You-Hoover-Fong syndrome (YHFS) is a rare autosomal recessive neurodevelopmental disorder caused by biallelic pathogenic variants in TELO2. Global developmental delay, intellectual disability, and microcephaly are the recurrent core features. Dysmorphic facial features, ocular abnormalities, movement and tone abnormalities, impaired balance or ataxia, sleep disturbance, poor growth, hearing impairment, and congenital anomalies are variably present. TELO2 is a component of the TELO2-TTI1-TTI2 (TTT) co-chaperone complex, but the cellular steps connecting destabilization of this complex to the human neurodevelopmental phenotype remain unresolved.
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Conditions with similar clinical presentations that must be differentiated from You-Hoover-Fong Syndrome:
name: You-Hoover-Fong Syndrome
creation_date: '2025-12-19T01:18:09Z'
description: >-
You-Hoover-Fong syndrome (YHFS) is a rare autosomal recessive
neurodevelopmental disorder caused by biallelic pathogenic variants in TELO2.
Global developmental delay, intellectual disability, and microcephaly are the
recurrent core features. Dysmorphic facial features, ocular abnormalities,
movement and tone abnormalities, impaired balance or ataxia, sleep disturbance,
poor growth, hearing impairment, and congenital anomalies are variably present.
TELO2 is a component of the TELO2-TTI1-TTI2 (TTT) co-chaperone complex, but the
cellular steps connecting destabilization of this complex to the human
neurodevelopmental phenotype remain unresolved.
category: Mendelian
synonyms:
- YHFS
- TELO2-related syndrome
- TELO2-related intellectual disability-neurodevelopmental disorder
disease_term:
preferred_term: TELO2-related intellectual disability-neurodevelopmental disorder
term:
id: MONDO:0014848
label: TELO2-related intellectual disability-neurodevelopmental disorder
parents:
- Neurodevelopmental disorders
- TTT complex disorders
mappings:
mondo_mappings:
- term:
id: MONDO:0014848
label: TELO2-related intellectual disability-neurodevelopmental disorder
mapping_predicate: skos:exactMatch
mapping_source: MONDO
mapping_justification: >-
MONDO:0014848 carries the You-Hoover-Fong syndrome synonym, OMIM:616954
cross-reference, and TELO2 causal-gene relationship that define this entry.
inheritance:
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
Affected individuals have biallelic TELO2 variants, including homozygous and
compound-heterozygous genotypes; parental testing can establish phase and
carrier status.
evidence:
- reference: PMID:27132593
reference_title: A Syndromic Intellectual Disability Disorder Caused by Variants in TELO2, a Gene Encoding a Component of the TTT Complex.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Here we report six affected individuals from four families with
intellectual disability (ID) and neurological and other congenital
abnormalities associated with compound heterozygous variants in TELO2.
explanation: >-
The discovery cohort establishes recessive disease associated with two
TELO2 variants in affected individuals from multiple families.
- reference: PMID:38421525
reference_title: "The first Iranian patient with You-Hoover-Fong syndrome and a review of the literature on 27 cases: expanding the genotypic and phenotypic spectrum."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Using WES, a novel homozygous missense variant, c.1799A > G (p.
Tyr600Cys), was identified in the TELO2 gene in a 4-year-old Iranian male
patient.
explanation: >-
A homozygous affected genotype complements the compound-heterozygous
families in the discovery cohort.
prevalence:
- population: Published literature worldwide
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
No population-based estimate is available in the reviewed literature. A
2025 review identified 31 previously reported cases across nine articles and
described one additional child; this is a literature head-count, not a
population prevalence estimate.
evidence:
- reference: PMID:38421525
reference_title: "The first Iranian patient with You-Hoover-Fong syndrome and a review of the literature on 27 cases: expanding the genotypic and phenotypic spectrum."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The ultra-rare autosomal recessive genetic disorder, You-Hoover-Fong
Syndrome (YHFS), is caused by defects in the TELO2 gene
explanation: >-
The review explicitly characterizes YHFS as ultra-rare.
- reference: PMID:41645377
reference_title: "[Analysis of a child with You-Hoover-Fong syndrome due to compound heterozygous variants of the TELO2 gene and a literature review]."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Literature review has identified 9 articles reporting 31 cases of YHFS
due to TELO2 gene variants
explanation: >-
This is the latest retrieved explicit count of previously published cases;
the same report separately describes a newly ascertained child.
pathophysiology:
- name: TELO2/TTT complex destabilization
biological_scale: MOLECULAR
description: >-
TELO2, TTI1, and TTI2 form the TTT co-chaperone complex involved in PIKK
maturation. In the discovery cohort, patient fibroblasts had reduced
steady-state TELO2, TTI1, and TTI2, supporting destabilization of the
complex. The tested PIKK functions were normal, so this entry does not infer
generalized ATM, ATR, DNA-PKcs, mTOR, SMG1, or TRRAP deficiency from the
variants.
genes:
- preferred_term: TELO2
term:
id: hgnc:29099
label: TELO2
biological_processes:
- preferred_term: protein stabilization
term:
id: GO:0050821
label: protein stabilization
modifier: DECREASED
evidence:
- reference: PMID:27132593
reference_title: A Syndromic Intellectual Disability Disorder Caused by Variants in TELO2, a Gene Encoding a Component of the TTT Complex.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Although their fibroblasts showed reduced steady-state levels of TELO2 and
the other components of the TTT complex, PIKK functions were normal in
cellular assays.
explanation: >-
Patient-fibroblast experiments directly support TTT-complex destabilization
while also setting the boundary against claiming demonstrable PIKK
dysfunction in those assays.
downstream:
- target: Intellectual disability
description: >-
TELO2/TTT-complex destabilization is associated with intellectual
disability through unresolved intermediates.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:27132593
reference_title: A Syndromic Intellectual Disability Disorder Caused by Variants in TELO2, a Gene Encoding a Component of the TTT Complex.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Our results suggest that these TELO2 missense variants result in loss of
function, perturb TTT complex stability, and cause an autosomal-recessive
syndromic form of ID.
explanation: >-
The study links TTT-complex destabilization to syndromic intellectual
disability without establishing a complete molecular chain.
- target: Microcephaly
description: >-
Microcephaly is a recurrent component of the TELO2-related syndrome, but
the path from TTT-complex destabilization to impaired brain growth is not
established.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:38421525
reference_title: "The first Iranian patient with You-Hoover-Fong syndrome and a review of the literature on 27 cases: expanding the genotypic and phenotypic spectrum."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
the most common features were microcephaly and intellectual impairment.
explanation: >-
The case review supports the recurring phenotype but does not establish
the intervening mechanism.
phenotypes:
- name: Global developmental delay
description: Global developmental delay is a reported feature of YHFS.
phenotype_term:
preferred_term: Global developmental delay
term:
id: HP:0001263
label: Global developmental delay
evidence:
- reference: PMID:36797513
reference_title: "TELO2-related syndrome (You-Hoover-Fong syndrome): Description of 14 new affected individuals and review of the literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Affected individuals were reported to have global developmental delay,
intellectual disability, microcephaly
explanation: >-
The 2023 cohort abstract explicitly includes global developmental delay;
no frequency is derived without cache-verifiable full-text counts.
- name: Intellectual disability
description: Intellectual disability is a reported feature of YHFS.
phenotype_term:
preferred_term: Intellectual disability
term:
id: HP:0001249
label: Intellectual disability
evidence:
- reference: PMID:36797513
reference_title: "TELO2-related syndrome (You-Hoover-Fong syndrome): Description of 14 new affected individuals and review of the literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Affected individuals were reported to have global developmental delay,
intellectual disability, microcephaly
explanation: >-
The 2023 cohort abstract explicitly includes intellectual disability; no
frequency is derived without cache-verifiable full-text counts.
- name: Microcephaly
description: Microcephaly is a reported feature of YHFS.
phenotype_term:
preferred_term: Microcephaly
term:
id: HP:0000252
label: Microcephaly
evidence:
- reference: PMID:36797513
reference_title: "TELO2-related syndrome (You-Hoover-Fong syndrome): Description of 14 new affected individuals and review of the literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Affected individuals were reported to have global developmental delay,
intellectual disability, microcephaly
explanation: >-
The 2023 cohort abstract explicitly includes microcephaly. No frequency
band is derived from the internally inconsistent published table totals.
