutarate), historically a useful supportive biochemical clue,
    though it is not present in all cases. No exact-quote abstract supporting the
    specific quantitative elevation was available among the cached references, so
    this is recorded as a note without an evidence snippet to avoid fabrication.
treatments:
- name: Antiseizure pharmacotherapy
  description: >
    Symptomatic pharmacologic management of seizures. No single regimen is
    established; seizures may be drug-resistant.
  treatment_term:
    preferred_term: anticonvulsant agent therapy
    term:
      id: MAXO:0000167
      label: anticonvulsant agent therapy
  evidence:
  - reference: PMID:25719194
    reference_title: "TBC1D24-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "symptomatic \npharmacologic management for seizures"
    explanation: GeneReviews recommends symptomatic pharmacologic seizure management.
- name: Hearing aids
  description: >
    Hearing aids are used as needed for hearing loss; annual audiologic
    evaluation assesses progression and efficacy.
  treatment_term:
    preferred_term: hearing aid usage
    term:
      id: MAXO:0009030
      label: hearing aid usage
  evidence:
  - reference: PMID:25719194
    reference_title: "TBC1D24-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hearing aids or cochlear implants as \nneeded for hearing loss"
    explanation: GeneReviews recommends hearing aids or cochlear implants for hearing loss.
- name: Cochlear implantation
  description: >
    Cochlear implantation may benefit selected individuals with profound
    sensorineural hearing loss.
  treatment_term:
    preferred_term: cochlear device implantation
    term:
      id: MAXO:0009025
      label: cochlear device implantation
  evidence:
  - reference: PMID:25719194
    reference_title: "TBC1D24-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hearing aids or cochlear implants as \nneeded for hearing loss"
    explanation: GeneReviews lists cochlear implants as an option for hearing loss.
- name: Physical therapy
  description: >
    Physical therapy as part of early intervention for developmental delay.
  treatment_term:
    preferred_term: physical therapy
    term:
      id: MAXO:0000011
      label: physical therapy
  evidence:
  - reference: PMID:25719194
    reference_title: "TBC1D24-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "early educational intervention and physical, \noccupational, and speech therapy for developmental delay"
    explanation: GeneReviews recommends physical therapy for developmental delay.
- name: Occupational therapy
  description: >
    Occupational therapy as part of early intervention for developmental delay.
  treatment_term:
    preferred_term: occupational therapy
    term:
      id: MAXO:0001351
      label: occupational therapy
  evidence:
  - reference: PMID:25719194
    reference_title: "TBC1D24-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "early educational intervention and physical, \noccupational, and speech therapy for developmental delay"
    explanation: GeneReviews recommends occupational therapy for developmental delay.
- name: Speech therapy
  description: >
    Speech therapy and augmentative communication support for developmental delay
    and communication impairment.
  treatment_term:
    preferred_term: speech therapy
    term:
      id: MAXO:0000930
      label: speech therapy
  evidence:
  - reference: PMID:25719194
    reference_title: "TBC1D24-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "early educational intervention and physical, \noccupational, and speech therapy for developmental delay"
    explanation: GeneReviews recommends speech therapy for developmental delay.
- name: Genetic counseling
  description: >
    Genetic counseling for the autosomal recessive recurrence risk; once familial
    pathogenic variants are known, prenatal and preimplantation genetic testing
    are possible.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:25719194
    reference_title: "TBC1D24-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Once the TBC1D24 pathogenic variant(s) have been identified in an affected \nfamily member, prenatal and preimplantation genetic testing are possible."
    explanation: GeneReviews describes genetic counseling and reproductive testing options.

📚

References & Deep Research

References

1

PMID:25719194

TBC1D24-Related Disorders.

No top-level findings curated for this source.

Deep Research

1

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 30 citations 2026-06-03T18:17:14.747625

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

Disease Name: DOORS Syndrome
MONDO ID: (if available)
Category: Mendelian

Research Objectives

Please provide a comprehensive research report on DOORS Syndrome covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

What is the disease? Provide a concise overview.
What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
What are the common synonyms and alternative names?
Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
Risk Factors:

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Pathogenic Variants:
Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
Variant type/class (missense, frameshift, nonsense, splice-site, structural)
Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
Functional consequences (loss of function, gain of function, dominant negative)
Modifier Genes: Genes that modify disease severity or expression
Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

Search first: PubMed, Gene Ontology, Reactome
Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Molecular Profiling (if available):
Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
Advanced Technologies (if applicable):
Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

Organ Level:
Primary organs directly affected
Secondary organ involvement (complications, secondary effects)
Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

Onset:
Typical age of onset (congenital, pediatric, adult, geriatric)
Onset pattern (acute, subacute, chronic, insidious)

Search first: OMIM, Orphanet, HPO, PubMed
Progression:
Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
Progression rate (rapid, slow, variable)
Disease course pattern (episodic, relapsing-remitting, progressive, stable)
Disease duration (self-limited, chronic lifelong)

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

Epidemiology:
Prevalence (cases per 100,000 at given time)
Incidence (new cases per 100,000 per year)

Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
For Genetic Etiology:
Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
Population Demographics:
Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
Geographic distribution of specific variants
Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

Clinical Tests:
Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
Genetic Testing:

Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
Overview of recommended genetic testing approach
Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
FISH > Search first: ClinVar, cytogenetics databases, PubMed
Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
Omics-Based Diagnostics (if applicable):
RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
Clinical Criteria:
Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
Screening:
Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

Survival and Mortality:
Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
Morbidity and Function:
Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
Disease Course:
Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
Prediction:
Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

Pharmacotherapy:
Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
Advanced Therapeutics:
Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
Surgical and Interventional:
Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
Supportive and Rehabilitative:
Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
Experimental:
Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
Treatment Outcomes:
Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
Treatment Strategy:
Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

Prevention Levels:
Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
Immunization: Vaccine strategies (if applicable)

Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Screening and Early Detection:
Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
Behavioral Interventions: Lifestyle modifications to reduce risk

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

Search first: NSGC resources, ACMG guidelines, GeneReviews
Public Health:
Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
Prophylaxis: Preventive medications or procedures

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

Search first: NCBI Gene
Natural Disease:
Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
Comparative Biology:
Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
Transmission (if applicable):
Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

Model Types:
Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
Genetic Models:
Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
Model Characteristics:
Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
Applications:
Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
Resources:
Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic and clinical claims
Prioritize recent reviews and landmark papers
Include direct quotes from abstracts where possible to support key statements
Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Comprehensive Research Report: DOORS Syndrome (Mendelian)

Target disease

Disease name: DOORS syndrome (Deafness, Onychodystrophy, Osteodystrophy, Intellectual disability/Developmental delay, Seizures) (danarti2020deafnessonychodystrophyosteodystrophy pages 1-3, beauregardlacroix2021doorssyndromeand pages 1-2)
Category: Mendelian (primarily autosomal recessive, genetically heterogeneous) (danarti2020deafnessonychodystrophyosteodystrophy pages 1-3, campeau2014thegeneticbasis pages 1-2)
MONDO ID: Not retrieved from the full-text sources available in this run (see “Limitations / missing identifiers”).

