Developmental and epileptic encephalopathy, 85, with or without midline brain defects

disease

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Also known as DEE85, with or without midline brain defectsdevelopmental and epileptic encephalopathy 85, with or without midline brain defects, X-linked dominantEIEE85epileptic encephalopathy, early infantile, 85, with or without midline brain defects

Summary

Developmental and epileptic encephalopathy, 85, with or without midline brain defects (MONDO:0026771) is a disease caused by SMC1A (GenCC Definitive), with 3 cohort genes.

At a glance

Causal gene: SMC1A (GenCC Definitive)
Cohort genes: 3
ClinVar variants: 102

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	developmental and epileptic encephalopathy, 85, with or without midline brain defects
Mondo ID	MONDO:0026771
OMIM	301044
DOID	DOID:0070380
UMLS	C5393312
MedGen	1708832
GARD	0025492
Is cancer (heuristic)	no

Also known as: DEE85, with or without midline brain defects · developmental and epileptic encephalopathy 85, with or without midline brain defects, X-linked dominant · EIEE85 · epileptic encephalopathy, early infantile, 85, with or without midline brain defects

Data availability: 102 ClinVar variants · 3 GenCC gene-disease records.

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, 85, with or without midline brain defects

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

102 retrieved; paginated sample, class counts are floors:

25 uncertain significance, 17 pathogenic, 15 likely benign, 15 likely pathogenic, 13 benign/likely benign, 10 conflicting classifications of pathogenicity, 6 pathogenic/likely pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
66092	NM_001278716.2(FBXL4):c.1703G>C (p.Gly568Ala)	FBXL4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
523210	NM_006306.4(SMC1A):c.2420G>A (p.Arg807His)	MIR6857	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068642	NM_006306.4(SMC1A):c.3145C>T (p.Arg1049Ter)	SMC1A	Pathogenic	criteria provided, multiple submitters, no conflicts
1076799	NM_006306.4(SMC1A):c.2132G>A (p.Arg711Gln)	SMC1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
159947	NM_006306.4(SMC1A):c.2131C>T (p.Arg711Trp)	SMC1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
159954	NM_006306.4(SMC1A):c.3146G>A (p.Arg1049Gln)	SMC1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1691864	NM_006306.4(SMC1A):c.2076del (p.Lys692fs)	SMC1A	Pathogenic	criteria provided, single submitter
1700232	NM_006306.4(SMC1A):c.2122del (p.Leu708fs)	SMC1A	Pathogenic	criteria provided, single submitter
1704281	NM_006306.4(SMC1A):c.3123del (p.Ser1042fs)	SMC1A	Pathogenic	no assertion criteria provided
208626	NM_006306.4(SMC1A):c.2853_2856del (p.Ser951fs)	SMC1A	Pathogenic	criteria provided, multiple submitters, no conflicts
208627	NM_006306.4(SMC1A):c.3549_3552dup (p.Ile1185fs)	SMC1A	Pathogenic	criteria provided, single submitter
2772432	NM_006306.4(SMC1A):c.2890_2893del (p.Ser964fs)	SMC1A	Pathogenic	criteria provided, multiple submitters, no conflicts
3024321	NM_006306.4(SMC1A):c.298+2T>C	SMC1A	Pathogenic	criteria provided, single submitter
4077103	NM_006306.4(SMC1A):c.550_556del (p.Phe184fs)	SMC1A	Pathogenic	criteria provided, single submitter
841238	NM_006306.4(SMC1A):c.1486C>T (p.Arg496Cys)	SMC1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
845949	NM_006306.4(SMC1A):c.2161C>T (p.Gln721Ter)	SMC1A	Pathogenic	criteria provided, multiple submitters, no conflicts
864840	NM_006306.4(SMC1A):c.1911+1G>T	SMC1A	Pathogenic	no assertion criteria provided
864843	NM_006306.4(SMC1A):c.2364del (p.Asn788fs)	SMC1A	Pathogenic	no assertion criteria provided
864844	NM_006306.4(SMC1A):c.2197G>T (p.Glu733Ter)	SMC1A	Pathogenic	no assertion criteria provided
864845	NM_006306.4(SMC1A):c.2477del (p.Asn826fs)	SMC1A	Pathogenic	no assertion criteria provided
864846	NM_006306.4(SMC1A):c.3115C>T (p.Gln1039Ter)	SMC1A	Pathogenic	no assertion criteria provided
864847	NM_006306.4(SMC1A):c.2683C>G (p.Arg895Gly)	SMC1A	Pathogenic	no assertion criteria provided
864848	NM_006306.4(SMC1A):c.2394del (p.Lys798fs)	SMC1A	Pathogenic	no assertion criteria provided
1184529	NM_006306.4(SMC1A):c.3181C>T (p.Gln1061Ter)	SMC1A	Likely pathogenic	no assertion criteria provided
1325813	NM_006306.4(SMC1A):c.1072_1073del (p.Gln359fs)	SMC1A	Likely pathogenic	criteria provided, single submitter
1343250	NM_006306.4(SMC1A):c.2029AAG[1] (p.Lys678del)	SMC1A	Likely pathogenic	criteria provided, single submitter
1895410	NM_006306.4(SMC1A):c.829CAG[2] (p.Gln279del)	SMC1A	Likely pathogenic	criteria provided, single submitter
2576567	NM_006306.4(SMC1A):c.3040C>T (p.Gln1014Ter)	SMC1A	Likely pathogenic	criteria provided, single submitter
3024232	NM_006306.4(SMC1A):c.2299del (p.Glu767fs)	SMC1A	Likely pathogenic	criteria provided, single submitter
3024284	NM_006306.4(SMC1A):c.3118G>A (p.Glu1040Lys)	SMC1A	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 5 · 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
SMC1A	Definitive	X-linked	developmental and epileptic encephalopathy, 85, with or without midline brain defects	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SMC1A	Orphanet:199	Cornelia de Lange syndrome
SMC1A	Orphanet:220386	Semilobar holoprosencephaly
SMC1A	Orphanet:3095	Atypical Rett syndrome
SMC1A	Orphanet:708203	Intellectual disability-small hands and feet-drug-resistant epilepsy syndrome
FBXL4	Orphanet:369897	Mitochondrial DNA depletion syndrome, encephalomyopathic form with variable craniofacial anomalies