- name: Abnormal facial shape
description: Dysmorphic facial features recur, without a single pathognomonic pattern.
phenotype_term:
preferred_term: Abnormal facial shape
term:
id: HP:0001999
label: Abnormal facial shape
evidence:
- reference: PMID:36797513
reference_title: "TELO2-related syndrome (You-Hoover-Fong syndrome): Description of 14 new affected individuals and review of the literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Affected individuals were reported to have global developmental delay,
intellectual disability, microcephaly, dysmorphic facial features
explanation: >-
The phenotype-expansion cohort identifies dysmorphic facial features as a
recurring part of the syndrome.
- name: Cataract
description: Congenital or early progressive bilateral cataracts occur in a subset of individuals.
phenotype_term:
preferred_term: Congenital or early progressive cataract
term:
id: HP:0000518
label: Cataract
evidence:
- reference: PMID:32940098
reference_title: "Cataract in You-Hoover-Fong syndrome: TELO2 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Ophthalmologically, both siblings were diagnosed with progressive
congenital bilateral nuclear-lamellar cataracts.
explanation: >-
The ophthalmic case series documents the timing, bilaterality, and
nuclear-lamellar morphology in two affected siblings.
- name: Cerebral visual impairment
description: Cortical or cerebral visual impairment has been reported in YHFS.
phenotype_term:
preferred_term: Cerebral visual impairment
term:
id: HP:0100704
label: Cerebral visual impairment
evidence:
- reference: PMID:36797513
reference_title: "TELO2-related syndrome (You-Hoover-Fong syndrome): Description of 14 new affected individuals and review of the literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
ocular involvement including cortical visual impairment, strabismus,
cataract and rotatory nystagmus
explanation: The 2023 cohort abstract explicitly reports cortical visual impairment.
- name: Rotatory nystagmus
description: Rotatory nystagmus has been reported in YHFS.
phenotype_term:
preferred_term: Rotatory nystagmus
term:
id: HP:0000639
label: Nystagmus
evidence:
- reference: PMID:36797513
reference_title: "TELO2-related syndrome (You-Hoover-Fong syndrome): Description of 14 new affected individuals and review of the literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
ocular involvement including cortical visual impairment, strabismus,
cataract and rotatory nystagmus
explanation: The 2023 cohort abstract explicitly reports rotatory nystagmus.
- name: Abnormality of movement
description: Abnormal movements were reported in affected individuals; the source does not establish an episodic course.
phenotype_term:
preferred_term: Abnormality of movement
term:
id: HP:0100022
label: Abnormality of movement
evidence:
- reference: PMID:36797513
reference_title: "TELO2-related syndrome (You-Hoover-Fong syndrome): Description of 14 new affected individuals and review of the literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
movement disorder, hypertonia and spasticity, balance disturbance and
ataxia, and abnormal sleep pattern.
explanation: >-
The expanded cohort explicitly includes movement and tone abnormalities.
- name: Abnormal muscle tone
description: Hypertonia, spasticity, and other tone abnormalities have been reported in YHFS.
phenotype_term:
preferred_term: Abnormal muscle tone
term:
id: HP:0003808
label: Abnormal muscle tone
evidence:
- reference: PMID:36797513
reference_title: "TELO2-related syndrome (You-Hoover-Fong syndrome): Description of 14 new affected individuals and review of the literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
movement disorder, hypertonia and spasticity, balance disturbance and
ataxia, and abnormal sleep pattern.
explanation: >-
The 2023 cohort abstract explicitly includes hypertonia and spasticity; no
frequency is derived without cache-verifiable full-text counts.
- name: Ataxia
description: Impaired balance and ataxia occur variably.
phenotype_term:
preferred_term: Ataxia
term:
id: HP:0001251
label: Ataxia
evidence:
- reference: PMID:36797513
reference_title: "TELO2-related syndrome (You-Hoover-Fong syndrome): Description of 14 new affected individuals and review of the literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
movement disorder, hypertonia and spasticity, balance disturbance and
ataxia, and abnormal sleep pattern.
explanation: The expanded cohort explicitly includes balance disturbance and ataxia.
- name: Sleep disturbance
description: Abnormal sleep patterns and behavioral sleep problems are variably reported.
phenotype_term:
preferred_term: Sleep disturbance
term:
id: HP:0002360
label: Sleep disturbance
evidence:
- reference: PMID:36797513
reference_title: "TELO2-related syndrome (You-Hoover-Fong syndrome): Description of 14 new affected individuals and review of the literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
movement disorder, hypertonia and spasticity, balance disturbance and
ataxia, and abnormal sleep pattern.
explanation: The expanded cohort explicitly includes abnormal sleep pattern.
- name: Postnatal growth retardation
description: Poor postnatal growth has been reported in affected children.
phenotype_term:
preferred_term: Postnatal growth retardation
term:
id: HP:0008897
label: Postnatal growth retardation
evidence:
- reference: PMID:37215500
reference_title: "Novel compound heterozygous mutations in TELO2 in an infant with You-Hoover-Fong syndrome: A case report and literature review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
global development delay complicated with postnatal growth retardation
for more than 1 year
explanation: >-
This infant report directly documents postnatal growth retardation.
- name: Strabismus
description: Strabismus has been reported in YHFS.
phenotype_term:
preferred_term: Strabismus
term:
id: HP:0000486
label: Strabismus
evidence:
- reference: PMID:36797513
reference_title: "TELO2-related syndrome (You-Hoover-Fong syndrome): Description of 14 new affected individuals and review of the literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
ocular involvement including cortical visual impairment, strabismus,
cataract and rotatory nystagmus
explanation: >-
The 2023 cohort abstract explicitly includes strabismus; no frequency is
derived without cache-verifiable full-text counts.
- name: Hearing impairment
description: Bilateral conductive hearing loss has been reported.
phenotype_term:
preferred_term: Hearing impairment
term:
id: HP:0000365
label: Hearing impairment
evidence:
- reference: PMID:28944240
reference_title: Novel compound heterozygous mutations in TELO2 in a patient with severe expression of You-Hoover-Fong syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Additional clinical findings include eye anomalies (bilateral congenital
cataracts, retinitis pigmentosa, convergent squint), bilateral conductive
hearing loss, an abnormal kidney and seizures.
explanation: The severe sibling report documents bilateral conductive hearing loss.
- name: Seizure
description: >-
Seizures have been reported in affected individuals. A 2026 report describes
one patient with developmental and epileptic encephalopathy consistent with
Lennox-Gastaut syndrome and regression at seizure onset; this single case is
not generalized to the syndrome as a whole.
phenotype_term:
preferred_term: Seizure
term:
id: HP:0001250
label: Seizure
evidence:
- reference: PMID:28944240
reference_title: Novel compound heterozygous mutations in TELO2 in a patient with severe expression of You-Hoover-Fong syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Additional clinical findings include eye anomalies (bilateral congenital
cataracts, retinitis pigmentosa, convergent squint), bilateral conductive
hearing loss, an abnormal kidney and seizures.
explanation: The severe sibling report directly documents seizures.
- reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC13276679/fullTextXML
reference_title: "AUTHOR CONTRIBUTIONS"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
From a developmental perspective, she walked before 1.5 years and could
say 2 words before 1.5 years; however, she had global developmental
regression at the time of seizure onset.
explanation: >-
The official full text directly documents regression at seizure onset in
this single patient. It supports that patient's seizure-associated DEE/LGS
presentation only, not a general regressive course in YHFS.
- name: Congenital heart defect
description: An atrial septal defect has been reported in an affected infant.
phenotype_term:
preferred_term: Congenital heart defect
term:
id: HP:0001627
label: Abnormal heart morphology
evidence:
- reference: PMID:37215500
reference_title: "Novel compound heterozygous mutations in TELO2 in an infant with You-Hoover-Fong syndrome: A case report and literature review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
congenital atrial septal defect
explanation: A disease-specific case report documents an atrial septal defect.
genetic:
- name: Biallelic pathogenic TELO2 variants
gene_term:
preferred_term: TELO2
term:
id: hgnc:29099
label: TELO2
relationship_type: CAUSATIVE
notes: >-
Pathogenic genotypes include homozygous and compound-heterozygous alleles.
