Sudden unexplained death in childhood

Summary

Sudden unexplained death in childhood (MONDO:1010117) is a disease with 5 cohort genes and 1 clinical trial.

At a glance

• Cohort genes: 5
• ClinVar variants: 6
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	sudden unexplained death in childhood
Mondo ID	MONDO:1010117
UMLS	C3827273
MedGen	820021
Is cancer (heuristic)	no

Data availability: 6 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › idiopathic disease › sudden unexpected death in pediatrics › sudden unexplained death in childhood

Related subtypes (1): sudden unexpected infant death

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

6 retrieved; paginated sample, class counts are floors:

3 likely pathogenic, 1 conflicting classifications of pathogenicity, 1 pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
985348	NM_013275.6(ANKRD11):c.7534C>T (p.Arg2512Trp)	ANKRD11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
810669	NM_001003694.2(BRPF1):c.1182_1183del (p.Ala396fs)	BRPF1	Pathogenic	criteria provided, multiple submitters, no conflicts
1327139	NM_198904.4(GABRG2):c.327+1G>A	GABRG2	Likely pathogenic	criteria provided, single submitter
1327141	NM_001165963.4(SCN1A):c.4357T>G (p.Tyr1453Asp)	LOC102724058	Likely pathogenic	criteria provided, single submitter
1327140	NM_001165963.4(SCN1A):c.182T>C (p.Leu61Pro)	SCN1A	Likely pathogenic	criteria provided, single submitter
658229	NM_001110556.2(FLNA):c.4772C>T (p.Pro1591Leu)	FLNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 27 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SCN1A	Orphanet:1942	Epilepsy with myoclonic-atonic seizures
SCN1A	Orphanet:2382	Lennox-Gastaut syndrome
SCN1A	Orphanet:293181	Epilepsy of infancy with migrating focal seizures
SCN1A	Orphanet:33069	Dravet syndrome
SCN1A	Orphanet:36387	Genetic epilepsy with febrile seizure plus
SCN1A	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
SCN1A	Orphanet:569	Familial or sporadic hemiplegic migraine
BRPF1	Orphanet:435638	3p25.3 microdeletion syndrome
BRPF1	Orphanet:698090	Ophthalmological abnormalities-facial dysmorphism-intellectual disability syndrome
ANKRD11	Orphanet:2332	KBG syndrome
ANKRD11	Orphanet:261250	16q24.3 microdeletion syndrome
FLNA	Orphanet:1826	Frontometaphyseal dysplasia
FLNA	Orphanet:2301	Congenital short bowel syndrome
FLNA	Orphanet:2484	Melnick-Needles syndrome
FLNA	Orphanet:482606	X-linked keloid scarring-reduced joint mobility-increased optic cup-to-disc ratio syndrome
FLNA	Orphanet:555877	FLNA-related X-linked myxomatous valvular dysplasia
FLNA	Orphanet:75497	X-linked Ehlers-Danlos syndrome
FLNA	Orphanet:88630	Terminal osseous dysplasia-pigmentary defects syndrome
FLNA	Orphanet:90650	Otopalatodigital syndrome type 1
FLNA	Orphanet:90652	Otopalatodigital syndrome type 2
FLNA	Orphanet:98892	Periventricular nodular heterotopia
FLNA	Orphanet:99811	Neuronal intestinal pseudoobstruction
GABRG2	Orphanet:1945	Self-limited epilepsy with centrotemporal spikes
GABRG2	Orphanet:33069	Dravet syndrome
GABRG2	Orphanet:36387	Genetic epilepsy with febrile seizure plus
GABRG2	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
GABRG2	Orphanet:64280	Childhood absence epilepsy

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SCN1A	HGNC:10585	ENSG00000144285	P35498	Sodium channel protein type 1 subunit alpha	clinvar
BRPF1	HGNC:14255	ENSG00000156983	P55201	Peregrin	clinvar
ANKRD11	HGNC:21316	ENSG00000167522	Q6UB99	Ankyrin repeat domain-containing protein 11	clinvar
FLNA	HGNC:3754	ENSG00000196924	P21333	Filamin-A	clinvar
GABRG2	HGNC:4087	ENSG00000113327	P18507	Gamma-aminobutyric acid receptor subunit gamma-2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SCN1A	Sodium channel protein type 1 subunit alpha	Pore-forming subunit of Nav1.1, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes.
BRPF1	Peregrin	Scaffold subunit of various histone acetyltransferase (HAT) complexes, such as the MOZ/MORF and HBO1 complexes, which have a histone H3 acetyltransferase activity.
ANKRD11	Ankyrin repeat domain-containing protein 11	Chromatin regulator which modulates histone acetylation and gene expression in neural precursor cells.
FLNA	Filamin-A	Promotes orthogonal branching of actin filaments and links actin filaments to membrane glycoproteins.
GABRG2	Gamma-aminobutyric acid receptor subunit gamma-2	Gamma subunit of the heteropentameric ligand-gated chloride channel gated by gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the brain.