1. Disease information

1.1 Overview (what is the disease?)

DOORS syndrome is a rare multisystem neurodevelopmental disorder classically defined by sensorineural deafness, nail anomalies (onychodystrophy), terminal phalangeal hypoplasia/absence (osteodystrophy), intellectual disability/developmental delay, and seizures (danarti2020deafnessonychodystrophyosteodystrophy pages 1-3, campeau2014thegeneticbasis pages 1-2). The acronym was coined to reflect the core clinical pentad, with “S” added because seizures are common (ny2020clarificationofthe pages 106-109).

1.2 Key identifiers and codes

OMIM/MIM disease: 220500 (danarti2020deafnessonychodystrophyosteodystrophy pages 1-3)
Causal-gene OMIM/MIM: TBC1D24 (MIM 613577) (danarti2020deafnessonychodystrophyosteodystrophy pages 1-3)
Other identifiers (Orphanet, ICD-10/ICD-11, MeSH, MONDO): not available in the retrieved full-text evidence in this run; see “Limitations / missing identifiers.”

1.3 Synonyms / alternative names

“Deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures syndrome” is used in the literature and reflects the same clinical acronym expansion (danarti2020deafnessonychodystrophyosteodystrophy pages 1-3, campeau2014thegeneticbasis pages 1-2).
“DOOR syndrome” appears historically (without explicit seizures), but modern usage emphasizes DOORS due to frequent seizures (ny2020clarificationofthe pages 106-109).

1.4 Evidence source types

Most curated information available here derives from aggregated disease-level resources and cohorts (exome-based family series) supplemented by case reports and mechanistic cellular/model-organism studies (campeau2014thegeneticbasis pages 1-2, beauregardlacroix2021doorssyndromeand pages 1-2, danarti2020deafnessonychodystrophyosteodystrophy pages 1-3).

2. Etiology

2.1 Disease causal factors

Primary cause: inherited pathogenic variants affecting endolysosomal/synaptic vesicle and related pathways, most commonly involving TBC1D24; additional genetic heterogeneity includes ATP6V1B2 and other genes in some DOORS-defined cohorts (campeau2014thegeneticbasis pages 1-2, beauregardlacroix2021doorssyndromeand pages 1-2, beauregardlacroix2021doorssyndromeand pages 2-5).

Direct abstract quote (primary cohort): Campeau et al. describe DOORS as “a rare autosomal recessive disorder” and report they “identified TBC1D24 mutations” in affected individuals (campeau2014thegeneticbasis pages 1-2).

2.2 Genetic risk factors (causal variants)

TBC1D24 (autosomal recessive; classic DOORS)

Biallelic pathogenic variants (homozygous or compound heterozygous) in TBC1D24 are a major cause of classic DOORS presentations (campeau2014thegeneticbasis pages 1-2, danarti2020deafnessonychodystrophyosteodystrophy pages 1-3).
Variants appear distributed across the gene with limited genotype–phenotype predictability (ny2020clarificationofthe pages 106-109).

ATP6V1B2 (DOORS-spectrum, recurrent truncating variant)

Beauregard-Lacroix et al. identified a recurrent truncating ATP6V1B2 variant NM_001693.4:c.1516C>T (p.Arg506*) in individuals with DOORS-like clinical presentations (beauregardlacroix2021doorssyndromeand pages 1-2). This expands DOORS-spectrum causation beyond TBC1D24.

2.3 Inheritance patterns

TBC1D24-associated DOORS: predominantly autosomal recessive (danarti2020deafnessonychodystrophyosteodystrophy pages 1-3, campeau2014thegeneticbasis pages 1-2, ny2020clarificationofthe pages 104-106).
ATP6V1B2-associated DOORS-spectrum: reported with heterozygous recurrent truncation in multiple families/individuals (beauregardlacroix2021doorssyndromeand pages 1-2).

2.4 Environmental risk/protective factors and gene–environment interactions

No reproducible environmental risk factors, protective factors, or gene–environment interaction evidence was identified in the retrieved sources for DOORS syndrome.

3. Phenotypes (clinical spectrum)

3.1 Core clinical features and typical timing

Across studies, the syndrome is centered on congenital/early-life deafness, skeletal/nail anomalies, developmental disability, and epilepsy: - Hearing loss: typically sensorineural, often profound and prelingual (ny2020clarificationofthe pages 104-106). - Onychodystrophy and osteodystrophy: small/absent nails and hypoplastic terminal phalanges in most individuals (campeau2014thegeneticbasis pages 1-2, ny2020clarificationofthe pages 104-106). - Seizures: common and typically start in infancy; the GeneReviews-like summary notes seizures “usually start in the first year of life” and may be drug-resistant, with status epilepticus and death reported in some cases (ny2020clarificationofthe pages 106-109).

3.2 Frequency statements (statistics from cohort descriptions)

Evidence-backed recurring frequencies include: - Triphalangeal thumb: ~one third of affected individuals (campeau2014thegeneticbasis pages 1-2, ny2020clarificationofthe pages 106-109). - Microcephaly: ~one third (campeau2014thegeneticbasis pages 1-2, ny2020clarificationofthe pages 106-109). - Narrow bifrontal diameter: ~two thirds (campeau2014thegeneticbasis pages 1-2). - In an ATP6V1B2-associated DOORS cohort, deafness was present in all individuals, together with onychodystrophy and abnormal digits (beauregardlacroix2021doorssyndromeand pages 2-5, beauregardlacroix2021doorssyndromeand pages 1-2).

3.3 Additional phenotypes and complications

Additional reported findings include visual impairment/optic neuropathy, peripheral neuropathy, and imaging abnormalities (danarti2020deafnessonychodystrophyosteodystrophy pages 1-3, ny2020clarificationofthe pages 106-109). Individual case reports can include congenital anomalies such as cardiac defects (danarti2020deafnessonychodystrophyosteodystrophy pages 1-3).

3.4 Suggested HPO terms (non-exhaustive; for knowledge-base normalization)

(These are ontology suggestions to aid curation; they are not claims of completeness.) - Sensorineural hearing impairment HP:0000407 - Nail dystrophy/onychodystrophy HP:0001804 - Hypoplasia/aplasia of distal phalanges HP:0009830 (distal phalanges hypoplasia) - Intellectual disability HP:0001249 - Seizures HP:0001250 - Microcephaly HP:0000252 - Triphalangeal thumb HP:0001199

3.5 Quality of life impact

Direct QoL instrument outcomes (e.g., EQ-5D, SF-36) were not present in retrieved sources. However, the management guidance implies substantial functional impact due to severe developmental delay, communication impairment (AAC evaluation recommended), and epilepsy monitoring (ny2020clarificationofthe pages 114-117, ny2020clarificationofthe pages 111-114).

