mitochondrial DNA depletion syndrome 20 (mngie type)

Summary

mitochondrial DNA depletion syndrome 20 (mngie type) (MONDO:0030696) is a disease caused by LIG3 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: LIG3 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 19

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial DNA depletion syndrome 20 (mngie type)
Mondo ID	MONDO:0030696
OMIM	619780
DOID	DOID:0070451
UMLS	C5676934
MedGen	1804209
GARD	0025615
Is cancer (heuristic)	no

Also known as: mitochondrial DNA depletion syndrome 20 (mngie type) · mitochondrial neurogastrointestinal encephalomyopathy syndrome, lig3-related · MTDPS20

Data availability: 19 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › mitochondrial neurogastrointestinal encephalomyopathy › mitochondrial DNA depletion syndrome 20 (mngie type)

Related subtypes (3): mitochondrial DNA depletion syndrome 1, mitochondrial DNA depletion syndrome 8a, mitochondrial DNA depletion syndrome 4b

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

19 retrieved; paginated sample, class counts are floors:

8 pathogenic, 6 uncertain significance, 4 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3770194	NM_001094.5(ASIC2):c.556-198516_556-198515insTTACCTGCAATGTGCTGGGTTATCTGTTCCTTCTCATTATCTTCCAGCTCTTCCCAGCCTTCCAGCTCTGTGAGGTCCTCGATYTTGTT	ASIC2	Pathogenic	criteria provided, single submitter
1343935	NM_013975.4(LIG3):c.1611G>C (p.Lys537Asn)	LIG3	Pathogenic	no assertion criteria provided
1343936	NM_013975.4(LIG3):c.2890G>C (p.Gly964Arg)	LIG3	Pathogenic	no assertion criteria provided
1343937	NM_013975.4(LIG3):c.2996G>A (p.Cys999Tyr)	LIG3	Pathogenic	no assertion criteria provided
1343939	NM_013975.4(LIG3):c.1826C>T (p.Pro609Leu)	LIG3	Pathogenic	no assertion criteria provided
1343940	NM_013975.4(LIG3):c.2431C>T (p.Arg811Ter)	LIG3	Pathogenic	no assertion criteria provided
1343941	NM_013975.4(LIG3):c.1611+209G>A	LIG3	Pathogenic	no assertion criteria provided
1343942	NM_013975.4(LIG3):c.86G>A (p.Trp29Ter)	LIG3	Pathogenic	no assertion criteria provided
3770193	NM_013975.4(LIG3):c.1209-2A>G	LIG3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1343938	NM_013975.4(LIG3):c.799C>T (p.Arg267Ter)	LIG3	Likely pathogenic	criteria provided, single submitter
1699182	NM_013975.4(LIG3):c.2653_2654del (p.Leu884_Ser885insTer)	LIG3	Likely pathogenic	criteria provided, single submitter
4056583	NM_013975.4(LIG3):c.535del (p.Gln179fs)	LIG3	Likely pathogenic	criteria provided, single submitter
4819568	NM_013975.4(LIG3):c.1684dup (p.Leu562fs)	LIG3	Likely pathogenic	criteria provided, single submitter
2584977	NM_013975.4(LIG3):c.967G>A (p.Asp323Asn)	LIG3	Uncertain significance	criteria provided, single submitter
4056580	NM_013975.4(LIG3):c.1502A>G (p.Asn501Ser)	LIG3	Uncertain significance	criteria provided, single submitter
4056582	NM_013975.4(LIG3):c.2993C>A (p.Ala998Glu)	LIG3	Uncertain significance	criteria provided, single submitter
4079197	NM_013975.4(LIG3):c.1943G>A (p.Arg648Gln)	LIG3	Uncertain significance	criteria provided, multiple submitters, no conflicts
4531648	NM_013975.4(LIG3):c.1286+35_1286+36insATGCAAAACATGTGTAAGTAGCAGCTCCGCTGACAGCCTGAGCTGTCA	LIG3	Uncertain significance	criteria provided, single submitter
4819569	NM_013975.4(LIG3):c.2011C>T (p.Arg671Trp)	LIG3	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · 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
LIG3	Strong	Autosomal recessive	mitochondrial DNA depletion syndrome 20 (mngie type)	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LIG3	Orphanet:298	Mitochondrial neurogastrointestinal encephalomyopathy

