Mandibuloacral dysplasia progeroid syndrome

Summary

Mandibuloacral dysplasia progeroid syndrome (MONDO:0030880) is a disease caused by MTX2 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MTX2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 7

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		7	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	mandibuloacral dysplasia progeroid syndrome
Mondo ID	MONDO:0030880
OMIM	619127
Orphanet	647667
UMLS	C5436867
MedGen	1741713
GARD	0025648
Is cancer (heuristic)	no

Also known as: mandibuloacral dysplasia associated to MTX2 · MDPS

Data availability: 7 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › progeroid syndrome › mandibuloacral dysplasia progeroid syndrome

Related subtypes (15): Hutchinson-Gilford progeria syndrome, Wiedemann-Rautenstrauch syndrome, Werner syndrome, progeroid facial appearance with hand anomalies, XFE progeroid syndrome, Fontaine progeroid syndrome, Nestor-Guillermo progeria syndrome, mandibular hypoplasia-deafness-progeroid syndrome, progeroid and marfanoid aspect-lipodystrophy syndrome, Cockayne syndrome, achalasia-progeroid syndrome, Fischer-Zirnsak progeroid syndrome, Marbach-Rustad progeroid syndrome, RECON progeroid syndrome, Garg-Mishra progeroid syndrome

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

7 retrieved; paginated sample, class counts are floors:

6 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
4294092	NM_006554.5(MTX2):c.136-1G>C	MTX2	Pathogenic	criteria provided, single submitter
805937	NM_006554.5(MTX2):c.2T>A (p.Met1Lys)	MTX2	Pathogenic	no assertion criteria provided
805938	NM_006554.5(MTX2):c.208+3_208+6del	MTX2	Pathogenic	no assertion criteria provided
805939	NM_006554.5(MTX2):c.544-1G>C	MTX2	Pathogenic	no assertion criteria provided
805940	NM_006554.5(MTX2):c.603del (p.Tyr202fs)	MTX2	Pathogenic	no assertion criteria provided
827676	NM_006554.5(MTX2):c.295_296del (p.Ser98_Leu99insTer)	MTX2	Pathogenic	no assertion criteria provided
2627385	NM_006554.5(MTX2):c.135+2T>C	MTX2	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
MTX2	Strong	Autosomal recessive	mandibuloacral dysplasia progeroid syndrome	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MTX2	Orphanet:647667	Mandibuloacral dysplasia associated to MTX2

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
MTX2	HGNC:7506	ENSG00000128654	O75431	Metaxin-2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MTX2	Metaxin-2	Involved in transport of proteins into the mitochondrion.

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)
MTX2	Other/Unknown	no		Sam37/metaxin_N, Metaxin_GST, Glutathione-S-Trfase_C_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
cortical plate	1
hindlimb stylopod muscle	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MTX2	288	ubiquitous	marker	hindlimb stylopod muscle, primordial germ cell in gonad, cortical plate

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MTX2	1,824

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MTX2	O75431	92.54

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. 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
Cristae formation	1	346.1×	0.007	MTX2
Protein localization	1	190.3×	0.007	MTX2
Mitochondrial protein import	1	167.9×	0.007	MTX2
Mitochondrial biogenesis	1	167.9×	0.007	MTX2
Organelle biogenesis and maintenance	1	66.0×	0.015	MTX2

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
protein insertion into mitochondrial outer membrane	1	1296.3×	0.002	MTX2
mitochondrial transport	1	1203.7×	0.002	MTX2
inner mitochondrial membrane organization	1	842.6×	0.002	MTX2
mitochondrion organization	1	151.8×	0.008	MTX2
protein transport	1	43.9×	0.023	MTX2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MTX2	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
MTX2	1	Binding:1

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	MTX2

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)
MTX2	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.