Missense variants predominate in the published spectrum. Variant
interpretation should incorporate segregation and phenotype. Two sisters
homozygous for p.Arg609His had a milder presentation, but the same allele
had previously occurred in a more severely affected compound heterozygote;
an allele-severity relationship is therefore suggestive, not established.
evidence:
- reference: PMID:27132593
reference_title: A Syndromic Intellectual Disability Disorder Caused by Variants in TELO2, a Gene Encoding a Component of the TTT Complex.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Our results suggest that these TELO2 missense variants result in loss of
function, perturb TTT complex stability, and cause an autosomal-recessive
syndromic form of ID.
explanation: The discovery cohort establishes the causal TELO2 relationship.
- reference: PMID:38421525
reference_title: "The first Iranian patient with You-Hoover-Fong syndrome and a review of the literature on 27 cases: expanding the genotypic and phenotypic spectrum."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Missense pathogenic variants were the most common type of pathogenic variant
explanation: The 27-case review supports the predominance of missense alleles.
- reference: PMID:33307281
reference_title: Milder presentation of TELO2-related syndrome in two sisters homozygous for the p.Arg609His pathogenic variant.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We describe the case of two sisters, carrying the homozygous p. Arg609His
variant of the gene, who present a milder phenotype of TELO2-related
syndrome. Such variant has been reported once in a more severely affected
patient, in compound heterozygous state associated with the p. Pro260Leu
variant, suggesting a possible role of the p. Arg609His variant in
determining milder phenotypes.
explanation: >-
The two sisters support a mild presentation associated with homozygous
p.Arg609His, while the contrasting compound-heterozygous case means the
proposed allele-severity relationship remains suggestive rather than
established.
- reference: CGGV:assertion_6995e858-919b-4a08-be40-54a56371a408-2022-06-01T160000.000Z
reference_title: "TELO2 / TELO2-related intellectual disability-neurodevelopmental disorder (Definitive)"
supports: SUPPORT
evidence_source: OTHER
snippet: "TELO2 | HGNC:29099 | TELO2-related intellectual disability-neurodevelopmental disorder | MONDO:0014848 | AR | Definitive"
explanation: >-
ClinGen classifies the autosomal recessive TELO2 gene-disease relationship
as definitive.
differential_diagnoses:
- name: TTI1-related neurodevelopmental disorder with microcephaly
description: >-
Biallelic TTI1 disease affects another component of the TTT complex and
overlaps with YHFS in intellectual disability, microcephaly, short stature,
and movement disorder.
distinguishing_features:
- Molecular testing identifies biallelic TTI1 variants rather than TELO2 variants.
- Clinical overlap is substantial, so the causal gene is the reliable discriminator.
evidence:
- reference: PMID:36724785
reference_title: Bi-allelic TTI1 variants cause an autosomal-recessive neurodevelopmental disorder with microcephaly.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We present clinical, genomic, and functional data from 11 individuals in 9
unrelated families with bi-allelic variants in TTI1. All present with ID,
and most with microcephaly, short stature, and a movement disorder.
explanation: >-
The TTI1 cohort documents the shared neurodevelopmental and growth phenotype.
- name: TTI2-related autosomal recessive intellectual disability
description: >-
Biallelic TTI2 disease affects the third TTT-complex component and overlaps
with YHFS in severe cognitive impairment, microcephaly, short stature,
skeletal anomalies, and facial dysmorphism.
distinguishing_features:
- Molecular testing identifies biallelic TTI2 variants rather than TELO2 variants.
- TTI2 patient cells may show reduced PIKK levels, a finding not demonstrated in the original TELO2 patient-cell assays.
evidence:
- reference: PMID:23956177
reference_title: Mutation in TTI2 reveals a role for triple T complex in human brain development.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
a missense c.1307T>A/p.I436N mutation in TTI2 causes a human autosomal
recessive condition characterized by severe cognitive impairment,
microcephaly, behavioral troubles, short stature, skeletal anomalies, and
facial dysmorphic features.
explanation: The TTI2 family establishes the overlapping recessive phenotype.
- reference: PMID:23956177
reference_title: Mutation in TTI2 reveals a role for triple T complex in human brain development.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Consistently, a drastically reduced steady-state level of all PIKKs tested
was also observed in the patient cells.
explanation: >-
This patient-cell finding contrasts with normal tested PIKK functions in
the original TELO2 cohort and may help frame mechanistic comparison.
treatments:
- name: Cataract surgery
description: >-
Ophthalmologic assessment should determine whether cataract surgery is
indicated; one reported infant had improved visual responses after bilateral
surgery.
therapeutic_modality: SURGERY
treatment_term:
preferred_term: surgical procedure
term:
id: NCIT:C15329
label: Surgical Procedure
evidence:
- reference: PMID:37215500
reference_title: "Novel compound heterozygous mutations in TELO2 in an infant with You-Hoover-Fong syndrome: A case report and literature review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
After bilateral cataract surgery, the infant obtained better visual acuity
and showed more responses and interactions with her parents.
explanation: >-
A single case supports possible visual benefit but not a generalized
syndrome-specific efficacy claim.
discussions:
- discussion_id: yhfs_downstream_mechanism
prompt: >-
Which TELO2-dependent cellular defects connect TTT-complex destabilization
to impaired human brain growth and neurodevelopment?
kind: KNOWLEDGE_GAP
status: OPEN
attaches_to:
- pathophysiology#TELO2/TTT complex destabilization
rationale: >-
TELO2 is required for TTT-complex stability, but the original patient
fibroblasts retained normal tested PIKK functions. A proximate human
neurodevelopmental mechanism has not been demonstrated.
proposed_experiments:
- experiment_id: exp_yhfs_patient_neural_models
name: Isogenic patient-allele neural-model study
description: >-
Compare representative TELO2 patient alleles with corrected isogenic
controls in human neural progenitors and brain organoids, measuring TTT
stability, individual PIKK abundance and activity, cell-cycle checkpoints,
proliferation, differentiation, and rescue by wild-type TELO2.
evidence:
- reference: PMID:27132593
reference_title: A Syndromic Intellectual Disability Disorder Caused by Variants in TELO2, a Gene Encoding a Component of the TTT Complex.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Although their fibroblasts showed reduced steady-state levels of TELO2 and
the other components of the TTT complex, PIKK functions were normal in
cellular assays.
explanation: >-
This discordance defines the unresolved step between TTT destabilization
and disease.
- reference: PMID:28944240
reference_title: Novel compound heterozygous mutations in TELO2 in a patient with severe expression of You-Hoover-Fong syndrome.
supports: SUPPORT
evidence_source: OTHER
snippet: >-
The underlying molecular pathogenesis of YHFS is still not completely understood.
explanation: The clinical expansion explicitly identifies the mechanism as unresolved.
- discussion_id: yhfs_cancer_susceptibility
prompt: >-
Does YHFS confer increased cancer susceptibility, or was the reported
hepatoblastoma coincidental?
kind: KNOWLEDGE_GAP
status: OPEN
attaches_to:
- pathophysiology#TELO2/TTT complex destabilization
rationale: >-
One child with YHFS developed hepatoblastoma, while prior reported
individuals had no tumors. A single observation cannot establish excess
risk or justify syndrome-specific tumor surveillance.
proposed_experiments:
- experiment_id: exp_yhfs_longitudinal_cancer_registry
name: Longitudinal YHFS cancer registry
description: >-
Follow an international molecularly confirmed cohort with age, genotype,
person-time, tumor diagnoses, and comparison with age-specific population
incidence before defining any surveillance recommendation.
evidence:
- reference: PMID:39704248
reference_title: Expansion of the Phenotype of You-Hoover-Fong Syndrome and Possible Increased Risk of Cancer.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Although the development of hepatoblastoma might be coincidental, given
the role of TELO2 in cell cycle, we suspect YHFS might be associated with
an increased cancer susceptibility. Further cases are needed to confirm
whether YHFS is associated with an increased risk of cancer.
explanation: >-
The authors explicitly frame the association as a hypothesis requiring
additional cases, not an established syndrome feature.
notes: >-
The original cellular study supports destabilization of TELO2 and the other
TTT-complex components but found normal PIKK functions in the assays performed.
Cancer susceptibility remains a hypothesis rather than an established
clinical feature. No GeneReviews chapter or population-based prevalence study
was identified during this review.
datasets: []
clinical_trials: []
references:
- reference: PMID:27132593
title: A Syndromic Intellectual Disability Disorder Caused by Variants in TELO2, a Gene Encoding a Component of the TTT Complex.
