Encephalopathy, progressive, early-onset, with episodic rhabdomyolysis

Summary

Encephalopathy, progressive, early-onset, with episodic rhabdomyolysis (MONDO:0032681) is a disease caused by TRAPPC2L (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: TRAPPC2L (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 15

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	encephalopathy, progressive, early-onset, with episodic rhabdomyolysis
Mondo ID	MONDO:0032681
OMIM	618331
UMLS	C5193033
MedGen	1682670
Is cancer (heuristic)	no

Also known as: PEERB

Data availability: 15 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › Mendelian encephalopathy › encephalopathy, progressive, early-onset, with episodic rhabdomyolysis

Related subtypes (18): encephalopathy, recurrent, of childhood, encephalopathy, axonal, with necrotizing myopathy, cardiomyopathy, and cataracts, Bonnemann-Meinecke-Reich syndrome, severe neonatal-onset encephalopathy with microcephaly, ethylmalonic encephalopathy, familial encephalopathy with neuroserpin inclusion bodies, spongiform encephalopathy with neuropsychiatric features, familial acute necrotizing encephalopathy, encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1, severe neurodegenerative syndrome with lipodystrophy, encephalopathy due to defective mitochondrial and peroxisomal fission 2, encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, encephalopathy, progressive, with amyotrophy and optic atrophy, encephalitis/encephalopathy, mild, with reversible myelin vacuolization, early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome, early-onset progressive encephalopathy-hearing loss-pons hypoplasia-brain atrophy syndrome, encephalopathy, neonatal severe, with lactic acidosis and brain abnormalities, encephalopathy, porphyria-related

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

15 retrieved; paginated sample, class counts are floors:

5 uncertain significance, 3 pathogenic, 2 likely pathogenic, 2 benign/likely benign, 1 pathogenic/likely pathogenic, 1 likely benign, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
217881	NM_013275.6(ANKRD11):c.7180C>T (p.Gln2394Ter)	ANKRD11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
803286	NC_000016.10:g.89282397dup	ANKRD11	Pathogenic	criteria provided, single submitter
619097	NM_001318525.2(TRAPPC2L):c.109G>T (p.Asp37Tyr)	TRAPPC2L	Pathogenic	no assertion criteria provided
803287	NC_000016.10:g.89282939dup	TRAPPC2L	Pathogenic	criteria provided, single submitter
2442007	NM_001318525.2(TRAPPC2L):c.33+2T>G	TRAPPC2L	Likely pathogenic	criteria provided, single submitter
2628106	NM_001318525.2(TRAPPC2L):c.164A>T (p.Glu55Val)	TRAPPC2L	Likely pathogenic	criteria provided, single submitter
932239	NM_001318525.2(TRAPPC2L):c.5C>G (p.Ala2Gly)	TRAPPC2L	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1030538	NM_001318525.2(TRAPPC2L):c.350A>G (p.Asn117Ser)	TRAPPC2L	Uncertain significance	criteria provided, multiple submitters, no conflicts
2431365	NM_001318525.2(TRAPPC2L):c.33+5G>A	TRAPPC2L	Uncertain significance	criteria provided, single submitter
2442210	NM_001318525.2(TRAPPC2L):c.33G>A (p.Glu11=)	TRAPPC2L	Uncertain significance	criteria provided, multiple submitters, no conflicts
3581376	NM_001318525.2(TRAPPC2L):c.97C>T (p.His33Tyr)	TRAPPC2L	Uncertain significance	criteria provided, multiple submitters, no conflicts
3581377	NM_001318525.2(TRAPPC2L):c.133G>A (p.Ala45Thr)	TRAPPC2L	Uncertain significance	criteria provided, single submitter
585399	NM_013275.6(ANKRD11):c.136G>A (p.Asp46Asn)	ANKRD11	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
588478	NM_013275.6(ANKRD11):c.5632T>C (p.Ser1878Pro)	ANKRD11	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
2647014	NM_001318525.2(TRAPPC2L):c.119A>G (p.Asp40Gly)	TRAPPC2L	Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
TRAPPC2L	Strong	Autosomal recessive	encephalopathy, progressive, early-onset, with episodic rhabdomyolysis	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ANKRD11	Orphanet:2332	KBG syndrome
ANKRD11	Orphanet:261250	16q24.3 microdeletion syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TRAPPC2L	HGNC:30887	ENSG00000167515	Q9UL33	Trafficking protein particle complex subunit 2-like protein	gencc,clinvar
ANKRD11	HGNC:21316	ENSG00000167522	Q6UB99	Ankyrin repeat domain-containing protein 11	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TRAPPC2L	Trafficking protein particle complex subunit 2-like protein	Plays a role in vesicular transport from endoplasmic reticulum to Golgi.
ANKRD11	Ankyrin repeat domain-containing protein 11	Chromatin regulator which modulates histone acetylation and gene expression in neural precursor cells.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Scaffold/PPI	1	8.6×	0.225
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TRAPPC2L	Other/Unknown	no		Sedlin, Longin-like_dom_sf, TRAPPC2L
ANKRD11	Scaffold/PPI	no		Ankyrin_rpt, Ankyrin_rpt-contain_sf, ANKRD11

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right adrenal gland	1
right adrenal gland cortex	1
right testis	1
stromal cell of endometrium	1
sural nerve	1
tendon of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TRAPPC2L	285	ubiquitous	marker	right adrenal gland cortex, right adrenal gland, right testis
ANKRD11	278	ubiquitous	marker	tendon of biceps brachii, sural nerve, stromal cell of endometrium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ANKRD11	2,384
TRAPPC2L	1,387

Structural data

PDB: 0 · AlphaFold-only: 2 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TRAPPC2L	Q9UL33	92.21
ANKRD11	Q6UB99	39.44

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 2 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
COPII-mediated vesicle transport	1	163.1×	0.008	TRAPPC2L
RAB GEFs exchange GTP for GDP on RABs	1	124.1×	0.008	TRAPPC2L

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
vesicle coat assembly	1	766.0×	0.006	TRAPPC2L
obsolete vesicle tethering	1	495.6×	0.006	TRAPPC2L
COPII vesicle coat assembly	1	351.1×	0.006	TRAPPC2L
skeletal system morphogenesis	1	247.8×	0.006	ANKRD11
face morphogenesis	1	247.8×	0.006	ANKRD11
odontogenesis of dentin-containing tooth	1	150.5×	0.008	ANKRD11
endoplasmic reticulum to Golgi vesicle-mediated transport	1	68.0×	0.015	TRAPPC2L

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TRAPPC2L	0	0
ANKRD11	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	TRAPPC2L, ANKRD11

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
TRAPPC2L	0	—
ANKRD11	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.