Beck-Fahrner Syndrome

Genetic MONDO:0032922 Pathograph 4 Show in embeddings browser syndromic intellectual disability

Beck-Fahrner syndrome is a neurodevelopmental disorder caused by pathogenic variants in TET3, and it belongs squarely to the Mendelian disorders of the epigenetic machinery (MDEMs, or chromatinopathies) - GeneReviews places it "within the spectrum" of that group. It sits in the **eraser** class of that machinery, and specifically on the DNA rather than the histone arm: TET3 is a ten-eleven translocation methylcytosine dioxygenase that oxidises 5-methylcytosine to 5-hydroxymethylcytosine, the committed first step of the two known DNA-demethylation routes. Losing TET3 dosage therefore does not merely fail to add a mark; it leaves methylated cytosine unable to be cleared, shifting the balance of chromatin states at the loci TET3 acts on. The clinical picture is intellectual disability and developmental delay spanning mild to severe and affecting motor and language skills, with infantile hypotonia that compounds motor and expressive-speech delay and can cause feeding difficulty severe enough to need tube feeding. About a third have epilepsy. Autism, anxiety and ADHD are common. Roughly half have strabismus or refractive error, and both conductive and sensorineural hearing loss occur. Two features are worth curating carefully because they cut against the usual MDEM expectation. First, **growth is disrupted in only about half of affected individuals, and when it is, overgrowth is more common than undergrowth**, with macrocephaly the commonest manifestation - the opposite direction from Kabuki or Cornelia de Lange. This is why the module this entry conforms to states the growth output as "disruption" rather than as short stature: the direction varies across the class while the dysregulation does not. Second, the facial features, though frequently present, are **nonspecific**, so unlike most chromatinopathies there is no recognisable gestalt to diagnose from. Inheritance is autosomal dominant, most often de novo. Biallelic cases exist, inherited from two heterozygous parents who themselves have milder features, but GeneReviews now reads these as autosomal dominant inheritance with variable expressivity rather than as recessive disease - a reinterpretation this entry follows and records explicitly, because the earlier recessive framing is still in circulation.

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🏷

Classifications

Harrison's Part

👪

Inheritance

Autosomal dominant, usually de novo HP:0000006

Most probands carry a de novo heterozygous TET3 variant, though inherited variants are reported. Rare individuals carry biallelic variants inherited from two mildly affected heterozygous parents; this is now interpreted as dominant inheritance with variable expressivity rather than as recessive disease.

Autosomal dominant inheritance

Show evidence (1 reference)

PMID:37200470 SUPPORT Human Clinical

"Rarely, affected individuals can have biallelic pathogenic variants inherited from both heterozygous parents who have milder features of TET3-BEFAHRS. This is now thought to represent autosomal dominant inheritance with variable expressivity as opposed to autosomal recessive inheritance."

Directly supports the dominant-with-variable-expressivity reading and the explicit retraction of the earlier recessive framing.

⚙

Pathophysiology

TET3 Dioxygenase Deficiency

Loss-of-function variation reduces the dosage of TET3, a member of the TET family of 5-methylcytosine oxidases. This places Beck-Fahrner syndrome in the eraser class of the epigenetic machinery, acting on DNA methylation rather than on histone marks.

DNA 5-methylcytosine dioxygenase activity (TET3) GO:0070579 ↓ DECREASED

Downstream

Impaired 5-Methylcytosine Oxidation and DNA Demethylation

Show evidence (1 reference)

PMID:31965999 SUPPORT Other

"the TET (Ten- Eleven Translocation) family of 5-methylcytosine oxidases, which use reduced iron, molecular oxygen and the tricarboxylic acid cycle metabolite 2-oxoglutarate (also known as a-ketoglutarate) to oxidise the methyl group of 5mC to 5-hydroxymethylcytosine (5hmC) and beyond"

Defines the enzymatic activity lost at this node. Source is a review by the laboratory that discovered the enzyme family.

Impaired 5-Methylcytosine Oxidation and DNA Demethylation

Reduced TET3 activity impairs oxidation of 5-methylcytosine to 5-hydroxymethylcytosine, the committed first step of both replication-dependent and replication-independent DNA demethylation. Methylated cytosine that should be cleared at TET3 target loci is retained, shifting the local chromatin state toward repression. This is the DNA-methylation counterpart of the histone-mark imbalance seen in the writer-class chromatinopathies.

chromatin organization GO:0006325 ⇓ LOSS OF FUNCTION

Downstream

Dysregulated Neurodevelopmental Gene Expression

Show evidence (2 references)

PMID:31965999 SUPPORT Other

"TET-generated oxidised methylcytosines are intermediates in at least two pathways of DNA demethylation, which differ in their dependence on DNA replication."

