THUMPD1-Related Neurodevelopmental Disorder with Speech Delay and Variable Ocular Anomalies

Mendelian MONDO:0859272 Pathograph 13 Show in embeddings browser Neurodevelopmental Disorder Intellectual Disability

THUMPD1-related neurodevelopmental disorder with speech delay and variable ocular anomalies is an autosomal recessive syndromic intellectual disability disorder caused by biallelic THUMPD1 loss of function. THUMPD1 regulates tRNA N4-acetylcytidine (ac4C) modification; loss of function reduces tRNA acetylation in patient-associated variants and knockout systems. The curated pathograph links the primary THUMPD1 defect to reduced tRNA ac4C acetylation, ribosome-mediated translational stress, and downstream neurodevelopmental phenotypes including global developmental delay, speech delay, intellectual disability, behavioral abnormalities, facial dysmorphism, ocular anomalies, and hearing impairment.

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1
Inheritance
4
Pathophys.
7
Phenotypes
13
Pathograph
1
Genes
🏷

Classifications

👪

Inheritance

1
Autosomal recessive HP:0000007
Affected individuals have biallelic THUMPD1 variants, consistent with autosomal recessive inheritance.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:35196516 SUPPORT Human Clinical
"One such gene, THUMPD1, is involved in regulating tRNA N4-acetylcytidine modification (ac4C), and recently was proposed as a candidate gene for autosomal-recessive intellectual disability."
The THUMPD1 disease paper explicitly frames the candidate disease as autosomal recessive intellectual disability.
PMID:35196516 SUPPORT Human Clinical
"Here, we present 13 individuals from 8 families who harbor rare loss-of-function variants in THUMPD1."
The human cohort consists of individuals with rare THUMPD1 loss-of-function variants across multiple families.
⚙

Pathophysiology

4
THUMPD1 Loss of Function
Biallelic THUMPD1 variants reduce or abolish THUMPD1 function, removing an adaptor needed for normal tRNA N4-acetylcytidine modification.
THUMPD1 hgnc:23807
tRNA N4-acetylcytidine modification GO:0006400 ↓ DECREASED
Downstream
Reduced tRNA ac4C Acetylation
Show evidence (1 reference)
PMID:35196516 SUPPORT Human Clinical
"Here, we present 13 individuals from 8 families who harbor rare loss-of-function variants in THUMPD1."
Human genetic evidence establishes rare THUMPD1 loss-of-function variants in affected individuals.
Reduced tRNA ac4C Acetylation
THUMPD1 loss reduces N4-acetylcytidine modification on cytosolic tRNAs, including tRNA-Ser-CGA in the human disease study and tRNALeu/tRNASer in model systems. This is the disease-specific biochemical pathway disruption.
THUMPD1 hgnc:23807
tRNA N4-acetylcytidine modification GO:0006400 ↓ DECREASED
Downstream
Ribosome-Mediated Translational Stress
Show evidence (2 references)
PMID:35196516 SUPPORT In Vitro
"We further corroborate this effect by showing a loss of tRNA acetylation in two CRISPR-Cas9-generated THUMPD1 KO cell lines."
Human cell-line knockout evidence corroborates THUMPD1-dependent tRNA acetylation loss.
PMID:39091849 SUPPORT Model Organism
"Thumpd1 knockout mice, which lack tRNA acetylation"
Thumpd1 knockout mice independently support the causal effect of THUMPD1/Thumpd1 loss on tRNA acetylation.
Ribosome-Mediated Translational Stress
Reduced tRNA acetylation decreases levels or function of affected tRNAs, increasing ribosome stalling/collisions and activating eIF2-alpha stress signaling. This node connects the tRNA modification defect to impaired cellular protein synthesis and neurodevelopmental vulnerability.
translation GO:0006412 ↓ DECREASED integrated stress response signaling GO:0140467 ↑ INCREASED
Downstream
Neurodevelopmental Dysfunction
Show evidence (2 references)
PMID:39091849 SUPPORT In Vitro
"associated with reduced levels of tRNALeu, ribosome stalling, and ribosome collisions."
Human THUMPD1 knockout cell-line data support ribosome pausing/collisions after tRNA acetylation loss.
PMID:39091849 SUPPORT In Vitro
"stimulates phosphorylation of the translation factor eIF2 a, causing a general defect in"
The cellular model connects ribosome stress to eIF2-alpha phosphorylation and reduced protein synthesis.
Neurodevelopmental Dysfunction
The tissue-level disease expression is a syndromic neurodevelopmental phenotype with intellectual disability, speech delay, behavioral abnormalities, dysmorphic facial features, variable ocular anomalies, and hearing impairment. The specific neuronal populations and developmental windows linking translational stress to these features remain incompletely resolved.
neuron CL:0000540
nervous system development GO:0007399 ⚠ ABNORMAL
Downstream
Global Developmental Delay
Speech Delay
Intellectual Disability
Behavioral Abnormalities
Facial Dysmorphism
Ocular Anomalies
Hearing Impairment
Show evidence (1 reference)
PMID:35196516 SUPPORT Human Clinical
"Common phenotypic findings included global developmental delay, speech delay, moderate to severe intellectual deficiency, behavioral abnormalities such as angry outbursts, facial dysmorphism, and ophthalmological abnormalities."
The human THUMPD1 cohort defines the syndromic neurodevelopmental phenotype.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for THUMPD1-Related Neurodevelopmental Disorder with Speech Delay and Variable Ocular Anomalies Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