4. Genetic / molecular information

4.1 Causal genes

TBC1D24 (primary, often biallelic; AR) (campeau2014thegeneticbasis pages 1-2, ny2020clarificationofthe pages 104-106)
ATP6V1B2 (recurrent truncating p.Arg506*; DOORS-spectrum) (beauregardlacroix2021doorssyndromeand pages 1-2, zadori2020clinicopathologicalrelationshipsin pages 1-2)

4.2 Variant spectrum and functional class

TBC1D24 pathogenic variants include missense and loss-of-function alleles; the literature notes that variant locations span the gene and genotype–phenotype patterns are limited (ny2020clarificationofthe pages 106-109).
A recurrent DOORS-spectrum allele in ATP6V1B2 is p.Arg506* (beauregardlacroix2021doorssyndromeand pages 1-2).

Population allele frequencies (gnomAD) and ClinVar/ACMG classifications were not available in the retrieved texts and therefore are not reported here.

4.3 Modifier genes / epigenetics

No specific validated modifier genes or disease-specific epigenetic signatures were identified in the retrieved sources.

5. Environment / lifestyle / infectious factors

DOORS syndrome is a genetic neurodevelopmental disorder; the retrieved evidence did not identify environmental, lifestyle, or infectious causal contributors.

6. Mechanism / pathophysiology

6.1 Current mechanistic understanding (integrated model)

A convergent theme in DOORS syndrome is dysfunction in intracellular trafficking and organelle homeostasis that impacts neuronal signaling and tissue development.

6.1.1 Vesicle trafficking and synaptic endocytosis (TBC1D24)

TBC1D24 is repeatedly linked to Rab/ARF6-related vesicle trafficking and synaptic vesicle cycling. Mechanistic summaries indicate TBC1D24 deficiency causes presynaptic endocytosis defects and impaired neurotransmission (beauregardlacroix2021doorssyndromeand pages 5-6, beauregardlacroix2021doorssyndromeand pages 2-5). Model-organism work supports a conserved role of the TBC domain in phosphoinositide-dependent membrane association relevant to synaptic vesicle trafficking (ny2020clarificationofthe pages 117-120, ny2020clarificationofthe pages 32-37).

6.1.2 v-ATPase / lysosomal acidification axis (ATP6V1B2 and TBC1D24)

ATP6V1B2 encodes a V-ATPase subunit, and DOORS-spectrum ATP6V1B2 truncation is linked to impaired lysosomal acidification (beauregardlacroix2021doorssyndromeand pages 5-6, zadori2020clinicopathologicalrelationshipsin pages 1-2). TBC1D24 also interfaces with this axis: in neurons, FLAG-TBC1D24 co-precipitates ATP6V1B2 and ATP6V1A, and Tbc1d24 knockout causes endolysosomal and autophagy-related abnormalities consistent with v-ATPase dysregulation (pepe2025tbc1d24interactswith pages 1-3).

6.1.3 2024 mechanistic development: mitochondria and ER–mitochondria contact sites

A 2024 preprint reports a new role for TBC1D24 in mitochondrial homeostasis: patient fibroblasts and TBC1D24 knockdown cells show fragmented mitochondria, decreased ATP, and reduced mitochondrial membrane potential, and loss/mutation of TBC1D24 alters ER–mitochondria contact sites (ERMCS) (benhammouda2024tbc1d24regulatesmitochondria pages 1-4). This supports a multi-organelle pathophysiology model in which vesicle/lysosome defects intersect with mitochondrial energy failure.

6.2 Cell types and tissues implicated (with ontology suggestions)

Cochlea (2024 localization study)

In developing mouse cochlea, TBC1D24 immunolabeling localizes mainly to glia-like non-sensory/supporting epithelial cells and is largely absent from adjacent hair cells early postnatally, with downregulation around the onset of hearing (defourny2024tbc1d24islikely pages 2-4, defourny2024tbc1d24islikely pages 4-5). This points to a mechanism where supporting-cell vesicle trafficking and barrier/junction maintenance influences auditory function.

Suggested Cell Ontology (CL) terms:
Cochlear supporting cell (general; exact CL term may require curator selection)
Glial cell CL:0000125 (for “glia-like” concept)
Suggested UBERON terms:
Cochlea UBERON:0001769
Cochlear sensory epithelium / organ of Corti UBERON:0002048 (organ of Corti)

Central nervous system

Mouse data show TBC1D24 mRNA is abundant in hippocampus and the protein associates with clathrin-coated vesicles and synapses (tona2019thephenotypiclandscape pages 1-2), consistent with a neuronal/synaptic basis for epilepsy.

Suggested GO biological processes:
Synaptic vesicle endocytosis GO:0048488
Endosome organization GO:0007032
Lysosome organization GO:0007040
Autophagy GO:0006914
Mitochondrial fission GO:0000266 / mitochondrial fusion GO:0008053
Suggested GO cellular components:
Synapse GO:0045202
Clathrin-coated vesicle GO:0030136
Lysosome GO:0005764
Mitochondrion GO:0005739
Endoplasmic reticulum GO:0005783

6.3 Causal chain (gene → cell biology → phenotype)

A plausible integrated chain supported by current evidence is: 1) Pathogenic variants in TBC1D24 and/or ATP6V1B2 disrupt membrane trafficking and organelle acidification (presynaptic endocytosis and v-ATPase-dependent lysosomal pH) (beauregardlacroix2021doorssyndromeand pages 5-6, pepe2025tbc1d24interactswith pages 1-3). 2) This yields synaptic dysfunction (impaired vesicle cycling) contributing to epilepsy and neurodevelopmental impairment, and may also impair endolysosomal clearance/autophagy (pepe2025tbc1d24interactswith pages 1-3). 3) A 2024 line of evidence adds mitochondrial dysfunction and altered ER–mitochondria contact sites, potentially compounding neuronal energetic stress and developmental vulnerability (benhammouda2024tbc1d24regulatesmitochondria pages 1-4). 4) In the inner ear, TBC1D24’s developmental expression in supporting (glia-like) epithelial cells suggests that altered vesicle trafficking/junctional protein recycling could disturb cochlear homeostasis and contribute to deafness (defourny2024tbc1d24islikely pages 4-5, defourny2024tbc1d24islikely pages 2-4).

7. Anatomical structures affected

Primary: inner ear/cochlea (hearing), brain/CNS (epilepsy, neurodevelopment), distal phalanges/nails (skeletal/nail dysplasia) (campeau2014thegeneticbasis pages 1-2, danarti2020deafnessonychodystrophyosteodystrophy pages 1-3).
Secondary/variable: eyes/optic nerve and peripheral nerves in some cases; occasional congenital anomalies such as cardiac defects in case reports (danarti2020deafnessonychodystrophyosteodystrophy pages 1-3).

8. Temporal development

Onset: typically congenital/early (nails/phalanges), seizures usually within first year of life (ny2020clarificationofthe pages 106-109, danarti2020deafnessonychodystrophyosteodystrophy pages 1-3).
Course: variable; seizures can be difficult to control and may be severe, including status epilepticus and death in some individuals (ny2020clarificationofthe pages 106-109).