- reference: PMID:28944240
title: Novel compound heterozygous mutations in TELO2 in a patient with severe expression of You-Hoover-Fong syndrome.
- reference: PMID:32940098
title: "Cataract in You-Hoover-Fong syndrome: TELO2 deficiency."
- reference: PMID:23956177
title: Mutation in TTI2 reveals a role for triple T complex in human brain development.
- reference: PMID:36724785
title: Bi-allelic TTI1 variants cause an autosomal-recessive neurodevelopmental disorder with microcephaly.
- reference: PMID:36797513
title: "TELO2-related syndrome (You-Hoover-Fong syndrome): Description of 14 new affected individuals and review of the literature."
- reference: PMID:37215500
title: "Novel compound heterozygous mutations in TELO2 in an infant with You-Hoover-Fong syndrome: A case report and literature review."
- reference: PMID:38421525
title: "The first Iranian patient with You-Hoover-Fong syndrome and a review of the literature on 27 cases: expanding the genotypic and phenotypic spectrum."
- reference: PMID:39704248
title: Expansion of the Phenotype of You-Hoover-Fong Syndrome and Possible Increased Risk of Cancer.
- reference: PMID:41645377
title: "[Analysis of a child with You-Hoover-Fong syndrome due to compound heterozygous variants of the TELO2 gene and a literature review]."
- reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC13276679/fullTextXML
title: "AUTHOR CONTRIBUTIONS"
- reference: PMID:33307281
title: Milder presentation of TELO2-related syndrome in two sisters homozygous for the p.Arg609His pathogenic variant.
- reference: CGGV:assertion_6995e858-919b-4a08-be40-54a56371a408-2022-06-01T160000.000Z
title: "TELO2 / TELO2-related intellectual disability-neurodevelopmental disorder (Definitive)"
Disease Pathophysiology Research Report
Target Disease - Disease Name: You‑Hoover‑Fong Syndrome (TELO2‑related neurodevelopmental disorder; OMIM 616954) - MONDO ID: Not specified in sources identified - Category: Mendelian
1) Core Pathophysiology (key concepts, definitions, current understanding) You‑Hoover‑Fong syndrome (YHFS) is an autosomal‑recessive neurodevelopmental disorder caused by biallelic loss‑of‑function variants in TELO2, which encodes a core subunit of the TTT (TELO2‑TTI1‑TTI2) co‑chaperone complex. TTT operates with R2TP and HSP90 to promote co‑translational maturation and stability of the phosphatidylinositol 3‑kinase–related kinase (PIKK) family, including ATM, ATR, PRKDC/DNA‑PKcs, MTOR, SMG1, and TRRAP. TELO2 deficiency destabilizes the TTT complex and reduces PIKK protein levels, leading to defects in DNA damage/replication checkpoints (ATM/ATR/PRKDC), growth signaling (mTOR), and mRNA surveillance (SMG1/NMD). Mechanistically, casein kinase 2 (CK2)‑mediated phosphorylation of TELO2 and TTI1 modulates TTT interactions and can selectively affect SMG1 and mTOR stability, implying pathway‑specific sensitivity to TELO2 perturbation. In vivo experimental evidence in C. elegans shows that CLK‑2 (TELO2 ortholog) is “a genuine player in the NMD pathway,” with genetic and reporter assays demonstrating NMD impairment upon clk‑2 loss; mammalian studies indicate that CK2‑dependent TELO2 phosphorylation augments NMD by increasing SMG1 stability. Together, these data support a model where TELO2 loss compromises PIKK proteostasis and NMD, producing a multisystem neurodevelopmental phenotype. (bhadra2023ttt(tel2tti1tti2)complex pages 2-4, bhadra2023ttt(tel2tti1tti2)complex pages 7-9, guo2021clk2tel2isa pages 6-9, guo2021clk2tel2isa pages 14-15) - Key quotes: - “CLK‑2/TEL2 is a conserved component of the nonsense‑mediated mRNA decay pathway.” (PLoS ONE, Jan 2021) (guo2021clk2tel2isa pages 13-14) URL: https://doi.org/10.1371/journal.pone.0244505 (Jan 2021) - “CK2‑mediated TEL2 phosphorylation augments nonsense‑mediated mRNA decay (NMD) by increase of SMG1 stability.” (PLoS ONE, Jan 2021) (guo2021clk2tel2isa pages 14-15) URL: https://doi.org/10.1371/journal.pone.0244505 (Jan 2021) - “Conditional Tel2 deletion… causes checkpoint defects that correlate with reduced protein levels (but not mRNA levels) of all six mammalian PIKKs.” (IJMS, May 2023) (bhadra2023ttt(tel2tti1tti2)complex pages 2-4) URL: https://doi.org/10.3390/ijms24098268 (May 2023) - “TTT… promotes co‑translational maturation of the PIKKs” and Tel2 CK2‑site mutations “selectively reduce mTOR and SMG1 protein levels.” (IJMS, May 2023) (bhadra2023ttt(tel2tti1tti2)complex pages 7-9) URL: https://doi.org/10.3390/ijms24098268 (May 2023)
2) Recent developments and latest research (prioritizing 2023–2024) - Clinical: A 2023 case report with literature review expanded the TELO2 variant spectrum by identifying novel compound heterozygous variants (p.K749X, p.R767C) in an infant with severe YHFS, and summarized characteristic features including severe neurodevelopmental delay, microcephaly, cataract, hearing impairment, growth failure, cleft palate, congenital heart defect (ASD), and brain hypoplasia/atrophy; authors noted that “the specific pathogenic mechanisms remain to be elucidated,” but compiled evidence that TELO2 mutations reduce TTT component levels and PIKK stability without affecting telomere length in human cells. (Open Life Sciences, Jan 2023) (zhao2023novelcompoundheterozygous pages 1-2) URL: https://doi.org/10.1515/biol-2022-0602 - Mechanistic: 2023 reviews provide updated structural/functional insights into TTT as a co‑chaperone for PIKKs, its co‑translational binding to the FATKIN region, and CK2‑regulated specificity that particularly impacts SMG1 and mTOR—mechanisms relevant to neurodevelopmental phenotypes in TELO2 deficiency. (IJMS reviews, May 2023) (bhadra2023ttt(tel2tti1tti2)complex pages 2-4, bhadra2023ttt(tel2tti1tti2)complex pages 7-9) URLs: https://doi.org/10.3390/ijms24098268; https://doi.org/10.3390/ijms24119256 - Oncology context informing mechanism: A 2023 GBM study demonstrated TELO2 knockdown reduces PIKK levels and modulates cell‑cycle, EMT, ROS, apoptosis, and telomerase activity and explored crosstalk of TELO2–TTI1–TTI2 with p53 and mitochondrial signaling, supporting TELO2’s role as a common stabilizer of PIKK signaling. Although not a YHFS study, these data substantiate TTT’s role in PIKK proteostasis. (IJMS, May 2023) (feng2023exploringthefunctional pages 10-11) URL: https://doi.org/10.3390/ijms24119256
3) Current applications and real‑world implementations - Diagnostics: Clinical exome sequencing or genome sequencing to identify biallelic TELO2 variants in individuals with syndromic neurodevelopmental delay and microcephaly. Case reports emphasize variant interpretation with genotype–phenotype correlations: truncating/null variants trend toward more severe phenotypes; specific missense variants (e.g., p.Arg609His) can present milder courses. (Jan 2023; Jan 2021) (zhao2023novelcompoundheterozygous pages 1-2, ciaccio2021milderpresentationof pages 1-3) URLs: https://doi.org/10.1515/biol-2022-0602; https://doi.org/10.1016/j.ejmg.2020.104116 - Clinical management: Cataract surgery improved visual engagement in one reported infant, indicating benefit of routine ophthalmologic evaluation and management. (Jan 2023) (zhao2023novelcompoundheterozygous pages 1-2) URL: https://doi.org/10.1515/biol-2022-0602 - Research tools/targets: Mechanistic literature suggests TELO2/TTT and CK2‑regulated interactions are potential levers to modulate specific PIKK pathways; ivermectin has been reported to bind TELO2 and inhibit PIKK signaling in cellular models, though this is investigational and outside current clinical practice. (May 2023) (bhadra2023ttt(tel2tti1tti2)complex pages 7-9, feng2023exploringthefunctional pages 10-11) URLs: https://doi.org/10.3390/ijms24098268; https://doi.org/10.3390/ijms24119256
