Developmental and epileptic encephalopathy, 65

Summary

Developmental and epileptic encephalopathy, 65 (MONDO:0033374) is a disease caused by CYFIP2 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: CYFIP2 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 65

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	developmental and epileptic encephalopathy, 65
Mondo ID	MONDO:0033374
OMIM	618008
DOID	DOID:0080430
UMLS	C4693925
MedGen	1634676
GARD	0016283
Is cancer (heuristic)	no

Also known as: DEE65 · developmental and epileptic encephalopathy 65 · EIEE65 · epileptic encephalopathy, early infantile, 65

Data availability: 65 ClinVar variants · 3 GenCC gene-disease records · 1 cell line.

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, 65

Related subtypes (104): developmental and epileptic encephalopathy, 9, developmental and epileptic encephalopathy, 8, developmental and epileptic encephalopathy, 2, multiple congenital anomalies-hypotonia-seizures syndrome 2, developmental and epileptic encephalopathy, 36, developmental and epileptic encephalopathy, 1, developmental and epileptic encephalopathy, 3, developmental and epileptic encephalopathy, 4, microcephaly, seizures, and developmental delay, developmental and epileptic encephalopathy, 5, developmental and epileptic encephalopathy, 7, developmental and epileptic encephalopathy, 11, neonatal-onset encephalopathy with rigidity and seizures, developmental and epileptic encephalopathy, 14, developmental and epileptic encephalopathy, 15, developmental and epileptic encephalopathy, 17, developmental and epileptic encephalopathy, 18, developmental and epileptic encephalopathy, 19, developmental and epileptic encephalopathy, 23, developmental and epileptic encephalopathy, 27, developmental and epileptic encephalopathy, 30, developmental and epileptic encephalopathy, 50, developmental and epileptic encephalopathy, 35, developmental and epileptic encephalopathy, 37, developmental and epileptic encephalopathy, 38, developmental and epileptic encephalopathy, 40, developmental and epileptic encephalopathy, 48, developmental and epileptic encephalopathy, 49, developmental and epileptic encephalopathy, 51, Lennox-Gastaut syndrome, developmental and epileptic encephalopathy 91, developmental and epileptic encephalopathy 92, developmental and epileptic encephalopathy 93, developmental and epileptic encephalopathy 96, developmental and epileptic encephalopathy, 90, developmental and epileptic encephalopathy, 85, with or without midline brain defects, developmental and epileptic encephalopathy, 67, developmental and epileptic encephalopathy, 86, developmental and epileptic encephalopathy, 87, developmental and epileptic encephalopathy, 88, developmental and epileptic encephalopathy 6B, developmental and epileptic encephalopathy 97, developmental and epileptic encephalopathy 98, developmental and epileptic encephalopathy 99, developmental and epileptic encephalopathy 100, developmental and epileptic encephalopathy 101, developmental and epileptic encephalopathy 89, developmental and epileptic encephalopathy 102, developmental and epileptic encephalopathy 103, developmental and epileptic encephalopathy 104, developmental and epileptic encephalopathy 105 with hypopituitarism, developmental and epileptic encephalopathy 106, developmental and epileptic encephalopathy 107, developmental and epileptic encephalopathy, 68, developmental and epileptic encephalopathy, 69, developmental and epileptic encephalopathy, 70, developmental and epileptic encephalopathy, 71, developmental and epileptic encephalopathy, 72, developmental and epileptic encephalopathy, 74, developmental and epileptic encephalopathy, 75, developmental and epileptic encephalopathy, 76, developmental and epileptic encephalopathy, 77, developmental and epileptic encephalopathy, 78, developmental and epileptic encephalopathy, 79, developmental and epileptic encephalopathy, 80, developmental and epileptic encephalopathy, 81, developmental and epileptic encephalopathy, 82, developmental and epileptic encephalopathy, 83, developmental and epileptic encephalopathy, 84, developmental and epileptic encephalopathy, 52, developmental and epileptic encephalopathy, 53, developmental and epileptic encephalopathy, 54, developmental and epileptic encephalopathy, 55, developmental and epileptic encephalopathy, 56, developmental and epileptic encephalopathy, 57, developmental and epileptic encephalopathy, 58, developmental and epileptic encephalopathy, 59, developmental and epileptic encephalopathy, 60, developmental and epileptic encephalopathy, 61, developmental and epileptic encephalopathy, 62, developmental and epileptic encephalopathy, 63, developmental and epileptic encephalopathy, 64, developmental and epileptic encephalopathy, 73, developmental and epileptic encephalopathy, 66, developmental and epileptic encephalopathy, 6A, non-neonatal early infantile epileptic encephalopathy, Dravet syndrome, neonatal-onset developmental and epileptic encephalopathy, hemiplegic migraine-developmental and epileptic encephalopathy spectrum, DNM1-encephalopathy and neurodevelopmental disorder, TMEM63B-related developmental and epileptic encephalopathy with anemia, developmental and epileptic encephalopathy 108, developmental and epileptic encephalopathy 109, developmental and epileptic encephalopathy 110, developmental and epileptic encephalopathy 111, developmental and epileptic encephalopathy 112, developmental and epileptic encephalopathy 113, developmental and epileptic encephalopathy 114, developmental and epileptic encephalopathy 115, developmental and epileptic encephalopathy 116, developmental and epileptic encephalopathy 118, developmental and epileptic encephalopathy 120, developmental and epileptic encephalopathy 121, developmental and epileptic encephalopathy 119

