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]

• 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).

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.

• 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

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.

All extracted references resolved successfully.

Term Validation

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

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