4) Expert opinions and analysis from authoritative sources - The 2021 PLoS ONE study provides experimental evidence and interpretation that “CLK‑2/TEL2 is a conserved component of the NMD pathway,” proposing that TELO2’s contribution to NMD (through SMG1 stabilization and possibly other targets) offers a mechanistic link to the neurodevelopmental phenotype in TELO2‑related disease, consistent with the known association between NMD defects and intellectual disability. (Jan 2021) (guo2021clk2tel2isa pages 6-9, guo2021clk2tel2isa pages 9-10) URL: https://doi.org/10.1371/journal.pone.0244505 - 2023 reviews interpret decades of TTT/PIKK biology to conclude that TTT is essential for PIKK proteostasis and that CK2 phosphorylation of TELO2/TTI1 confers differential effects on PIKKs (notably mTOR and SMG1), providing a plausible basis for tissue‑ and pathway‑specific vulnerabilities in TELO2 deficiency. (May 2023) (bhadra2023ttt(tel2tti1tti2)complex pages 2-4, bhadra2023ttt(tel2tti1tti2)complex pages 7-9) URLs: https://doi.org/10.3390/ijms24098268
5) Relevant statistics and data from recent studies - Protein-level effects of TTT disruption: In human lymphocytes from individuals with TTI2 mutations (a TTT subunit), TTI2 protein was reduced to ~30–65% of control, with associated decreases in TTI1 (~17–37% of control) and near‑absence of TELO2 protein, illustrating destabilization of the entire TTT complex; the truncating allele was predicted to undergo NMD. Although centered on TTI2, these data demonstrate quantitative destabilization across TTT subunits relevant to TELO2‑related disease. (Frontiers in Genetics, Oct 2019) (wang2019novelcompoundheterozygous pages 6-7) URL: https://doi.org/10.3389/fgene.2019.01060 - Clinical spectrum: The 2023 case report catalogs multisystem features including global developmental delay, microcephaly, cataracts, congenital heart defects, and brain hypoplasia/atrophy; it also notes that human TELO2 variants reduce TTT component protein levels, while telomere length remains comparable to controls. (Open Life Sciences, Jan 2023) (zhao2023novelcompoundheterozygous pages 5-6, zhao2023novelcompoundheterozygous pages 1-2) URL: https://doi.org/10.1515/biol-2022-0602
Detailed Pathophysiology Description - Primary mechanism: Loss‑of‑function of TELO2 (HGNC: TELO2) destabilizes the TTT complex (TELO2‑TTI1‑TTI2), impairing co‑translational maturation and stability of PIKKs (ATM, ATR, PRKDC/DNA‑PKcs, MTOR, SMG1, TRRAP). This reduces protein abundance and activity of these kinases, compromising DNA damage checkpoints (ATM/ATR), DSB repair (PRKDC), growth and metabolic signaling (mTOR), and mRNA surveillance (SMG1/NMD). CK2‑dependent phosphorylation of TELO2/TTI1 determines interaction with R2TP/HSP90 and selectively affects SMG1 and mTOR levels, possibly conferring selective pathway impairment in neural tissues. (bhadra2023ttt(tel2tti1tti2)complex pages 2-4, bhadra2023ttt(tel2tti1tti2)complex pages 7-9, guo2021clk2tel2isa pages 14-15) - NMD involvement: Experimental data show that CLK‑2 (TELO2 ortholog) is required for NMD in C. elegans, with reporter de‑repression and transcriptome signatures matching smg‑gene mutants; mammalian data indicate that TELO2 phosphorylation by CK2 stabilizes SMG1, a core NMD kinase. Thus, TELO2 deficiency may cause defective NMD in human tissues, including the developing brain. (guo2021clk2tel2isa pages 4-6, guo2021clk2tel2isa pages 6-9, guo2021clk2tel2isa pages 14-15) - Cellular processes affected: protein folding and assembly (co‑translational PIKK maturation), protein stability, DNA damage response/checkpoint signaling, mTOR/TOR signaling, RNA surveillance (NMD), apoptosis and oxidative stress responses (supportive cellular models). (bhadra2023ttt(tel2tti1tti2)complex pages 2-4, bhadra2023ttt(tel2tti1tti2)complex pages 7-9, feng2023exploringthefunctional pages 10-11) - Cellular and anatomical context: Neurons and glia in the CNS are implicated by predominant neurodevelopmental phenotypes (ID/GDD, microcephaly) and white‑matter abnormalities seen in some individuals; lens (congenital cataract) and heart (congenital septal defects) reflect broader developmental requirements for PIKK‑dependent signaling. (zhao2023novelcompoundheterozygous pages 1-2, ciaccio2021milderpresentationof pages 5-6)
Sequence of Disease Progression (model) 1) Genetic trigger: Biallelic TELO2 pathogenic variants (often truncating/missense combinations) reduce TELO2 protein and destabilize TTI1/TTI2, compromising TTT integrity. (zhao2023novelcompoundheterozygous pages 1-2) 2) Proteostatic failure: Co‑translational maturation/stability of PIKKs declines; CK2‑regulated deficits disproportionately affect SMG1 and mTOR, with broader reduction in ATM/ATR/PRKDC/TRRAP. (bhadra2023ttt(tel2tti1tti2)complex pages 7-9, bhadra2023ttt(tel2tti1tti2)complex pages 2-4) 3) Pathway dysfunctions: Impaired NMD (via reduced SMG1 stability) produces accumulation of aberrant transcripts; impaired ATM/ATR/PRKDC signaling weakens DNA damage response and replication checkpoints; reduced mTOR activity perturbs growth, metabolism, and neurodevelopmental programs. (guo2021clk2tel2isa pages 14-15, guo2021clk2tel2isa pages 6-9, bhadra2023ttt(tel2tti1tti2)complex pages 2-4) 4) Cellular consequences: Neuronal/glial differentiation and survival are affected; potential white‑matter dysmyelination or gliopathy may occur in subsets; ocular lens fiber cell homeostasis is perturbed, producing cataract. (ciaccio2021milderpresentationof pages 5-6, zhao2023novelcompoundheterozygous pages 1-2) 5) Clinical manifestation: Global developmental delay/intellectual disability, microcephaly, growth retardation/failure to thrive, congenital cataracts, congenital heart defects (e.g., atrial septal defect), variable seizures and spasticity; neuroimaging may show brain hypoplasia/atrophy and, in some cases, white‑matter hyperintensities. (zhao2023novelcompoundheterozygous pages 1-2, ciaccio2021milderpresentationof pages 5-6)
Key Molecular Players - Genes/Proteins: TELO2 (disease gene), TTI1/TTI2 (TTT subunits), PIKKs—ATM, ATR, PRKDC (DNA‑PKcs), MTOR, SMG1, TRRAP; chaperone network—HSP90, RUVBL1/2; regulator—CK2. (bhadra2023ttt(tel2tti1tti2)complex pages 2-4, guo2021clk2tel2isa pages 14-15, bhadra2023ttt(tel2tti1tti2)complex pages 7-9) - Chemical entities: Ivermectin described as a TELO2‑binding small molecule that reduces PIKK activity in cells; in oncology models, temozolomide and curcumin modulate pathways interacting with TELO2 status. These are research findings, not clinical treatments for YHFS. (bhadra2023ttt(tel2tti1tti2)complex pages 7-9, feng2023exploringthefunctional pages 10-11) - Cell types: Neurons and glia (brain); lens fiber cells (eye); cardiomyocytes/embryonic heart tissues (development). (zhao2023novelcompoundheterozygous pages 1-2, ciaccio2021milderpresentationof pages 5-6) - Anatomical locations: Brain (including white matter), eye lens, heart. (zhao2023novelcompoundheterozygous pages 1-2, ciaccio2021milderpresentationof pages 5-6)