Establishes that the oxidation step lost upstream is required for DNA demethylation by either route, which is what makes reduced TET3 activity a demethylation defect rather than only a missing oxidation product.

PMID:37200470 SUPPORT Human Clinical

"DNA methylation profiling can help confirm variant pathogenicity."

Weak, corroborative evidence only: the sentence states that methylation profiling has diagnostic utility for TET3 variants, which is consistent with a methylation defect at this node but does not itself measure one. Explicitly NOT a claim that the methylation profile mediates the phenotype - see the module's standing KNOWLEDGE_GAP on episignatures.

Dysregulated Neurodevelopmental Gene Expression

Retained methylation at TET3 target loci dysregulates the developmental gene programs those loci encode. This is the point at which Beck-Fahrner syndrome converges with the rest of the chromatinopathies, whichever machinery component they lesion, and it is why TET3 deficiency produces a clinical picture recognisable as an MDEM rather than a metabolic or structural brain disorder.

regulation of DNA-templated transcription GO:0006355 ⇓ LOSS OF FUNCTION nervous system development GO:0007399 ↓ DECREASED

Downstream

Neurodevelopmental and Growth Phenotype

Show evidence (2 references)

PMID:31965999 SUPPORT Other

"In the decade since their discovery, TET enzymes have been shown to have important roles in embryonic development, cell lineage specification, neuronal function and cancer."

Establishes that TET enzymes have demonstrated roles in embryonic development, cell lineage specification and neuronal function. That is the dependence this node relies on; the step from losing TET3 to dysregulated neurodevelopmental transcription specifically is an inference from it, supported for this disorder by the MDEM classification in the next item.

PMID:37200470 SUPPORT Human Clinical

"TET3-related Beck-Fahrner syndrome (TET3-BEFAHRS) is a condition within the spectrum of mendelian disorders of the epigenetic machinery (MDEMs) or chromatinopathies."

Explicit classification of this disorder into the MDEM class, which is the warrant for the conforms_to edge on this node.

Neurodevelopmental and Growth Phenotype

The clinical output: intellectual disability and developmental delay across motor and language domains, infantile hypotonia, epilepsy in about a third, neurobehavioural features, sensory involvement, and growth disruption in about half - biased toward overgrowth and macrocephaly rather than the growth restriction typical of several other chromatinopathies.

learning or memory GO:0007611 ↓ DECREASED

Show evidence (2 references)

PMID:37200470 SUPPORT Human Clinical

"Clinical features typically include intellectual disability / developmental delay ranging from mild to severe affecting both motor and language skills."

States the core cognitive and developmental output of the chain.

PMID:37200470 SUPPORT Human Clinical

"Approximately half of individuals exhibit typical growth and half exhibit growth abnormalities, with overgrowth being more common than undergrowth and macrocephaly being the most common manifestation of altered growth."

Supports the growth arm of this node and, importantly, its direction: overgrowth predominates, which is why the conforming module node is phrased as growth disruption rather than growth restriction.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

Cardiovascular 1

Congenital heart defect OCCASIONAL Abnormal heart morphology HP:0001627

Show evidence (1 reference)

PMID:37200470 SUPPORT Human Clinical

"Congenital heart defects, brain malformations, and genitourinary anomalies are less common findings."

Supports the phenotype and the OCCASIONAL band; the source describes these as less common findings.

Digestive 1

Feeding difficulties HP:0011968

Show evidence (1 reference)

PMID:37200470 SUPPORT Human Clinical

"cause feeding difficulties that require nasogastric or gastrostomy tube feeding"

Supports both the phenotype and the severity that drives the tube-feeding management recommendation.

Ear 2

Conductive hearing impairment HP:0000405

Show evidence (1 reference)

PMID:37200470 SUPPORT Human Clinical

"Both conductive and sensorineural hearing loss have been observed."

Conductive hearing loss is explicitly reported.

Sensorineural hearing impairment HP:0000407

Show evidence (1 reference)

PMID:37200470 SUPPORT Human Clinical

"Both conductive and sensorineural hearing loss have been observed."

Sensorineural hearing loss is explicitly reported.

