Familial encephalopathy with neuroserpin inclusion bodies

Summary

Familial encephalopathy with neuroserpin inclusion bodies (MONDO:0011412) is a disease caused by SERPINI1 (GenCC Strong), with 2 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SERPINI1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 364
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		6	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	familial encephalopathy with neuroserpin inclusion bodies
Mondo ID	MONDO:0011412
MeSH	C536841
OMIM	604218
Orphanet	85110
DOID	DOID:0050831
ICD-11	453919434
SNOMED CT	702421006
UMLS	C1858680
MedGen	346965
GARD	0010037
NORD	1123
Is cancer (heuristic)	no

Also known as: encephalopathy, familial, with neuroserpin inclusion bodies · FENIB

Data availability: 364 ClinVar variants · 4 GenCC gene-disease records · 3 cell lines.

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 › familial encephalopathy with neuroserpin inclusion bodies

Related subtypes (14): Lafora disease, Unverricht-Lundborg syndrome, action myoclonus-renal failure syndrome, MERRF syndrome, 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, progressive myoclonic epilepsy type 9, 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

364 retrieved; paginated sample, class counts are floors:

211 uncertain significance, 114 likely benign, 17 benign, 9 conflicting classifications of pathogenicity, 7 benign/likely benign, 5 pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1686176	NM_001122752.2(SERPINI1):c.1174G>C (p.Gly392Arg)	SERPINI1	Pathogenic	criteria provided, single submitter
7086	NM_001122752.2(SERPINI1):c.145T>C (p.Ser49Pro)	SERPINI1	Pathogenic	criteria provided, single submitter
7087	NM_001122752.2(SERPINI1):c.154A>C (p.Ser52Arg)	SERPINI1	Pathogenic	no assertion criteria provided
7088	NM_001122752.2(SERPINI1):c.1013A>G (p.His338Arg)	SERPINI1	Pathogenic	no assertion criteria provided
7089	NM_001122752.2(SERPINI1):c.1175G>A (p.Gly392Glu)	SERPINI1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
7090	NM_001122752.2(SERPINI1):c.1174G>A (p.Gly392Arg)	SERPINI1	Pathogenic	criteria provided, single submitter
3246888	NC_000003.11:g.(?167437830)(167543111_?)del	PDCD10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1047456	NM_001122752.2(SERPINI1):c.107G>A (p.Arg36His)	SERPINI1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
344124	NM_001122752.2(SERPINI1):c.281C>T (p.Ser94Leu)	SERPINI1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
466617	NM_001122752.2(SERPINI1):c.473A>G (p.Asn158Ser)	SERPINI1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
534956	NM_001122752.2(SERPINI1):c.248A>T (p.Asn83Ile)	SERPINI1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
570487	NM_001122752.2(SERPINI1):c.508A>G (p.Arg170Gly)	SERPINI1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
845018	NM_001122752.2(SERPINI1):c.917T>C (p.Val306Ala)	SERPINI1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
901125	NM_001122752.2(SERPINI1):c.1067-6C>T	SERPINI1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
952379	NM_001122752.2(SERPINI1):c.76A>G (p.Ile26Val)	SERPINI1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1002011	NM_001122752.2(SERPINI1):c.778C>A (p.Gln260Lys)	SERPINI1	Uncertain significance	criteria provided, single submitter
1004826	NM_001122752.2(SERPINI1):c.965T>G (p.Leu322Trp)	SERPINI1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1005716	NM_001122752.2(SERPINI1):c.109C>T (p.Leu37Phe)	SERPINI1	Uncertain significance	criteria provided, single submitter
1006954	NM_001122752.2(SERPINI1):c.302A>T (p.Glu101Val)	SERPINI1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1007229	NM_001122752.2(SERPINI1):c.923A>C (p.Lys308Thr)	SERPINI1	Uncertain significance	criteria provided, single submitter
1014022	NM_001122752.2(SERPINI1):c.311A>T (p.Tyr104Phe)	SERPINI1	Uncertain significance	criteria provided, single submitter
1019699	NM_001122752.2(SERPINI1):c.898G>A (p.Glu300Lys)	SERPINI1	Uncertain significance	criteria provided, single submitter
1021441	NM_001122752.2(SERPINI1):c.493G>A (p.Asp165Asn)	SERPINI1	Uncertain significance	criteria provided, single submitter
1021760	NM_001122752.2(SERPINI1):c.841A>C (p.Asn281His)	SERPINI1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1023386	NM_001122752.2(SERPINI1):c.220C>G (p.His74Asp)	SERPINI1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1023387	NM_001122752.2(SERPINI1):c.796A>G (p.Thr266Ala)	SERPINI1	Uncertain significance	criteria provided, single submitter
1023520	NM_001122752.2(SERPINI1):c.575C>T (p.Ser192Leu)	SERPINI1	Uncertain significance	criteria provided, single submitter
1025218	NM_001122752.2(SERPINI1):c.462G>A (p.Trp154Ter)	SERPINI1	Uncertain significance	criteria provided, single submitter
1026069	NM_001122752.2(SERPINI1):c.629G>T (p.Ser210Ile)	SERPINI1	Uncertain significance	criteria provided, single submitter
1036215	NM_001122752.2(SERPINI1):c.674A>G (p.Tyr225Cys)	SERPINI1	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
SERPINI1	Strong	Autosomal dominant	familial encephalopathy with neuroserpin inclusion bodies	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SERPINI1	Orphanet:530303	Progressive dementia with neuroserpin inclusion bodies
PDCD10	Orphanet:221061	Familial cerebral cavernous malformation