Biological Processes (GO concepts; representative names) - Nonsense‑mediated mRNA decay (NMD); PIKK complex assembly/maturation; protein folding; DNA damage response and checkpoint signaling; TOR/mTOR signaling; co‑translational protein targeting/quality control. (guo2021clk2tel2isa pages 6-9, guo2021clk2tel2isa pages 14-15, bhadra2023ttt(tel2tti1tti2)complex pages 7-9, bhadra2023ttt(tel2tti1tti2)complex pages 2-4)
Cellular Components - TTT complex (cytoplasmic co‑chaperone with R2TP/HSP90); PIKK complexes (nuclear and cytoplasmic locales—e.g., mTORC1/2, ATM/ATR/DNA‑PKcs at chromatin); ribosome‑proximal co‑translational assembly sites. (bhadra2023ttt(tel2tti1tti2)complex pages 7-9, bhadra2023ttt(tel2tti1tti2)complex pages 2-4)
Phenotypic Manifestations (HP concept names) - Intellectual disability; global developmental delay; microcephaly; congenital cataract; growth retardation/failure to thrive; congenital heart defect (e.g., atrial septal defect); white‑matter abnormality; seizures; spasticity/ataxia (variable). (zhao2023novelcompoundheterozygous pages 1-2, ciaccio2021milderpresentationof pages 1-3, ciaccio2021milderpresentationof pages 5-6)
Ontology-ready Annotations (summary table) | Category | Entity (Name) | Ontology | ID | Role / Annotation | Key Process / Location (GO / CL / UBERON / CHEBI) | Evidence | |---|---|---|---|---|---|---| | Gene / Protein | TELO2 | HGNC | TELO2 | Core TTT subunit; required for TTT stability and PIKK maturation; disease gene for You-Hoover-Fong syndrome | PIKK co-chaperone activity; cytoplasm / nucleus (assembly) | (zhao2023novelcompoundheterozygous pages 1-2), https://doi.org/10.1515/biol-2022-0602, Jan 2023 | | Gene / Protein | TTI1 | HGNC | TTI1 | TTT subunit; interacts with TELO2/TTI2; required for PIKK stability | PIKK complex assembly; cytoplasmic co-chaperone function | (bhadra2023ttt(tel2tti1tti2)complex pages 2-4), https://doi.org/10.3390/ijms24098268, May 2023 | | Gene / Protein | TTI2 | HGNC | TTI2 | TTT subunit; loss-of-function destabilizes TTT and reduces PIKK levels (causes syndromic ID) | PIKK maturation/stability; loss triggers reduced TTT/PIKK protein abundance | (wang2019novelcompoundheterozygous pages 1-2), https://doi.org/10.3389/fgene.2019.01060, Oct 2019 | | Gene / Protein | ATM | HGNC | ATM | PIKK client of TTT; genome-stability kinase involved in DSB response | DNA damage response (checkpoint signaling) in nucleus | (bhadra2023ttt(tel2tti1tti2)complex pages 2-4), https://doi.org/10.3390/ijms24098268, May 2023 | | Gene / Protein | ATR | HGNC | ATR | PIKK client of TTT; replication/checkpoint kinase sensitive to TELO2/TTT perturbation | Replication stress response / checkpoint signaling | (bhadra2023ttt(tel2tti1tti2)complex pages 2-4), https://doi.org/10.3390/ijms24098268, May 2023 | | Gene / Protein | PRKDC (DNA-PKcs) | HGNC | PRKDC | PIKK involved in double-strand break repair; protein stability supported by TTT | Non-homologous end-joining / DSB repair | (bhadra2023ttt(tel2tti1tti2)complex pages 2-4), https://doi.org/10.3390/ijms24098268, May 2023 | | Gene / Protein | MTOR | HGNC | MTOR | Growth-control PIKK whose stability/mTORC1 regulation can be modulated by TTT/TELO2 | mTOR signaling pathway; cytoplasm (mTORC1/2) | (feng2023exploringthefunctional pages 10-11), https://doi.org/10.3390/ijms24119256, May 2023 | | Gene / Protein | SMG1 | HGNC | SMG1 | PIKK kinase that phosphorylates UPF1 in nonsense-mediated mRNA decay (NMD); stability regulated by TELO2/TTT | Nonsense-mediated mRNA decay (NMD) pathway | (guo2021clk2tel2isa pages 14-15), https://doi.org/10.1371/journal.pone.0244505, Jan 2021 | | Gene / Protein | RUVBL1/2 | HGNC | RUVBL1 / RUVBL2 | AAA+ ATPases that cooperate with R2TP/TTT for PIKK assembly and NMD functions | Co-chaperone/R2TP interactions; cytoplasmic/nucleoplasmic roles | (guo2021clk2tel2isa pages 14-15), https://doi.org/10.1371/journal.pone.0244505, Jan 2021 | | Gene / Protein | CSNK2 (CK2) | HGNC | CSNK2A1 / CSNK2B | Casein kinase II phosphorylates TELO2/TTI1; phosphorylation modulates specificity/stability of select PIKKs (e.g., SMG1, mTOR) | Post-translational regulation of TTT → selective PIKK stability | (bhadra2023ttt(tel2tti1tti2)complex pages 7-9), https://doi.org/10.3390/ijms24098268, May 2023 | | Process | Nonsense-mediated mRNA decay (NMD) | GO | nonsense-mediated mRNA decay | TELO2/CLK-2 and R2TP/TTT contribute to SMG1 stability and NMD function; CLK-2 shown as NMD component in C. elegans | GO:nonsense-mediated mRNA decay; impacts RNA surveillance | (guo2021clk2tel2isa pages 6-9), https://doi.org/10.1371/journal.pone.0244505, Jan 2021 | | Process | PIKK maturation / stability | GO | PIKK complex assembly / maturation | TTT (TELO2-TTI1-TTI2) acts as co-chaperone with R2TP/HSP90 to promote co-translational PIKK folding and stability | GO:protein complex assembly; co-translational chaperone activity | (bhadra2023ttt(tel2tti1tti2)complex pages 2-4), https://doi.org/10.3390/ijms24098268, May 2023 | | Process | DNA damage response | GO | DNA damage response / checkpoint signaling | Loss of TTT/TELO2 can impair ATM/ATR/DNA-PKcs signaling leading to genome-stability defects | GO:DNA damage response; checkpoint signaling | (bhadra2023ttt(tel2tti1tti2)complex pages 2-4), https://doi.org/10.3390/ijms24098268, May 2023 | | Process | mTOR signaling | GO | mTOR signaling pathway | TELO2/TTT influence mTOR stability and downstream growth signaling; implicated in cell growth and neurodevelopment | GO:mTOR signaling; growth regulation | (feng2023exploringthefunctional pages 10-11), https://doi.org/10.3390/ijms24119256, May 2023 | | Process | Checkpoint signaling (replication/DSB) | GO | cell-cycle / checkpoint signaling | TTT required for ATR/ATM-mediated checkpoint activation (replication stress, DSB repair) | GO:cell-cycle checkpoint; replication stress response | (bhadra2023ttt(tel2tti1tti2)complex pages 2-4), https://doi.org/10.3390/ijms24098268, May 2023 | | Cell type | Neuronal cell | CL | neuronal cell | Primary affected cell population inferred from neurodevelopmental phenotypes (ID, microcephaly); TELO2 variants linked to neuronal dysfunction | CL:neuronal cell; central nervous system neurons (brain) | (zhao2023novelcompoundheterozygous pages 1-2), https://doi.org/10.1515/biol-2022-0602, Jan 2023 | | Cell type | Glial cell | CL | glial cell (astrocyte/oligodendrocyte) | TTT/TELO2 expressed in glia; TELO2 perturbation studied in GBM models (impacts mTOR/PIKK pathways) | CL:glial cell; relevance to white-matter pathology | (feng2023exploringthefunctional pages 10-11), https://doi.org/10.3390/ijms24119256, May 2023 | | Anatomical site | Brain | UBERON | brain | Principal organ affected in YHFS: neurodevelopmental delay, microcephaly, atrophy/hypoplasia reported | UBERON:brain; CNS | (zhao2023novelcompoundheterozygous pages 1-2), https://doi.org/10.1515/biol-2022-0602, Jan 2023 | | Anatomical site | White matter | UBERON | cerebral white matter | Symmetric T2 hyperintensities / white-matter abnormalities reported in some TELO2 cases | UBERON:white matter; MRI abnormalities noted | (ciaccio2021milderpresentationof pages 