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SMC1A	HGNC:11111	ENSG00000072501	Q14683	Structural maintenance of chromosomes protein 1A	gencc,clinvar
FBXL4	HGNC:13601	ENSG00000112234	Q9UKA2	F-box/LRR-repeat protein 4	clinvar
MIR6857	HGNC:50263	ENSG00000278204		microRNA 6857	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SMC1A	Structural maintenance of chromosomes protein 1A	Involved in chromosome cohesion during cell cycle and in DNA repair.
FBXL4	F-box/LRR-repeat protein 4	Substrate-recognition component of the mitochondria-localized SCF-FBXL4 ubiquitin E3 ligase complex that plays a role in the restriction of mitophagy by controlling the degradation of BNIP3 and NIX mitophagy receptors.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · 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
Other/Unknown	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	InterPro (top 3)
SMC1A	Other/Unknown	no	RecF/RecN/SMC_N, SMC_hinge, SMC
FBXL4	Other/Unknown	no	F-box_dom, Leu-rich_rpt_Cys-con_subtyp, LRR_dom_sf
MIR6857	Other/Unknown	no

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)	1
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
embryo	1
sural nerve	1
trabecular bone tissue	1
adrenal tissue	1
calcaneal tendon	1
corpus epididymis	1
adult mammalian kidney	1
blood	1
esophagogastric junction muscularis propria	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SMC1A	289	ubiquitous	marker	sural nerve, trabecular bone tissue, embryo
FBXL4	265	ubiquitous	marker	adrenal tissue, corpus epididymis, calcaneal tendon
MIR6857	17		yes	blood, adult mammalian kidney, esophagogastric junction muscularis propria