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
LIG3	HGNC:6600	ENSG00000005156	P49916	DNA ligase 3	gencc,clinvar
ASIC2	HGNC:99	ENSG00000108684	Q16515	Acid-sensing ion channel 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LIG3	DNA ligase 3	Isoform 3 functions as a heterodimer with DNA-repair protein XRCC1 in the nucleus and can correct defective DNA strand-break repair and sister chromatid exchange following treatment with ionizing radiation and alkylating agents.
ASIC2	Acid-sensing ion channel 2	Forms pH-gated trimeric sodium channels that act as postsynaptic excitatory sensors in the nervous system.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
LIG3	Transcription factor	no	6.5.1.1	DNA_ligase_ATP-dep, BRCT_dom, Znf_PARP
ASIC2	Other/Unknown	no		ENaC, ENaC_chordates, ENaC_CS

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
buccal mucosa cell	1
globus pallidus	1
medial globus pallidus	1
anterior cingulate cortex	1
cingulate cortex	1
prefrontal cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LIG3	266	ubiquitous	yes	buccal mucosa cell, medial globus pallidus, globus pallidus
ASIC2	131	tissue_specific	marker	prefrontal cortex, cingulate cortex, anterior cingulate cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LIG3	2,540
ASIC2	1,493

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LIG3	P49916	13
ASIC2	Q16515	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Resolution of AP sites via the single-nucleotide replacement pathway	1	1142.0×	0.005	LIG3
APEX1-Independent Resolution of AP Sites via the Single Nucleotide Replacement Pathway	1	815.7×	0.005	LIG3
Strand-asynchronous mitochondrial DNA replication	1	571.0×	0.005	LIG3
HDR through MMEJ (alt-NHEJ)	1	439.2×	0.005	LIG3
Gap-filling DNA repair synthesis and ligation in GG-NER	1	219.6×	0.008	LIG3
Gap-filling DNA repair synthesis and ligation in TC-NER	1	89.2×	0.017	LIG3
Stimuli-sensing channels	1	68.0×	0.019	ASIC2
Ion channel transport	1	48.0×	0.023	ASIC2
Transport of small molecules	1	12.6×	0.078	ASIC2

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
negative regulation of mitochondrial DNA replication	1	8426.0×	0.003	LIG3
regulation of systemic arterial blood pressure by aortic arch baroreceptor feedback	1	4213.0×	0.003	ASIC2
lagging strand elongation	1	2808.7×	0.003	LIG3
detection of mechanical stimulus involved in sensory perception	1	1404.3×	0.005	ASIC2
mitochondrial DNA repair	1	1203.7×	0.005	LIG3
sensory perception of sour taste	1	842.6×	0.005	ASIC2
double-strand break repair via alternative nonhomologous end joining	1	842.6×	0.005	LIG3
base-excision repair, gap-filling	1	561.7×	0.006	LIG3
regulation of vasoconstriction	1	401.2×	0.006	ASIC2
DNA biosynthetic process	1	401.2×	0.006	LIG3
protein localization to synapse	1	383.0×	0.006	ASIC2
regulation of monoatomic ion transmembrane transport	1	366.4×	0.006	ASIC2
cellular response to acidic pH	1	366.4×	0.006	ASIC2
phototransduction	1	247.8×	0.008	ASIC2
base-excision repair	1	234.1×	0.008	LIG3
regulation of postsynapse assembly	1	172.0×	0.010	ASIC2
positive regulation of synapse assembly	1	122.1×	0.012	ASIC2
cellular response to xenobiotic stimulus	1	120.4×	0.012	ASIC2
synapse assembly	1	115.4×	0.012	ASIC2
regulation of membrane potential	1	115.4×	0.012	ASIC2
double-strand break repair	1	101.5×	0.013	LIG3
sodium ion transmembrane transport	1	101.5×	0.013	ASIC2
establishment of localization in cell	1	80.2×	0.015	ASIC2
double-strand break repair via homologous recombination	1	78.0×	0.015	LIG3
mitochondrion organization	1	75.9×	0.015	LIG3
sensory perception of sound	1	50.5×	0.021	ASIC2
cell division	1	23.1×	0.044	LIG3
negative regulation of apoptotic process	1	17.4×	0.057	ASIC2

Therapeutics

Drug target analysis

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

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
LIG3	1	2
ASIC2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	LIG3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
LIG3	9	Binding:9

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
LIG3	6.5.1.1	DNA ligase (ATP)

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

1 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)
MOLIBRESIB	2	LIG3

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	1	LIG3
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ASIC2

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)
ASIC2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.