5-6), https://doi.org/10.1016/j.ejmg.2020.104116, Jan 2021 | | Anatomical site | Eye lens | UBERON | lens of eye | Congenital cataracts reported in multiple TELO2-deficient patients | UBERON:lens; ocular findings | (zhao2023novelcompoundheterozygous pages 1-2), https://doi.org/10.1515/biol-2022-0602, Jan 2023 | | Anatomical site | Heart | UBERON | heart | Congenital cardiac malformations (e.g., atrial septal defect) reported in YHFS case reports | UBERON:heart; congenital heart defect annotations | (zhao2023novelcompoundheterozygous pages 1-2), https://doi.org/10.1515/biol-2022-0602, Jan 2023 | | Phenotype (HP) | Intellectual disability | HP | intellectual disability | Core neurodevelopmental phenotype in TELO2-related You-Hoover-Fong syndrome | HP:intellectual disability; developmental defect | (zhao2023novelcompoundheterozygous pages 1-2), https://doi.org/10.1515/biol-2022-0602, Jan 2023 | | Phenotype (HP) | Microcephaly | HP | microcephaly | Recurrent feature associated with TELO2 biallelic variants; correlates with severity | HP:microcephaly; reduced brain growth | (ciaccio2021milderpresentationof pages 1-3), https://doi.org/10.1016/j.ejmg.2020.104116, Jan 2021 | | Phenotype (HP) | Cataract | HP | congenital cataract | Reported in multiple cases; surgical correction improves visual responses in at least one case report | HP:cataract; lens opacity | (zhao2023novelcompoundheterozygous pages 1-2), https://doi.org/10.1515/biol-2022-0602, Jan 2023 | | Phenotype (HP) | Growth retardation / FTT | HP | failure to thrive / growth retardation | Postnatal growth failure reported in case series | HP:failure to thrive; growth retardation | (zhao2023novelcompoundheterozygous pages 1-2), https://doi.org/10.1515/biol-2022-0602, Jan 2023 | | Phenotype (HP) | Congenital heart defect | HP | congenital heart malformation | ASD and other cardiac anomalies reported in YHFS patients | HP:congenital heart defect | (zhao2023novelcompoundheterozygous pages 1-2), https://doi.org/10.1515/biol-2022-0602, Jan 2023 | | Phenotype (HP) | Seizures | HP | seizure / epilepsy | Seizures reported in some TELO2-deficient individuals | HP:seizure | (zhao2023novelcompoundheterozygous pages 1-2), https://doi.org/10.1515/biol-2022-0602, Jan 2023 | | Chemical | Ivermectin | CHEBI | ivermectin | Small molecule reported to bind Tel2 and reduce PIKK activity; proposed repurposing mechanism in cancer models | CHEBI:ivermectin; experimental PIKK inhibition | (bhadra2023ttt(tel2tti1tti2)complex pages 7-9), https://doi.org/10.3390/ijms24098268, May 2023 | | Chemical | Temozolomide (TMZ) | CHEBI | temozolomide | Chemotherapeutic context where TELO2 expression modulates drug responsiveness in GBM models | CHEBI:temozolomide; drug-response studies | (feng2023exploringthefunctional pages 10-11), https://doi.org/10.3390/ijms24119256, May 2023 | | Chemical | Curcumin | CHEBI | curcumin | Reported in cell studies to interact with TELO2-related pathways and modify drug response | CHEBI:curcumin; experimental modulator in GBM contexts | (feng2023exploringthefunctional pages 10-11), https://doi.org/10.3390/ijms24119256, May 2023 |
Table: Concise ontology-ready table summarizing genes, processes, cell types, anatomical sites, phenotypes (HP), and chemicals relevant to You-Hoover-Fong syndrome (TELO2-related), with supporting citations and DOIs for mechanistic and clinical evidence.
Evidence Items (primary literature with URLs and dates) - Zhao Y et al. Novel compound heterozygous mutations in TELO2 in an infant with You‑Hoover‑Fong syndrome: A case report and literature review. Open Life Sciences. Jan 2023. DOI: 10.1515/biol-2022-0602. URL: https://doi.org/10.1515/biol-2022-0602 (mechanism/phenotype summary; clinical features; telomere length unaffected; novel variants; surgery outcome). (zhao2023novelcompoundheterozygous pages 1-2, zhao2023novelcompoundheterozygous pages 5-6) - Guo Y et al. CLK‑2/TEL2 is a conserved component of the nonsense‑mediated mRNA decay pathway. PLoS ONE. Jan 2021. DOI: 10.1371/journal.pone.0244505. URL: https://doi.org/10.1371/journal.pone.0244505 (NMD genetic evidence; CK2‑TELO2‑SMG1 link; tissue specificity). (guo2021clk2tel2isa pages 6-9, guo2021clk2tel2isa pages 13-14, guo2021clk2tel2isa pages 14-15, guo2021clk2tel2isa pages 9-10, guo2021clk2tel2isa pages 4-6) - Bhadra S, Xu Y‑j. TTT (Tel2‑Tti1‑Tti2) Complex, the Co‑Chaperone of PIKKs and a Potential Target for Cancer Chemotherapy. IJMS. May 2023. DOI: 10.3390/ijms24098268. URL: https://doi.org/10.3390/ijms24098268 (TTT promotes co‑translational PIKK maturation; Tel2 deletion reduces PIKKs; CK2‑site selectivity for SMG1/mTOR; ivermectin interaction). (bhadra2023ttt(tel2tti1tti2)complex pages 2-4, bhadra2023ttt(tel2tti1tti2)complex pages 7-9) - Feng S‑W et al. Exploring the Functional Roles of TELO2 in GBM and TMZ responsiveness. IJMS. May 2023. DOI: 10.3390/ijms24119256. URL: https://doi.org/10.3390/ijms24119256 (TELO2 as common stabilizer of PIKKs; pathway modulation; oncology context). (feng2023exploringthefunctional pages 10-11) - Ciaccio C et al. Milder presentation of TELO2‑related syndrome in two sisters homozygous for p.Arg609His. Eur J Med Genet. Jan 2021. DOI: 10.1016/j.ejmg.2020.104116. URL: https://doi.org/10.1016/j.ejmg.2020.104116 (genotype–phenotype; white‑matter abnormalities in some patients; differential diagnosis). (ciaccio2021milderpresentationof pages 6-7, ciaccio2021milderpresentationof pages 1-3, ciaccio2021milderpresentationof pages 5-6) - Wang R et al. Novel Compound Heterozygous Mutations in TTI2 Cause Syndromic Intellectual Disability. Front Genet. Oct 2019. DOI: 10.3389/fgene.2019.01060. URL: https://doi.org/10.3389/fgene.2019.01060 (TTT destabilization across subunits; predicted NMD of truncating allele; supports TTT mechanism relevant to TELO2 disease). (wang2019novelcompoundheterozygous pages 1-2, wang2019novelcompoundheterozygous pages 6-7)
Notes and limitations - While 2023–2024 clinical expansions are referenced in some sources, detailed cohort statistics were not available in the evidence set retrieved here; therefore, quantitative prevalence or penetrance estimates beyond individual case and small series reports are limited. Where oncology or model‑organism data are cited, they are used to support mechanistic plausibility of TTT‑PIKK‑NMD biology relevant to TELO2‑related neurodevelopmental disease. (zhao2023novelcompoundheterozygous pages 1-2, guo2021clk2tel2isa pages 6-9, bhadra2023ttt(tel2tti1tti2)complex pages 2-4)
References
(zhao2023novelcompoundheterozygous pages 1-2): Yong Zhao, Yu Han, Nuo Li, Wen-jie Fu, Guanjun Luo, Yuan Tan, and Xu-guang Qian. Novel compound heterozygous mutations in telo2 in an infant with you-hoover-fong syndrome: a case report and literature review. Open Life Sciences, Jan 2023. URL: https://doi.org/10.1515/biol-2022-0602, doi:10.1515/biol-2022-0602. This article has 1 citations and is from a peer-reviewed journal.
(bhadra2023ttt(tel2tti1tti2)complex pages 2-4): Sankhadip Bhadra and Yong-jie Xu. Ttt (tel2-tti1-tti2) complex, the co-chaperone of pikks and a potential target for cancer chemotherapy. International Journal of Molecular Sciences, 24:8268, May 2023. URL: https://doi.org/10.3390/ijms24098268, doi:10.3390/ijms24098268. This article has 6 citations and is from a poor quality or predatory journal.