Eye 1

Strabismus FREQUENT HP:0000486

Show evidence (1 reference)

PMID:37200470 SUPPORT Human Clinical

"Strabismus and refractive errors are found in about half of affected individuals."

Quantitative support for the FREQUENT band: about half falls within the 79-30% HPO range.

Head and Neck 1

Macrocephaly HP:0000256

Show evidence (1 reference)

PMID:37200470 SUPPORT Human Clinical

"with overgrowth being more common than undergrowth and macrocephaly being the most common manifestation of altered growth"

Supports macrocephaly as the leading growth finding and records the direction of growth disruption.

Musculoskeletal 1

Infantile hypotonia HP:0001252

Temporal: CHRONIC

Show evidence (1 reference)

PMID:37200470 SUPPORT Human Clinical

"Hypotonia in infancy and childhood can exacerbate motor and expressive speech delay and, in some cases, cause feeding difficulties that require nasogastric or gastrostomy tube feeding."

Supports the phenotype and its downstream contribution to the motor, speech and feeding phenotypes.

Nervous System 7

Intellectual disability HP:0001249

Show evidence (1 reference)

PMID:37200470 SUPPORT Human Clinical

"Clinical features typically include intellectual disability / developmental delay ranging from mild to severe affecting both motor and language skills. Most affected individuals are verbal and ambulatory, with most walking by age 15-36 months."

Establishes the phenotype and its severity range and functional ceiling.

Global developmental delay HP:0001263

Show evidence (1 reference)

PMID:37200470 SUPPORT Human Clinical

"Clinical features typically include intellectual disability / developmental delay ranging from mild to severe affecting both motor and language skills."

Delay is reported across both motor and language domains.

Epilepsy OCCASIONAL Seizure HP:0001250

Show evidence (1 reference)

PMID:37200470 SUPPORT Human Clinical

"About one third of affected individuals have epilepsy."

Quantitative support for the OCCASIONAL frequency band: one third falls within the 29-5% HPO range.

Delayed speech and language development HP:0000750

Show evidence (1 reference)

PMID:37200470 SUPPORT Human Clinical

"Hypotonia in infancy and childhood can exacerbate motor and expressive speech delay"

Expressive speech delay is a reported feature.

Autism HP:0000717

Show evidence (1 reference)

PMID:37200470 SUPPORT Human Clinical

"Other neurobehavioral features can include autism, anxiety, and attention-deficit/hyperactivity disorder."

Autism is listed among the neurobehavioural features.

Anxiety HP:0000739

Show evidence (1 reference)

PMID:37200470 SUPPORT Human Clinical

"Other neurobehavioral features can include autism, anxiety, and attention-deficit/hyperactivity disorder."

Anxiety is listed among the neurobehavioural features.

Attention deficit hyperactivity disorder HP:0007018

Show evidence (1 reference)

PMID:37200470 SUPPORT Human Clinical

"Other neurobehavioral features can include autism, anxiety, and attention-deficit/hyperactivity disorder."

ADHD is listed among the neurobehavioural features.

Growth 1

Overgrowth HP:0001548

Show evidence (1 reference)

PMID:37200470 SUPPORT Human Clinical

"Approximately half of individuals exhibit typical growth and half exhibit growth abnormalities, with overgrowth being more common than undergrowth"

Supports overgrowth as the predominant direction of growth abnormality.

Other 1

Refractive error FREQUENT Abnormality of refraction HP:0000539

Show evidence (1 reference)

PMID:37200470 SUPPORT Human Clinical

"Strabismus and refractive errors are found in about half of affected individuals."

Quantitative support for the FREQUENT band: about half falls within the 79-30% HPO range.

🧬

Genetic Associations

TET3

Gene: TET3 hgnc:28313 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:37200470 SUPPORT Human Clinical

"The diagnosis of TET3-BEFAHRS is established in a proband with suggestive findings and a heterozygous pathogenic variant in TET3 identified by molecular genetic testing."

Establishes TET3 as the causal gene and the heterozygous state as the diagnostic finding.

💊

Medical Actions

Anti-Seizure Medication

Action: Pharmacotherapy NCIT:C15986

Standardized anti-seizure treatment supervised by an experienced neurologist for the roughly one third of affected individuals with epilepsy. No disorder-specific agent is indicated.

Show evidence (1 reference)

PMID:37200470 SUPPORT Human Clinical

"Standardized treatment with anti-seizure medication (ASM) by an experienced neurologist"

States the recommended management of the epilepsy component.