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

65 retrieved; paginated sample, class counts are floors:

26 uncertain significance, 9 likely pathogenic, 9 conflicting classifications of pathogenicity, 6 benign, 6 pathogenic, 5 benign/likely benign, 2 likely benign, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
430807	NM_001037333.3(CYFIP2):c.259C>T (p.Arg87Cys)	CYFIP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
545429	NM_001037333.3(CYFIP2):c.260G>C (p.Arg87Pro)	CYFIP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
973747	NM_001037333.3(CYFIP2):c.3594+1G>T	CYFIP2	Pathogenic	no assertion criteria provided
973748	NM_001037333.3(CYFIP2):c.2099A>G (p.Gln700Arg)	CYFIP2	Pathogenic	no assertion criteria provided
973749	NM_001037333.3(CYFIP2):c.1917C>G (p.Ile639Met)	CYFIP2	Pathogenic	criteria provided, single submitter
973750	NM_001037333.3(CYFIP2):c.1918G>A (p.Glu640Lys)	CYFIP2	Pathogenic	criteria provided, multiple submitters, no conflicts
973751	NM_001037333.3(CYFIP2):c.1363G>C (p.Ala455Pro)	CYFIP2	Pathogenic	criteria provided, single submitter
973752	NM_001037333.3(CYFIP2):c.2095G>C (p.Asp699His)	CYFIP2	Pathogenic	criteria provided, multiple submitters, no conflicts
1065625	NM_001037333.3(CYFIP2):c.2089T>C (p.Cys697Arg)	CYFIP2	Likely pathogenic	criteria provided, single submitter
2500808	NM_001037333.3(CYFIP2):c.1651G>C (p.Val551Leu)	CYFIP2	Likely pathogenic	criteria provided, single submitter
2626976	NM_001037333.3(CYFIP2):c.887A>T (p.Asp296Val)	CYFIP2	Likely pathogenic	criteria provided, single submitter
545427	NM_001037333.3(CYFIP2):c.260G>T (p.Arg87Leu)	CYFIP2	Likely pathogenic	criteria provided, single submitter
802171	NM_001037333.3(CYFIP2):c.259C>A (p.Arg87Ser)	CYFIP2	Likely pathogenic	criteria provided, single submitter
827782	NM_001037333.3(CYFIP2):c.2095G>T (p.Asp699Tyr)	CYFIP2	Likely pathogenic	criteria provided, single submitter
827810	NM_001037333.3(CYFIP2):c.2096A>G (p.Asp699Gly)	CYFIP2	Likely pathogenic	criteria provided, single submitter
973753	NM_001037333.3(CYFIP2):c.322T>C (p.Tyr108His)	CYFIP2	Likely pathogenic	criteria provided, single submitter
987225	NM_001037333.3(CYFIP2):c.2066A>G (p.Glu689Gly)	CYFIP2	Likely pathogenic	criteria provided, single submitter
1398792	NM_001037333.3(CYFIP2):c.2447C>T (p.Thr816Met)	CYFIP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1478609	NM_001037333.3(CYFIP2):c.3164C>T (p.Pro1055Leu)	CYFIP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1484688	NM_001037333.3(CYFIP2):c.3349G>A (p.Val1117Ile)	CYFIP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1527912	NM_001037333.3(CYFIP2):c.3186C>G (p.Ile1062Met)	CYFIP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1960694	NM_001037333.3(CYFIP2):c.493A>G (p.Ile165Val)	CYFIP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2440664	NM_001037333.3(CYFIP2):c.8C>T (p.Thr3Met)	CYFIP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2572568	NM_001037333.3(CYFIP2):c.2086C>A (p.Leu696Met)	CYFIP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3381220	NM_001037333.3(CYFIP2):c.2423A>G (p.His808Arg)	CYFIP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
807590	NM_001037333.3(CYFIP2):c.1404G>C (p.Glu468Asp)	CYFIP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1028474	NM_001037333.3(CYFIP2):c.1540C>T (p.Arg514Ter)	CYFIP2	Uncertain significance	criteria provided, single submitter
1028475	NM_001037333.3(CYFIP2):c.1834C>A (p.Gln612Lys)	CYFIP2	Uncertain significance	criteria provided, single submitter
1028476	NM_001037333.3(CYFIP2):c.2011A>G (p.Asn671Asp)	CYFIP2	Uncertain significance	criteria provided, single submitter
1028477	NM_001037333.3(CYFIP2):c.2558A>G (p.Asn853Ser)	CYFIP2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · 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
CYFIP2	Definitive	Autosomal dominant	developmental and epileptic encephalopathy, 65	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CYFIP2	Orphanet:442835	Non-specific early-onset epileptic encephalopathy