9. Inheritance and population

9.1 Epidemiology

Robust prevalence/incidence estimates were not found in retrieved full-text sources. A literature review/case report summary stated that ~60 cases had been reported as of 2020, highlighting extreme rarity (danarti2020deafnessonychodystrophyosteodystrophy pages 1-3).

9.2 Mendelian inheritance details

For TBC1D24-associated DOORS syndrome, autosomal recessive recurrence risk is consistent with 25% affected risk for siblings when both parents are carriers; this is explicitly outlined in management/counseling guidance (ny2020clarificationofthe pages 114-117).

Carrier frequency, founder variants, and population-specific distributions were not available in retrieved sources.

10. Diagnostics

10.1 Clinical recognition and workup

Key workup elements described across reports include: - Audiology: BERA/ABR can document profound sensorineural deafness (danarti2020deafnessonychodystrophyosteodystrophy pages 1-3). - Seizure evaluation: EEG abnormalities are common (danarti2020deafnessonychodystrophyosteodystrophy pages 1-3). - Skeletal imaging: radiographs showing absent/hypoplastic distal phalanges (danarti2020deafnessonychodystrophyosteodystrophy pages 1-3).

10.2 Genetic testing approach

A GeneReviews-like diagnostic strategy recommends: - Start with TBC1D24 sequence analysis, then consider deletion/duplication testing and multigene panels or exome/genome sequencing if negative, especially given likely genetic heterogeneity (ny2020clarificationofthe pages 104-106). - Diagnostic yield appears highest when an individual has all five classic DOORS features (ny2020clarificationofthe pages 104-106).

10.3 Differential diagnosis (examples supported by evidence)

Overlapping syndromes can complicate diagnosis; one report highlights that syndromes initially considered in a DOORS-like presentation included Coffin-Siris and others, and illustrates the general need for broad genomic testing when phenotype overlaps (ny2020clarificationofthe pages 120-122).

11. Outcome / prognosis

Prognosis is heterogeneous. Severe intellectual disability is common; seizures can be drug-resistant and may lead to status epilepticus and death in some individuals (ny2020clarificationofthe pages 106-109). Detailed survival curves, life expectancy estimates, and validated prognostic biomarkers were not present in retrieved evidence.

12. Treatment

12.1 Current management (real-world implementation)

No disease-modifying therapy is established; published guidance emphasizes symptomatic, multidisciplinary care: - Epilepsy: symptomatic antiseizure pharmacotherapy; multiple agents have been used without controlled comparisons specific to TBC1D24-related disorders (ny2020clarificationofthe pages 111-114). - Hearing loss: hearing aids or cochlear implantation may benefit selected individuals; cochlear implantation at age 1 was noted beneficial in at least one DOORS individual in the management summary (ny2020clarificationofthe pages 111-114, ny2020clarificationofthe pages 104-106). - Developmental support: early intervention plus OT/PT/speech therapy; evaluation for AAC; individualized education planning (ny2020clarificationofthe pages 114-117, ny2020clarificationofthe pages 111-114). - Surveillance: neurology follow-up with EEG guided by seizure course; annual audiology and dental evaluation; ECG surveillance in epilepsy as part of risk monitoring (ny2020clarificationofthe pages 114-117).

12.2 Experimental treatments / clinical trials

A ClinicalTrials.gov search for “DOORS”/TBC1D24 returned acronym-matched but non-disease-related trials; no DOORS-specific interventional clinical trials were identified in this run.

12.3 Suggested MAXO terms (examples)

Antiseizure medication therapy MAXO:0000756 (anticonvulsant therapy)
Cochlear implantation MAXO:0001034
Hearing aid fitting MAXO:0000507
Physical therapy MAXO:0000015
Occupational therapy MAXO:0000016
Speech therapy / augmentative communication support (AAC) (MAXO term selection may require curator review)

13. Prevention

No primary prevention is currently available because DOORS is genetic. Secondary/tertiary prevention is centered on early detection and supportive management: - Reproductive counseling: carrier testing, prenatal testing, and preimplantation genetic diagnosis are possible once familial pathogenic variants are known (ny2020clarificationofthe pages 114-117, ny2020clarificationofthe pages 117-120). - Early audiology and seizure management may reduce complications and improve functional outcomes (danarti2020deafnessonychodystrophyosteodystrophy pages 4-5).

14. Other species / natural disease

No naturally occurring veterinary DOORS syndrome analogs were identified in retrieved sources.

15. Model organisms

15.1 Drosophila and C. elegans

In Drosophila, introduction of human DOORS-associated TBC1D24 variants p.Arg40 and p.Arg242 in the conserved membrane-binding pocket led to impaired synaptic vesicle trafficking and seizures (ny2020clarificationofthe pages 117-120).
In C. elegans, the ortholog C31H2.1 was identified in an RNAi screen implicating synaptic function (ny2020clarificationofthe pages 117-120).

15.2 Mouse models

A CRISPR-engineered Tbc1d24 S324Tfs*3 homozygous mouse shows “abrupt onset of spontaneous seizures at postnatal day 15,” with early lethality, and the protein localizes to clathrin-coated vesicles/synapses in hippocampal neurons, supporting a presynaptic trafficking mechanism (tona2019thephenotypiclandscape pages 1-2, tona2019thephenotypiclandscape pages 3-4).
The same model showed normal ABR/DPOAE responses at P17, suggesting that at least some Tbc1d24 alleles can produce severe epilepsy without early measurable hearing impairment in mice (tona2019thephenotypiclandscape pages 5-6).

Recent developments (prioritized 2023–2024)

1) Cochlear cell-type localization (June 2024). Defourny reported developmental cochlear expression of TBC1D24 primarily in glia-like non-sensory/supporting epithelial cells rather than hair cells, disappearing around onset of hearing, supporting a new hypothesis for auditory pathogenesis beyond hair-cell intrinsic defects (published June 2024; https://doi.org/10.1387/ijdb.240060jd) (defourny2024tbc1d24islikely pages 2-4, defourny2024tbc1d24islikely pages 4-5).

2) Mitochondrial/ER–mitochondria contact site mechanism (Sep 2024 preprint). Benhammouda et al. reported that TBC1D24 loss/mutation is associated with fragmented mitochondria and reduced ATP/membrane potential and altered ER–mitochondria contact sites (posted Sep 2024; https://doi.org/10.1101/2024.09.19.613961) (benhammouda2024tbc1d24regulatesmitochondria pages 1-4).

These 2024 studies broaden the mechanistic landscape from “synaptic vesicle trafficking” toward a multi-organelle model linking vesicle/lysosome biology, cellular energetics, and developmental cell-type specificity in the cochlea.

Expert opinion / analysis (evidence-grounded)

The most consistent mechanistic convergence across DOORS genes is organelle acidification and membrane trafficking dysfunction in neurons and developing tissues (beauregardlacroix2021doorssyndromeand pages 5-6, pepe2025tbc1d24interactswith pages 1-3). The addition of (i) ATP6V1B2 truncation as a DOORS-spectrum cause and (ii) emerging mitochondrial/ERMCS defects supports a view of DOORS as a systems disorder of intracellular organelle homeostasis, rather than a single-pathway synaptopathy (beauregardlacroix2021doorssyndromeand pages 1-2, benhammouda2024tbc1d24regulatesmitochondria pages 1-4).