Developmental and Rehabilitative Therapy

Action: Supportive Care NCIT:C15747

Feeding therapy for persistent feeding difficulty, with gastrostomy placement where needed, alongside standard developmental intervention for delay and intellectual disability.

Show evidence (1 reference)

PMID:37200470 SUPPORT Human Clinical

"feeding therapy; gastrostomy tube placement may be required for persistent feeding issues"

Supports the feeding-therapy component of supportive management.

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Counseling covers dominant inheritance, the high de novo rate, and the recurrence figures that follow from parental carrier status; prenatal and preimplantation testing are possible once the familial variant is known.

Show evidence (1 reference)

PMID:37200470 SUPPORT Human Clinical

"Once the TET3 pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible."

Supports the reproductive-testing content of genetic counseling for this disorder.

🔬

Diagnosis

TET3 molecular genetic testing

Diagnosis is established in a proband with suggestive findings plus a heterozygous pathogenic TET3 variant. DNA methylation profiling is available as an adjunct to resolve variant pathogenicity.

Show evidence (1 reference)

PMID:37200470 SUPPORT Human Clinical

"The diagnosis of TET3-BEFAHRS is established in a proband with suggestive findings and a heterozygous pathogenic variant in TET3 identified by molecular genetic testing. DNA methylation profiling can help confirm variant pathogenicity."

States both the primary diagnostic route and the episignature adjunct.

{ }

Source YAML

click to show

name: Beck-Fahrner Syndrome
creation_date: "2026-08-22T18:45:00Z"
category: Genetic
synonyms:
- BEFAHRS
- TET3-BEFAHRS
- TET3-related Beck-Fahrner syndrome
- TET3 deficiency
description: >
  Beck-Fahrner syndrome is a neurodevelopmental disorder caused by pathogenic
  variants in TET3, and it belongs squarely to the Mendelian disorders of the
  epigenetic machinery (MDEMs, or chromatinopathies) - GeneReviews places it
  "within the spectrum" of that group. It sits in the **eraser** class of that
  machinery, and specifically on the DNA rather than the histone arm: TET3 is a
  ten-eleven translocation methylcytosine dioxygenase that oxidises
  5-methylcytosine to 5-hydroxymethylcytosine, the committed first step of the
  two known DNA-demethylation routes. Losing TET3 dosage therefore does not
  merely fail to add a mark; it leaves methylated cytosine unable to be cleared,
  shifting the balance of chromatin states at the loci TET3 acts on.

  The clinical picture is intellectual disability and developmental delay
  spanning mild to severe and affecting motor and language skills, with infantile
  hypotonia that compounds motor and expressive-speech delay and can cause
  feeding difficulty severe enough to need tube feeding. About a third have
  epilepsy. Autism, anxiety and ADHD are common. Roughly half have strabismus or
  refractive error, and both conductive and sensorineural hearing loss occur.

  Two features are worth curating carefully because they cut against the usual
  MDEM expectation. First, **growth is disrupted in only about half of affected
  individuals, and when it is, overgrowth is more common than undergrowth**, with
  macrocephaly the commonest manifestation - the opposite direction from Kabuki
  or Cornelia de Lange. This is why the module this entry conforms to states the
  growth output as "disruption" rather than as short stature: the direction
  varies across the class while the dysregulation does not. Second, the facial
  features, though frequently present, are **nonspecific**, so unlike most
  chromatinopathies there is no recognisable gestalt to diagnose from.

  Inheritance is autosomal dominant, most often de novo. Biallelic cases exist,
  inherited from two heterozygous parents who themselves have milder features,
  but GeneReviews now reads these as autosomal dominant inheritance with variable
  expressivity rather than as recessive disease - a reinterpretation this entry
  follows and records explicitly, because the earlier recessive framing is still
  in circulation.
disease_term:
  preferred_term: Beck-Fahrner syndrome
  term:
    id: MONDO:0032922
    label: Beck-Fahrner syndrome
parents:
- syndromic intellectual disability
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
references:
- reference: PMID:37200470
  title: "TET3-Related Beck-Fahrner Syndrome."
  tags:
  - GeneReviews
- reference: PMID:31965999
  title: "TET methylcytosine oxidases: new insights from a decade of research."
notes: >-
  Curated as part of a review of Mendelian intellectual disability coverage. The
  entry conforms to the `epigenetic_machinery_neurodevelopmental_dysregulation`
  module at the trigger, transcriptional and clinical-output nodes, and is the
  module's worked example of the **eraser** class acting on DNA methylation
  rather than on histone marks.

