🏷

Classifications

Harrison's Part

🔗

Mappings

MONDO

MONDO:0980751 Ramond-Elliott neurodevelopmental syndrome

MONDO:0980751 cross-references OMIM:621421 and declares TRA2B as its causal gene, matching the curated entity.

👪

Inheritance

1

Autosomal dominant inheritance HP:0000006

Affected individuals carry a single (monoallelic) TRA2B variant, mostly arising de novo.

Autosomal dominant inheritance

Show evidence (2 references)

PMID:36549593 SUPPORT Human clinical

"A total of 12 individuals from 11 unrelated families who harbored predicted loss-of-function monoallelic variants, mostly de novo, were recruited."

Monoallelic, mostly de novo variants indicate dominant inheritance.

PMID:37958557 SUPPORT Human clinical

"The proband harbored a de novo c.170+1G>A variant in the RS1 domain of Tra2β, which was confirmed to be pathogenic through mRNA analysis, resulting in exon 2 deletion and a frameshift (p.Glu13Valfs*2)."

A second, independent proband with a heterozygous de novo variant.

⚙

Pathophysiology

3

TRA2B 5' Variant Isoform Switch

The truncating variants all lie in the 5' part of TRA2B, upstream of an alternative translation start site. In patient-derived cells they lower the canonical full-length Tra2-beta-1 isoform and raise the noncanonical Tra2-beta-3 isoform, which starts downstream and lacks the N-terminal RS1 domain. Tra2-beta is a sequence-specific splicing regulator that binds GAA-rich motifs in pre-mRNA; the bound molecular function is marked dysregulated because the binding-and-activating canonical protein is replaced by a shorter repressive form. RNA binding by Tra2-beta-3 was not measured.

TRA2B hgnc:10781

Genetic context variant_origin: GERMLINE functional_impact_category: DOMINANT_NEGATIVE

pre-mRNA binding GO:0036002 ↕ DYSREGULATED

Downstream

Disrupted Tra2-beta-Dependent Exon Inclusion

Show evidence (3 references)

PMID:36549593 SUPPORT Human clinical

"All variants clustered in the 5' part of TRA2B, upstream of an alternative translation start site responsible for the expression of the noncanonical Tra2β-3 isoform."

The variant cluster sits upstream of the alternative start site.

PMID:36549593 SUPPORT In vitro / ex vivo

"Experimental studies showed that these variants decreased the expression of the canonical Tra2β-1 isoform, whereas they increased the expression of the Tra2β-3 isoform, which is shorter and lacks the N-terminal RS1 domain."

Patient-cell studies show the isoform switch.

PMID:24586484 SUPPORT BACKGROUND Model organism

"The splicing factor Tra2b (Sfrs10) can modulate splicing inclusion of exons by specifically detecting GAA-rich binding motifs and its absence causes early embryonic lethality in mice."

Background on Tra2-beta as a sequence-specific pre-mRNA binding splicing regulator.

Disrupted Tra2-beta-Dependent Exon Inclusion

Tra2-beta-3 interferes with inclusion of exons that canonical Tra2-beta-1 normally promotes, shown for CHEK1 exon 3 in transfected HEK-293 cells. Which neural splicing targets are affected in patients is not known.

regulation of alternative mRNA splicing, via spliceosome GO:0000381 ↕ DYSREGULATED

Downstream

Cortical Neural Precursor Apoptosis

Intellectual Disability

Global Developmental Delay

Infantile Spasms

Seizure

Generalized Hypotonia

Motor Delay

Autistic Behavior

Feeding Difficulties

Short Stature

Show evidence (2 references)

PMID:36549593 SUPPORT In vitro / ex vivo

"Increased expression of Tra2β-3-GFP were shown to interfere with the incorporation of CHEK1 exon 3 into its mature transcript, normally incorporated by Tra2β-1."

A Tra2-beta-1-dependent exon is repressed by the short isoform.

PMID:24586484 SUPPORT Model organism

"Using whole brain RNA on exon arrays we identified differentially expressed alternative exons of Tubulinδ1 and Shugoshin-like2 as in vivo targets of Tra2b."

In mouse brain, loss of Tra2b alters alternative exon use of specific targets.

Cortical Neural Precursor Apoptosis

In Nestin-Cre neural-specific Tra2b knockout mice, neural and glial precursors in the cortical ventricular layers undergo massive apoptosis, with p21 (Cdkn1a) upregulation, and cortical development is severely abnormal. Shown only for complete loss of Tra2b in mice; whether the human dominant-negative alleles cause precursor loss is not known.

neural progenitor cell CL:0011020

apoptotic process GO:0006915 ↑ INCREASED

Animal models

Nestin-Cre neural-specific Tra2b knockout mouse Mouse recapitulates Massive apoptosis in the cortical ventricular layers of the knockout.

Downstream

Microcephaly

Abnormal Brain Morphology

Show evidence (2 references)

PMID:24586484 SUPPORT Model organism

"Neuronal-specific Tra2b knock-out mice die immediately after birth and show severe abnormalities in cortical development, which are caused by massive apoptotic events in the ventricular layers of the cortex, demonstrating a pivotal role of Tra2b for the developing central nervous system."

Apoptosis of cortical ventricular-layer precursors in the knockout.

PMID:24586484 SUPPORT Model organism

"we found increased expression of the cyclin dependent kinase inhibitor 1a (p21) which we could functionally link to neuronal precursor cells in the affected brain regions."

p21 upregulation in the affected neural precursors.

⬡

Pathograph

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Phenotypes

15

Digestive 1

Feeding Difficulties HP:0011968

Show evidence (1 reference)

PMID:36549593 SUPPORT Human clinical

"All affected individuals presented intellectual disability and/or developmental delay, frequently associated with infantile spasms, microcephaly, brain anomalies, autism spectrum disorder, feeding difficulties, and short stature."

Feeding difficulties are a frequent feature.

Head and Neck 1

Microcephaly HP:0000252

Show evidence (1 reference)

PMID:36549593 SUPPORT Human clinical

"All affected individuals presented intellectual disability and/or developmental delay, frequently associated with infantile spasms, microcephaly, brain anomalies, autism spectrum disorder, feeding difficulties, and short stature."

Microcephaly is a frequent feature.

Limbs 1

Clinodactyly of the 5th Finger HP:0004209

Show evidence (1 reference)

PMID:37958557 SUPPORT Human clinical

"The individual had some skeletal anomalies, including cutaneous syndactyly (fusion) of the second and third toes and clinodactyly of the fifth finger."

Reported in the second proband; the authors suggest it may belong to the syndrome.

Musculoskeletal 1

Generalized Hypotonia HP:0001290

Show evidence (1 reference)

PMID:37958557 SUPPORT Human clinical

"The proband can be described as displaying severe developmental delay with global hypotonia."

Global hypotonia in the second reported proband.

Nervous System 10

Intellectual Disability HP:0001249

Show evidence (1 reference)

PMID:36549593 SUPPORT Human clinical

"All affected individuals presented intellectual disability and/or developmental delay, frequently associated with infantile spasms, microcephaly, brain anomalies, autism spectrum disorder, feeding difficulties, and short stature."

Intellectual disability is a core feature.

Global Developmental Delay HP:0001263

Show evidence (2 references)

PMID:36549593 SUPPORT Human clinical

"All affected individuals presented intellectual disability and/or developmental delay, frequently associated with infantile spasms, microcephaly, brain anomalies, autism spectrum disorder, feeding difficulties, and short stature."

Developmental delay is a core feature.

PMID:37958557 SUPPORT Human clinical

"In this study, we report a novel splice variant in the TRA2B gene identified in a patient presenting with seizures and neurodevelopmental delay."

Neurodevelopmental delay in the second reported proband.

Infantile Spasms HP:0012469

Show evidence (1 reference)

PMID:36549593 SUPPORT Human clinical

"All affected individuals presented intellectual disability and/or developmental delay, frequently associated with infantile spasms, microcephaly, brain anomalies, autism spectrum disorder, feeding difficulties, and short stature."

Infantile spasms are a frequent feature.

Seizure HP:0001250

Show evidence (1 reference)

PMID:37958557 SUPPORT Human clinical

"In this study, we report a novel splice variant in the TRA2B gene identified in a patient presenting with seizures and neurodevelopmental delay."

Seizures in the second reported proband.

Hypsarrhythmia HP:0002521

Show evidence (1 reference)

PMID:37958557 SUPPORT Human clinical

"Electroencephalogram (EEG) results indicated hypsarrhythmia."

EEG finding accompanying infantile spasms in the second reported proband.

Developmental Regression HP:0002376

Show evidence (1 reference)

PMID:37958557 SUPPORT Human clinical

"These seizures led to the loss of acquired skills and the development of a head tilt to the right."

Skills were lost after onset of infantile spasms in the second reported proband.