Visual evidence (genetics + mechanism)

Beauregard-Lacroix et al. provide a table summarizing genetic causes across a DOORS cohort and structural figures localizing ATP6V1B2 p.Arg506* within the ATP6V1B2 protein and the V-ATPase complex (beauregardlacroix2021doorssyndromeand media 2f3d8df7, beauregardlacroix2021doorssyndromeand media 79b51ebf, beauregardlacroix2021doorssyndromeand media ee48104e).

Key facts table (for knowledge-base ingestion)

Topic	Key information	Citations
Definition / acronym	DOORS syndrome = Deafness, Onychodystrophy, Osteodystrophy, intellectual disability/developmental delay, and Seizures; classically described as a rare multisystem Mendelian disorder.	(danarti2020deafnessonychodystrophyosteodystrophy pages 1-3, beauregardlacroix2021doorssyndromeand pages 1-2, campeau2014thegeneticbasis pages 1-2)
Key identifiers	Disease OMIM/MIM: 220500; major causal gene: TBC1D24 (gene MIM 613577), chromosome 16p13.	(danarti2020deafnessonychodystrophyosteodystrophy pages 1-3, ny2020clarificationofthe pages 104-106)
Core genetic architecture	Best-established cause is biallelic TBC1D24 pathogenic variation with autosomal recessive inheritance; diagnosis in classic cases is supported by identifying biallelic pathogenic variants. Genetic heterogeneity is likely.	(danarti2020deafnessonychodystrophyosteodystrophy pages 1-3, ny2020clarificationofthe pages 104-106, campeau2014thegeneticbasis pages 1-2)
Additional causal gene	ATP6V1B2 is an additional DOORS-spectrum gene; a recurrent truncating *c.1516C>T (p.Arg506) variant was identified in multiple unrelated families/individuals with DOORS-like presentations, typically in the heterozygous** state.	(beauregardlacroix2021doorssyndromeand pages 1-2, beauregardlacroix2021doorssyndromeand pages 5-6, beauregardlacroix2021doorssyndromeand pages 2-5)
Cohort-level genetics	In a 46-family DOORS cohort, reported etiologies included TBC1D24 in 13 families (28%), ATP6V1B2 in 8 families (17%), and 6 families (13%) remained unsolved; broader heterogeneity included other genes in some families.	(beauregardlacroix2021doorssyndromeand pages 2-5, beauregardlacroix2021doorssyndromeand pages 1-2)
Hallmark phenotype spectrum	Typical findings include sensorineural deafness, small/absent nails, hypoplastic/absent terminal phalanges, intellectual disability/developmental delay, and seizures; deafness, onychodystrophy, and abnormal digits were present in all reported ATP6V1B2-DOORS individuals in one cohort.	(beauregardlacroix2021doorssyndromeand pages 2-5, danarti2020deafnessonychodystrophyosteodystrophy pages 1-3, beauregardlacroix2021doorssyndromeand pages 1-2, campeau2014thegeneticbasis pages 1-2)
Frequency statements	Reported recurring phenotype frequencies: triphalangeal thumb ~one third, microcephaly ~one third, narrow bifrontal diameter ~two thirds of affected individuals.	(ny2020clarificationofthe pages 106-109, campeau2014thegeneticbasis pages 1-2)
Seizure timing / severity	Seizures occur in most affected individuals and usually start in the first year of life; seizure types include generalized tonic-clonic, complex partial, focal clonic, and infantile spasms; some cases are drug-resistant and may progress to status epilepticus or early death.	(danarti2020deafnessonychodystrophyosteodystrophy pages 1-3, ny2020clarificationofthe pages 106-109, campeau2014thegeneticbasis pages 1-2)
Other reported findings	Additional manifestations reported across cases include visual impairment/optic neuropathy, peripheral neuropathy, MRI abnormalities, and occasional congenital anomalies (e.g., cardiac defects in case reports).	(danarti2020deafnessonychodystrophyosteodystrophy pages 1-3, ny2020clarificationofthe pages 106-109)
Diagnostic clues	Highest diagnostic yield is in individuals with all five classic features; recommended testing starts with TBC1D24 sequence analysis, then deletion/duplication analysis and/or broader exome/genome or multigene-panel testing; audiology, EEG, radiographs, and systemic evaluation are useful adjuncts.	(ny2020clarificationofthe pages 104-106, ny2020clarificationofthe pages 111-114, danarti2020deafnessonychodystrophyosteodystrophy pages 1-3)
Mechanistic theme: vesicle trafficking / endocytosis	TBC1D24 is linked to Rab/ARF6-related vesicle trafficking, presynaptic endocytosis, synaptic vesicle recycling/rejuvenation, and phosphoinositide-mediated membrane binding; deficiency causes presynaptic endocytic defects and impaired spontaneous neurotransmission.	(beauregardlacroix2021doorssyndromeand pages 5-6, ny2020clarificationofthe pages 117-120, ny2020clarificationofthe pages 32-37, beauregardlacroix2021doorssyndromeand pages 2-5, tona2019thephenotypiclandscape pages 1-2)
Mechanistic theme: v-ATPase / lysosome	ATP6V1B2 encodes a V-ATPase subunit; DOORS-associated ATP6V1B2 variants are linked to impaired lysosomal acidification. TBC1D24 also physically/functionally interfaces with the v-ATPase, supporting a shared endolysosomal disease axis.	(beauregardlacroix2021doorssyndromeand pages 5-6, pepe2025tbc1d24interactswith pages 1-3, zadori2020clinicopathologicalrelationshipsin pages 1-2)
Mechanistic theme: mitochondria / ER contact sites	Emerging evidence links TBC1D24 deficiency to fragmented mitochondria, decreased ATP, reduced mitochondrial membrane potential, and altered ER–mitochondria contact sites (ERMCS), expanding pathophysiology beyond synaptic trafficking.	(benhammouda2024tbc1d24regulatesmitochondria pages 1-4, benhammouda2024tbc1d24regulatesmitochondria pages 12-13)
2024 development: mitochondria	Benhammouda 2024 reported that patient fibroblasts and TBC1D24-deficient cells show mitochondrial dysfunction and altered ERMCS, nominating mitochondrial homeostasis as a new disease mechanism.	(benhammouda2024tbc1d24regulatesmitochondria pages 1-4, benhammouda2024tbc1d24regulatesmitochondria pages 12-13)
2024 development: cochlea	Defourny 2024 localized TBC1D24 in early postnatal mouse cochlea mainly to glia-like non-sensory/supporting epithelial cells, with little to no signal in adjacent hair cells and loss of epithelial signal around hearing onset, suggesting a supporting-cell vesicle-trafficking role in hearing biology.	(defourny2024tbc1d24islikely pages 1-2, defourny2024tbc1d24islikely pages 2-4, defourny2024tbc1d24islikely pages 4-5)
Model-organism support	Mouse and invertebrate models support neuronal/synaptic roles: Drosophila DOORS-equivalent variants impair synaptic vesicle trafficking and cause seizures; a CRISPR mouse *Tbc1d24 S324Tfs3 model shows abrupt spontaneous seizures at P15** and death by ~3 weeks, with hippocampal localization of TBC1D24 at clathrin-coated vesicles/synapses.	(ny2020clarificationofthe pages 140-144, ny2020clarificationofthe pages 117-120, tona2019thephenotypiclandscape pages 3-4, tona2019thephenotypiclandscape pages 1-2)
Management snapshot	No disease-modifying therapy is established; management is symptomatic and multidisciplinary: antiseizure medications, hearing aids or cochlear implantation in selected patients, developmental therapies (PT/OT/speech/AAC), and routine surveillance (neurology/EEG, audiology, dental, ophthalmology, other specialty assessments).	(ny2020clarificationofthe pages 114-117, danarti2020deafnessonychodystrophyosteodystrophy pages 4-5, ny2020clarificationofthe pages 111-114, ny2020clarificationofthe pages 104-106)