  Deliberately not asserted: GeneReviews notes that "DNA methylation profiling
  can help confirm variant pathogenicity", i.e. that BEFAHRS has a usable
  episignature. That is curated here as a diagnostic aid only. Consistent with
  the module's standing KNOWLEDGE_GAP, no claim is made that the measured
  methylation changes mediate the neurodevelopmental phenotype.

  Prevalence is not curated: no population estimate is available for this
  recently delineated disorder, and inventing a band would be worse than the
  gap.
inheritance:
- name: Autosomal dominant, usually de novo
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Most probands carry a de novo heterozygous TET3 variant, though inherited
    variants are reported. Rare individuals carry biallelic variants inherited
    from two mildly affected heterozygous parents; this is now interpreted as
    dominant inheritance with variable expressivity rather than as recessive
    disease.
  evidence:
  - reference: PMID:37200470
    reference_title: "TET3-Related Beck-Fahrner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Rarely, affected individuals can have biallelic pathogenic variants
      inherited from both heterozygous parents who have milder features of
      TET3-BEFAHRS. This is now thought to represent autosomal dominant
      inheritance with variable expressivity as opposed to autosomal recessive
      inheritance.
    explanation: >-
      Directly supports the dominant-with-variable-expressivity reading and the
      explicit retraction of the earlier recessive framing.
genetic:
- name: TET3
  gene_term:
    preferred_term: TET3
    term:
      id: hgnc:28313
      label: TET3
  relationship_type: CAUSATIVE
  notes: >-
    TET3 encodes a ten-eleven translocation methylcytosine dioxygenase. Loss of
    TET3 function is the cause of Beck-Fahrner syndrome; heterozygous pathogenic
    variants are the usual finding.
  evidence:
  - reference: PMID:37200470
    reference_title: "TET3-Related Beck-Fahrner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of TET3-BEFAHRS is established in a proband with suggestive
      findings and a heterozygous pathogenic variant in TET3 identified by
      molecular genetic testing.
    explanation: >-
      Establishes TET3 as the causal gene and the heterozygous state as the
      diagnostic finding.
pathophysiology:
- name: TET3 Dioxygenase Deficiency
  description: >-
    Loss-of-function variation reduces the dosage of TET3, a member of the TET
    family of 5-methylcytosine oxidases. This places Beck-Fahrner syndrome in the
    eraser class of the epigenetic machinery, acting on DNA methylation rather
    than on histone marks.
  role: trigger
  biological_scale: MOLECULAR
  conforms_to: "epigenetic_machinery_neurodevelopmental_dysregulation#Epigenetic Machinery Component Haploinsufficiency"
  molecular_functions:
  - preferred_term: DNA 5-methylcytosine dioxygenase activity (TET3)
    term:
      id: GO:0070579
      label: DNA 5-methylcytosine dioxygenase activity
    modifier: DECREASED
  evidence:
  - reference: PMID:31965999
    reference_title: "TET methylcytosine oxidases: new insights from a decade of research."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the TET (Ten- Eleven Translocation) family of 5-methylcytosine oxidases,
      which use reduced iron, molecular oxygen and the tricarboxylic acid cycle
      metabolite 2-oxoglutarate (also known as a-ketoglutarate) to oxidise the
      methyl group of 5mC to 5-hydroxymethylcytosine (5hmC) and beyond
    explanation: >-
      Defines the enzymatic activity lost at this node. Source is a review by the
      laboratory that discovered the enzyme family.
  downstream:
  - target: Impaired 5-Methylcytosine Oxidation and DNA Demethylation
    causal_link_type: DIRECT