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SMC1A	5,246
FBXL4	1,620
MIR6857	0

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SMC1A	Q14683	18

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FBXL4	Q9UKA2	86.50

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 26. Enrichment computed across 3 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Mitotic Telophase/Cytokinesis	1	713.8×	0.017	SMC1A
Cohesin Loading onto Chromatin	1	571.0×	0.017	SMC1A
Establishment of Sister Chromatid Cohesion	1	519.1×	0.017	SMC1A
Meiosis	1	142.8×	0.037	SMC1A
Reproduction	1	95.2×	0.037	SMC1A
S Phase	1	90.6×	0.037	SMC1A
SUMO E3 ligases SUMOylate target proteins	1	89.2×	0.037	SMC1A
SUMOylation	1	81.6×	0.037	SMC1A
SUMOylation of DNA damage response and repair proteins	1	73.2×	0.037	SMC1A
Meiotic synapsis	1	70.5×	0.037	SMC1A
ESR-mediated signaling	1	64.2×	0.037	SMC1A
Signaling by Nuclear Receptors	1	51.0×	0.038	SMC1A
Mitotic Metaphase and Anaphase	1	48.4×	0.038	SMC1A
Mitotic Anaphase	1	48.4×	0.038	SMC1A
Resolution of Sister Chromatid Cohesion	1	43.3×	0.040	SMC1A
Estrogen-dependent gene expression	1	37.8×	0.043	SMC1A
Mitotic Prometaphase	1	34.6×	0.043	SMC1A
M Phase	1	33.0×	0.043	SMC1A
Separation of Sister Chromatids	1	30.4×	0.045	SMC1A
Cell Cycle, Mitotic	1	24.1×	0.052	SMC1A
Neddylation	1	23.7×	0.052	FBXL4
Antigen processing: Ubiquitination & Proteasome degradation	1	18.6×	0.062	FBXL4
Cell Cycle	1	18.0×	0.062	SMC1A
Post-translational protein modification	1	9.6×	0.110	SMC1A
Metabolism of proteins	1	6.2×	0.161	SMC1A
Signal Transduction	1	5.1×	0.187	SMC1A

GO biological processes by enrichment

GO term	Cohort genes	Fold	FDR	Sample cohort genes
response to DNA damage checkpoint signaling	1	4213.0×	0.004	SMC1A
establishment of meiotic sister chromatid cohesion	1	2106.5×	0.004	SMC1A
establishment of mitotic sister chromatid cohesion	1	1203.7×	0.004	SMC1A
negative regulation of mitophagy	1	766.0×	0.005	FBXL4
response to radiation	1	601.9×	0.005	SMC1A
mitotic sister chromatid cohesion	1	561.7×	0.005	SMC1A
sister chromatid cohesion	1	383.0×	0.005	SMC1A
autophagy of mitochondrion	1	366.4×	0.005	FBXL4
mitotic sister chromatid segregation	1	240.7×	0.007	SMC1A
SCF-dependent proteasomal ubiquitin-dependent protein catabolic process	1	187.2×	0.008	FBXL4
mitotic spindle assembly	1	172.0×	0.008	SMC1A
somatic stem cell population maintenance	1	123.9×	0.010	SMC1A
meiotic cell cycle	1	122.1×	0.010	SMC1A
ubiquitin-dependent protein catabolic process	1	37.1×	0.031	FBXL4
DNA repair	1	31.9×	0.033	SMC1A
cell division	1	23.1×	0.043	SMC1A

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
SMC1A	SELUMETINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SMC1A	2	4
FBXL4	0	0
MIR6857	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SELUMETINIB	4	SMC1A
MOLIBRESIB	2	SMC1A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SMC1A	10	Binding:10

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

2 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.

Compound	Max phase	Cohort target (bioactivity)
SELUMETINIB	4	SMC1A
MOLIBRESIB	2	SMC1A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SMC1A
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	FBXL4, MIR6857

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)
FBXL4	0	—
MIR6857	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.

Cohort genes: SMC1A, FBXL4, MIR6857