Developmental and epileptic encephalopathy, 66

disease

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Also known as DEE66developmental and epileptic encephalopathy 66EIEE66epileptic encephalopathy, early infantile, 66

Summary

Developmental and epileptic encephalopathy, 66 (MONDO:0054845) is a disease caused by PACS2 (GenCC Strong), with 2 cohort genes.

At a glance

Causal gene: PACS2 (GenCC Strong)
Cohort genes: 2
ClinVar variants: 42

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	developmental and epileptic encephalopathy, 66
Mondo ID	MONDO:0054845
OMIM	618067
DOID	DOID:0080446
UMLS	C4748070
MedGen	1648486
GARD	0025985
Is cancer (heuristic)	no

Also known as: DEE66 · developmental and epileptic encephalopathy 66 · EIEE66 · epileptic encephalopathy, early infantile, 66

Data availability: 42 ClinVar variants · 4 GenCC gene-disease records · 2 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary neurological disease › Mendelian neurodevelopmental disorder › genetic developmental and epileptic encephalopathy › developmental and epileptic encephalopathy, 66

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

42 retrieved; paginated sample, class counts are floors:

26 uncertain significance, 13 conflicting classifications of pathogenicity, 2 benign/likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
495141	NM_001100913.3(PACS2):c.625G>A (p.Glu209Lys)	PACS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1367519	NM_001100913.3(PACS2):c.119+6C>T	BRF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1213703	NM_001100913.3(PACS2):c.827C>T (p.Ala276Val)	PACS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1364592	NM_001100913.3(PACS2):c.2272G>A (p.Glu758Lys)	PACS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1397191	NM_001100913.3(PACS2):c.598G>A (p.Glu200Lys)	PACS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1491047	NM_001100913.3(PACS2):c.502G>A (p.Glu168Lys)	PACS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1621296	NM_001100913.3(PACS2):c.1294C>T (p.Arg432Trp)	PACS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1708350	NM_001100913.3(PACS2):c.1049C>T (p.Pro350Leu)	PACS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2434559	NM_001100913.3(PACS2):c.1873C>T (p.Leu625=)	PACS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2434561	NM_001100913.3(PACS2):c.2626G>A (p.Val876Ile)	PACS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2434563	NM_001100913.3(PACS2):c.643G>A (p.Asp215Asn)	PACS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
930460	NM_001100913.3(PACS2):c.1381G>A (p.Asp461Asn)	PACS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
977391	NM_001100913.3(PACS2):c.1072C>T (p.Arg358Trp)	PACS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
983365	NM_001100913.3(PACS2):c.452A>G (p.Gln151Arg)	PACS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1029076	NM_001100913.3(PACS2):c.58G>A (p.Val20Met)	BRF1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1441469	NM_001100913.3(PACS2):c.7G>C (p.Glu3Gln)	BRF1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1098672	NM_001100913.3(PACS2):c.2315C>G (p.Pro772Arg)	PACS2	Uncertain significance	criteria provided, single submitter
1184372	NM_001100913.3(PACS2):c.2263G>A (p.Val755Ile)	PACS2	Uncertain significance	criteria provided, single submitter
1328390	NM_001100913.3(PACS2):c.1507T>C (p.Trp503Arg)	PACS2	Uncertain significance	criteria provided, single submitter
1341720	NM_001100913.3(PACS2):c.2647G>A (p.Ala883Thr)	PACS2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1349224	NM_001100913.3(PACS2):c.257G>A (p.Gly86Glu)	PACS2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1512419	NM_001100913.3(PACS2):c.1813G>A (p.Val605Met)	PACS2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1709848	NM_001100913.3(PACS2):c.622T>G (p.Ser208Ala)	PACS2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1810540	NM_001100913.3(PACS2):c.986C>G (p.Ser329Trp)	PACS2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1878613	NM_001100913.3(PACS2):c.2479A>C (p.Lys827Gln)	PACS2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2434556	NM_001100913.3(PACS2):c.1454T>A (p.Leu485His)	PACS2	Uncertain significance	criteria provided, single submitter
2434557	NM_001100913.3(PACS2):c.1541G>A (p.Arg514Lys)	PACS2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2434558	NM_001100913.3(PACS2):c.371G>T (p.Arg124Ile)	PACS2	Uncertain significance	criteria provided, single submitter
2434560	NM_001100913.3(PACS2):c.1927C>T (p.Gln643Ter)	PACS2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2434562	NM_001100913.3(PACS2):c.368A>C (p.Asn123Thr)	PACS2	Uncertain significance	criteria provided, single submitter