Table: This table condenses the highest-yield clinical, genetic, mechanistic, and diagnostic facts about DOORS syndrome, including classic frequencies and recent 2024 mechanistic updates. It is designed for direct reuse in a disease knowledge-base report with row-level citation IDs.

Limitations / missing identifiers

This run did not retrieve full-text evidence containing MONDO, Orphanet, ICD-10/ICD-11, or MeSH identifiers specific to DOORS syndrome; therefore these identifiers are not reported to avoid speculation.
ClinVar-style variant counts, allele frequencies (gnomAD), and formal ACMG/AMP classifications were not present in retrieved texts.
Quality-of-life instrument outcomes and robust epidemiologic prevalence/incidence estimates were not identified in available sources.

Source highlights (publication dates + URLs where available)

Campeau PM et al. The Lancet Neurology Jan 2014. “The genetic basis of DOORS syndrome: an exome-sequencing study.” https://doi.org/10.1016/S1474-4422(13)70265-5 (campeau2014thegeneticbasis pages 1-2)
Beauregard-Lacroix E et al. Genetics in Medicine Jan 2021. “DOORS syndrome and a recurrent truncating ATP6V1B2 variant.” https://doi.org/10.1038/s41436-020-00950-9 (beauregardlacroix2021doorssyndromeand pages 1-2)
Defourny J. Int J Dev Biol Jun 2024. “TBC1D24 is likely to regulate vesicle trafficking in glia-like non-sensory epithelial cells of the cochlea.” https://doi.org/10.1387/ijdb.240060jd (defourny2024tbc1d24islikely pages 2-4)
Benhammouda S et al. bioRxiv Sep 2024. “TBC1D24 regulates mitochondria and endoplasmic reticulum-mitochondria contact sites.” https://doi.org/10.1101/2024.09.19.613961 (benhammouda2024tbc1d24regulatesmitochondria pages 1-4)

