Research report: developmental delay with or without dysmorphic facies and autism (TRRAP-related; MONDO:0032760)

Verification status. I checked the following in this session: the Cogné 2019 cohort data (via PMC6407527), the ClinGen gene-validity row already in the repo, the repo stub, the PanelApp listing, and the Trrap mouse-knockout lethality (via search snippets). The MIM number #618454 comes from a conference poster and one search snippet, so confirm it in OMIM before binding. Everything else is marked "not verified" or "from memory". No curation entry exists yet. The stub stubs/Developmental_Delay_With_Or_Without_Dysmorphic_Facies_And_Autism.yaml is UNDECIDED and lists one causal gene, hgnc:12347 (TRRAP). I have not edited the repo.

1. Disease information

• Overview. This is an autosomal dominant neurodevelopmental disorder caused by heterozygous, mostly de novo, missense variants in TRRAP. Core features are global developmental delay and intellectual disability. Variable features include autism, seizures, facial dysmorphism, and malformations of the brain, heart, kidney, genitalia and palate.
• Identifiers.
• MONDO:0032760.
• OMIM phenotype #618454. This is secondary-source only, from the LSU Health case-report poster, and is unconfirmed.
• The TRRAP gene MIM is 603015, as listed on PanelApp.
• HGNC: hgnc:12347.
• Orphanet, ICD-10 and MeSH: not checked.
• Synonyms. DEDDFA (abbreviation not verified). Also described as "TRRAP-related neurodevelopmental disorder".
• Overlap with ClinGen's broader term. ClinGen curates TRRAP against a different, broader MONDO term, "complex neurodevelopmental disorder with or without congenital anomalies" (MONDO:0100465). The rating is Definitive, autosomal dominant, from the Intellectual Disability and Autism GCEP, dated 2022-07-19: CGGV:assertion_03424cde-a847-4bd0-91eb-9707a7e51fa2-2022-07-19T100000.000Z. This row is in kb/genes/ingest/clingen_gene_validity.tsv. The assertion belongs to MONDO:0100465, not to this entry's term. Under the repo's "assertion must be for this entry's disease" rule, record it only if you decide the two terms are the same entity, or map with an exactMatch.
• Source level. Findings come from individual patients in sequencing cohorts, aggregated by the papers cited below. This is not an EHR-derived resource.
• Lump/split note. Cogné et al. describe two genotype-defined phenotypic clusters (see section 3). They are not separate named diseases, so the default is one entry with has_subtypes or per-phenotype notes, not two entries.

2. Etiology

• Cause. Heterozygous missense variants in TRRAP. In the primary cohort, 17 distinct variants occurred in 24 individuals, mostly de novo or "apparently de novo" (parentage not confirmed). Source: Cogné et al., Am J Hum Genet 2019, PMID:30827496.
• Genetic risk and modifiers. No modifier genes are known (not found).
• Environmental risk, protective factors and gene–environment interactions. None identified.

3. Phenotypes (Cogné 2019, Table 2)

The paper compares individuals with variants in the codon 1031–1159 cluster to those outside it.

• Facial dysmorphism. It was present in 19/24 (79%). Features were upslanted palpebral fissures, epicanthus, telecanthus, a wide nasal bridge, a broad smooth philtrum and a thin upper lip. Suggested HPO terms: HP:0000582 (upslanted palpebral fissures), HP:0000286 (epicanthus), HP:0000319 (smooth philtrum). I have not looked these up in this session, so check each CURIE and label against the ontology before binding.
• Brain MRI. 7 of 10 scanned cluster individuals had structural anomalies. The most common was cerebellar vermis hypoplasia, in 6/10.
• Neurology. Peripheral neuropathy was severe in one individual. Lower-limb hyperreflexia was noted in five others.
• Two clusters.
• Cluster 1 (codons 1031–1159, centred on p.Ala1043Thr) is the multisystem malformation syndrome with ID.
• The outside-cluster group shows ASD and/or ID with epilepsy.
• Note the naming tension: the cluster-1 variants carry no ASD in this cohort, while the disease name includes "autism". Ascertainment and sample size limit the conclusion.
• Later case report. The LSU poster reports a 9-year-old with a de novo variant in the 1031–1159 region who fits the OMIM phenotype. It is a single case and a poster, so do not cite it as evidence.
• Onset, progression and quality of life. Onset is developmental (infancy to childhood). Progression and quality-of-life data were not found.

4. Genetic and molecular information

• Gene. TRRAP (transformation/transcription domain-associated protein, 3q… locus not verified). It is a large pseudokinase scaffold in the SAGA and TIP60 histone acetyltransferase complexes.
• Variants.
• All are missense.
• Recurrent: p.Ala1043Thr (c.3127G>A) in 5 individuals, and p.Glu1106Lys and p.Gly1883Arg in 2 each.
• Thirteen individuals carried variants in codons 1031–1159. Clustering was significant (p = 9×10⁻⁸). A second, smaller aggregate sits at codons 1859–1932.
• No loss-of-function variants and no intragenic deletions (DECIPHER) were reported.
• Constraint. Missense z = 10.1 (ExAC), among the top five genes by missense intolerance. pLI = 1.00.
• Functional consequence. The authors propose gain-of-function or dominant-negative effects for the clustered variants. They consider haploinsufficiency likely lethal prenatally, since no LoF variants were seen. This is inferred, not demonstrated.
• Origin. De novo germline. Two sisters inherited a variant from a mother with low-level mosaicism, and p.Pro1932Leu is listed as germline mosaicism.
• Epigenetic and chromosomal. Not applicable. No specific methylation signature has been reported (not found).

5. Environmental information

None is established. There are no known infectious or toxic triggers.