Motor Delay HP:0001270

Show evidence (1 reference)

PMID:37958557 SUPPORT Human clinical

"Motor milestones were significantly delayed, with no independent walking achieved."

Delayed motor milestones without independent walking in the second reported proband.

Abnormal Brain Morphology HP:0012443

Coarse binding: source unspecified

Show evidence (1 reference)

PMID:36549593 SUPPORT Human clinical

"All affected individuals presented intellectual disability and/or developmental delay, frequently associated with infantile spasms, microcephaly, brain anomalies, autism spectrum disorder, feeding difficulties, and short stature."

Brain anomalies are a frequent feature; the source does not specify them.

Abnormal Cerebral White Matter Morphology HP:0002500

Show evidence (1 reference)

PMID:37958557 SUPPORT Human clinical

"Brain MRI of the proband at the age of five months, in a T2-weighted sequence, revealed abnormal paraventricular and subcortical white matter signals and an accumulation of cerebrospinal fluid over the frontotemporal areas."

Specific MRI finding in the second reported proband.

Autistic Behavior HP:0000729

Show evidence (1 reference)

PMID:36549593 SUPPORT Human clinical

"All affected individuals presented intellectual disability and/or developmental delay, frequently associated with infantile spasms, microcephaly, brain anomalies, autism spectrum disorder, feeding difficulties, and short stature."

Autism spectrum disorder is a frequent feature.

Growth 1

Short Stature HP:0004322

Show evidence (1 reference)

PMID:36549593 SUPPORT Human clinical

"All affected individuals presented intellectual disability and/or developmental delay, frequently associated with infantile spasms, microcephaly, brain anomalies, autism spectrum disorder, feeding difficulties, and short stature."

Short stature is a frequent feature.

🧬

Genetic Associations

1

TRA2B (Heterozygous predicted loss-of-function variants (truncating and splice-site) clustered in the 5' coding region of TRA2B, upstream of the alternative translation start that produces Tra2-beta-3. The proposed mechanism is dominant negative, through overexpression of the short repressive isoform.)

Gene: TRA2B hgnc:10781 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:36549593 SUPPORT Human clinical

"A total of 12 individuals from 11 unrelated families who harbored predicted loss-of-function monoallelic variants, mostly de novo, were recruited."

The defining cohort establishes TRA2B as the causal gene.

PMID:36549593 SUPPORT Human clinical

"All variants clustered in the 5' part of TRA2B, upstream of an alternative translation start site responsible for the expression of the noncanonical Tra2β-3 isoform."

Positional clustering of the pathogenic variants.

Variants (1)

c.170+1G>A (p.Glu13Valfs*2)

single nucleotide variant

Variant detail: splice site

De novo splice-donor variant; mRNA analysis showed skipping of exon 2 and a frameshift. Reported in the second published proband.

Show evidence (1 reference)

PMID:37958557 SUPPORT Human clinical

"The proband harbored a de novo c.170+1G>A variant in the RS1 domain of Tra2β, which was confirmed to be pathogenic through mRNA analysis, resulting in exon 2 deletion and a frameshift (p.Glu13Valfs*2)."

Identity and functional confirmation of the splice variant.

💊

Medical Actions

2

Antiseizure Pharmacotherapy for Infantile Spasms

Action: Pharmacotherapy NCIT:C15986

Agent: tetracosactide CHEBI:3901 topiramate CHEBI:63631 ethosuximide CHEBI:4887

Platform: Small molecule

In the second reported proband, pharmacoresistant infantile spasms were controlled for four months by tetracosactide with topiramate and recurred after topiramate was stopped; ethosuximide with a ketogenic diet then controlled them for five months before they recurred again. This is a single case; no treatment specific to this syndrome has been studied.

Target Phenotypes: Infantile spasms HP:0012469

Show evidence (1 reference)

PMID:37958557 SUPPORT Human clinical

"These seizures were initially controlled with the medication Synacthen Depot (tetracosactide) in combination with Topamax (topiramate) for four months. However, after discontinuing Topamax, the seizures recurred."

Temporary seizure control with tetracosactide and topiramate in one patient.

Ketogenic Diet

Action: Ketogenic diet Ontology label: Ketogenic Diet NCIT:C173168

Platform: Behavioral / lifestyle

Used with ethosuximide in the second reported proband, giving five months of seizure control; the authors also note cognitive progress on the diet. Single case.

Target Phenotypes: Infantile spasms HP:0012469

Show evidence (2 references)

PMID:37958557 SUPPORT Human clinical

"Subsequently, the seizures were managed for five months with a ketogenic diet in combination with Ethosuximide, but they returned after this period."

Temporary seizure control with the diet plus ethosuximide in one patient.

PMID:37958557 SUPPORT Human clinical

"On a ketogenic diet, she has shown cognitive development progress."

Developmental progress observed on the diet in the same patient.

🔬

Diagnosis

1

Genome Sequencing with RNA Confirmation

Affected individuals have been identified by exome or genome sequencing. In the second reported case, whole genome sequencing with Sanger confirmation and parental testing identified a de novo splice variant, and mRNA analysis confirmed its effect on splicing.

whole genome sequencing NCIT:C101294

Show evidence (1 reference)

PMID:37958557 SUPPORT Human clinical

"Comprehensive genetic testing, including whole genome sequencing, Sanger sequencing, and mRNA analysis, was performed on the proband and her parents."

Diagnostic workup used in the second reported case.

🐁

Animal Models

1

Nestin-Cre neural-specific Tra2b knockout mouse

Mice lacking Tra2b in neural precursors die immediately after birth with severe abnormalities of cortical development caused by apoptosis in the cortical ventricular layers, accompanied by p21 upregulation.

Species

Mouse

Genotype

Tra2b conditional knockout in neuronal and glial precursors (Nestin-Cre)

Publication

PMID:24586484

Pathograph links

Cortical Neural Precursor Apoptosis recapitulates fidelity: low observes: cellular Massive apoptosis in the cortical ventricular layers of the knockout.

Limitations: Complete loss of Tra2b, whereas the human alleles are heterozygous and act through overexpression of the short Tra2-beta-3 isoform; the knockout is perinatally lethal, unlike the human disorder.

Show evidence (1 reference)

PMID:24586484 SUPPORT Model organism

"Neuronal-specific Tra2b knock-out mice die immediately after birth and show severe abnormalities in cortical development, which are caused by massive apoptotic events in the ventricular layers of the cortex, demonstrating a pivotal role of Tra2b for the developing central nervous system."

Establishes the knockout phenotype in neural precursors.