Protein-family classification

Druggable: 2 · Difficult: 2 · Unknown: 1 · Druggable fraction: 0.4

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
Ion channel	1	22.3×	0.220
Antibody/Immunoglobulin	1	5.8×	0.400
Scaffold/PPI	1	3.5×	0.429
Transcription factor	1	1.6×	0.595
Other/Unknown	1	0.4×	0.983

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SCN1A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_channel_a1su
BRPF1	Transcription factor	no		PWWP_dom, Bromodomain, Znf_PHD
ANKRD11	Scaffold/PPI	no		Ankyrin_rpt, Ankyrin_rpt-contain_sf, ANKRD11
FLNA	Antibody/Immunoglobulin	yes		Filamin/ABP280_rpt, Actinin_actin-bd_CS, CH_dom
GABRG2	Other/Unknown	no		GABRG-1/4, GABBAg2_rcpt, GABAA/Glycine_rcpt

Expression context

Cohort genes with no expression data: 0.

5 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	2
lateral nuclear group of thalamus	1
primary visual cortex	1
granulocyte	1
oocyte	1
secondary oocyte	1
stromal cell of endometrium	1
sural nerve	1
tendon of biceps brachii	1
popliteal artery	1
right coronary artery	1
tibial artery	1
middle temporal gyrus	1
superior frontal gyrus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SCN1A	154	tissue_specific	marker	Brodmann (1909) area 23, lateral nuclear group of thalamus, primary visual cortex
BRPF1	254	ubiquitous	marker	oocyte, secondary oocyte, granulocyte
ANKRD11	278	ubiquitous	marker	tendon of biceps brachii, sural nerve, stromal cell of endometrium
FLNA	285	ubiquitous	marker	right coronary artery, popliteal artery, tibial artery
GABRG2	174	tissue_specific	marker	middle temporal gyrus, Brodmann (1909) area 23, superior frontal gyrus

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FLNA	5,321
GABRG2	2,392
ANKRD11	2,384
SCN1A	2,287
BRPF1	1,685

Intra-cohort edges

A	B	Sources
GABRG2	SCN1A	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GABRG2	P18507	75
BRPF1	P55201	66
FLNA	P21333	26
SCN1A	P35498	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ANKRD11	Q6UB99	39.44

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 24. Enrichment computed across 5 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
OAS antiviral response	1	317.2×	0.038	FLNA
GP1b-IX-V activation signalling	1	237.9×	0.038	FLNA
Cell-extracellular matrix interactions	1	167.9×	0.038	FLNA
RHO GTPases activate PAKs	1	135.9×	0.038	FLNA
Regulation of TP53 Activity through Acetylation	1	114.2×	0.038	BRPF1
Interaction between L1 and Ankyrins	1	92.1×	0.038	SCN1A
Phase 0 - rapid depolarisation	1	86.5×	0.038	SCN1A
GABA receptor activation	1	79.3×	0.038	GABRG2
Signaling by ERBB4	1	68.0×	0.039	GABRG2
Regulation of TP53 Activity	1	33.2×	0.071	BRPF1
L1CAM interactions	1	30.1×	0.072	SCN1A
Cardiac conduction	1	27.2×	0.073	SCN1A
Platelet degranulation	1	22.0×	0.076	FLNA
Chromatin organization	1	20.4×	0.076	BRPF1
HATs acetylate histones	1	19.8×	0.076	BRPF1
Muscle contraction	1	19.3×	0.076	SCN1A
Chromatin modifying enzymes	1	18.1×	0.077	BRPF1
Transcriptional Regulation by TP53	1	15.5×	0.084	BRPF1
Axon guidance	1	11.3×	0.108	SCN1A
Nervous system development	1	10.7×	0.108	SCN1A
RNA Polymerase II Transcription	1	5.6×	0.190	BRPF1
Gene expression (Transcription)	1	4.5×	0.225	BRPF1
Generic Transcription Pathway	1	3.8×	0.249	BRPF1
Developmental Biology	1	3.6×	0.249	SCN1A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of membrane repolarization during atrial cardiac muscle cell action potential	1	3370.4×	0.010	FLNA
regulation of membrane repolarization during cardiac muscle cell action potential	1	3370.4×	0.010	FLNA
tubulin deacetylation	1	1123.5×	0.014	FLNA
formation of radial glial scaffolds	1	842.6×	0.014	FLNA
adenylate cyclase-inhibiting dopamine receptor signaling pathway	1	674.1×	0.014	FLNA
establishment of Sertoli cell barrier	1	674.1×	0.014	FLNA
cellular response to histamine	1	561.7×	0.014	GABRG2
protein localization to bicellular tight junction	1	561.7×	0.014	FLNA
negative regulation of transcription by RNA polymerase I	1	481.5×	0.014	FLNA
regulation of developmental process	1	481.5×	0.014	BRPF1
blood coagulation, intrinsic pathway	1	421.3×	0.014	FLNA
membrane depolarization during action potential	1	337.0×	0.014	SCN1A
regulation of hemopoiesis	1	306.4×	0.014	BRPF1
neuronal action potential propagation	1	280.9×	0.014	SCN1A
positive regulation of platelet activation	1	259.3×	0.014	FLNA
positive regulation of integrin-mediated signaling pathway	1	259.3×	0.014	FLNA
positive regulation of actin filament bundle assembly	1	240.7×	0.014	FLNA
actin crosslink formation	1	240.7×	0.014	FLNA
wound healing, spreading of cells	1	224.7×	0.014	FLNA
detection of mechanical stimulus involved in sensory perception of pain	1	224.7×	0.014	SCN1A
neuromuscular process controlling posture	1	210.7×	0.014	SCN1A
positive regulation of potassium ion transmembrane transport	1	198.3×	0.014	FLNA
positive regulation of neuron migration	1	198.3×	0.014	FLNA
nerve development	1	187.2×	0.015	SCN1A
positive regulation of neural precursor cell proliferation	1	153.2×	0.017	FLNA
obsolete negative regulation of DNA-binding transcription factor activity	1	146.5×	0.017	FLNA
megakaryocyte development	1	140.4×	0.017	FLNA
cardiac muscle cell action potential involved in contraction	1	140.4×	0.017	SCN1A
receptor clustering	1	124.8×	0.018	FLNA
inhibitory synapse assembly	1	124.8×	0.018	GABRG2