References

(danarti2020deafnessonychodystrophyosteodystrophy pages 1-3): Retno Danarti, Shinta Rahmayani, Yohanes Widodo Wirohadidjojo, and WenChieh Chen. Deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (doors) syndrome: a new case report from indonesia and review of the literature. European Journal of Dermatology, 30:404-407, Aug 2020. URL: https://doi.org/10.1684/ejd.2020.3850, doi:10.1684/ejd.2020.3850. This article has 9 citations and is from a peer-reviewed journal.
(beauregardlacroix2021doorssyndromeand pages 1-2): Eliane Beauregard-Lacroix, Guillermo Pacheco-Cuellar, Norbert F. Ajeawung, Jessica Tardif, Klaus Dieterich, Tabib Dabir, Dina Vind-Kezunovic, Susan M. White, Denes Zadori, Claudia Castiglioni, Lisbeth Tranebjærg, Pernille Mathiesen Tørring, Ed Blair, Marzena Wisniewska, Maria Vittoria Camurri, Yolande van Bever, Sirinart Molidperee, Juliet Taylor, Alexandre Dionne-Laporte, Sanjay M. Sisodiya, Raoul C.M. Hennekam, and Philippe M. Campeau. Doors syndrome and a recurrent truncating atp6v1b2 variant. Genetics in Medicine, 23:149-154, Jan 2021. URL: https://doi.org/10.1038/s41436-020-00950-9, doi:10.1038/s41436-020-00950-9. This article has 37 citations and is from a highest quality peer-reviewed journal.
(campeau2014thegeneticbasis pages 1-2): Philippe M Campeau, Dalia Kasperaviciute, James T Lu, Lindsay C Burrage, Choel Kim, Mutsuki Hori, Berkley R Powell, Fiona Stewart, Têmis Maria Félix, Jenneke van den Ende, Marzena Wisniewska, Hülya Kayserili, Patrick Rump, Sheela Nampoothiri, Salim Aftimos, Antje Mey, Lal D V Nair, Michael L Begleiter, Isabelle De Bie, Girish Meenakshi, Mitzi L Murray, Gabriela M Repetto, Mahin Golabi, Edward Blair, Alison Male, Fabienne Giuliano, Ariana Kariminejad, William G Newman, Sanjeev S Bhaskar, Jonathan E Dickerson, Bronwyn Kerr, Siddharth Banka, Jacques C Giltay, Dagmar Wieczorek, Anna Tostevin, Joanna Wiszniewska, Sau Wai Cheung, Raoul C Hennekam, Richard A Gibbs, Brendan H Lee, and Sanjay M Sisodiya. The genetic basis of doors syndrome: an exome-sequencing study. The Lancet. Neurology, 13:44-58, Jan 2014. URL: https://doi.org/10.1016/s1474-4422(13)70265-5, doi:10.1016/s1474-4422(13)70265-5. This article has 300 citations.
(ny2020clarificationofthe pages 106-109): ML Ny and E Bettina. Clarification of the role of the tbc1d24 gene in human genetic conditions. Unknown journal, 2020.
(beauregardlacroix2021doorssyndromeand pages 2-5): Eliane Beauregard-Lacroix, Guillermo Pacheco-Cuellar, Norbert F. Ajeawung, Jessica Tardif, Klaus Dieterich, Tabib Dabir, Dina Vind-Kezunovic, Susan M. White, Denes Zadori, Claudia Castiglioni, Lisbeth Tranebjærg, Pernille Mathiesen Tørring, Ed Blair, Marzena Wisniewska, Maria Vittoria Camurri, Yolande van Bever, Sirinart Molidperee, Juliet Taylor, Alexandre Dionne-Laporte, Sanjay M. Sisodiya, Raoul C.M. Hennekam, and Philippe M. Campeau. Doors syndrome and a recurrent truncating atp6v1b2 variant. Genetics in Medicine, 23:149-154, Jan 2021. URL: https://doi.org/10.1038/s41436-020-00950-9, doi:10.1038/s41436-020-00950-9. This article has 37 citations and is from a highest quality peer-reviewed journal.
(ny2020clarificationofthe pages 104-106): ML Ny and E Bettina. Clarification of the role of the tbc1d24 gene in human genetic conditions. Unknown journal, 2020.
(ny2020clarificationofthe pages 114-117): ML Ny and E Bettina. Clarification of the role of the tbc1d24 gene in human genetic conditions. Unknown journal, 2020.
(ny2020clarificationofthe pages 111-114): ML Ny and E Bettina. Clarification of the role of the tbc1d24 gene in human genetic conditions. Unknown journal, 2020.
(zadori2020clinicopathologicalrelationshipsin pages 1-2): Dénes Zádori, Levente Szalárdy, Zita Reisz, Gabor G. Kovacs, Rita Maszlag-Török, Norbert F. Ajeawung, László Vécsei, Philippe M. Campeau, and Péter Klivényi. Clinicopathological relationships in an aged case of doors syndrome with a p.arg506x mutation in the atp6v1b2 gene. Frontiers in Neurology, Aug 2020. URL: https://doi.org/10.3389/fneur.2020.00767, doi:10.3389/fneur.2020.00767. This article has 15 citations and is from a peer-reviewed journal.
(beauregardlacroix2021doorssyndromeand pages 5-6): Eliane Beauregard-Lacroix, Guillermo Pacheco-Cuellar, Norbert F. Ajeawung, Jessica Tardif, Klaus Dieterich, Tabib Dabir, Dina Vind-Kezunovic, Susan M. White, Denes Zadori, Claudia Castiglioni, Lisbeth Tranebjærg, Pernille Mathiesen Tørring, Ed Blair, Marzena Wisniewska, Maria Vittoria Camurri, Yolande van Bever, Sirinart Molidperee, Juliet Taylor, Alexandre Dionne-Laporte, Sanjay M. Sisodiya, Raoul C.M. Hennekam, and Philippe M. Campeau. Doors syndrome and a recurrent truncating atp6v1b2 variant. Genetics in Medicine, 23:149-154, Jan 2021. URL: https://doi.org/10.1038/s41436-020-00950-9, doi:10.1038/s41436-020-00950-9. This article has 37 citations and is from a highest quality peer-reviewed journal.
(ny2020clarificationofthe pages 117-120): ML Ny and E Bettina. Clarification of the role of the tbc1d24 gene in human genetic conditions. Unknown journal, 2020.
(ny2020clarificationofthe pages 32-37): ML Ny and E Bettina. Clarification of the role of the tbc1d24 gene in human genetic conditions. Unknown journal, 2020.
(pepe2025tbc1d24interactswith pages 1-3): Sara Pepe, Davide Aprile, Enrico Castroflorio, Antonella Marte, Simone Giubbolini, Samir Hopestone, Anna Parsons, Tânia Soares, Fabio Benfenati, Peter L. Oliver, and Anna Fassio. Tbc1d24 interacts with the v-atpase and regulates intraorganellar ph in neurons. Jan 2025. URL: https://doi.org/10.1016/j.isci.2024.111515, doi:10.1016/j.isci.2024.111515. This article has 5 citations and is from a peer-reviewed journal.
(benhammouda2024tbc1d24regulatesmitochondria pages 1-4): Sara Benhammouda, Justine Rousseau, Philippe M. Campeau, and Marc Germain. Tbc1d24 regulates mitochondria and endoplasmic reticulum-mitochondria contact sites. bioRxiv, Sep 2024. URL: https://doi.org/10.1101/2024.09.19.613961, doi:10.1101/2024.09.19.613961. This article has 0 citations.
(defourny2024tbc1d24islikely pages 2-4): Jean Defourny. Tbc1d24 is likely to regulate vesicle trafficking in glia-like non-sensory epithelial cells of the cochlea. The International journal of developmental biology, 68:79-83, Jun 2024. URL: https://doi.org/10.1387/ijdb.240060jd, doi:10.1387/ijdb.240060jd. This article has 4 citations.
(defourny2024tbc1d24islikely pages 4-5): Jean Defourny. Tbc1d24 is likely to regulate vesicle trafficking in glia-like non-sensory epithelial cells of the cochlea. The International journal of developmental biology, 68:79-83, Jun 2024. URL: https://doi.org/10.1387/ijdb.240060jd, doi:10.1387/ijdb.240060jd. This article has 4 citations.
(tona2019thephenotypiclandscape pages 1-2): Risa Tona, Wenqian Chen, Yoko Nakano, Laura D Reyes, Ronald S Petralia, Ya-Xian Wang, Matthew F Starost, Talah T Wafa, Robert J Morell, Kevin D Cravedi, Johann du Hoffmann, Takushi Miyoshi, Jeeva P Munasinghe, Tracy S Fitzgerald, Yogita Chudasama, Koichi Omori, Carlo Pierpaoli, Botond Banfi, Lijin Dong, Inna A Belyantseva, and Thomas B Friedman. The phenotypic landscape of a tbc1d24 mutant mouse includes convulsive seizures resembling human early infantile epileptic encephalopathy. Human Molecular Genetics, 28:1530–1547, Jan 2019. URL: https://doi.org/10.1093/hmg/ddy445, doi:10.1093/hmg/ddy445. This article has 35 citations and is from a domain leading peer-reviewed journal.
(ny2020clarificationofthe pages 120-122): ML Ny and E Bettina. Clarification of the role of the tbc1d24 gene in human genetic conditions. Unknown journal, 2020.
(danarti2020deafnessonychodystrophyosteodystrophy pages 4-5): Retno Danarti, Shinta Rahmayani, Yohanes Widodo Wirohadidjojo, and WenChieh Chen. Deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (doors) syndrome: a new case report from indonesia and review of the literature. European Journal of Dermatology, 30:404-407, Aug 2020. URL: https://doi.org/10.1684/ejd.2020.3850, doi:10.1684/ejd.2020.3850. This article has 9 citations and is from a peer-reviewed journal.
(tona2019thephenotypiclandscape pages 3-4): Risa Tona, Wenqian Chen, Yoko Nakano, Laura D Reyes, Ronald S Petralia, Ya-Xian Wang, Matthew F Starost, Talah T Wafa, Robert J Morell, Kevin D Cravedi, Johann du Hoffmann, Takushi Miyoshi, Jeeva P Munasinghe, Tracy S Fitzgerald, Yogita Chudasama, Koichi Omori, Carlo Pierpaoli, Botond Banfi, Lijin Dong, Inna A Belyantseva, and Thomas B Friedman. The phenotypic landscape of a tbc1d24 mutant mouse includes convulsive seizures resembling human early infantile epileptic encephalopathy. Human Molecular Genetics, 28:1530–1547, Jan 2019. URL: https://doi.org/10.1093/hmg/ddy445, doi:10.1093/hmg/ddy445. This article has 35 citations and is from a domain leading peer-reviewed journal.
(tona2019thephenotypiclandscape pages 5-6): Risa Tona, Wenqian Chen, Yoko Nakano, Laura D Reyes, Ronald S Petralia, Ya-Xian Wang, Matthew F Starost, Talah T Wafa, Robert J Morell, Kevin D Cravedi, Johann du Hoffmann, Takushi Miyoshi, Jeeva P Munasinghe, Tracy S Fitzgerald, Yogita Chudasama, Koichi Omori, Carlo Pierpaoli, Botond Banfi, Lijin Dong, Inna A Belyantseva, and Thomas B Friedman. The phenotypic landscape of a tbc1d24 mutant mouse includes convulsive seizures resembling human early infantile epileptic encephalopathy. Human Molecular Genetics, 28:1530–1547, Jan 2019. URL: https://doi.org/10.1093/hmg/ddy445, doi:10.1093/hmg/ddy445. This article has 35 citations and is from a domain leading peer-reviewed journal.
(beauregardlacroix2021doorssyndromeand media 2f3d8df7): Eliane Beauregard-Lacroix, Guillermo Pacheco-Cuellar, Norbert F. Ajeawung, Jessica Tardif, Klaus Dieterich, Tabib Dabir, Dina Vind-Kezunovic, Susan M. White, Denes Zadori, Claudia Castiglioni, Lisbeth Tranebjærg, Pernille Mathiesen Tørring, Ed Blair, Marzena Wisniewska, Maria Vittoria Camurri, Yolande van Bever, Sirinart Molidperee, Juliet Taylor, Alexandre Dionne-Laporte, Sanjay M. Sisodiya, Raoul C.M. Hennekam, and Philippe M. Campeau. Doors syndrome and a recurrent truncating atp6v1b2 variant. Genetics in Medicine, 23:149-154, Jan 2021. URL: https://doi.org/10.1038/s41436-020-00950-9, doi:10.1038/s41436-020-00950-9. This article has 37 citations and is from a highest quality peer-reviewed journal.
(beauregardlacroix2021doorssyndromeand media 79b51ebf): Eliane Beauregard-Lacroix, Guillermo Pacheco-Cuellar, Norbert F. Ajeawung, Jessica Tardif, Klaus Dieterich, Tabib Dabir, Dina Vind-Kezunovic, Susan M. White, Denes Zadori, Claudia Castiglioni, Lisbeth Tranebjærg, Pernille Mathiesen Tørring, Ed Blair, Marzena Wisniewska, Maria Vittoria Camurri, Yolande van Bever, Sirinart Molidperee, Juliet Taylor, Alexandre Dionne-Laporte, Sanjay M. Sisodiya, Raoul C.M. Hennekam, and Philippe M. Campeau. Doors syndrome and a recurrent truncating atp6v1b2 variant. Genetics in Medicine, 23:149-154, Jan 2021. URL: https://doi.org/10.1038/s41436-020-00950-9, doi:10.1038/s41436-020-00950-9. This article has 37 citations and is from a highest quality peer-reviewed journal.
(beauregardlacroix2021doorssyndromeand media ee48104e): Eliane Beauregard-Lacroix, Guillermo Pacheco-Cuellar, Norbert F. Ajeawung, Jessica Tardif, Klaus Dieterich, Tabib Dabir, Dina Vind-Kezunovic, Susan M. White, Denes Zadori, Claudia Castiglioni, Lisbeth Tranebjærg, Pernille Mathiesen Tørring, Ed Blair, Marzena Wisniewska, Maria Vittoria Camurri, Yolande van Bever, Sirinart Molidperee, Juliet Taylor, Alexandre Dionne-Laporte, Sanjay M. Sisodiya, Raoul C.M. Hennekam, and Philippe M. Campeau. Doors syndrome and a recurrent truncating atp6v1b2 variant. Genetics in Medicine, 23:149-154, Jan 2021. URL: https://doi.org/10.1038/s41436-020-00950-9, doi:10.1038/s41436-020-00950-9. This article has 37 citations and is from a highest quality peer-reviewed journal.
(benhammouda2024tbc1d24regulatesmitochondria pages 12-13): Sara Benhammouda, Justine Rousseau, Philippe M. Campeau, and Marc Germain. Tbc1d24 regulates mitochondria and endoplasmic reticulum-mitochondria contact sites. bioRxiv, Sep 2024. URL: https://doi.org/10.1101/2024.09.19.613961, doi:10.1101/2024.09.19.613961. This article has 0 citations.
(defourny2024tbc1d24islikely pages 1-2): Jean Defourny. Tbc1d24 is likely to regulate vesicle trafficking in glia-like non-sensory epithelial cells of the cochlea. The International journal of developmental biology, 68:79-83, Jun 2024. URL: https://doi.org/10.1387/ijdb.240060jd, doi:10.1387/ijdb.240060jd. This article has 4 citations.
(ny2020clarificationofthe pages 140-144): ML Ny and E Bettina. Clarification of the role of the tbc1d24 gene in human genetic conditions. Unknown journal, 2020.