7
Ear 1
Hearing Impairment Hearing impairment HP:0000365
Show evidence (1 reference)
PMID:35196516 SUPPORT Human Clinical
"syndromic form of intellectual disability associated with developmental delay, behavioral abnormalities, hearing loss, and facial dysmorphism."
The paper's conclusion lists hearing loss among associated THUMPD1 syndrome features.
Head and Neck 1
Facial Dysmorphism Abnormal facial shape HP:0001999
Show evidence (1 reference)
PMID:35196516 SUPPORT Human Clinical
"facial dysmorphism, and ophthalmological abnormalities."
The human cohort lists facial dysmorphism as a common phenotype.
Nervous System 4
Global Developmental Delay Global developmental delay HP:0001263
Show evidence (1 reference)
PMID:35196516 SUPPORT Human Clinical
"Common phenotypic findings included global developmental delay, speech delay, moderate to severe intellectual deficiency, behavioral abnormalities such as angry outbursts, facial dysmorphism, and ophthalmological abnormalities."
The THUMPD1 cohort lists global developmental delay among common findings.
Speech Delay Delayed speech and language development HP:0000750
Show evidence (1 reference)
PMID:35196516 SUPPORT Human Clinical
"Common phenotypic findings included global developmental delay, speech delay, moderate to severe intellectual deficiency, behavioral abnormalities such as angry outbursts, facial dysmorphism, and ophthalmological abnormalities."
The THUMPD1 cohort lists speech delay among common findings.
Intellectual Disability Intellectual disability HP:0001249
Show evidence (1 reference)
PMID:35196516 SUPPORT Human Clinical
"Common phenotypic findings included global developmental delay, speech delay, moderate to severe intellectual deficiency, behavioral abnormalities such as angry outbursts, facial dysmorphism, and ophthalmological abnormalities."
The THUMPD1 cohort describes moderate to severe intellectual deficiency.
Behavioral Abnormalities Atypical behavior HP:0000708
Show evidence (1 reference)
PMID:35196516 SUPPORT Human Clinical
"behavioral abnormalities such as angry outbursts"
The human cohort specifically describes behavioral abnormalities.
Other 1
Ocular Anomalies Abnormality of the eye HP:0000478
Show evidence (1 reference)
PMID:35196516 SUPPORT Human Clinical
"facial dysmorphism, and ophthalmological abnormalities."
The human cohort lists ophthalmological abnormalities as common findings.
🧬

Genetic Associations

1
THUMPD1 biallelic loss-of-function variants (Causative)
Gene: THUMPD1 hgnc:23807 relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (1 reference)
PMID:35196516 SUPPORT Human Clinical
"Here, we present 13 individuals from 8 families who harbor rare loss-of-function variants in THUMPD1."
The disease paper establishes THUMPD1 loss-of-function variation in affected individuals.
🔬

Biochemical Markers

1
tRNA ac4C acetylation (DECREASED)
Context: Reduced tRNA N4-acetylcytidine/ac4C modification is the biochemical readout of THUMPD1 loss of function.
Pathograph Readouts
Readout Of Reduced tRNA ac4C Acetylation Negative Diagnostic
Lower ac4C modification reports the THUMPD1-dependent tRNA acetylation defect.
Show evidence (1 reference)
PMID:35196516 SUPPORT In Vitro
"We demonstrate that the bi-allelic variants identified cause loss of function of THUMPD1 and that this defect results in a loss of ac4C modification in small RNAs, and of individually purified tRNA-Ser-CGA."
The human disease study directly measures loss of ac4C modification after THUMPD1 loss of function.
{ }