{ }

Source YAML

click to show

name: Ramond-Elliott Neurodevelopmental Syndrome
creation_date: "2026-10-23T01:58:03Z"
category: Mendelian
parents:
- Mendelian neurodevelopmental disorder
synonyms:
- TRA2B-related neurodevelopmental syndrome
description: >-
  An autosomal dominant neurodevelopmental syndrome caused by heterozygous,
  mostly de novo, predicted loss-of-function variants in TRA2B, which encodes
  the sequence-specific splicing regulator Tra2-beta. The defining report
  described 12 individuals from 11 families; a second report added one child
  with a de novo splice-donor variant. All affected individuals have
  intellectual disability and/or developmental delay, frequently with
  infantile spasms or other seizures, microcephaly, brain anomalies, autism
  spectrum disorder, feeding difficulties and short stature. The variants
  cluster in the 5' coding region, upstream of an alternative translation
  start site. In patient cells they reduce the canonical Tra2-beta-1 isoform
  and raise the shorter Tra2-beta-3 isoform, which lacks the N-terminal RS1
  domain and represses inclusion of a Tra2-beta-1-dependent exon, so the
  proposed mechanism is dominant negative rather than simple haploinsufficiency.
  A neural-specific Tra2b knockout mouse dies at birth with apoptosis of
  cortical neural precursors. No disease-specific treatment exists.
references:
- reference: PMID:36549593
  title: "Clustered variants in the 5' coding region of TRA2B cause a distinctive neurodevelopmental syndrome."
- reference: PMID:37958557
  title: "TRA2B Gene Splice Variant Linked to Seizures and Neurodevelopmental Delay: A Second Case Study."
- reference: PMID:24586484
  title: "Neuronal-specific deficiency of the splicing factor Tra2b causes apoptosis in neurogenic areas of the developing mouse brain."
disease_term:
  preferred_term: Ramond-Elliott neurodevelopmental syndrome
  term:
    id: MONDO:0980751
    label: Ramond-Elliott neurodevelopmental syndrome
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0980751
      label: Ramond-Elliott neurodevelopmental syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: OMIM:621421
    mapping_justification: MONDO:0980751 cross-references OMIM:621421 and declares TRA2B as its causal gene, matching the curated entity.
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Affected individuals carry a single (monoallelic) TRA2B variant, mostly
    arising de novo.
  evidence:
  - reference: PMID:36549593
    reference_title: "Clustered variants in the 5' coding region of TRA2B cause a distinctive neurodevelopmental syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A total of 12 individuals from 11 unrelated families who harbored predicted loss-of-function monoallelic variants, mostly de novo, were recruited."
    explanation: Monoallelic, mostly de novo variants indicate dominant inheritance.
  - reference: PMID:37958557
    reference_title: "TRA2B Gene Splice Variant Linked to Seizures and Neurodevelopmental Delay: A Second Case Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The proband harbored a de novo c.170+1G>A variant in the RS1 domain of Tra2β, which was confirmed to be pathogenic through mRNA analysis, resulting in exon 2 deletion and a frameshift (p.Glu13Valfs*2)."
    explanation: A second, independent proband with a heterozygous de novo variant.
pathophysiology:
- name: TRA2B 5' Variant Isoform Switch
  biological_scale: MOLECULAR
  description: >-
    The truncating variants all lie in the 5' part of TRA2B, upstream of an
    alternative translation start site. In patient-derived cells they lower
    the canonical full-length Tra2-beta-1 isoform and raise the noncanonical
    Tra2-beta-3 isoform, which starts downstream and lacks the N-terminal RS1
    domain. Tra2-beta is a sequence-specific splicing regulator that binds
    GAA-rich motifs in pre-mRNA; the bound molecular function is marked
    dysregulated because the binding-and-activating canonical protein is
    replaced by a shorter repressive form. RNA binding by Tra2-beta-3 was
    not measured.
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: DOMINANT_NEGATIVE
  genes:
  - preferred_term: TRA2B
    term:
      id: hgnc:10781
      label: TRA2B
  molecular_functions:
  - preferred_term: pre-mRNA binding
    modifier: DYSREGULATED
    term:
      id: GO:0036002
      label: pre-mRNA binding
  evidence:
  - reference: PMID:36549593
    reference_title: "Clustered variants in the 5' coding region of TRA2B cause a distinctive neurodevelopmental syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All variants clustered in the 5' part of TRA2B, upstream of an alternative translation start site responsible for the expression of the noncanonical Tra2β-3 isoform."
    explanation: The variant cluster sits upstream of the alternative start site.
  - reference: PMID:36549593
    reference_title: "Clustered variants in the 5' coding region of TRA2B cause a distinctive neurodevelopmental syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Experimental studies showed that these variants decreased the expression of the canonical Tra2β-1 isoform, whereas they increased the expression of the Tra2β-3 isoform, which is shorter and lacks the N-terminal RS1 domain."
    explanation: Patient-cell studies show the isoform switch.
  - reference: PMID:24586484
    reference_title: "Neuronal-specific deficiency of the splicing factor Tra2b causes apoptosis in neurogenic areas of the developing mouse brain."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: BACKGROUND
    snippet: "The splicing factor Tra2b (Sfrs10) can modulate splicing inclusion of exons by specifically detecting GAA-rich binding motifs and its absence causes early embryonic lethality in mice."
    explanation: Background on Tra2-beta as a sequence-specific pre-mRNA binding splicing regulator.
  downstream:
  - target: Disrupted Tra2-beta-Dependent Exon Inclusion
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36549593
      reference_title: "Clustered variants in the 5' coding region of TRA2B cause a distinctive neurodevelopmental syndrome."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Increased expression of Tra2β-3-GFP were shown to interfere with the incorporation of CHEK1 exon 3 into its mature transcript, normally incorporated by Tra2β-1."
      explanation: Overexpressed Tra2-beta-3 interferes with a Tra2-beta-1-dependent splicing event in HEK-293 cells.
- name: Disrupted Tra2-beta-Dependent Exon Inclusion
  biological_scale: MOLECULAR
  description: >-
    Tra2-beta-3 interferes with inclusion of exons that canonical Tra2-beta-1
    normally promotes, shown for CHEK1 exon 3 in transfected HEK-293 cells.
    Which neural splicing targets are affected in patients is not known.
  biological_processes:
  - preferred_term: regulation of alternative mRNA splicing, via spliceosome
    modifier: DYSREGULATED
    term:
      id: GO:0000381
      label: regulation of alternative mRNA splicing, via spliceosome
  evidence:
  - reference: PMID:36549593
    reference_title: "Clustered variants in the 5' coding region of TRA2B cause a distinctive neurodevelopmental syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Increased expression of Tra2β-3-GFP were shown to interfere with the incorporation of CHEK1 exon 3 into its mature transcript, normally incorporated by Tra2β-1."
    explanation: A Tra2-beta-1-dependent exon is repressed by the short isoform.
  - reference: PMID:24586484
    reference_title: "Neuronal-specific deficiency of the splicing factor Tra2b causes apoptosis in neurogenic areas of the developing mouse brain."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Using whole brain RNA on exon arrays we identified differentially expressed alternative exons of Tubulinδ1 and Shugoshin-like2 as in vivo targets of Tra2b."
    explanation: In mouse brain, loss of Tra2b alters alternative exon use of specific targets.
  downstream:
  - target: Cortical Neural Precursor Apoptosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:24586484
      reference_title: "Neuronal-specific deficiency of the splicing factor Tra2b causes apoptosis in neurogenic areas of the developing mouse brain."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "These findings demonstrate that Tra2b regulates splicing events essential for maintaining neuronal viability during development."
      explanation: >-
        Shown for complete loss of Tra2b in mouse neural precursors, not for the
        human dominant-negative isoform switch.
  - target: Intellectual Disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36549593
      reference_title: "Clustered variants in the 5' coding region of TRA2B cause a distinctive neurodevelopmental syndrome."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Predicted loss-of-function variants clustered in the 5' portion of TRA2B cause a new neurodevelopmental syndrome through an apparently dominant negative disease mechanism involving the use of an alternative translation start site and the overexpression of a shorter, repressive Tra2β protein."
      explanation: The authors attribute the syndrome to the repressive short isoform; intermediate steps are not identified.
  - target: Global Developmental Delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36549593
      reference_title: "Clustered variants in the 5' coding region of TRA2B cause a distinctive neurodevelopmental syndrome."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Predicted loss-of-function variants clustered in the 5' portion of TRA2B cause a new neurodevelopmental syndrome through an apparently dominant negative disease mechanism involving the use of an alternative translation start site and the overexpression of a shorter, repressive Tra2β protein."
      explanation: The authors attribute the syndrome to the repressive short isoform; intermediate steps are not identified.
  - target: Infantile Spasms
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36549593
      reference_title: "Clustered variants in the 5' coding region of TRA2B cause a distinctive neurodevelopmental syndrome."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Predicted loss-of-function variants clustered in the 5' portion of TRA2B cause a new neurodevelopmental syndrome through an apparently dominant negative disease mechanism involving the use of an alternative translation start site and the overexpression of a shorter, repressive Tra2β protein."
      explanation: The authors attribute the syndrome, including its epilepsy, to the repressive short isoform; no epilepsy-specific pathway is identified.
  - target: Seizure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36549593
      reference_title: "Clustered variants in the 5' coding region of TRA2B cause a distinctive neurodevelopmental syndrome."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Predicted loss-of-function variants clustered in the 5' portion of TRA2B cause a new neurodevelopmental syndrome through an apparently dominant negative disease mechanism involving the use of an alternative translation start site and the overexpression of a shorter, repressive Tra2β protein."
      explanation: The authors attribute the syndrome, including its epilepsy, to the repressive short isoform; no epilepsy-specific pathway is identified.
  - target: Generalized Hypotonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36549593
      reference_title: "Clustered variants in the 5' coding region of TRA2B cause a distinctive neurodevelopmental syndrome."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Predicted loss-of-function variants clustered in the 5' portion of TRA2B cause a new neurodevelopmental syndrome through an apparently dominant negative disease mechanism involving the use of an alternative translation start site and the overexpression of a shorter, repressive Tra2β protein."
      explanation: The authors attribute the syndrome to the repressive short isoform; the route to hypotonia is not identified.
  - target: Motor Delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36549593
      reference_title: "Clustered variants in the 5' coding region of TRA2B cause a distinctive neurodevelopmental syndrome."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Predicted loss-of-function variants clustered in the 5' portion of TRA2B cause a new neurodevelopmental syndrome through an apparently dominant negative disease mechanism involving the use of an alternative translation start site and the overexpression of a shorter, repressive Tra2β protein."
