| Domain | Summary | Ontology term suggestions | Key evidence |
|---|---|---|---|
| Definition / names | Ultra-rare Mendelian neurodevelopmental disorder caused by biallelic TRAPPC12 variants, first linked in 2017 to progressive childhood encephalopathy with Golgi dysfunction. Names used in the literature include **TRAPPC12-related encephalopathy**, **progressive encephalopathy with brain atrophy and spasticity (PEBAS)**, and **early-onset progressive encephalopathy–hearing loss–pons hypoplasia–brain atrophy syndrome**. MIM/OMIM association reported in the literature: **614139**. MONDO, Orphanet, ICD, MeSH: **not established from retrieved sources**. | MONDO: not established; HP: Neurodevelopmental abnormality [suggest HP:0012759] | (pqac-00000011, pqac-00000017, pqac-00000009) |
| Inheritance | **Autosomal recessive** / biallelic disease. Discovery cohort included one consanguineous family and one non-consanguineous family. | HP: Autosomal recessive inheritance (suggest HP:0000007) | (pqac-00000011, pqac-00000014) |
| Gene and aliases | Causal gene: **TRAPPC12**. Reported aliases: **TTC15, TRAMM, CGI-87**. TRAPPC12 is a **TRAPPIII-specific subunit** involved in vesicle trafficking; it has **no yeast ortholog** in retrieved mechanistic studies. | HGNC gene symbol: TRAPPC12; GO CC suggestions: ER exit site, ER-Golgi intermediate compartment, Golgi apparatus | (pqac-00000015, pqac-00000004, pqac-00000017) |
| Established variants | Discovery cohort variants: **c.145delG (p.Glu49Argfs*14)** homozygous; **c.360dupC (p.Glu121Argfs*7)** and **c.1880C>T (p.Ala627Val)** compound heterozygous. Additional reported variant from later Turkish report/preprint: **c.679T>G (p.Phe227Val)** homozygous. 2024 review states ClinVar lists **21 pathogenic/likely pathogenic variants** including frameshift, nonsense, and splicing variants, but complete curated list was not extracted here. | SO terms suggested: frameshift_variant, missense_variant, splice_region_variant; HP: Homozygosity / Compound heterozygosity not typically HPO-coded | (pqac-00000011, pqac-00000013, pqac-00000017, pqac-00000009) |
| Hallmark phenotypes and discovery-cohort frequencies | In the original 3-patient cohort: severe global developmental delay **3/3**, regression **3/3**, truncal hypotonia **3/3**, appendicular spasticity **3/3**, dystonia/myoclonus **3/3**, hearing loss/failed otoacoustic screening **3/3**, scoliosis **3/3**, dysphagia/reflux **3/3**, severe disability **3/3**; microcephaly **3/3** (acquired in 1, congenital in 2); epilepsy **2/3**; West syndrome **1/3**; optic pathway/visual abnormalities **3/3**; neurogenic bladder **1/3**. Later reports broaden phenotype to milder disease and fetal hydrocephalus/ventriculomegaly. | HP suggestions: Global developmental delay HP:0001263; Developmental regression HP:0002376; Hypotonia HP:0001252; Spasticity HP:0001257; Dystonia HP:0001332; Myoclonus HP:0001336; Sensorineural/mixed hearing impairment HP:0000407; Microcephaly HP:0000252; Seizure HP:0001250; West syndrome/Infantile spasms HP:0012469; Scoliosis HP:0002650; Dysphagia HP:0002015; Optic atrophy HP:0000648 | (pqac-00000011, pqac-00000014, pqac-00000002, pqac-00000017) |
| MRI / neuroimaging signature | Discovery cohort imaging signature: severe cortical/supratentorial atrophy **3/3**, ventriculomegaly **3/3**, prominent extra-axial spaces **3/3**, increased T2 cortical white matter signal **3/3**, severe pons hypoplasia **3/3**, agenesis or severe thinning of corpus callosum **3/3**, relatively spared basal ganglia **3/3**, mild cerebellar hypoplasia **2/3**, small optic chiasm **2/3**. One patient had progressive ventriculomegaly beyond expected cortical volume loss; later literature mentions severe hydrocephalus/hydrocephaly in some cases. | HP suggestions: Cerebral atrophy HP:0002059; Ventriculomegaly HP:0002119; Abnormal corpus callosum morphology / Agenesis HP:0001274 / HP:0001273; Pontine hypoplasia HP:0007366; Cerebellar hypoplasia HP:0001321; Delayed myelination / abnormal white matter signal HP:0012448 | (pqac-00000013, pqac-00000014, pqac-00000009) |