Source YAML

click to show 
name: THUMPD1-Related Neurodevelopmental Disorder with Speech Delay and Variable Ocular Anomalies
creation_date: '2026-07-06T03:59:09Z'
category: Mendelian
synonyms:
- THUMPD1-related disorder
- THUMPD1-related neurodevelopmental disorder
- Neurodevelopmental disorder with speech delay and variable ocular anomalies
- NEDSOA
description: >-
  THUMPD1-related neurodevelopmental disorder with speech delay and variable
  ocular anomalies is an autosomal recessive syndromic intellectual disability
  disorder caused by biallelic THUMPD1 loss of function. THUMPD1 regulates
  tRNA N4-acetylcytidine (ac4C) modification; loss of function reduces tRNA
  acetylation in patient-associated variants and knockout systems. The curated
  pathograph links the primary THUMPD1 defect to reduced tRNA ac4C acetylation,
  ribosome-mediated translational stress, and downstream neurodevelopmental
  phenotypes including global developmental delay, speech delay, intellectual
  disability, behavioral abnormalities, facial dysmorphism, ocular anomalies,
  and hearing impairment.
classifications:
  icimd_category:
  - classification_value: non_mitochondrial_trna_metabolism
    notes: >-
      WP-047 code 16.4.47.01. THUMPD1 is curated under non-mitochondrial tRNA
      metabolism because the disease mechanism is reduced cytosolic tRNA
      acetylation.
disease_term:
  preferred_term: neurodevelopmental disorder with speech delay and variable ocular anomalies
  term:
    id: MONDO:0859272
    label: neurodevelopmental disorder with speech delay and variable ocular anomalies
parents:
- Neurodevelopmental Disorder
- Intellectual Disability
notes: >-
  MONDO:0859272 cross-references OMIM:619989 and has a causal-gene
  relationship to THUMPD1. The WP-047 seed OMIM:616662 is the THUMPD1 gene
  record.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Affected individuals have biallelic THUMPD1 variants, consistent with
    autosomal recessive inheritance.
  evidence:
  - reference: PMID:35196516
    reference_title: THUMPD1 bi-allelic variants cause loss of tRNA acetylation and a syndromic neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One such gene, THUMPD1, is involved in regulating tRNA N4-acetylcytidine modification (ac4C), and recently was proposed as a candidate gene for autosomal-recessive intellectual disability."
    explanation: The THUMPD1 disease paper explicitly frames the candidate disease as autosomal recessive intellectual disability.
  - reference: PMID:35196516
    reference_title: THUMPD1 bi-allelic variants cause loss of tRNA acetylation and a syndromic neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we present 13 individuals from 8 families who harbor rare loss-of-function variants in THUMPD1."
    explanation: The human cohort consists of individuals with rare THUMPD1 loss-of-function variants across multiple families.
pathophysiology:
- name: THUMPD1 Loss of Function
  description: >-
    Biallelic THUMPD1 variants reduce or abolish THUMPD1 function, removing an
    adaptor needed for normal tRNA N4-acetylcytidine modification.
  genes:
  - preferred_term: THUMPD1
    term:
      id: hgnc:23807
      label: THUMPD1
  biological_processes:
  - preferred_term: tRNA N4-acetylcytidine modification
    term:
      id: GO:0006400
      label: tRNA modification
    modifier: DECREASED
  evidence:
  - reference: PMID:35196516
    reference_title: THUMPD1 bi-allelic variants cause loss of tRNA acetylation and a syndromic neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we present 13 individuals from 8 families who harbor rare loss-of-function variants in THUMPD1."
    explanation: Human genetic evidence establishes rare THUMPD1 loss-of-function variants in affected individuals.
  downstream:
  - target: Reduced tRNA ac4C Acetylation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35196516
      reference_title: THUMPD1 bi-allelic variants cause loss of tRNA acetylation and a syndromic neurodevelopmental disorder.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We demonstrate that the bi-allelic variants identified cause loss of
        function of THUMPD1 and that this defect results in a loss of ac4C
        modification in small RNAs, and of individually purified tRNA-Ser-CGA.
      explanation: Functional assays link biallelic THUMPD1 variants to loss of ac4C modification.
- name: Reduced tRNA ac4C Acetylation
  description: >-
    THUMPD1 loss reduces N4-acetylcytidine modification on cytosolic tRNAs,
    including tRNA-Ser-CGA in the human disease study and tRNALeu/tRNASer in
    model systems. This is the disease-specific biochemical pathway disruption.
  genes:
  - preferred_term: THUMPD1
    term:
      id: hgnc:23807
      label: THUMPD1
  biological_processes:
  - preferred_term: tRNA N4-acetylcytidine modification
    term:
      id: GO:0006400
      label: tRNA modification
    modifier: DECREASED
  evidence:
  - reference: PMID:35196516
    reference_title: THUMPD1 bi-allelic variants cause loss of tRNA acetylation and a syndromic neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We further corroborate this effect by showing a loss of tRNA acetylation in two CRISPR-Cas9-generated THUMPD1 KO cell lines."
    explanation: Human cell-line knockout evidence corroborates THUMPD1-dependent tRNA acetylation loss.