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CYFIP2	HGNC:13760	ENSG00000055163	Q96F07	Cytoplasmic FMR1-interacting protein 2	gencc,clinvar
NIPAL4-DT	HGNC:55542	ENSG00000251405		NIPAL4 divergent transcript	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CYFIP2	Cytoplasmic FMR1-interacting protein 2	Involved in T-cell adhesion and p53/TP53-dependent induction of apoptosis.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CYFIP2	Other/Unknown	no		Cytoplasmic_FMR1-int, CYRIA/CYRIB_Rac1-bd
NIPAL4-DT	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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
middle temporal gyrus	1
renal medulla	1
saphenous vein	1
bone marrow cell	1
colonic epithelium	1
muscle layer of sigmoid colon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CYFIP2	286	ubiquitous	marker	renal medulla, middle temporal gyrus, saphenous vein
NIPAL4-DT	113	tissue_specific	yes	bone marrow cell, colonic epithelium, muscle layer of sigmoid colon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CYFIP2	1,771
NIPAL4-DT	0

Structural data

PDB: 0 · AlphaFold-only: 1 · No structure: 1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CYFIP2	Q96F07	87.28

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. 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
RHO GTPases Activate WASPs and WAVEs	1	317.2×	0.009	CYFIP2
FCGR3A-mediated phagocytosis	1	187.2×	0.009	CYFIP2
Regulation of actin dynamics for phagocytic cup formation	1	184.2×	0.009	CYFIP2
VEGFA-VEGFR2 Pathway	1	139.3×	0.009	CYFIP2
RAC1 GTPase cycle	1	61.1×	0.016	CYFIP2

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of neurotrophin TRK receptor signaling pathway	1	3370.4×	0.003	CYFIP2
dendrite extension	1	1685.2×	0.003	CYFIP2
cell projection assembly	1	936.2×	0.003	CYFIP2
positive regulation of proteolysis	1	802.5×	0.003	CYFIP2
regulation of actin filament polymerization	1	581.1×	0.003	CYFIP2
regulation of postsynapse assembly	1	343.9×	0.005	CYFIP2
cell morphogenesis	1	157.5×	0.009	CYFIP2
cell-cell adhesion	1	101.5×	0.012	CYFIP2
axon guidance	1	90.6×	0.012	CYFIP2
apoptotic process	1	28.7×	0.035	CYFIP2

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
CYFIP2	0	0
NIPAL4-DT	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
CYFIP2	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	CYFIP2, NIPAL4-DT

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)
CYFIP2	1	—
NIPAL4-DT	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.