| Mechanism / pathophysiology | Best-supported mechanism is **loss of TRAPPC12 protein leading to Golgi fragmentation and delayed ER-to-Golgi trafficking**. Patient fibroblasts showed fragmented Golgi rescued by wild-type TRAPPC12; trafficking into and through the Golgi was delayed. Independent cell studies place TRAPPC12 at **ER exit sites and ERGIC**, where it promotes **Sec13/Sec31 COPII outer-coat recruitment**. Additional roles include **mitosis/kinetochore function** and **ciliogenesis via OFD1**, but the human encephalopathy phenotype is most directly linked to membrane-trafficking defects. | GO BP suggestions: vesicle-mediated transport, ER to Golgi vesicle-mediated transport, COPII-coated vesicle budding, protein localization to Golgi, ciliogenesis, mitotic chromosome congression; GO CC: ER exit site, ERGIC, Golgi apparatus, kinetochore, primary cilium | (pqac-00000013, pqac-00000015, pqac-00000004, pqac-00000010) |
| Diagnostics | Diagnosis in published cases relied on **exome sequencing/WES** with segregation confirmation by **Sanger sequencing**. Supportive tests included **brain MRI**, **EEG** (hypsarrhythmia in the West syndrome case), newborn **otoacoustic emission hearing screening**, and clinical neurologic assessment. One case had extensive metabolic workup negative except **moderately elevated CSF lactate 3.2 mM**. No validated disease-specific biochemical biomarker is established. | NCIT/LOINC-style suggestions not established; HP: Hypsarrhythmia HP:0010849; Abnormal CSF lactate HP:0025435 | (pqac-00000014, pqac-00000001, pqac-00000011) |
| Treatment / management | **No disease-modifying therapy established.** Published management is supportive/symptom-directed: seizure management, feeding support including **G-tube dependence** in 2 patients, hearing evaluation, and multidisciplinary neurologic/rehabilitative care. No TRAPPC12-specific interventional clinical trials were identified. | NCIT suggestions: Supportive care; Gastrostomy; Anticonvulsant therapy; Physical therapy; Speech/feeding therapy | (pqac-00000011, pqac-00000014) |
| Epidemiology / population | **Extremely rare**; only a small number of families/cases reported in the retrieved literature. No validated prevalence or incidence estimate. Discovery paper cites progressive childhood encephalopathy overall at **0.60 per 1,000 live births**, but that figure applies to the broad syndrome class, **not specifically to TRAPPC12-related disease**. No established founder effect, penetrance estimate, carrier frequency for the disease overall, sex ratio, or geographic distribution. Variant-specific population note: p.Phe227Val observed **2/237,118 gnomAD exome alleles** in heterozygous state in the 2023 preprint. | MONDO/epidemiology ontology: not established | (pqac-00000011, pqac-00000017) |
| Prognosis | Available data suggest **early-onset, progressive, high-morbidity encephalopathy** with severe long-term disability. In the discovery cohort, **1/3 died at 4 years 9 months** (presumed respiratory insufficiency). Later reports indicate phenotypic expansion to milder forms without epilepsy or without microcephaly in some cases, so prognosis appears variable but generally serious. Formal survival curves, life expectancy, and QoL studies are **not established**. | HP suggestions: Progressive neurologic deterioration HP:0002344; Respiratory insufficiency HP:0002093 | (pqac-00000014, pqac-00000017, pqac-00000009) |
| Evidence gaps | No confirmed MONDO/Orphanet/ICD identifier from retrieved sources; no disease-specific guidelines; no controlled treatment studies; no prevalence/incidence study; no penetrance/expressivity quantification; no established modifier genes; no epigenetic, transcriptomic, proteomic, metabolomic, lipidomic, single-cell, spatial, iPSC, organoid, or animal disease model specific to TRAPPC12 retrieved here; no validated preventive intervention beyond genetic counseling/testing in at-risk families. | Suggested annotations: “not established” where identifier or evidence is unavailable | (pqac-00000009, pqac-00000017, pqac-00000015) |


*Table: This table provides a concise knowledge-base style summary of TRAPPC12-related encephalopathy, emphasizing established human genetic and clinical evidence while clearly marking identifiers and data elements that are not yet established.*