Therapeutics

Drug target analysis

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

Druggability breadth: 4 of 5 evidence-associated genes (80%) 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
SCN1A	MEXILETINE HYDROCHLORIDE
GABRG2	ENZALUTAMIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCN1A	94	4
GABRG2	55	4
FLNA	1	2
BRPF1	0	0
ANKRD11	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MEXILETINE HYDROCHLORIDE	4	SCN1A
BEPRIDIL	4	SCN1A
DIBUCAINE	4	SCN1A
ARTICAINE	4	SCN1A
BUPIVACAINE	4	SCN1A
IMIPRAMINE	4	SCN1A
DROPERIDOL	4	SCN1A
DICYCLOMINE	4	SCN1A
TETRABENAZINE	4	SCN1A
PHENIRAMINE	4	SCN1A
PRILOCAINE	4	SCN1A
PROPOXYCAINE	4	SCN1A
PROPARACAINE	4	SCN1A
HEXYLCAINE	4	SCN1A
PRAMOXINE	4	SCN1A
BENOXINATE	4	SCN1A
QUINIDINE	4	SCN1A
FELODIPINE	4	SCN1A
PHENYTOIN	4	SCN1A
QUININE	4	SCN1A
NISOLDIPINE	4	SCN1A
NIFEDIPINE	4	SCN1A
PRAZOSIN	4	SCN1A
DILTIAZEM	4	SCN1A
PRENYLAMINE	4	SCN1A
COCAINE	4	SCN1A
TRIFLUOPERAZINE	4	SCN1A
CINNARIZINE	4	SCN1A
THIORIDAZINE	4	SCN1A
ETIDOCAINE	4	SCN1A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
GABRG2	1,155	Binding:940, Functional:201, ADMET:10, Toxicity:4
BRPF1	175	Binding:172, Functional:3
SCN1A	149	Binding:115, Functional:18, ADMET:14, Toxicity:2
FLNA	7	Binding:7

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
SCN1A	149
BRPF1	175
GABRG2	1,155

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 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)
MEXILETINE HYDROCHLORIDE	4	SCN1A
BEPRIDIL	4	SCN1A
DIBUCAINE	4	SCN1A
ARTICAINE	4	SCN1A
BUPIVACAINE	4	SCN1A
IMIPRAMINE	4	SCN1A
DROPERIDOL	4	SCN1A
DICYCLOMINE	4	SCN1A
TETRABENAZINE	4	SCN1A
PHENIRAMINE	4	SCN1A
PRILOCAINE	4	SCN1A
PROPOXYCAINE	4	SCN1A
PROPARACAINE	4	SCN1A
HEXYLCAINE	4	SCN1A
PRAMOXINE	4	SCN1A
BENOXINATE	4	SCN1A
QUINIDINE	4	SCN1A
FELODIPINE	4	SCN1A
PHENYTOIN	4	SCN1A
QUININE	4	SCN1A
NISOLDIPINE	4	SCN1A
NIFEDIPINE	4	SCN1A
PRAZOSIN	4	SCN1A
DILTIAZEM	4	SCN1A
PRENYLAMINE	4	SCN1A
COCAINE	4	SCN1A
TRIFLUOPERAZINE	4	SCN1A
CINNARIZINE	4	SCN1A
THIORIDAZINE	4	SCN1A
ETIDOCAINE	4	SCN1A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	SCN1A, GABRG2
B	Phased (≥1) drug, not yet approved	1	FLNA
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	BRPF1, ANKRD11

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)
BRPF1	175	—
ANKRD11	0	—

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
NCT03109197	Not specified	RECRUITING	Sudden Unexplained Death in Childhood (SUDC) Registry