  - reference: PMID:39091849
    reference_title: Transfer RNA acetylation regulates in vivo mammalian stress signaling.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Thumpd1 knockout mice, which  lack tRNA acetylation"
    explanation: Thumpd1 knockout mice independently support the causal effect of THUMPD1/Thumpd1 loss on tRNA acetylation.
  downstream:
  - target: Ribosome-Mediated Translational Stress
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - reduced type II cytosolic tRNA levels
    - ribosome stalling and collisions
    - GCN2/eIF2-alpha stress signaling
    evidence:
    - reference: PMID:39091849
      reference_title: Transfer RNA acetylation regulates in vivo mammalian stress signaling.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "loss of Thumpd1-dependent tRNA acetylation leads to reduced levels of tRNALeu"
      explanation: The mouse-model paper links Thumpd1-dependent tRNA acetylation loss to reduced tRNALeu.
    - reference: PMID:39091849
      reference_title: Transfer RNA acetylation regulates in vivo mammalian stress signaling.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "ribosome stalling, and activation of eIF2α phosphorylation"
      explanation: The same model-system evidence links reduced tRNA acetylation to ribosome stalling and eIF2-alpha activation.
- name: Ribosome-Mediated Translational Stress
  description: >-
    Reduced tRNA acetylation decreases levels or function of affected tRNAs,
    increasing ribosome stalling/collisions and activating eIF2-alpha stress
    signaling. This node connects the tRNA modification defect to impaired
    cellular protein synthesis and neurodevelopmental vulnerability.
  biological_processes:
  - preferred_term: translation
    term:
      id: GO:0006412
      label: translation
    modifier: DECREASED
  - preferred_term: integrated stress response signaling
    term:
      id: GO:0140467
      label: integrated stress response signaling
    modifier: INCREASED
  evidence:
  - reference: PMID:39091849
    reference_title: Transfer RNA acetylation regulates in vivo mammalian stress signaling.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "associated with reduced levels of tRNALeu, ribosome stalling, and ribosome collisions."
    explanation: Human THUMPD1 knockout cell-line data support ribosome pausing/collisions after tRNA acetylation loss.
  - reference: PMID:39091849
    reference_title: Transfer RNA acetylation regulates in vivo mammalian stress signaling.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "stimulates phosphorylation of  the translation factor eIF2 a, causing a general defect in"
    explanation: The cellular model connects ribosome stress to eIF2-alpha phosphorylation and reduced protein synthesis.
  downstream:
  - target: Neurodevelopmental Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Neurodevelopmental Dysfunction
  description: >-
    The tissue-level disease expression is a syndromic neurodevelopmental
    phenotype with intellectual disability, speech delay, behavioral
    abnormalities, dysmorphic facial features, variable ocular anomalies, and
    hearing impairment. The specific neuronal populations and developmental
    windows linking translational stress to these features remain incompletely
    resolved.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: nervous system development
    term:
      id: GO:0007399
      label: nervous system development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:35196516
    reference_title: THUMPD1 bi-allelic variants cause loss of tRNA acetylation and a syndromic neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common phenotypic findings included global developmental delay, speech delay, moderate to severe intellectual deficiency, behavioral abnormalities such as angry outbursts, facial dysmorphism, and ophthalmological abnormalities."
    explanation: The human THUMPD1 cohort defines the syndromic neurodevelopmental phenotype.
  downstream:
  - target: Global Developmental Delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Speech Delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Intellectual Disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Behavioral Abnormalities
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Facial Dysmorphism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Ocular Anomalies
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hearing Impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
biochemical:
- name: tRNA ac4C acetylation
  presence: DECREASED
  context: >-
    Reduced tRNA N4-acetylcytidine/ac4C modification is the biochemical readout
    of THUMPD1 loss of function.
  readouts:
  - target: Reduced tRNA ac4C Acetylation
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Lower ac4C modification reports the THUMPD1-dependent tRNA acetylation defect.
  evidence:
  - reference: PMID:35196516
    reference_title: THUMPD1 bi-allelic variants cause loss of tRNA acetylation and a syndromic neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We demonstrate that the bi-allelic variants identified cause loss of
      function of THUMPD1 and that this defect results in a loss of ac4C
      modification in small RNAs, and of individually purified tRNA-Ser-CGA.