(bhadra2023ttt(tel2tti1tti2)complex pages 7-9): Sankhadip Bhadra and Yong-jie Xu. Ttt (tel2-tti1-tti2) complex, the co-chaperone of pikks and a potential target for cancer chemotherapy. International Journal of Molecular Sciences, 24:8268, May 2023. URL: https://doi.org/10.3390/ijms24098268, doi:10.3390/ijms24098268. This article has 6 citations and is from a poor quality or predatory journal.
(feng2023exploringthefunctional pages 10-11): Shao-Wei Feng, Zih-Syuan Wu, Yi-Lin Chiu, and Shih-Ming Huang. Exploring the functional roles of telomere maintenance 2 in the tumorigenesis of glioblastoma multiforme and drug responsiveness to temozolomide. International Journal of Molecular Sciences, 24:9256, May 2023. URL: https://doi.org/10.3390/ijms24119256, doi:10.3390/ijms24119256. This article has 4 citations and is from a poor quality or predatory journal.
(guo2021clk2tel2isa pages 6-9): Yanwu Guo, Cristina Tocchini, and Rafal Ciosk. Clk-2/tel2 is a conserved component of the nonsense-mediated mrna decay pathway. PLoS ONE, 16:e0244505, Jan 2021. URL: https://doi.org/10.1371/journal.pone.0244505, doi:10.1371/journal.pone.0244505. This article has 10 citations and is from a peer-reviewed journal.
(guo2021clk2tel2isa pages 14-15): Yanwu Guo, Cristina Tocchini, and Rafal Ciosk. Clk-2/tel2 is a conserved component of the nonsense-mediated mrna decay pathway. PLoS ONE, 16:e0244505, Jan 2021. URL: https://doi.org/10.1371/journal.pone.0244505, doi:10.1371/journal.pone.0244505. This article has 10 citations and is from a peer-reviewed journal.
(guo2021clk2tel2isa pages 4-6): Yanwu Guo, Cristina Tocchini, and Rafal Ciosk. Clk-2/tel2 is a conserved component of the nonsense-mediated mrna decay pathway. PLoS ONE, 16:e0244505, Jan 2021. URL: https://doi.org/10.1371/journal.pone.0244505, doi:10.1371/journal.pone.0244505. This article has 10 citations and is from a peer-reviewed journal.
(ciaccio2021milderpresentationof pages 1-3): Claudia Ciaccio, Valentina Duga, Chiara Pantaleoni, Silvia Esposito, Isabella Moroni, Michele Pinelli, Raffaele Castello, Vincenzo Nigro, Luisa Chiapparini, Stefano D'Arrigo, Annalaura Torella, Gerarda Cappuccio, Francesco Musacchia, Margherita Mutarelli, Diego Carrella, Giuseppina Vitiello, Giancarlo Parenti, Valeria Capra, Vincenzo Leuzzi, Angelo Selicorni, Silvia Maitz, Nicola Brunetti-Pierri, Sandro Banfi, Marcella Zollino, Martino Montomoli, Donatella Milani, Corrado Romano, Albina Tummolo, Daniele De Brasi, Antonietta Coppola, and Claudia Santoro. Milder presentation of telo2-related syndrome in two sisters homozygous for the p.arg609his pathogenic variant. European Journal of Medical Genetics, 64:104116, Jan 2021. URL: https://doi.org/10.1016/j.ejmg.2020.104116, doi:10.1016/j.ejmg.2020.104116. This article has 7 citations and is from a peer-reviewed journal.
(wang2019novelcompoundheterozygous pages 1-2): Rongrong Wang, Shirui Han, Hong-yan Liu, Amjad Khan, Habulieti Xiaerbati, Xueping Yu, Jia Huang, and Xue Zhang. Novel compound heterozygous mutations in tti2 cause syndromic intellectual disability in a chinese family. Frontiers in Genetics, Oct 2019. URL: https://doi.org/10.3389/fgene.2019.01060, doi:10.3389/fgene.2019.01060. This article has 7 citations and is from a peer-reviewed journal.
(ciaccio2021milderpresentationof pages 5-6): Claudia Ciaccio, Valentina Duga, Chiara Pantaleoni, Silvia Esposito, Isabella Moroni, Michele Pinelli, Raffaele Castello, Vincenzo Nigro, Luisa Chiapparini, Stefano D'Arrigo, Annalaura Torella, Gerarda Cappuccio, Francesco Musacchia, Margherita Mutarelli, Diego Carrella, Giuseppina Vitiello, Giancarlo Parenti, Valeria Capra, Vincenzo Leuzzi, Angelo Selicorni, Silvia Maitz, Nicola Brunetti-Pierri, Sandro Banfi, Marcella Zollino, Martino Montomoli, Donatella Milani, Corrado Romano, Albina Tummolo, Daniele De Brasi, Antonietta Coppola, and Claudia Santoro. Milder presentation of telo2-related syndrome in two sisters homozygous for the p.arg609his pathogenic variant. European Journal of Medical Genetics, 64:104116, Jan 2021. URL: https://doi.org/10.1016/j.ejmg.2020.104116, doi:10.1016/j.ejmg.2020.104116. This article has 7 citations and is from a peer-reviewed journal.
(guo2021clk2tel2isa pages 13-14): Yanwu Guo, Cristina Tocchini, and Rafal Ciosk. Clk-2/tel2 is a conserved component of the nonsense-mediated mrna decay pathway. PLoS ONE, 16:e0244505, Jan 2021. URL: https://doi.org/10.1371/journal.pone.0244505, doi:10.1371/journal.pone.0244505. This article has 10 citations and is from a peer-reviewed journal.
(guo2021clk2tel2isa pages 9-10): Yanwu Guo, Cristina Tocchini, and Rafal Ciosk. Clk-2/tel2 is a conserved component of the nonsense-mediated mrna decay pathway. PLoS ONE, 16:e0244505, Jan 2021. URL: https://doi.org/10.1371/journal.pone.0244505, doi:10.1371/journal.pone.0244505. This article has 10 citations and is from a peer-reviewed journal.
(wang2019novelcompoundheterozygous pages 6-7): Rongrong Wang, Shirui Han, Hong-yan Liu, Amjad Khan, Habulieti Xiaerbati, Xueping Yu, Jia Huang, and Xue Zhang. Novel compound heterozygous mutations in tti2 cause syndromic intellectual disability in a chinese family. Frontiers in Genetics, Oct 2019. URL: https://doi.org/10.3389/fgene.2019.01060, doi:10.3389/fgene.2019.01060. This article has 7 citations and is from a peer-reviewed journal.
(zhao2023novelcompoundheterozygous pages 5-6): Yong Zhao, Yu Han, Nuo Li, Wen-jie Fu, Guanjun Luo, Yuan Tan, and Xu-guang Qian. Novel compound heterozygous mutations in telo2 in an infant with you-hoover-fong syndrome: a case report and literature review. Open Life Sciences, Jan 2023. URL: https://doi.org/10.1515/biol-2022-0602, doi:10.1515/biol-2022-0602. This article has 1 citations and is from a peer-reviewed journal.
(ciaccio2021milderpresentationof pages 6-7): Claudia Ciaccio, Valentina Duga, Chiara Pantaleoni, Silvia Esposito, Isabella Moroni, Michele Pinelli, Raffaele Castello, Vincenzo Nigro, Luisa Chiapparini, Stefano D'Arrigo, Annalaura Torella, Gerarda Cappuccio, Francesco Musacchia, Margherita Mutarelli, Diego Carrella, Giuseppina Vitiello, Giancarlo Parenti, Valeria Capra, Vincenzo Leuzzi, Angelo Selicorni, Silvia Maitz, Nicola Brunetti-Pierri, Sandro Banfi, Marcella Zollino, Martino Montomoli, Donatella Milani, Corrado Romano, Albina Tummolo, Daniele De Brasi, Antonietta Coppola, and Claudia Santoro. Milder presentation of telo2-related syndrome in two sisters homozygous for the p.arg609his pathogenic variant. European Journal of Medical Genetics, 64:104116, Jan 2021. URL: https://doi.org/10.1016/j.ejmg.2020.104116, doi:10.1016/j.ejmg.2020.104116. This article has 7 citations and is from a peer-reviewed journal.