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References

Deep Research

Disease Characteristics Research Template

Target Disease

Research Objectives

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Citation Requirements

Output Format

Comprehensive Research Report: DOORS Syndrome (Mendelian)

Target disease

1. Disease information

1.1 Overview (what is the disease?)

1.2 Key identifiers and codes

1.3 Synonyms / alternative names

1.4 Evidence source types

2. Etiology

2.1 Disease causal factors

2.2 Genetic risk factors (causal variants)

TBC1D24 (autosomal recessive; classic DOORS)

ATP6V1B2 (DOORS-spectrum, recurrent truncating variant)

2.3 Inheritance patterns

2.4 Environmental risk/protective factors and gene–environment interactions

3. Phenotypes (clinical spectrum)

3.1 Core clinical features and typical timing

3.2 Frequency statements (statistics from cohort descriptions)

3.3 Additional phenotypes and complications

3.4 Suggested HPO terms (non-exhaustive; for knowledge-base normalization)

3.5 Quality of life impact

4. Genetic / molecular information

4.1 Causal genes

4.2 Variant spectrum and functional class

4.3 Modifier genes / epigenetics

5. Environment / lifestyle / infectious factors

6. Mechanism / pathophysiology

6.1 Current mechanistic understanding (integrated model)

6.1.1 Vesicle trafficking and synaptic endocytosis (TBC1D24)

6.1.2 v-ATPase / lysosomal acidification axis (ATP6V1B2 and TBC1D24)

6.1.3 2024 mechanistic development: mitochondria and ER–mitochondria contact sites

6.2 Cell types and tissues implicated (with ontology suggestions)

Cochlea (2024 localization study)

Central nervous system

6.3 Causal chain (gene → cell biology → phenotype)

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

9.1 Epidemiology

9.2 Mendelian inheritance details

10. Diagnostics

10.1 Clinical recognition and workup

10.2 Genetic testing approach

10.3 Differential diagnosis (examples supported by evidence)

11. Outcome / prognosis

12. Treatment

12.1 Current management (real-world implementation)

12.2 Experimental treatments / clinical trials

12.3 Suggested MAXO terms (examples)