Progressive myoclonic epilepsy type 9

Summary

Progressive myoclonic epilepsy type 9 (MONDO:0014685) is a disease caused by LMNB2 (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: LMNB2 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 578

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	progressive myoclonic epilepsy type 9
Mondo ID	MONDO:0014685
OMIM	616540
Orphanet	457265
DOID	DOID:0111450
UMLS	C4225289
MedGen	901242
GARD	0017801
Is cancer (heuristic)	no

Also known as: epilepsy, progressive myoclonic, 9 · epilepsy, progressive myoclonic, type 9 · EPM9 · LMNB2 progressive myoclonic epilepsy · PME type 9 · progressive myoclonic epilepsy caused by mutation in LMNB2 · progressive myoclonic epilepsy due to LMNB2 deficiency · progressive myoclonus epilepsy type 9

Data availability: 578 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 › hereditary neurological disease › progressive myoclonus epilepsy › progressive myoclonic epilepsy type 9

Related subtypes (14): Lafora disease, Unverricht-Lundborg syndrome, action myoclonus-renal failure syndrome, MERRF syndrome, familial encephalopathy with neuroserpin inclusion bodies, neuronal ceroid lipofuscinosis 8 northern epilepsy variant, progressive myoclonic epilepsy type 3, epilepsy, progressive myoclonic, 1B, progressive myoclonic epilepsy type 6, progressive myoclonic epilepsy type 7, progressive myoclonic epilepsy type 8, early-onset Lafora body disease, epilepsy, progressive myoclonic, 11, epilepsy, progressive myoclonic, 12

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

578 retrieved; paginated sample, class counts are floors:

257 likely benign, 255 uncertain significance, 30 benign, 26 conflicting classifications of pathogenicity, 9 benign/likely benign, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
208980	NM_032737.4(LMNB2):c.469C>T (p.His157Tyr)	LMNB2	Pathogenic	no assertion criteria provided
1053135	NM_032737.4(LMNB2):c.1016A>C (p.Glu339Ala)	LMNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1113094	NM_032737.4(LMNB2):c.999T>G (p.Asp333Glu)	LMNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1396806	NM_032737.4(LMNB2):c.698C>T (p.Thr233Met)	LMNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1413080	NM_032737.4(LMNB2):c.1475C>T (p.Ser492Leu)	LMNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1473987	NM_032737.4(LMNB2):c.395A>G (p.Asn132Ser)	LMNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1644524	NM_032737.4(LMNB2):c.1535A>G (p.Glu512Gly)	LMNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1649494	NM_032737.4(LMNB2):c.750G>C (p.Gln250His)	LMNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1665539	NM_032737.4(LMNB2):c.1852T>C (p.Tyr618His)	LMNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2064424	NM_032737.4(LMNB2):c.1744G>A (p.Val582Met)	LMNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2100666	NM_032737.4(LMNB2):c.1677C>G (p.Ser559Arg)	LMNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
445837	NM_032737.4(LMNB2):c.265-19C>T	LMNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
475775	NM_032737.4(LMNB2):c.1403C>G (p.Ala468Gly)	LMNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
542428	NM_032737.4(LMNB2):c.700C>T (p.Arg234Trp)	LMNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
542437	NM_032737.4(LMNB2):c.574G>T (p.Ala192Ser)	LMNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
542438	NM_032737.4(LMNB2):c.1312C>T (p.Arg438Trp)	LMNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
576766	NM_032737.4(LMNB2):c.1298G>A (p.Arg433His)	LMNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
578090	NM_032737.4(LMNB2):c.512G>A (p.Arg171His)	LMNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
644388	NM_032737.4(LMNB2):c.1057C>A (p.Leu353Met)	LMNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
647572	NM_032737.4(LMNB2):c.1750C>T (p.Arg584Cys)	LMNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
652532	NM_032737.4(LMNB2):c.281C>T (p.Ala94Val)	LMNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
660656	NM_032737.4(LMNB2):c.1553C>T (p.Thr518Met)	LMNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
772460	NM_032737.4(LMNB2):c.1796G>A (p.Gly599Asp)	LMNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
804992	NM_032737.4(LMNB2):c.1063G>A (p.Ala355Thr)	LMNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
845810	NM_032737.4(LMNB2):c.1232G>A (p.Arg411His)	LMNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
859972	NM_032737.4(LMNB2):c.757G>A (p.Asp253Asn)	LMNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
965151	NM_032737.4(LMNB2):c.1406C>T (p.Ser469Leu)	LMNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2427064	NC_000019.9:g.(?1456055)(2456931_?)dup	ABHD17A	Uncertain significance	criteria provided, single submitter
3248492	NC_000019.9:g.(?2430909)(3121177_?)dup	DIRAS1	Uncertain significance	criteria provided, single submitter
1002507	NM_032737.4(LMNB2):c.481G>C (p.Val161Leu)	LMNB2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · 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
LMNB2	Strong	Autosomal recessive	progressive myoclonic epilepsy type 9	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LMNB2	Orphanet:457265	Progressive myoclonic epilepsy type 9
LMNB2	Orphanet:79087	Acquired partial lipodystrophy