    explanation: The human disease study directly measures loss of ac4C modification after THUMPD1 loss of function.
phenotypes:
- category: Clinical
  name: Global Developmental Delay
  description: Global developmental delay is a common presenting neurodevelopmental phenotype.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:35196516
    reference_title: THUMPD1 bi-allelic variants cause loss of tRNA acetylation and a syndromic neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common phenotypic findings included global developmental delay, speech delay, moderate to severe intellectual deficiency, behavioral abnormalities such as angry outbursts, facial dysmorphism, and ophthalmological abnormalities."
    explanation: The THUMPD1 cohort lists global developmental delay among common findings.
- category: Clinical
  name: Speech Delay
  description: Speech delay is part of the named MONDO/OMIM phenotype.
  phenotype_term:
    preferred_term: Speech delay
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:35196516
    reference_title: THUMPD1 bi-allelic variants cause loss of tRNA acetylation and a syndromic neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common phenotypic findings included global developmental delay, speech delay, moderate to severe intellectual deficiency, behavioral abnormalities such as angry outbursts, facial dysmorphism, and ophthalmological abnormalities."
    explanation: The THUMPD1 cohort lists speech delay among common findings.
- category: Clinical
  name: Intellectual Disability
  description: Moderate to severe intellectual disability is a core feature.
  phenotype_term:
    preferred_term: Moderate to severe intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:35196516
    reference_title: THUMPD1 bi-allelic variants cause loss of tRNA acetylation and a syndromic neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common phenotypic findings included global developmental delay, speech delay, moderate to severe intellectual deficiency, behavioral abnormalities such as angry outbursts, facial dysmorphism, and ophthalmological abnormalities."
    explanation: The THUMPD1 cohort describes moderate to severe intellectual deficiency.
- category: Clinical
  name: Behavioral Abnormalities
  description: Behavioral abnormalities, including angry outbursts, are common in the reported cohort.
  phenotype_term:
    preferred_term: Behavioral abnormalities
    term:
      id: HP:0000708
      label: Atypical behavior
  evidence:
  - reference: PMID:35196516
    reference_title: THUMPD1 bi-allelic variants cause loss of tRNA acetylation and a syndromic neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "behavioral abnormalities such as angry outbursts"
    explanation: The human cohort specifically describes behavioral abnormalities.
- category: Clinical
  name: Facial Dysmorphism
  description: Dysmorphic facial features are part of the THUMPD1 syndrome.
  phenotype_term:
    preferred_term: Facial dysmorphism
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:35196516
    reference_title: THUMPD1 bi-allelic variants cause loss of tRNA acetylation and a syndromic neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "facial dysmorphism, and ophthalmological abnormalities."
    explanation: The human cohort lists facial dysmorphism as a common phenotype.
- category: Clinical
  name: Ocular Anomalies
  description: Variable ophthalmological abnormalities are part of the named disorder.
  phenotype_term:
    preferred_term: Ophthalmological abnormalities
    term:
      id: HP:0000478
      label: Abnormality of the eye
  evidence:
  - reference: PMID:35196516
    reference_title: THUMPD1 bi-allelic variants cause loss of tRNA acetylation and a syndromic neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "facial dysmorphism, and ophthalmological abnormalities."
    explanation: The human cohort lists ophthalmological abnormalities as common findings.
- category: Clinical
  name: Hearing Impairment
  description: Hearing impairment is reported as part of the broader THUMPD1 syndrome.
  phenotype_term:
    preferred_term: Hearing loss
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:35196516
    reference_title: THUMPD1 bi-allelic variants cause loss of tRNA acetylation and a syndromic neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "syndromic form of intellectual disability associated with developmental delay, behavioral abnormalities, hearing loss, and facial dysmorphism."
    explanation: The paper's conclusion lists hearing loss among associated THUMPD1 syndrome features.
genetic:
- name: THUMPD1 biallelic loss-of-function variants
  association: Causative
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: THUMPD1
    term:
      id: hgnc:23807
      label: THUMPD1
  variant_origin: GERMLINE
  notes: >-
    The reported cohort includes affected individuals from eight families with
    rare biallelic THUMPD1 loss-of-function variants.
  evidence:
  - reference: PMID:35196516
    reference_title: THUMPD1 bi-allelic variants cause loss of tRNA acetylation and a syndromic neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we present 13 individuals from 8 families who harbor rare loss-of-function variants in THUMPD1."
    explanation: The disease paper establishes THUMPD1 loss-of-function variation in affected individuals.