Neonatal-onset encephalopathy with rigidity and seizures

Summary

Neonatal-onset encephalopathy with rigidity and seizures (MONDO:0013784) is a disease caused by BRAT1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: BRAT1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 1,169

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		8	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	neonatal-onset encephalopathy with rigidity and seizures
Mondo ID	MONDO:0013784
OMIM	614498
Orphanet	435845
UMLS	C3281029
MedGen	482659
GARD	0017718
Is cancer (heuristic)	no

Also known as: lethal neonatal rigidity-multifocal seizure syndrome · lethal neonatal spasticity-epileptic encephalopathy syndrome · neonatal-onset encephalopathy with rigidity and seizures · rigidity and multifocal seizure syndrome, lethal neonatal · RMFSL

Data availability: 1,169 ClinVar variants · 5 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › epilepsy › monogenic epilepsy › neonatal-onset encephalopathy with rigidity and seizures

Related subtypes (17): Mowat-Wilson syndrome, developmental and epileptic encephalopathy, 2, severe neonatal-onset encephalopathy with microcephaly, familial infantile myoclonic epilepsy, neuronal ceroid lipofuscinosis 8 northern epilepsy variant, polyhydramnios, megalencephaly, and symptomatic epilepsy, developmental and epileptic encephalopathy, 23, spastic paraplegia-severe developmental delay-epilepsy syndrome, X-linked intellectual disability-epilepsy syndrome, focal epilepsy-intellectual disability-cerebro-cerebellar malformation, infantile-onset mesial temporal lobe epilepsy with severe cognitive regression, autosomal recessive cerebellar ataxia - epilepsy - intellectual disability syndrome, developmental and epileptic encephalopathy, 73, neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination, intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies, epilepsy, X-linked, with or without impaired intellectual development and dysmorphic features, neurodevelopmental disorder with motor abnormalities, seizures, and facial dysmorphism

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

600 retrieved; paginated sample, class counts are floors:

299 likely benign, 231 uncertain significance, 32 pathogenic, 12 benign, 11 conflicting classifications of pathogenicity, 8 likely pathogenic, 4 benign/likely benign, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1031685	NM_152743.4(BRAT1):c.617T>A (p.Leu206Ter)	BRAT1	Pathogenic	criteria provided, single submitter
1069574	NC_000007.13:g.(?2584533)(2594065_?)del	BRAT1	Pathogenic	criteria provided, single submitter
1070797	NM_152743.4(BRAT1):c.1768C>T (p.Gln590Ter)	BRAT1	Pathogenic	criteria provided, single submitter
1072484	NM_152743.4(BRAT1):c.2023del (p.Tyr675fs)	BRAT1	Pathogenic	criteria provided, single submitter
1073449	NC_000007.13:g.(?2559496)(2594065_?)del	BRAT1	Pathogenic	criteria provided, single submitter
1073760	NM_152743.4(BRAT1):c.453_454insATCTTCTC (p.Leu152fs)	BRAT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074999	NM_152743.4(BRAT1):c.1823del (p.Pro608fs)	BRAT1	Pathogenic	criteria provided, single submitter
1324687	NM_152743.4(BRAT1):c.1996_1997del (p.Leu666fs)	BRAT1	Pathogenic	criteria provided, single submitter
1356724	NM_152743.4(BRAT1):c.1083_1095del (p.Gly363fs)	BRAT1	Pathogenic	criteria provided, single submitter
1377471	NM_152743.4(BRAT1):c.1711C>T (p.Gln571Ter)	BRAT1	Pathogenic	criteria provided, single submitter
1393495	NM_152743.4(BRAT1):c.34del (p.Leu12fs)	BRAT1	Pathogenic	criteria provided, single submitter
1452250	NM_152743.4(BRAT1):c.1590del (p.Trp531fs)	BRAT1	Pathogenic	criteria provided, single submitter
1453640	NM_152743.4(BRAT1):c.1007del (p.Gly336fs)	BRAT1	Pathogenic	criteria provided, single submitter
1458549	NM_152743.4(BRAT1):c.920del (p.His307fs)	BRAT1	Pathogenic	criteria provided, single submitter
1458796	NM_152743.4(BRAT1):c.2284C>T (p.Gln762Ter)	BRAT1	Pathogenic	criteria provided, single submitter
180136	NM_152743.4(BRAT1):c.453_454insGAGAAGAT (p.Leu152fs)	BRAT1	Pathogenic	no assertion criteria provided
180137	NM_152743.4(BRAT1):c.176T>C (p.Leu59Pro)	BRAT1	Pathogenic	no assertion criteria provided
180138	NM_152743.4(BRAT1):c.962_963del (p.Leu321fs)	BRAT1	Pathogenic	no assertion criteria provided
180139	NM_152743.4(BRAT1):c.1177del (p.Ala393fs)	BRAT1	Pathogenic	no assertion criteria provided
1933360	NM_152743.4(BRAT1):c.560_561insCG (p.Asp190fs)	BRAT1	Pathogenic	criteria provided, single submitter
1957621	NM_152743.4(BRAT1):c.280C>T (p.Gln94Ter)	BRAT1	Pathogenic	criteria provided, single submitter
202197	NM_152743.4(BRAT1):c.1857G>A (p.Trp619Ter)	BRAT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2030476	NM_152743.4(BRAT1):c.2075_2091del (p.Leu692fs)	BRAT1	Pathogenic	criteria provided, single submitter
2080436	NM_152743.4(BRAT1):c.2104_2107dup (p.Phe703Ter)	BRAT1	Pathogenic	criteria provided, single submitter
2110761	NM_152743.4(BRAT1):c.1486C>T (p.Gln496Ter)	BRAT1	Pathogenic	criteria provided, single submitter
2114572	NM_152743.4(BRAT1):c.1461C>A (p.Cys487Ter)	BRAT1	Pathogenic	criteria provided, single submitter
2131739	NM_152743.4(BRAT1):c.1414C>T (p.Gln472Ter)	BRAT1	Pathogenic	criteria provided, single submitter
2183060	NM_152743.4(BRAT1):c.529C>T (p.Arg177Ter)	BRAT1	Pathogenic	criteria provided, single submitter
2184776	NM_152743.4(BRAT1):c.566dup (p.Gly189_Asp190insTer)	BRAT1	Pathogenic	criteria provided, multiple submitters, no conflicts
2427405	NC_000007.13:g.(?2586938)(2594065_?)del	BRAT1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
BRAT1	Definitive	Autosomal recessive	neonatal-onset encephalopathy with rigidity and seizures	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BRAT1	Orphanet:435845	Lethal neonatal spasticity-epileptic encephalopathy syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BRAT1	HGNC:21701	ENSG00000106009	Q6PJG6	Integrator complex assembly factor BRAT1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BRAT1	Integrator complex assembly factor BRAT1	Component of a multiprotein complex required for the assembly of the RNA endonuclease module of the integrator complex.

Protein-family classification

Druggable: 0 · Difficult: 0 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BRAT1	Other/Unknown	no		HEAT, ARM-like, ARM-type_fold

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	1
left adrenal gland cortex	1
right adrenal gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BRAT1	176	ubiquitous	marker	left adrenal gland cortex, granulocyte, right adrenal gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BRAT1	1,105

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BRAT1	Q6PJG6	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
integrator complex assembly	1	16852.0×	7e-04	BRAT1
mitochondrion localization	1	1685.2×	0.003	BRAT1
response to ionizing radiation	1	411.0×	0.007	BRAT1
protein localization to nucleus	1	351.1×	0.007	BRAT1
positive regulation of protein phosphorylation	1	276.3×	0.007	BRAT1
glucose metabolic process	1	255.3×	0.007	BRAT1
positive regulation of cell growth	1	183.2×	0.009	BRAT1
cell population proliferation	1	102.8×	0.013	BRAT1
cell migration	1	61.5×	0.020	BRAT1
DNA damage response	1	53.5×	0.021	BRAT1
apoptotic process	1	28.7×	0.035	BRAT1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BRAT1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	1	BRAT1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
BRAT1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.