      explanation: The authors attribute the syndrome to the repressive short isoform; intermediate steps are not identified.
  - target: Autistic Behavior
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36549593
      reference_title: "Clustered variants in the 5' coding region of TRA2B cause a distinctive neurodevelopmental syndrome."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Predicted loss-of-function variants clustered in the 5' portion of TRA2B cause a new neurodevelopmental syndrome through an apparently dominant negative disease mechanism involving the use of an alternative translation start site and the overexpression of a shorter, repressive Tra2β protein."
      explanation: The authors attribute the syndrome to the repressive short isoform; the route to autistic features is not identified.
  - target: Feeding Difficulties
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36549593
      reference_title: "Clustered variants in the 5' coding region of TRA2B cause a distinctive neurodevelopmental syndrome."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Predicted loss-of-function variants clustered in the 5' portion of TRA2B cause a new neurodevelopmental syndrome through an apparently dominant negative disease mechanism involving the use of an alternative translation start site and the overexpression of a shorter, repressive Tra2β protein."
      explanation: The authors attribute the syndrome to the repressive short isoform; whether feeding difficulty is neurological or has another cause is not addressed.
  - target: Short Stature
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36549593
      reference_title: "Clustered variants in the 5' coding region of TRA2B cause a distinctive neurodevelopmental syndrome."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Predicted loss-of-function variants clustered in the 5' portion of TRA2B cause a new neurodevelopmental syndrome through an apparently dominant negative disease mechanism involving the use of an alternative translation start site and the overexpression of a shorter, repressive Tra2β protein."
      explanation: The authors attribute the syndrome to the repressive short isoform; the route to growth restriction is not identified.
- name: Cortical Neural Precursor Apoptosis
  biological_scale: CELLULAR
  description: >-
    In Nestin-Cre neural-specific Tra2b knockout mice, neural and glial
    precursors in the cortical ventricular layers undergo massive apoptosis,
    with p21 (Cdkn1a) upregulation, and cortical development is severely
    abnormal. Shown only for complete loss of Tra2b in mice; whether the
    human dominant-negative alleles cause precursor loss is not known.
  biological_processes:
  - preferred_term: apoptotic process
    modifier: INCREASED
    term:
      id: GO:0006915
      label: apoptotic process
  cell_types:
  - preferred_term: neural progenitor cell
    term:
      id: CL:0011020
      label: neural progenitor cell
  evidence:
  - reference: PMID:24586484
    reference_title: "Neuronal-specific deficiency of the splicing factor Tra2b causes apoptosis in neurogenic areas of the developing mouse brain."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Neuronal-specific Tra2b knock-out mice die immediately after birth and show severe abnormalities in cortical development, which are caused by massive apoptotic events in the ventricular layers of the cortex, demonstrating a pivotal role of Tra2b for the developing central nervous system."
    explanation: Apoptosis of cortical ventricular-layer precursors in the knockout.
  - reference: PMID:24586484
    reference_title: "Neuronal-specific deficiency of the splicing factor Tra2b causes apoptosis in neurogenic areas of the developing mouse brain."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "we found increased expression of the cyclin dependent kinase inhibitor 1a (p21) which we could functionally link to neuronal precursor cells in the affected brain regions."
    explanation: p21 upregulation in the affected neural precursors.
  downstream:
  - target: Microcephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:24586484
      reference_title: "Neuronal-specific deficiency of the splicing factor Tra2b causes apoptosis in neurogenic areas of the developing mouse brain."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "Neuronal-specific Tra2b knock-out mice die immediately after birth and show severe abnormalities in cortical development, which are caused by massive apoptotic events in the ventricular layers of the cortex, demonstrating a pivotal role of Tra2b for the developing central nervous system."
      explanation: >-
        Loss of cortical precursors in the knockout mouse is a plausible route
        to reduced brain growth; the link to human microcephaly is inferred.
  - target: Abnormal Brain Morphology
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:24586484
      reference_title: "Neuronal-specific deficiency of the splicing factor Tra2b causes apoptosis in neurogenic areas of the developing mouse brain."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "Neuronal-specific Tra2b knock-out mice die immediately after birth and show severe abnormalities in cortical development, which are caused by massive apoptotic events in the ventricular layers of the cortex, demonstrating a pivotal role of Tra2b for the developing central nervous system."
      explanation: Abnormal cortical development in the knockout mouse; the link to the human brain anomalies is inferred.
phenotypes:
- name: Intellectual Disability
  category: Neurodevelopmental
  description: >-
    Intellectual disability and/or developmental delay is present in every
    reported individual.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:36549593
    reference_title: "Clustered variants in the 5' coding region of TRA2B cause a distinctive neurodevelopmental syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All affected individuals presented intellectual disability and/or developmental delay, frequently associated with infantile spasms, microcephaly, brain anomalies, autism spectrum disorder, feeding difficulties, and short stature."
    explanation: Intellectual disability is a core feature.
- name: Global Developmental Delay
  category: Neurodevelopmental
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:36549593
    reference_title: "Clustered variants in the 5' coding region of TRA2B cause a distinctive neurodevelopmental syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All affected individuals presented intellectual disability and/or developmental delay, frequently associated with infantile spasms, microcephaly, brain anomalies, autism spectrum disorder, feeding difficulties, and short stature."
    explanation: Developmental delay is a core feature.
  - reference: PMID:37958557
    reference_title: "TRA2B Gene Splice Variant Linked to Seizures and Neurodevelopmental Delay: A Second Case Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this study, we report a novel splice variant in the TRA2B gene identified in a patient presenting with seizures and neurodevelopmental delay."
    explanation: Neurodevelopmental delay in the second reported proband.
- name: Infantile Spasms
  category: Neurological
  phenotype_term:
    preferred_term: Infantile spasms
    term:
      id: HP:0012469
      label: Infantile spasms
  evidence:
  - reference: PMID:36549593
    reference_title: "Clustered variants in the 5' coding region of TRA2B cause a distinctive neurodevelopmental syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All affected individuals presented intellectual disability and/or developmental delay, frequently associated with infantile spasms, microcephaly, brain anomalies, autism spectrum disorder, feeding difficulties, and short stature."
    explanation: Infantile spasms are a frequent feature.
- name: Seizure
  category: Neurological
  description: >-
    Seizures were the presenting feature of the second reported proband;
    the seizure type is not given in the abstract.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:37958557
    reference_title: "TRA2B Gene Splice Variant Linked to Seizures and Neurodevelopmental Delay: A Second Case Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this study, we report a novel splice variant in the TRA2B gene identified in a patient presenting with seizures and neurodevelopmental delay."
    explanation: Seizures in the second reported proband.
- name: Hypsarrhythmia
  category: Neurological
  phenotype_term:
    preferred_term: Hypsarrhythmia
    term:
      id: HP:0002521
      label: Hypsarrhythmia
  evidence:
  - reference: PMID:37958557
    reference_title: "TRA2B Gene Splice Variant Linked to Seizures and Neurodevelopmental Delay: A Second Case Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Electroencephalogram (EEG) results indicated hypsarrhythmia."
    explanation: EEG finding accompanying infantile spasms in the second reported proband.
- name: Developmental Regression
  category: Neurodevelopmental
  phenotype_term:
    preferred_term: Developmental regression
    term:
      id: HP:0002376
      label: Developmental regression
  evidence:
  - reference: PMID:37958557
    reference_title: "TRA2B Gene Splice Variant Linked to Seizures and Neurodevelopmental Delay: A Second Case Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These seizures led to the loss of acquired skills and the development of a head tilt to the right."
    explanation: Skills were lost after onset of infantile spasms in the second reported proband.
- name: Generalized Hypotonia
  category: Neurological
  description: >-
    Global hypotonia in the second reported proband. The deep-research report gives hypotonia in most of the defining cohort, but that figure is in the Ramond et al. full text, which is not available in the reference cache.
  phenotype_term:
    preferred_term: Global hypotonia
    term:
      id: HP:0001290
      label: Generalized hypotonia
  evidence:
  - reference: PMID:37958557
    reference_title: "TRA2B Gene Splice Variant Linked to Seizures and Neurodevelopmental Delay: A Second Case Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The proband can be described as displaying severe developmental delay with global hypotonia."
    explanation: Global hypotonia in the second reported proband.
- name: Motor Delay
  category: Neurodevelopmental
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
  evidence:
  - reference: PMID:37958557
    reference_title: "TRA2B Gene Splice Variant Linked to Seizures and Neurodevelopmental Delay: A Second Case Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Motor milestones were significantly delayed, with no independent walking achieved."
    explanation: Delayed motor milestones without independent walking in the second reported proband.
- name: Microcephaly
  category: Neurological
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:36549593
    reference_title: "Clustered variants in the 5' coding region of TRA2B cause a distinctive neurodevelopmental syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All affected individuals presented intellectual disability and/or developmental delay, frequently associated with infantile spasms, microcephaly, brain anomalies, autism spectrum disorder, feeding difficulties, and short stature."
    explanation: Microcephaly is a frequent feature.
- name: Abnormal Brain Morphology
  category: Neurological
  description: >-
    Brain anomalies on imaging are frequent; their specific types are not
    given in the abstract.
  phenotype_term:
    preferred_term: Brain anomalies
    coarse_binding_basis: SOURCE_UNSPECIFIED
    term:
      id: HP:0012443
      label: Abnormal brain morphology
  evidence:
  - reference: PMID:36549593
    reference_title: "Clustered variants in the 5' coding region of TRA2B cause a distinctive neurodevelopmental syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All affected individuals presented intellectual disability and/or developmental delay, frequently associated with infantile spasms, microcephaly, brain anomalies, autism spectrum disorder, feeding difficulties, and short stature."
    explanation: Brain anomalies are a frequent feature; the source does not specify them.
- name: Abnormal Cerebral White Matter Morphology
  category: Neurological
  phenotype_term:
    preferred_term: Abnormal paraventricular and subcortical white matter signal
    term:
      id: HP:0002500
      label: Abnormal cerebral white matter morphology
  evidence:
  - reference: PMID:37958557
    reference_title: "TRA2B Gene Splice Variant Linked to Seizures and Neurodevelopmental Delay: A Second Case Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain MRI of the proband at the age of five months, in a T2-weighted sequence, revealed abnormal paraventricular and subcortical white matter signals and an accumulation of cerebrospinal fluid over the frontotemporal areas."
    explanation: Specific MRI finding in the second reported proband.
- name: Clinodactyly of the 5th Finger
  category: Skeletal
  phenotype_term:
    preferred_term: Clinodactyly of the fifth finger
    term:
      id: HP:0004209
      label: Clinodactyly of the 5th finger
  evidence:
  - reference: PMID:37958557
    reference_title: "TRA2B Gene Splice Variant Linked to Seizures and Neurodevelopmental Delay: A Second Case Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The individual had some skeletal anomalies, including cutaneous syndactyly (fusion) of the second and third toes and clinodactyly of the fifth finger."
    explanation: Reported in the second proband; the authors suggest it may belong to the syndrome.
- name: Autistic Behavior
  category: Behavioral
  phenotype_term:
    preferred_term: Autism spectrum disorder
    term:
      id: HP:0000729
      label: Autistic behavior
  evidence:
  - reference: PMID:36549593
    reference_title: "Clustered variants in the 5' coding region of TRA2B cause a distinctive neurodevelopmental syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All affected individuals presented intellectual disability and/or developmental delay, frequently associated with infantile spasms, microcephaly, brain anomalies, autism spectrum disorder, feeding difficulties, and short stature."
    explanation: Autism spectrum disorder is a frequent feature.
- name: Feeding Difficulties
  category: Gastrointestinal
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:36549593
    reference_title: "Clustered variants in the 5' coding region of TRA2B cause a distinctive neurodevelopmental syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All affected individuals presented intellectual disability and/or developmental delay, frequently associated with infantile spasms, microcephaly, brain anomalies, autism spectrum disorder, feeding difficulties, and short stature."
    explanation: Feeding difficulties are a frequent feature.
- name: Short Stature
  category: Growth
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:36549593
    reference_title: "Clustered variants in the 5' coding region of TRA2B cause a distinctive neurodevelopmental syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All affected individuals presented intellectual disability and/or developmental delay, frequently associated with infantile spasms, microcephaly, brain anomalies, autism spectrum disorder, feeding difficulties, and short stature."
    explanation: Short stature is a frequent feature.
genetic:
- name: TRA2B
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: TRA2B
    term:
      id: hgnc:10781
      label: TRA2B
  variant_origin: GERMLINE
  presence: PRESENT
  association: >-
    Heterozygous predicted loss-of-function variants (truncating and
    splice-site) clustered in the 5' coding region of TRA2B, upstream of the
    alternative translation start that produces Tra2-beta-3. The proposed
    mechanism is dominant negative, through overexpression of the short
    repressive isoform.
  notes: >-
    No ClinGen gene-disease validity record for this pair was found in the
    repository cache, so no validity tier is recorded.
  evidence:
  - reference: PMID:36549593
    reference_title: "Clustered variants in the 5' coding region of TRA2B cause a distinctive neurodevelopmental syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A total of 12 individuals from 11 unrelated families who harbored predicted loss-of-function monoallelic variants, mostly de novo, were recruited."
    explanation: The defining cohort establishes TRA2B as the causal gene.
  - reference: PMID:36549593
    reference_title: "Clustered variants in the 5' coding region of TRA2B cause a distinctive neurodevelopmental syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All variants clustered in the 5' part of TRA2B, upstream of an alternative translation start site responsible for the expression of the noncanonical Tra2β-3 isoform."
    explanation: Positional clustering of the pathogenic variants.
  variants:
  - name: c.170+1G>A (p.Glu13Valfs*2)
    type: splice site
    variant_type: single nucleotide variant
    description: >-
      De novo splice-donor variant; mRNA analysis showed skipping of exon 2
      and a frameshift. Reported in the second published proband.
    evidence:
    - reference: PMID:37958557
      reference_title: "TRA2B Gene Splice Variant Linked to Seizures and Neurodevelopmental Delay: A Second Case Study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The proband harbored a de novo c.170+1G>A variant in the RS1 domain of Tra2β, which was confirmed to be pathogenic through mRNA analysis, resulting in exon 2 deletion and a frameshift (p.Glu13Valfs*2)."
      explanation: Identity and functional confirmation of the splice variant.
diagnosis:
- name: Genome Sequencing with RNA Confirmation
  description: >-
    Affected individuals have been identified by exome or genome sequencing.
    In the second reported case, whole genome sequencing with Sanger
    confirmation and parental testing identified a de novo splice variant,
    and mRNA analysis confirmed its effect on splicing.
  diagnosis_term:
    preferred_term: whole genome sequencing
    term:
      id: NCIT:C101294
      label: Whole Genome Sequencing
  evidence:
  - reference: PMID:37958557
    reference_title: "TRA2B Gene Splice Variant Linked to Seizures and Neurodevelopmental Delay: A Second Case Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Comprehensive genetic testing, including whole genome sequencing, Sanger sequencing, and mRNA analysis, was performed on the proband and her parents."
    explanation: Diagnostic workup used in the second reported case.
treatments:
- name: Antiseizure Pharmacotherapy for Infantile Spasms
  description: >-
    In the second reported proband, pharmacoresistant infantile spasms were
    controlled for four months by tetracosactide with topiramate and recurred
    after topiramate was stopped; ethosuximide with a ketogenic diet then
    controlled them for five months before they recurred again. This is a
    single case; no treatment specific to this syndrome has been studied.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: tetracosactide
      term:
        id: CHEBI:3901
        label: cosyntropin
    - preferred_term: topiramate
      term:
        id: CHEBI:63631
        label: topiramate
    - preferred_term: ethosuximide
      term:
        id: CHEBI:4887
        label: ethosuximide
  target_phenotypes:
  - preferred_term: Infantile spasms
    term:
      id: HP:0012469
      label: Infantile spasms
  evidence:
  - reference: PMID:37958557
    reference_title: "TRA2B Gene Splice Variant Linked to Seizures and Neurodevelopmental Delay: A Second Case Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These seizures were initially controlled with the medication Synacthen Depot (tetracosactide) in combination with Topamax (topiramate) for four months. However, after discontinuing Topamax, the seizures recurred."
    explanation: Temporary seizure control with tetracosactide and topiramate in one patient.
- name: Ketogenic Diet
  description: >-
    Used with ethosuximide in the second reported proband, giving five months
    of seizure control; the authors also note cognitive progress on the diet.
    Single case.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Ketogenic diet
    term:
      id: NCIT:C173168
      label: Ketogenic Diet
  target_phenotypes:
  - preferred_term: Infantile spasms
    term:
      id: HP:0012469
      label: Infantile spasms
  evidence:
  - reference: PMID:37958557
    reference_title: "TRA2B Gene Splice Variant Linked to Seizures and Neurodevelopmental Delay: A Second Case Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Subsequently, the seizures were managed for five months with a ketogenic diet in combination with Ethosuximide, but they returned after this period."
    explanation: Temporary seizure control with the diet plus ethosuximide in one patient.
  - reference: PMID:37958557
    reference_title: "TRA2B Gene Splice Variant Linked to Seizures and Neurodevelopmental Delay: A Second Case Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "On a ketogenic diet, she has shown cognitive development progress."
    explanation: Developmental progress observed on the diet in the same patient.
animal_models:
- name: Nestin-Cre neural-specific Tra2b knockout mouse
  species: Mouse
  genotype: Tra2b conditional knockout in neuronal and glial precursors (Nestin-Cre)
  publication: PMID:24586484
  description: >-
    Mice lacking Tra2b in neural precursors die immediately after birth with
    severe abnormalities of cortical development caused by apoptosis in the
    cortical ventricular layers, accompanied by p21 upregulation.
  modeled_mechanisms:
  - target: Cortical Neural Precursor Apoptosis
    relationship: RECAPITULATES
    fidelity: LOW
    model_scale: CELLULAR
    description: Massive apoptosis in the cortical ventricular layers of the knockout.
    limitations: >-
      Complete loss of Tra2b, whereas the human alleles are heterozygous and
      act through overexpression of the short Tra2-beta-3 isoform; the
      knockout is perinatally lethal, unlike the human disorder.
    evidence:
    - reference: PMID:24586484
      reference_title: "Neuronal-specific deficiency of the splicing factor Tra2b causes apoptosis in neurogenic areas of the developing mouse brain."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Neuronal-specific Tra2b knock-out mice die immediately after birth and show severe abnormalities in cortical development, which are caused by massive apoptotic events in the ventricular layers of the cortex, demonstrating a pivotal role of Tra2b for the developing central nervous system."
      explanation: Establishes the knockout phenotype in neural precursors.
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
    notes: >-
      The clinical burden is neurodevelopmental: intellectual disability,
      developmental delay, epilepsy and microcephaly.
    evidence:
    - reference: PMID:36549593
      reference_title: "Clustered variants in the 5' coding region of TRA2B cause a distinctive neurodevelopmental syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "All affected individuals presented intellectual disability and/or developmental delay, frequently associated with infantile spasms, microcephaly, brain anomalies, autism spectrum disorder, feeding difficulties, and short stature."
      explanation: Neurodevelopmental features dominate the phenotype.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: A monogenic disorder of a splicing regulator.
    evidence:
    - reference: PMID:36549593
      reference_title: "Clustered variants in the 5' coding region of TRA2B cause a distinctive neurodevelopmental syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "A total of 12 individuals from 11 unrelated families who harbored predicted loss-of-function monoallelic variants, mostly de novo, were recruited."
      explanation: Germline variants in a single gene define the disorder.
notes: >-
  Evidence comes from two publications covering 13 individuals. The Ramond
  et al. 2023 cohort paper (PMID:36549593) is cached as abstract only: it is
  not in PMC, and both a forced PMID re-fetch and the DOI fetch returned no
  full text. Per-feature cohort counts, the specific MRI findings, and features
  named only in its full text (absent speech, constipation, scoliosis,
  self-injury, a father-to-son transmission) are therefore not recorded here.
  The Shatokhina et al. case report is cached as full text and supplies the
  hypotonia, motor delay, regression, hypsarrhythmia, white matter, skeletal
  and treatment details for its single proband. The mouse data are for
  complete loss of Tra2b and are used only as indirect support for the neural
  precursor step.