- name: Impaired 5-Methylcytosine Oxidation and DNA Demethylation
  conforms_to: "epigenetic_machinery_neurodevelopmental_dysregulation#Permissive-Repressive Chromatin State Imbalance"
  description: >-
    Reduced TET3 activity impairs oxidation of 5-methylcytosine to
    5-hydroxymethylcytosine, the committed first step of both replication-dependent
    and replication-independent DNA demethylation. Methylated cytosine that should
    be cleared at TET3 target loci is retained, shifting the local chromatin state
    toward repression. This is the DNA-methylation counterpart of the
    histone-mark imbalance seen in the writer-class chromatinopathies.
  role: amplifier
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: chromatin organization
    term:
      id: GO:0006325
      label: chromatin organization
    modifier: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:31965999
    reference_title: "TET methylcytosine oxidases: new insights from a decade of research."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      TET-generated oxidised methylcytosines are intermediates in at least two
      pathways of DNA demethylation, which differ in their dependence on DNA
      replication.
    explanation: >-
      Establishes that the oxidation step lost upstream is required for DNA
      demethylation by either route, which is what makes reduced TET3 activity a
      demethylation defect rather than only a missing oxidation product.
  - reference: PMID:37200470
    reference_title: "TET3-Related Beck-Fahrner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      DNA methylation profiling can help confirm variant pathogenicity.
    explanation: >-
      Weak, corroborative evidence only: the sentence states that methylation
      profiling has diagnostic utility for TET3 variants, which is consistent
      with a methylation defect at this node but does not itself measure one.
      Explicitly NOT a claim that the methylation profile mediates the
      phenotype - see the module's standing KNOWLEDGE_GAP on episignatures.
  downstream:
  - target: Dysregulated Neurodevelopmental Gene Expression
    causal_link_type: DIRECT

- name: Dysregulated Neurodevelopmental Gene Expression
  description: >-
    Retained methylation at TET3 target loci dysregulates the developmental gene
    programs those loci encode. This is the point at which Beck-Fahrner syndrome
    converges with the rest of the chromatinopathies, whichever machinery
    component they lesion, and it is why TET3 deficiency produces a clinical
    picture recognisable as an MDEM rather than a metabolic or structural brain
    disorder.
  role: central_effector
  biological_scale: MOLECULAR
  conforms_to: "epigenetic_machinery_neurodevelopmental_dysregulation#Dysregulated Neurodevelopmental Transcriptional Program"
  biological_processes:
  - preferred_term: regulation of DNA-templated transcription
    term:
      id: GO:0006355
      label: regulation of DNA-templated transcription
    modifier: LOSS_OF_FUNCTION
  - preferred_term: nervous system development
    term:
      id: GO:0007399
      label: nervous system development
    modifier: DECREASED
  evidence:
  - reference: PMID:31965999
    reference_title: "TET methylcytosine oxidases: new insights from a decade of research."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In the decade since their discovery, TET enzymes have been shown to have
      important roles in embryonic development, cell lineage specification,
      neuronal function and cancer.
    explanation: >-
      Establishes that TET enzymes have demonstrated roles in embryonic
      development, cell lineage specification and neuronal function. That is the
      dependence this node relies on; the step from losing TET3 to dysregulated
      neurodevelopmental transcription specifically is an inference from it,
      supported for this disorder by the MDEM classification in the next item.
  - reference: PMID:37200470
    reference_title: "TET3-Related Beck-Fahrner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      TET3-related Beck-Fahrner syndrome (TET3-BEFAHRS) is a condition within the
      spectrum of mendelian disorders of the epigenetic machinery (MDEMs) or
      chromatinopathies.
    explanation: >-
      Explicit classification of this disorder into the MDEM class, which is the
      warrant for the conforms_to edge on this node.
  downstream:
  - target: Neurodevelopmental and Growth Phenotype
    causal_link_type: DIRECT

