mitochondrial DNA depletion syndrome 13

Summary

mitochondrial DNA depletion syndrome 13 (MONDO:0014198) is a disease caused by FBXL4 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: FBXL4 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 420

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		20	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial DNA depletion syndrome 13
Mondo ID	MONDO:0014198
OMIM	615471
Orphanet	369897
DOID	DOID:0080131
NCIT	C172095
SNOMED CT	765403009
UMLS	C3809592
MedGen	815922
GARD	0013298
Is cancer (heuristic)	no

Also known as: BXL4-related early-onset mitochondrial encephalopathy · encephalomyopathic mitochondrial DNA depletion syndrome-13 · FBXL4 deficiency · FBXL4 mitochondrial DNA depletion syndrome · FBXL4-related encephalomyopathic mitochondrial DNA depletion syndrome · mitochondrial DNA depletion syndrome 13 (encephalomyopathic type) · mitochondrial DNA depletion syndrome caused by mutation in FBXL4 · mitochondrial DNA depletion syndrome type 13 · mtDNA depletion syndrome, encephalomyopathic form with variable craniofacial anomalies · MTDPS13

Data availability: 420 ClinVar variants · 5 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › inborn mitochondrial metabolism disorder › mitochondrial oxidative phosphorylation disorder › mitochondrial DNA depletion syndrome › mitochondrial DNA depletion syndrome, encephalomyopathic form › mitochondrial DNA depletion syndrome 13

Related subtypes (3): mitochondrial DNA depletion syndrome 9, mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria, mitochondrial DNA depletion syndrome 8a

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

420 retrieved; paginated sample, class counts are floors:

262 uncertain significance, 82 conflicting classifications of pathogenicity, 30 likely pathogenic, 23 pathogenic, 14 pathogenic/likely pathogenic, 6 benign, 2 benign/likely benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3779648	NC_000005.10:g.99987653_99987654del		Pathogenic	criteria provided, single submitter
1186102	NM_001278716.2(FBXL4):c.486T>A (p.Tyr162Ter)	FBXL4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1696828	NM_001278716.2(FBXL4):c.736dup (p.Ile246fs)	FBXL4	Pathogenic	criteria provided, single submitter
209153	NM_001278716.2(FBXL4):c.64C>T (p.Arg22Ter)	FBXL4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
235493	NM_001278716.2(FBXL4):c.1440dup (p.Leu481fs)	FBXL4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265143	NM_001278716.2(FBXL4):c.1641_1642del (p.Cys547_Asp548delinsTer)	FBXL4	Pathogenic	criteria provided, multiple submitters, no conflicts
280414	NM_001278716.2(FBXL4):c.618_621dup (p.Glu208fs)	FBXL4	Pathogenic	criteria provided, multiple submitters, no conflicts
3363190	NM_001278716.2(FBXL4):c.517G>T (p.Glu173Ter)	FBXL4	Pathogenic	criteria provided, single submitter
3594181	NM_001278716.2(FBXL4):c.141del (p.Asn48fs)	FBXL4	Pathogenic	criteria provided, multiple submitters, no conflicts
375387	NM_001278716.2(FBXL4):c.419T>C (p.Val140Ala)	FBXL4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
430470	NM_001278716.2(FBXL4):c.1304G>A (p.Arg435Gln)	FBXL4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
437475	NM_001278716.2(FBXL4):c.1232G>A (p.Cys411Tyr)	FBXL4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
437483	NM_001278716.2(FBXL4):c.1698A>G (p.Ile566Met)	FBXL4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
437488	NM_001278716.2(FBXL4):c.106A>T (p.Arg36Ter)	FBXL4	Pathogenic	criteria provided, multiple submitters, no conflicts
437489	NM_001278716.2(FBXL4):c.219T>A (p.Tyr73Ter)	FBXL4	Pathogenic	criteria provided, multiple submitters, no conflicts
437490	NM_001278716.2(FBXL4):c.292C>T (p.Arg98Ter)	FBXL4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
437491	NM_001278716.2(FBXL4):c.316C>T (p.Gln106Ter)	FBXL4	Pathogenic	criteria provided, multiple submitters, no conflicts
437492	NM_001278716.2(FBXL4):c.616C>T (p.Arg206Ter)	FBXL4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
437493	NM_001278716.2(FBXL4):c.1210C>T (p.Gln404Ter)	FBXL4	Pathogenic	criteria provided, single submitter
437494	NM_001278716.2(FBXL4):c.1687C>T (p.Gln563Ter)	FBXL4	Pathogenic	criteria provided, single submitter
437495	NM_001278716.2(FBXL4):c.273_277del (p.Phe91fs)	FBXL4	Pathogenic	criteria provided, single submitter
437496	NM_001278716.2(FBXL4):c.326del (p.Ser109fs)	FBXL4	Pathogenic	criteria provided, single submitter
437498	NM_001278716.2(FBXL4):c.1067del (p.Gly356fs)	FBXL4	Pathogenic	criteria provided, multiple submitters, no conflicts
437499	NM_001278716.2(FBXL4):c.1648_1649del (p.Asp550fs)	FBXL4	Pathogenic	criteria provided, multiple submitters, no conflicts
437500	NM_001278716.2(FBXL4):c.513-1G>A	FBXL4	Pathogenic	criteria provided, single submitter
437502	NM_001278716.2(FBXL4):c.858+1G>T	FBXL4	Pathogenic	criteria provided, single submitter
437503	NM_001278716.2(FBXL4):c.1317G>A (p.Glu439=)	FBXL4	Pathogenic	criteria provided, single submitter
437505	NM_001278716.2(FBXL4):c.1389+3_1389+6del	FBXL4	Pathogenic	criteria provided, single submitter
437565	NM_001278716.2(FBXL4):c.370C>T (p.Gln124Ter)	FBXL4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
437644	NM_001278716.2(FBXL4):c.859-1G>T	FBXL4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
FBXL4	Definitive	Autosomal recessive	mitochondrial DNA depletion syndrome 13	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FBXL4	Orphanet:369897	Mitochondrial DNA depletion syndrome, encephalomyopathic form with variable craniofacial anomalies

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
FBXL4	HGNC:13601	ENSG00000112234	Q9UKA2	F-box/LRR-repeat protein 4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FBXL4	F-box/LRR-repeat protein 4	Substrate-recognition component of the mitochondria-localized SCF-FBXL4 ubiquitin E3 ligase complex that plays a role in the restriction of mitophagy by controlling the degradation of BNIP3 and NIX mitophagy receptors.

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)
FBXL4	Other/Unknown	no		F-box_dom, Leu-rich_rpt_Cys-con_subtyp, LRR_dom_sf

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
adrenal tissue	1
calcaneal tendon	1
corpus epididymis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FBXL4	265	ubiquitous	marker	adrenal tissue, corpus epididymis, calcaneal tendon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FBXL4	1,620

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FBXL4	Q9UKA2	86.50

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 1 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
Neddylation	1	47.4×	0.027	FBXL4
Antigen processing: Ubiquitination & Proteasome degradation	1	37.2×	0.027	FBXL4

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
negative regulation of mitophagy	1	1532.0×	0.003	FBXL4
autophagy of mitochondrion	1	732.7×	0.003	FBXL4
SCF-dependent proteasomal ubiquitin-dependent protein catabolic process	1	374.5×	0.004	FBXL4
ubiquitin-dependent protein catabolic process	1	74.2×	0.013	FBXL4

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
FBXL4	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	FBXL4

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)
FBXL4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.