📚

References & Deep Research

References

3

PMID:36549593

Clustered variants in the 5' coding region of TRA2B cause a distinctive neurodevelopmental syndrome.

No top-level findings curated for this source.

PMID:37958557

TRA2B Gene Splice Variant Linked to Seizures and Neurodevelopmental Delay: A Second Case Study.

No top-level findings curated for this source.

PMID:24586484

Neuronal-specific deficiency of the splicing factor Tra2b causes apoptosis in neurogenic areas of the developing mouse brain.

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Ramond-Elliott Neurodevelopmental Syndrome · 2026-10-23T02:12:36Z · View source

New entry for the TRA2B neurodevelopmental syndrome (MONDO:0980751), curated from the defining 12-person cohort (PMID:36549593), the second case report (PMID:37958557) and the neural-specific Tra2b knockout mouse (PMID:24586484). The pathograph runs from the 5' variant isoform switch (canonical Tra2-beta-1 down, repressive Tra2-beta-3 up; pre-mRNA binding, dominant negative) to disrupted exon inclusion and, via the mouse-only precursor apoptosis step, to microcephaly and brain anomalies. Both human sources are abstract-only in the cache, so per-feature frequencies reported in the full text are not recorded. A claude_code deep-research report was used as leads. just preflight-dr was not run (no local MONDO build). Validated with validate, validate-terms, count-verified-snippets, entity-ref, causal-target, duplicate-key, gene-activity-grounding and coarse-phenotype checks.

Claude Code ▸

Ramond-Elliott Neurodevelopmental Syndrome (RAMELN; TRA2B): Research Report

claude-haiku-5-5, claude-opus-5-5 8 citations 2026-10-23T01:58:41.642187

Ramond-Elliott Neurodevelopmental Syndrome (RAMELN; TRA2B): Research Report

Target: Ramond-Elliott neurodevelopmental syndrome, MONDO:0980751. Causal gene: TRA2B (transformer 2 beta homolog; OMIM gene 602719; NCBI Gene 6434). The disease is OMIM 621421.

How this was researched. My PubMed tool call was declined, so the evidence comes from three places. The first is the full text of the founding paper, Ramond et al. 2023 (CC BY 4.0, read from the Newcastle ePrints PDF). The second is the full text of the second case report on PMC (Shatokhina et al. 2023). The third is database records (KEGG, PanelApp) and the abstracts of two mouse knockout papers. Quotes marked [abstract] match the cached references_cache/PMID_36549593.md exactly. Other quotes are from full text and should be re-checked before they are used as snippets. Every ontology CURIE below is a lead written from memory and not looked up. Under this repo's term contract, each one must be resolved with OAK/OLS before it is bound.

1. Disease Information

Overview. RAMELN is an autosomal dominant neurodevelopmental syndrome. It is caused by heterozygous, predicted loss-of-function variants that cluster in the 5′ coding region of TRA2B, upstream of an alternative translation start site in exon 3. Its core features are: - intellectual disability or developmental delay, usually severe; - infantile-onset epilepsy, often infantile spasms; - axial or global hypotonia; - microcephaly and nonspecific brain anomalies; - behavioural problems, including autism; - feeding difficulties and short stature.

It is the first human disease linked to germline variants in a transformer-2 gene.

"Predicted loss-of-function variants clustered in the 5' portion of TRA2B cause a new neurodevelopmental syndrome through an apparently dominant negative disease mechanism involving the use of an alternative translation start site and the overexpression of a shorter, repressive Tra2β protein." [abstract, PMID:36549593]

Identifier	Value	Source
MONDO	MONDO:0980751	task input
OMIM (phenotype)	621421	KEGG H03032; Disease Ontology xref
OMIM (gene)	602719	search result
KEGG Disease	H03032	KEGG
DOID	DOID:0070715 (appears in search results; confirm it is this disease)	Disease Ontology
ICD-11	LD90.Y, a nonspecific "conditions with disorders of intellectual development" code	KEGG
Orphanet / MeSH / ICD-10	none found	—
HGNC	believed to be hgnc:10781 (unverified, look up)	—

Synonyms: RAMELN; TRA2B-related neurodevelopmental disorder. The name honours the first and last authors, Francis Ramond and David Elliott.
Nature of the data: Everything comes from individual patient case series and reports. One is a GeneMatcher cohort of 12 individuals; the other is a single case. There are no registry or EHR data.
No GeneReviews chapter was found.

2. Etiology

Cause: Heterozygous germline variants in the 5′ part of TRA2B: start-loss, nonsense, and splice variants at the exon 2/3 boundary.
Origin:
De novo in 10 of 11 Ramond families.
In one family, an affected father (individual 8, age 31) passed the variant to his affected son (individual 9). Grandparents were not available for testing.
The Shatokhina proband's variant was de novo. Parental germline mosaicism was not excluded.
Genetic risk factors beyond the causal variant: none known. No susceptibility loci, modifier genes or protective alleles are reported.
Environmental risk, protective factors and gene-environment interactions: none reported, and none expected for a de novo monogenic developmental disorder.

3. Phenotypes

The frequencies below come from Ramond et al. 2023 (n=12: 5 female, 7 male; aged 2–14 years plus one adult aged 31), unless marked as coming from the Shatokhina case (S).