- name: Neurodevelopmental and Growth Phenotype
  description: >-
    The clinical output: intellectual disability and developmental delay across
    motor and language domains, infantile hypotonia, epilepsy in about a third,
    neurobehavioural features, sensory involvement, and growth disruption in about
    half - biased toward overgrowth and macrocephaly rather than the growth
    restriction typical of several other chromatinopathies.
  role: consequence
  biological_scale: ORGANISM
  conforms_to: "epigenetic_machinery_neurodevelopmental_dysregulation#Intellectual Disability with Growth and Craniofacial Dysmorphism"
  biological_processes:
  - preferred_term: learning or memory
    term:
      id: GO:0007611
      label: learning or memory
    modifier: DECREASED
  evidence:
  - reference: PMID:37200470
    reference_title: "TET3-Related Beck-Fahrner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical features typically include intellectual disability /
      developmental delay ranging from mild to severe affecting both motor and
      language skills.
    explanation: >-
      States the core cognitive and developmental output of the chain.
  - reference: PMID:37200470
    reference_title: "TET3-Related Beck-Fahrner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Approximately half of individuals exhibit typical growth and half exhibit
      growth abnormalities, with overgrowth being more common than undergrowth
      and macrocephaly being the most common manifestation of altered growth.
    explanation: >-
      Supports the growth arm of this node and, importantly, its direction:
      overgrowth predominates, which is why the conforming module node is phrased
      as growth disruption rather than growth restriction.
phenotypes:
- category: Neurologic
  name: Intellectual disability
  description: >-
    Ranges from mild to severe, affecting motor and language skills. Most
    affected individuals are verbal and ambulatory.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:37200470
    reference_title: "TET3-Related Beck-Fahrner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical features typically include intellectual disability /
      developmental delay ranging from mild to severe affecting both motor and
      language skills. Most affected individuals are verbal and ambulatory, with
      most walking by age 15-36 months.
    explanation: >-
      Establishes the phenotype and its severity range and functional ceiling.
- category: Neurologic
  name: Global developmental delay
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:37200470
    reference_title: "TET3-Related Beck-Fahrner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical features typically include intellectual disability /
      developmental delay ranging from mild to severe affecting both motor and
      language skills.
    explanation: Delay is reported across both motor and language domains.
- category: Neurologic
  name: Infantile hypotonia
  description: >-
    Present in infancy and childhood; exacerbates motor and expressive speech
    delay and can cause feeding difficulty.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
    temporality: CHRONIC
  evidence:
  - reference: PMID:37200470
    reference_title: "TET3-Related Beck-Fahrner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hypotonia in infancy and childhood can exacerbate motor and expressive
      speech delay and, in some cases, cause feeding difficulties that require
      nasogastric or gastrostomy tube feeding.
    explanation: >-
      Supports the phenotype and its downstream contribution to the motor,
      speech and feeding phenotypes.
- category: Neurologic
  name: Epilepsy
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:37200470
    reference_title: "TET3-Related Beck-Fahrner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      About one third of affected individuals have epilepsy.
    explanation: >-
      Quantitative support for the OCCASIONAL frequency band: one third falls
      within the 29-5% HPO range.
- category: Neurologic
  name: Delayed speech and language development
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:37200470
    reference_title: "TET3-Related Beck-Fahrner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hypotonia in infancy and childhood can exacerbate motor and expressive
      speech delay
    explanation: Expressive speech delay is a reported feature.
- category: Behavioral
  name: Autism
  phenotype_term:
    preferred_term: Autism
    term:
      id: HP:0000717
      label: Autism
  evidence:
  - reference: PMID:37200470
    reference_title: "TET3-Related Beck-Fahrner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other neurobehavioral features can include autism, anxiety, and
      attention-deficit/hyperactivity disorder.
    explanation: Autism is listed among the neurobehavioural features.
- category: Behavioral
  name: Anxiety
  phenotype_term:
    preferred_term: Anxiety
    term:
      id: HP:0000739
      label: Anxiety
  evidence:
  - reference: PMID:37200470
    reference_title: "TET3-Related Beck-Fahrner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other neurobehavioral features can include autism, anxiety, and
      attention-deficit/hyperactivity disorder.
    explanation: Anxiety is listed among the neurobehavioural features.
- category: Behavioral
  name: Attention deficit hyperactivity disorder
  phenotype_term:
    preferred_term: Attention deficit hyperactivity disorder
    term:
      id: HP:0007018
      label: Attention deficit hyperactivity disorder
  evidence:
  - reference: PMID:37200470
    reference_title: "TET3-Related Beck-Fahrner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other neurobehavioral features can include autism, anxiety, and
      attention-deficit/hyperactivity disorder.
    explanation: ADHD is listed among the neurobehavioural features.
- category: Gastrointestinal
  name: Feeding difficulties
  description: >-
    Secondary to hypotonia; in some cases severe enough to require nasogastric or
    gastrostomy tube feeding.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:37200470
    reference_title: "TET3-Related Beck-Fahrner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      cause feeding difficulties that require nasogastric or gastrostomy tube
      feeding
    explanation: >-
      Supports both the phenotype and the severity that drives the tube-feeding
      management recommendation.
- category: Ophthalmologic