6. Mechanism and pathophysiology

Causal chain. 1. A de novo heterozygous missense variant changes TRRAP. Clustered variants fall near codons 1031–1159 (inferred to be a hotspot domain; the specific domain was not confirmed). 2. The altered protein is thought to act as gain-of-function or dominant-negative in SAGA/TIP60 histone acetyltransferase complexes (inferred, not demonstrated here). 3. Dysregulated chromatin acetylation and transcription follows. This step is also inferred. The only direct data are the fibroblast RNA-seq findings below. 4. Disrupted neurodevelopment results, giving global developmental delay and intellectual disability. 5. The mechanism branches. Variants in the cluster are linked to multisystem malformations (heart, kidney, genitalia, palate, cerebellar vermis). Variants outside it are linked to ASD and seizures. The cause of the branching is unexplained.

Direct supporting data. - Fibroblast RNA-seq from two individuals (p.Leu805Phe and p.Trp1866Cys; both outside the cluster) versus two controls showed mostly upregulated genes. GO enrichment pointed to adrenergic receptor signalling, neuronal function and potassium/ATP-sensitive ion transport. Cogné et al. did not report HAT-activity or p53 assays. They acknowledge that non-HAT TRRAP interactions could account for the signature. - Suggested ontology terms: GO:0016573 (histone acetylation), GO:0006357 (regulation of transcription by RNA polymerase II), and the SAGA and NuA4 complexes in the GO cellular-component branch. Look all of these up before binding. Candidate Cell Ontology terms are neural progenitor cell or neuron.

Cell and tissue context. Neural progenitors are implicated by animal data. A search snippet of a 2021 zebrafish paper says Nestin-Cre conditional deletion of Trrap in mice causes premature differentiation of neural progenitors. I did not retrieve the original mouse paper.

7. Anatomical structures affected

Brain (cerebellar vermis), heart, kidney, genitalia, palate and face; occasionally peripheral nerves. Suggested UBERON terms (to be looked up): cerebellar vermis, heart, kidney. Subcellular: nucleus and chromatin, in the SAGA/TIP60 complexes.

8. Temporal development

Onset is congenital to infantile. The course appears stable. I found no natural-history, remission or critical-period data.

9. Inheritance and population

• Inheritance. Autosomal dominant, with de novo variants predominating. HP:0000006 is the mode-of-inheritance term. Mosaic parental transmission is documented (see section 4).
• Epidemiology. No prevalence or incidence data found. Penetrance, expressivity, sex ratio and founder effects: not reported.

10. Diagnostics

• Genetic testing. Exome sequencing, trio where possible, or a gene panel including TRRAP. TRRAP is Green on the PanelApp intellectual disability panel. Cogné et al. found variants mainly by exome sequencing and through GeneMatcher.
• Imaging. Brain MRI for cerebellar vermis hypoplasia.
• Differential diagnosis, screening and criteria. Not researched. There are no formal criteria.

11. Outcome and prognosis

No survival, mortality or quality-of-life data found. Lifelong intellectual disability is expected, based on 100% GDD in the cohort.

12. Treatment

No disease-specific therapy. Management is supportive: early intervention, speech, physical and occupational therapy, and seizure treatment where present. Suggested NCIT terms: NCIT:C15747 (Supportive Care), NCIT:C15302 (Physical Therapy), NCIT:C15315 (Rehabilitation). Both are in this repo's list of common NCIT terms. No clinical trials, pharmacogenomics or gene therapy were found.

13. Prevention

Genetic counselling is warranted. Recurrence risk is low for de novo cases but not zero, given documented parental mosaicism and germline mosaicism in this cohort.

14–15. Other species and model organisms

• Mouse. Complete Trrap loss is embryonic lethal. A 2001 study (Herceg et al., Nat Genet; I did not retrieve the PMID, so verify before citing) found that null mutation of Trrap causes peri-implantation lethality from blocked blastocyst proliferation. A figshare record carries a related title.
• Neural-specific deletion. Nestin-Cre conditional deletion causes premature differentiation of neural progenitors (second-hand, see section 6).
• Zebrafish. A trrap knockout shows craniofacial phenotypes (PMC8692476, Sci Rep 2021; I did not read it directly).
• Fidelity. Null models test haploinsufficiency, which the human genetics argue is not the disease mechanism. Missense knock-in models of the clustered variants were not found.
• Yeast. Tra1 deletion data are cited by Cogné et al. from prior literature.
• Natural disease in other species (OMIA). Not checked.

Curation notes for the entry

1. Evidence snippets must be exact substrings. Run just fetch-reference PMID:30827496, then quote from the cached abstract or full text. I did not quote the paper verbatim here, because the fetch tool would not return long verbatim text.
2. Decide how to relate this entry to MONDO:0100465 and the ClinGen assertion (see section 1).
3. Look up every CURIE listed above before writing it into YAML.
4. The gene-disease validity row cannot go on this entry unless the two terms are judged the same.
5. Create a claim issue first: Curate developmental delay with or without dysmorphic facies and autism (MONDO:0032760).
6. Delete the stub and add a history record in the curation PR.

Sources

• Cogné et al. 2019, AJHG (PMID:30827496)
• HAL record of Cogné et al. 2019
• PanelApp intellectual disability panel, TRRAP
• LSU Health case-report poster (OMIM #618454)
• Zebrafish trrap, Sci Rep 2021 (PMC8692476)
• Trrap embryonic lethality, figshare

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:

• HP:0000077 (1 mention) - the report calls it "coarse; prefer a more specific term"; HP calls it Abnormality of the kidney

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

• GO:0016573 (obsolete histone acetylation) (1 mention)

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:

• GO:0016573 (1 mention) - the report calls it "histone acetylation"; GO calls it obsolete histone acetylation