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
LMNB2	HGNC:6638	ENSG00000176619	Q03252	Lamin-B2	gencc,clinvar
DIRAS1	HGNC:19127	ENSG00000176490	O95057	GTP-binding protein Di-Ras1	clinvar
ABHD17A	HGNC:28756	ENSG00000129968	Q96GS6	Alpha/beta hydrolase domain-containing protein 17A	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LMNB2	Lamin-B2	Lamins are intermediate filament proteins that assemble into a filamentous meshwork, and which constitute the major components of the nuclear lamina, a fibrous layer on the nucleoplasmic side of the inner nuclear membrane.
DIRAS1	GTP-binding protein Di-Ras1	Displays low GTPase activity and exists predominantly in the GTP-bound form.
ABHD17A	Alpha/beta hydrolase domain-containing protein 17A	Hydrolyzes fatty acids from S-acylated cysteine residues in proteins.

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?	EC	InterPro (top 3)
LMNB2	Other/Unknown	no		Lamin_tail_dom, IF_conserved, Lamin_tail_dom_sf
DIRAS1	Other/Unknown	no		Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type
ABHD17A	Other/Unknown	no		ABHD17C-like, AB_hydrolase_fold

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left testis	1
right testis	1
ventricular zone	1
apex of heart	1
left ventricle myocardium	1
right frontal lobe	1
Ammon’s horn	1
granulocyte	1
primary visual cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LMNB2	194	ubiquitous	marker	ventricular zone, left testis, right testis
DIRAS1	196	ubiquitous	yes	left ventricle myocardium, apex of heart, right frontal lobe
ABHD17A	139	ubiquitous	marker	granulocyte, primary visual cortex, Ammon’s horn

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LMNB2	3,562
DIRAS1	2,973
ABHD17A	752

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LMNB2	Q03252	2
DIRAS1	O95057	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ABHD17A	Q96GS6	89.99

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 3 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
RAS processing	1	475.8×	0.011	ABHD17A
MAPK1/MAPK3 signaling	1	131.3×	0.016	ABHD17A
MAPK family signaling cascades	1	102.9×	0.016	ABHD17A
RAF/MAP kinase cascade	1	61.1×	0.020	ABHD17A
Signal Transduction	1	10.2×	0.098	ABHD17A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 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 protein localization to endosome	1	1872.4×	0.003	ABHD17A
nuclear pore localization	1	1123.5×	0.003	LMNB2
negative regulation of protein localization to microtubule	1	1123.5×	0.003	ABHD17A
protein depalmitoylation	1	936.2×	0.003	ABHD17A
protein localization to nuclear envelope	1	702.2×	0.003	LMNB2
nuclear envelope organization	1	330.4×	0.005	LMNB2
negative regulation of NLRP3 inflammasome complex assembly	1	330.4×	0.005	ABHD17A
nuclear migration	1	244.2×	0.006	LMNB2
protein localization to membrane	1	200.6×	0.007	ABHD17A
regulation of postsynapse organization	1	175.5×	0.007	ABHD17A
heterochromatin formation	1	85.1×	0.013	LMNB2
signal transduction	1	5.3×	0.176	DIRAS1

Therapeutics

Drug target analysis

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

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

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LMNB2	0	0
DIRAS1	0	0
ABHD17A	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
LMNB2	2	Binding:2

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	3	LMNB2, DIRAS1, ABHD17A

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
LMNB2	2	—
DIRAS1	0	—
ABHD17A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.