  name: Strabismus
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: PMID:37200470
    reference_title: "TET3-Related Beck-Fahrner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Strabismus and refractive errors are found in about half of affected
      individuals.
    explanation: >-
      Quantitative support for the FREQUENT band: about half falls within the
      79-30% HPO range.
- category: Ophthalmologic
  name: Refractive error
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Abnormality of refraction
    term:
      id: HP:0000539
      label: Abnormality of refraction
  evidence:
  - reference: PMID:37200470
    reference_title: "TET3-Related Beck-Fahrner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Strabismus and refractive errors are found in about half of affected
      individuals.
    explanation: >-
      Quantitative support for the FREQUENT band: about half falls within the
      79-30% HPO range.
- category: Otologic
  name: Conductive hearing impairment
  phenotype_term:
    preferred_term: Conductive hearing impairment
    term:
      id: HP:0000405
      label: Conductive hearing impairment
  evidence:
  - reference: PMID:37200470
    reference_title: "TET3-Related Beck-Fahrner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both conductive and sensorineural hearing loss have been observed.
    explanation: Conductive hearing loss is explicitly reported.
- category: Otologic
  name: Sensorineural hearing impairment
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:37200470
    reference_title: "TET3-Related Beck-Fahrner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both conductive and sensorineural hearing loss have been observed.
    explanation: Sensorineural hearing loss is explicitly reported.
- category: Growth
  name: Macrocephaly
  description: >-
    The commonest manifestation of altered growth in this disorder; overgrowth
    predominates over undergrowth.
  phenotype_term:
    preferred_term: Macrocephaly
    term:
      id: HP:0000256
      label: Macrocephaly
  evidence:
  - reference: PMID:37200470
    reference_title: "TET3-Related Beck-Fahrner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      with overgrowth being more common than undergrowth and macrocephaly being
      the most common manifestation of altered growth
    explanation: >-
      Supports macrocephaly as the leading growth finding and records the
      direction of growth disruption.
- category: Growth
  name: Overgrowth
  phenotype_term:
    preferred_term: Overgrowth
    term:
      id: HP:0001548
      label: Overgrowth
  evidence:
  - reference: PMID:37200470
    reference_title: "TET3-Related Beck-Fahrner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Approximately half of individuals exhibit typical growth and half exhibit
      growth abnormalities, with overgrowth being more common than undergrowth
    explanation: >-
      Supports overgrowth as the predominant direction of growth abnormality.
- category: Cardiovascular
  name: Congenital heart defect
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Abnormal heart morphology
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:37200470
    reference_title: "TET3-Related Beck-Fahrner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Congenital heart defects, brain malformations, and genitourinary anomalies
      are less common findings.
    explanation: >-
      Supports the phenotype and the OCCASIONAL band; the source describes these
      as less common findings.
diagnosis:
- name: TET3 molecular genetic testing
  description: >-
    Diagnosis is established in a proband with suggestive findings plus a
    heterozygous pathogenic TET3 variant. DNA methylation profiling is available
    as an adjunct to resolve variant pathogenicity.
  evidence:
  - reference: PMID:37200470
    reference_title: "TET3-Related Beck-Fahrner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of TET3-BEFAHRS is established in a proband with suggestive
      findings and a heterozygous pathogenic variant in TET3 identified by
      molecular genetic testing. DNA methylation profiling can help confirm
      variant pathogenicity.
    explanation: >-
      States both the primary diagnostic route and the episignature adjunct.
treatments:
- name: Anti-Seizure Medication
  description: >-
    Standardized anti-seizure treatment supervised by an experienced neurologist
    for the roughly one third of affected individuals with epilepsy. No
    disorder-specific agent is indicated.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:37200470
    reference_title: "TET3-Related Beck-Fahrner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Standardized treatment with anti-seizure medication (ASM) by an
      experienced neurologist
    explanation: States the recommended management of the epilepsy component.
- name: Developmental and Rehabilitative Therapy
  description: >-
    Feeding therapy for persistent feeding difficulty, with gastrostomy placement
    where needed, alongside standard developmental intervention for delay and
    intellectual disability.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:37200470
    reference_title: "TET3-Related Beck-Fahrner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      feeding therapy; gastrostomy tube placement may be required for persistent
      feeding issues
    explanation: >-
      Supports the feeding-therapy component of supportive management.
- name: Genetic Counseling
  description: >-
    Counseling covers dominant inheritance, the high de novo rate, and the
    recurrence figures that follow from parental carrier status; prenatal and
    preimplantation testing are possible once the familial variant is known.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:37200470
    reference_title: "TET3-Related Beck-Fahrner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Once the TET3 pathogenic variant(s) have been identified in an affected
      family member, prenatal and preimplantation genetic testing are possible.
    explanation: >-
      Supports the reproductive-testing content of genetic counseling for this
      disorder.

📚

References & Deep Research

References

PMID:37200470

TET3-Related Beck-Fahrner Syndrome.

No top-level findings curated for this source.

PMID:31965999

TET methylcytosine oxidases: new insights from a decade of research.

No top-level findings curated for this source.

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