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
SERPINI1	HGNC:8943	ENSG00000163536	Q99574	Neuroserpin	gencc,clinvar
PDCD10	HGNC:8761	ENSG00000114209	Q9BUL8	Programmed cell death protein 10	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SERPINI1	Neuroserpin	Serine protease inhibitor that inhibits plasminogen activators and plasmin but not thrombin.
PDCD10	Programmed cell death protein 10	Promotes cell proliferation.

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)
SERPINI1	Other/Unknown	no		Serpin_fam, Serpin_CS, Serpin_dom
PDCD10	Other/Unknown	no		PDCD10, PDC10_dimerisation_sf, PDCD10_N

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
Brodmann (1909) area 10	1
frontal pole	1
orbitofrontal cortex	1
colonic mucosa	1
jejunal mucosa	1
mucosa of sigmoid colon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SERPINI1	288	ubiquitous	marker	frontal pole, orbitofrontal cortex, Brodmann (1909) area 10
PDCD10	295	ubiquitous	marker	jejunal mucosa, mucosa of sigmoid colon, colonic mucosa

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PDCD10	1,792
SERPINI1	950

Intra-cohort edges

A	B	Sources
PDCD10	SERPINI1	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PDCD10	Q9BUL8	10
SERPINI1	Q99574	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 2 evidence-associated genes (0 with Reactome annotation).

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
intrinsic apoptotic signaling pathway in response to hydrogen peroxide	1	2808.7×	0.007	PDCD10
Golgi reassembly	1	1685.2×	0.007	PDCD10
negative regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis	1	1053.2×	0.007	PDCD10
establishment of Golgi localization	1	936.2×	0.007	PDCD10
endothelium development	1	648.1×	0.007	PDCD10
positive regulation of protein serine/threonine kinase activity	1	648.1×	0.007	PDCD10
wound healing, spreading of cells	1	561.7×	0.007	PDCD10
negative regulation of cell migration involved in sprouting angiogenesis	1	495.6×	0.007	PDCD10
positive regulation of stress-activated MAPK cascade	1	401.2×	0.007	PDCD10
positive regulation of peptidyl-serine phosphorylation	1	383.0×	0.007	PDCD10
positive regulation of intracellular protein transport	1	337.0×	0.007	PDCD10
positive regulation of MAP kinase activity	1	324.1×	0.007	PDCD10
peripheral nervous system development	1	290.6×	0.007	SERPINI1
regulation of angiogenesis	1	210.7×	0.009	PDCD10
positive regulation of Notch signaling pathway	1	175.5×	0.010	PDCD10
cellular response to leukemia inhibitory factor	1	79.5×	0.020	PDCD10
positive regulation of neuron projection development	1	68.5×	0.022	SERPINI1
central nervous system development	1	57.7×	0.025	SERPINI1
negative regulation of gene expression	1	34.5×	0.038	PDCD10
protein stabilization	1	33.4×	0.038	PDCD10
angiogenesis	1	31.2×	0.038	PDCD10
positive regulation of cell migration	1	30.9×	0.038	PDCD10
positive regulation of gene expression	1	19.4×	0.056	PDCD10
intracellular signal transduction	1	19.1×	0.056	PDCD10
negative regulation of apoptotic process	1	17.4×	0.059	PDCD10
positive regulation of cell population proliferation	1	16.8×	0.059	PDCD10

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
SERPINI1	0	0
PDCD10	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
PDCD10	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	SERPINI1, PDCD10

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)
SERPINI1	0	—
PDCD10	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00916903	Not specified	TERMINATED	Genetic Disease Gene Identification