Phenotype	Frequency / detail	Candidate HPO (verify)
DD/ID	12/12 (100%): severe–profound 6, moderate–severe 2, mild–moderate 3, unknown 1	HP:0001249 Intellectual disability; HP:0001263 Global developmental delay
Axial/global hypotonia, neonatal–infantile onset	10/12 (83%); also S	HP:0001252 Hypotonia (HP:0008936 for axial)
Motor delay	12/12. Walked independently at 20 mo–6 y in 6/11; not yet walking in 5/11. S not walking at 14 mo	HP:0001270 Motor delay
Nonverbal (age 3–14 y)	7/12 (58%); some speech in 4/12	HP:0001344 Absent speech
Behavioural problems	8/12 (66%)	—
Autism spectrum disorder	4/12 (33%)	HP:0000729 Autistic behavior
Self-injury	4/12 (33%)	HP:0100716 Self-injurious behavior
Frustration intolerance	2/12	—
Epilepsy, onset 3–9 months	7/12 (58%); also S, onset 5 mo	HP:0001250 Seizure
Infantile spasms as first presentation	6/12 (50%); also S, pharmacoresistant	HP:0012469 Infantile spasms
Hypsarrhythmia	3 individuals; also S	HP:0002521 Hypsarrhythmia
Unclassified epileptic encephalopathy	1	HP:0200134 Epileptic encephalopathy
Evolution to Lennox-Gastaut syndrome	1	—
Head circumference below average	10 individuals	—
Microcephaly (−2 to −4 SD)	5/12 (42%)	HP:0000252 Microcephaly
Any brain anomaly on MRI	10/11 (90%)	—
Mild diffuse atrophy or ventricular enlargement	6/11 (54%)	HP:0002059 Cerebral atrophy; HP:0002119 Ventriculomegaly
Thin or hypoplastic corpus callosum	4/11 (36%)	HP:0002079 Hypoplasia of the corpus callosum
Delayed myelination	2; S had abnormal periventricular/subcortical white-matter signal	HP:0012448 Delayed myelination
Cerebellar hypoplasia	1	HP:0001321 Cerebellar hypoplasia
Focal cortical dysplasia (histology-proven, epilepsy surgery)	1	look up
Feeding difficulties	7/12 (58%); 1 needed a gastrostomy	HP:0011968 Feeding difficulties
Height and weight < −2 SD	4/12 (33%)	HP:0004322 Short stature
Chronic constipation	5/12 (42%)	HP:0002019 Constipation
Sleep disturbance (night waking)	3/12 (25%); 1 responded to melatonin	HP:0002360 Sleep abnormality
Minor cardiac malformations	2/12 (17%); S had patent foramen ovale and mild left pulmonary artery stenosis	HP:0001627 Abnormal heart morphology
Cortical visual impairment	3	HP:0100704 Cortical visual impairment
Intermittent exotropia	2	HP:0000577 Exotropia
Astigmatism	2	HP:0000483 Astigmatism
Hearing	normal in all	—
Scoliosis	4/12 (33%)	HP:0002650 Scoliosis
Hand/foot brachydactyly	3/12 (25%)	HP:0001156 Brachydactyly
Cutaneous syndactyly	2/12 (17%); S had toe 2–3 syndactyly	look up
Pectus excavatum	1	HP:0000767 Pectus excavatum
Fifth-finger clinodactyly	S only	HP:0004209 Clinodactyly of the 5th finger
Alopecia areata	S only	look up

Facial gestalt. Features are "common but not constant" and only mildly specific. They include: - long, slightly upslanting palpebral fissures; deep-set eyes; epicanthus; - high nasal bridge, bulbous nasal tip, anteverted nares; - smooth, short philtrum; thin upper lip; fleshy lower lip; open mouth; - widely spaced teeth; low-set fleshy ears; rectangular chin.

The authors note some resemblance to Angelman syndrome and to chromatinopathies. The S proband also had a high forehead, low-set ears, macrostomia and macroglossia.

Onset, severity and course. Onset is congenital or infantile: hypotonia in the neonatal period or infancy, seizures at 3–9 months. Severity is usually severe and varies between patients. The disorder is neurodevelopmental and has not been described as degenerative. In the S proband, skills regressed after spasm onset.

Quality of life. No formal QoL instruments have been used. The main burdens are severe ID, the fact that most patients are nonverbal, refractory epilepsy in a subset, and feeding problems, including tube feeding.

4. Genetic and Molecular Information

Gene and protein. TRA2B is on chromosome 3 and has 9 protein-coding exons. It produces two isoforms that matter here: - Tra2β-1 (NP_004584.1, from NM_004593.3, the MANE transcript). This is the full-length protein, with domains in the order RS1 – RRM – RS2. It is expressed ubiquitously, including in the developing brain. - Tra2β-3 (NP_001230808.1, from NM_001243879.2). This transcript skips exon 2 and starts translation at a downstream ATG in exon 3. The resulting protein keeps the RRM and RS2 but lacks RS1. The isoform is normally expressed at low levels and in a tissue-restricted, developmentally regulated way.

Variants. Ramond reported 11 variants in 12 individuals, all heterozygous and all on NM_004593.3. All were absent from gnomAD, and none lies downstream of the Tra2β-3 start codon. - Start-loss (6): c.1A>G, c.1A>T, c.2T>C, c.2T>G, c.2_4del, and a small 5′ deletion read from the figure as c.-11_22del. Confirm the exact HGVS against Supplemental Table 2. - Nonsense (2): read from the figure as c.16G>T p.(Glu6Ter) and a second variant near codon 7. Confirm both in Supplemental Table 2. - Splice (3): c.170+1del, c.170+2T>C, c.171-2A>G. - Shatokhina: c.170+1G>A, p.Glu13Valfs*2, ClinVar SCV004032532. Classified pathogenic (PVS1, PS2, PM2). Fibroblast RT-PCR showed an aberrant transcript lacking exon 2 (134 bp shorter).

The authors state that the Ramond variants would meet ACMG criteria for likely pathogenic or pathogenic if TRA2B were an established disease gene.

Functional class. Each variant looks like loss-of-function on its own, but the authors argue the disease acts through a dominant-negative mechanism: Tra2β-1 is lost and the RS1-less Tra2β-3 is relatively overexpressed. They explicitly leave open a gain-of-function effect of Tra2β-3 that does not depend on Tra2β-1. Three findings argue against simple haploinsufficiency: 1. Heterozygous Tra2b knockout mice appear normal. 2. In individual 5 (c.2_4del), the mutant allele's mRNA is expressed at about 50% and is not degraded by nonsense-mediated decay. 3. The variants cluster tightly in the 5′ region.

Other genetic categories. No modifier genes, epigenetic findings, chromosomal abnormalities or somatic contributions are reported. Population carrier frequency is effectively zero, since the variants are absent from gnomAD.

Panel curation. - PanelApp Australia: Green (high evidence), monoallelic, on its ID/epilepsy panels. - Genomics England "Severe microcephaly" panel: Amber, because only two unrelated cases had severe microcephaly.

5. Environmental Information

Not applicable. No environmental, lifestyle or infectious contributors are known.

6. Mechanism and Pathophysiology

Causal chain: 1. A heterozygous variant in the 5′ coding region (exon 1 to the exon 2/3 boundary) prevents production of full-length Tra2β-1 from that allele. It does this by removing the start codon, adding a premature stop, or causing exon 2 to be skipped. This was shown by western blot with an N-terminal antibody in 4 patient cell lines. 2. On the mutant allele, translation re-initiates at the alternative ATG in exon 3, which increases expression of the ~20 kDa Tra2β-3 isoform. This was shown with a C-terminal antibody in fibroblasts and lymphoblastoid cells. Whether Tra2β-3 comes specifically from the mutant allele is inferred, not proven. 3. Tra2β-3 still has its RRM, so it binds the same exonic sites (AGAA-rich) as Tra2β-1. Because it lacks RS1, it cannot recruit the spliceosome. It therefore acts as a competitive splicing repressor. This part is demonstrated in vitro: in HEK293 cells, a Tra2β-3-GFP construct reduced CHEK1 exon 3 inclusion in a dose-dependent way, even when Tra2β-1-GFP was co-expressed. 4. This reduces inclusion of exons that depend on Tra2β in patient cells. CHEK1 exon 3 PSI was 56% in patient lymphoblastoid cells against 88% in controls. The genes whose missplicing actually causes the brain phenotype are unknown. The authors suggest candidates whose loss causes overlapping syndromes: NIPBL (Cornelia de Lange), ATRX (ATR-X) and SON (ZTTK). This step is inferred. 5. Abnormal splicing during brain development (inferred) leads to: - 5a. disturbed cortical and white-matter development, giving microcephaly, atrophy, ventriculomegaly, a thin corpus callosum and delayed myelination. Mouse data suggest apoptosis of neural progenitors as one route: neuron-specific Tra2b knockout mice show massive apoptosis in the cortical ventricular layers and p21 upregulation (PMID:24586484). - 5b. cortical network hyperexcitability, giving infantile spasms and epileptic encephalopathy. The mechanism is unknown. 6. The clinical result is ID/DD, epilepsy, hypotonia, behavioural problems including autism, and feeding difficulties and growth failure. How systemic features such as short stature and skeletal anomalies arise is not established.

Cellular and subcellular context. Splicing regulation happens in the nucleus; SR-type proteins localise to nuclear speckles. The likely relevant cells are neurons and neural progenitors of the developing cortex. Patient-derived assays used lymphoblastoid cells and fibroblasts. No metabolic, immune or omics signatures have been described beyond RNA-seq in one patient's lymphoblastoid cells, which showed no global change in TRA2B expression.

Candidate ontology terms (verify all): - GO biological process: GO:0000381 regulation of alternative mRNA splicing, via spliceosome; GO:0048025 negative regulation of mRNA splicing, via spliceosome; GO:0021987 cerebral cortex development; GO:0006915 apoptotic process. - GO molecular function / cellular component: GO:0003729 mRNA binding; GO:0016607 nuclear speck. - Cell types: CL:0000540 neuron; CL:0011020 neural progenitor cell.