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
PACS2	Strong	Autosomal dominant	developmental and epileptic encephalopathy, 66	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PACS2	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
BRF1	Orphanet:444072	Cerebellar-facial-dental 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
PACS2	HGNC:23794	ENSG00000179364	Q86VP3	Phosphofurin acidic cluster sorting protein 2	gencc,clinvar
BRF1	HGNC:11551	ENSG00000185024	Q92994	Transcription factor IIIB 90 kDa subunit	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PACS2	Phosphofurin acidic cluster sorting protein 2	Multifunctional sorting protein that controls the endoplasmic reticulum (ER)-mitochondria communication, including the apposition of mitochondria with the ER and ER homeostasis.
BRF1	Transcription factor IIIB 90 kDa subunit	General activator of RNA polymerase which utilizes different TFIIIB complexes at structurally distinct promoters.

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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PACS2	Other/Unknown	no		PACS1/2_C, PACS1/2_N
BRF1	Transcription factor	no		TFIIB, BRF1_TBP-bd_dom, Znf_TFIIB

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 hemisphere of cerebellum	2
C1 segment of cervical spinal cord	1
spinal cord	1
right uterine tube	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PACS2	281	ubiquitous	marker	C1 segment of cervical spinal cord, spinal cord, right hemisphere of cerebellum
BRF1	198	ubiquitous	marker	sural nerve, right uterine tube, right hemisphere of cerebellum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BRF1	1,175
PACS2	934

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
BRF1	Q92994	70.22
PACS2	Q86VP3	67.10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. 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
RNA Polymerase III Transcription Initiation From Type 2 Promoter	1	423.0×	0.004	BRF1
RNA Polymerase III Transcription Initiation From Type 1 Promoter	1	407.9×	0.004	BRF1
RNA Polymerase III Transcription Initiation	1	335.9×	0.004	BRF1
RNA Polymerase III Transcription	1	326.3×	0.004	BRF1
RNA Polymerase III Abortive And Retractive Initiation	1	278.5×	0.004	BRF1
Gene expression (Transcription)	1	17.8×	0.056	BRF1

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
tRNA transcription	1	4213.0×	0.002	BRF1
transcription preinitiation complex assembly	1	2808.7×	0.002	BRF1
transcription initiation at RNA polymerase III promoter	1	1203.7×	0.003	BRF1
obsolete mitochondrion-endoplasmic reticulum membrane tethering	1	1053.2×	0.003	PACS2
rRNA transcription	1	495.6×	0.003	BRF1
protein localization to phagophore assembly site	1	495.6×	0.003	PACS2
DNA-templated transcription initiation	1	468.1×	0.003	BRF1
endoplasmic reticulum calcium ion homeostasis	1	421.3×	0.003	PACS2
transcription by RNA polymerase III	1	383.0×	0.003	BRF1
autophagosome assembly	1	112.3×	0.011	PACS2
protein localization to plasma membrane	1	54.4×	0.020	PACS2
apoptotic process	1	14.3×	0.068	PACS2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PACS2	0	0
BRF1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
BRF1	1	Binding:1

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	PACS2, BRF1

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)
PACS2	0	—
BRF1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.

Cohort genes: PACS2, BRF1