7. Anatomical Structures Affected

Primary site: the brain. Candidate UBERON terms: cerebral cortex UBERON:0000956, corpus callosum UBERON:0002336, cerebral white matter, cerebellum UBERON:0002037.
Secondary involvement:
visual pathways (cortical visual impairment);
gastrointestinal tract (feeding problems, constipation);
skeleton (scoliosis, brachydactyly, pectus excavatum);
heart (minor malformations);
growth.
Lateralisation: findings are bilateral and diffuse. The one focal cortical dysplasia was a single lesion.

8. Temporal Development

Onset: congenital or infantile. Hypotonia starts in the neonatal period or infancy, and seizures start at 3–9 months.
Epilepsy course in the Ramond cohort:
Spasms resolved in late infancy in 3 individuals. Two of them were seizure-free and off medication in adolescence; the third became seizure-free at 6 years after steroids and valproate.
Epilepsy evolved unfavourably in 3: one had an unspecified epileptic encephalopathy, one became drug-resistant despite vagus nerve stimulation, and one progressed to Lennox-Gastaut syndrome.
Overall course: lifelong and static. No staging exists. Infancy, when spasms start, is the critical window for treatment.

9. Inheritance and Population

Inheritance: autosomal dominant (candidate term HP:0000006). Penetrance was "possibly full" according to the authors, but is unproven with only one transmitting family. Expressivity is variable.
Epidemiology: no prevalence or incidence data. About 13 cases have been published worldwide, which places it in the Orphanet band below 1 in 1,000,000. Record the measure as CASES_IN_LITERATURE.
Population features: the 7 males and 6 females come from Europe (France, Germany, Italy, UK, Denmark), Israel, Chile, the USA and Russia. No founder effects, no role for consanguinity, and no carrier frequency are reported.

10. Diagnostics

Recommended test: exome or genome sequencing. All cases were found by clinical exome sequencing. TRA2B is on ID, epilepsy and microcephaly panels (PanelApp Australia; Genomics England).
Supporting tests:
EEG, which may show hypsarrhythmia.
Brain MRI, which may show nonspecific atrophy, ventriculomegaly, a thin corpus callosum or delayed myelination.
RT-PCR or RNA studies to confirm splice variants, as Shatokhina did with exon 2 skipping.
Western blot for the Tra2β-1 to Tra2β-3 ratio. This is research use only.
Not useful: chromosomal microarray, karyotype and FISH, which do not detect point variants.
Biomarkers and criteria: there are no biochemical biomarkers and no formal diagnostic criteria.
Differential diagnosis: the authors tested for and excluded several conditions in some patients:
Angelman syndrome (methylation PCR);
ARX and MECP2 disorders;
Coffin-Siris syndrome and other chromatinopathies;
mitochondrial disease (mtDNA sequencing). Other infantile spasm aetiologies should also be considered.
Screening: there is no newborn or carrier screening.

11. Outcome and Prognosis

Survival: no data on survival or mortality. The oldest known individual is a 31-year-old father with a milder presentation, so survival into adulthood is possible.
Morbidity: severe ID in most patients, a nonverbal majority, delayed or absent walking, and refractory epilepsy in about a quarter of the cohort (3/12).
Prognostic factors: none established. Early resolution of spasms was seen in 3 patients.

12. Treatment

There is no disease-specific therapy. Care is symptomatic. Suggested NCIT terms for this care (Supportive Care NCIT:C15747, Physical Therapy NCIT:C15302, Genetic Counseling NCIT:C15240) are listed in section 13.

Treatment	Evidence	Candidate NCIT term (verify)
ACTH (tetracosactide) or steroids for spasms	S: seizures controlled for 4 months with tetracosactide plus topiramate, relapsing when topiramate was stopped. Ramond: seizure-free after steroids and valproate	Pharmacotherapy NCIT:C15986 + therapeutic_agent
Valproate, topiramate, ethosuximide	anecdotal	as above
Ketogenic diet	S: seizures controlled for 5 months, with cognitive gains. Ramond: one patient seizure-free from age 1 to 5 on the diet	Dietary Intervention NCIT:C15447
Vagus nerve stimulation	failed in one patient	—
Epilepsy surgery	one resection, with focal cortical dysplasia on histology	Surgical Procedure NCIT:C15329
Gastrostomy	one patient	—
Melatonin for sleep	helped one patient	—
Physical, occupational and speech therapy	standard care	NCIT:C15302 and others

No clinical trials were found.
Possible future direction: isoform-switching antisense oligonucleotides that reduce Tra2β-3 or restore Tra2β-1. This is speculation only.

13. Prevention

Prevention is through genetic counselling (NCIT:C15240).
Recurrence risk is 50% when a parent carries the variant, as in the one transmitting family. In de novo cases it is low, but parental germline mosaicism cannot be excluded.
Prenatal or preimplantation testing is possible once the family variant is known.
Tertiary prevention: early treatment of spasms, and surveillance of feeding, vision and the spine.

14. Other Species / Natural Disease

No naturally occurring animal disease was found (OMIA not checked). TRA2B is conserved across vertebrates: the mouse orthologue Tra2b (also called Sfrs10) and a zebrafish orthologue in ZFIN (ZDB-GENE-040426-1094). The Tra2 family itself is conserved across the animal kingdom.

15. Model Organisms

Model	Finding	PMID
Mouse, ubiquitous homozygous Tra2b (Sfrs10) knockout	Embryonic lethality around E7.5; heterozygotes normal	20190275 (Mende et al. 2010, Hum Mol Genet; PMID taken from a database RDF link, so confirm it)
Mouse, Nestin-Cre neuronal Tra2b knockout	Death right after birth, severe cortical abnormalities, massive apoptosis in cortical ventricular layers, p21 upregulation	24586484 (Storbeck et al. 2014, PLoS ONE)
Mouse, cortex-specific knockout	Brain abnormalities, but mice survive to adulthood	cited in Ramond; not retrieved
HEK293 overexpression and CHEK1 exon 3 minigene	Tra2β-3 represses the exon in a dose-dependent way	36549593
Patient fibroblasts and lymphoblastoid cells	Tra2β-1 reduced, Tra2β-3 increased, CHEK1 exon 3 PSI reduced	36549593

Key limitation. No model carries the patients' allele. Heterozygous knockouts do not reproduce the disease, which supports the dominant-negative model but means causality has not been shown in an animal. This fits the repo's HUMAN_MODEL_MISMATCH discussion kind and its FAILS_TO_RECAPITULATE model link. A knock-in mouse carrying a start-loss or exon-2 splice variant, or a human iPSC-derived cortical organoid, would be the natural next experiment.

Key References

Ramond F, et al. Clustered variants in the 5′ coding region of TRA2B cause a distinctive neurodevelopmental syndrome. Genet Med 2023;25:100003. PMID:36549593. doi:10.1016/j.gim.2022.100003 (NCL ePrints)
Shatokhina O, et al. TRA2B gene splice variant linked to seizures and neurodevelopmental delay: a second case study. Int J Mol Sci 2023;24:15572. PMID:37958557. doi:10.3390/ijms242115572 (PMC10648248)
Storbeck M, et al. Neuronal-specific deficiency of the splicing factor Tra2b causes apoptosis in neurogenic areas of the developing mouse brain. PLoS ONE 2014. PMID:24586484 (PMC3929626)
Mende Y, et al. Deficiency of the splicing factor Sfrs10 results in early embryonic lethality in mice. Hum Mol Genet 2010;19:2154–67. PMID:20190275 (confirm) (MGI)
KEGG H03032; PanelApp Australia; Genomics England PanelApp

Gaps. My searches found no TRA2B case reports from 2024–2026, but this is not a complete PubMed sweep. There is no Orphanet entry, no GeneReviews chapter, and no ClinGen validity curation was found.

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome	Count
References checked	8
Resolved	8
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	8
On topic	6
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	50
Resolved	50
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	0
Terms whose name was checked	3
Terms named correctly	0
Terms named as a different term	2
Terms whose name is worth a second look	1

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

MONDO:0980751 (2 mentions) - the report calls it "MONDO"; MONDO calls it Ramond-Elliott neurodevelopmental syndrome
DOID:0070715 (3 mentions) - the report calls it "appears in search results; confirm it is this disease"; DOID calls it Ramond-Elliott neurodevelopmental syndrome

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

NCIT:C15240 (2 mentions) - the report calls it "Prevention is through genetic counselling"; NCIT calls it Genetic Counseling

Ramond-Elliott Neurodevelopmental Syndrome

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Ramond-Elliott Neurodevelopmental Syndrome (RAMELN; TRA2B): Research Report

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic and Molecular Information

5. Environmental Information

6. Mechanism and Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome and Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Key References

Reference Validation

Term Validation

Terms the report names something else

Terms whose name is worth a second look