autosomal recessive spondylometaphyseal dysplasia, Megarbane type

Summary

autosomal recessive spondylometaphyseal dysplasia, Megarbane type (MONDO:0013223) is a disease caused by PAM16 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PAM16 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 3

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		4	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive spondylometaphyseal dysplasia, Megarbane type
Mondo ID	MONDO:0013223
MeSH	C567644
OMIM	613320
Orphanet	401979
DOID	DOID:0112304
UMLS	C2750075
MedGen	413221
GARD	0017667
Is cancer (heuristic)	no

Also known as: PAM16 spondylodysplastic dysplasia · SMDMDM · spondylodysplastic dysplasia caused by mutation in PAM16 · spondylometaphyseal dysplasia, Megarbane-Dagher-Melike type · spondylometaphyseal dysplasia, MEGARBANE-DAGHER-MELKI type

Data availability: 3 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › skeletal dysplasia › spondylometaphyseal dysplasia › autosomal recessive spondylometaphyseal dysplasia, Megarbane type

Related subtypes (18): Kniest dysplasia, spondyloepimetaphyseal dysplasia, Strudwick type, spondylometaphyseal dysplasia, Kozlowski type, spondylometaphyseal dysplasia, Schmidt type, spondylometaphyseal dysplasia, ‘corner fracture’ type, spondylometaphyseal dysplasia, Sedaghatian type, spondylometaphyseal dysplasia, Golden type, axial spondylometaphyseal dysplasia, spondylometaphyseal dysplasia-bowed forearms-facial dysmorphism syndrome, Spondyloenchondrodysplasia with immune dysregulation, spondylometaphyseal dysplasia-cone-rod dystrophy syndrome, spondylometaphyseal dysplasia, A4 type, spondylometaphyseal dysplasia, East African type, spondylometaphyseal dysplasia, Czarny-Ratajczak type, regressive spondylometaphyseal dysplasia, spondylometaphyseal dysplasia, pagnamenta type, odontochondrodysplasia, SBDS-related severe neonatal spondylometaphyseal dysplasia

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

3 retrieved; paginated sample, class counts are floors:

2 pathogenic, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
187811	NM_016069.11(PAM16):c.226A>G (p.Asn76Asp)	CORO7-PAM16	Pathogenic	no assertion criteria provided
636277	NM_016069.11(PAM16):c.221A>C (p.Gln74Pro)	CORO7-PAM16	Pathogenic	no assertion criteria provided
585054	NM_016069.11(PAM16):c.112C>G (p.Arg38Gly)	CORO7-PAM16	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
PAM16	Strong	Autosomal recessive	autosomal recessive spondylometaphyseal dysplasia, Megarbane type	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PAM16	Orphanet:401979	Autosomal recessive spondylometaphyseal dysplasia, Mégarbané type

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PAM16	HGNC:29679	ENSG00000217930	Q9Y3D7	Mitochondrial import inner membrane translocase subunit TIM16	gencc
CORO7-PAM16	HGNC:44424	ENSG00000103426		CORO7-PAM16 readthrough	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PAM16	Mitochondrial import inner membrane translocase subunit TIM16	Regulates ATP-dependent protein translocation into the mitochondrial matrix.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PAM16	Other/Unknown	no		Tim16, J_dom_sf
CORO7-PAM16	Other/Unknown	no

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
gastrocnemius	1
hindlimb stylopod muscle	1
right lobe of liver	1
blood	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PAM16	134	ubiquitous	marker	gastrocnemius, right lobe of liver, hindlimb stylopod muscle
CORO7-PAM16	116	ubiquitous	yes	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, blood

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PAM16	975
CORO7-PAM16	0

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PAM16	Q9Y3D7	89.52

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 2 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
Mitochondrial protein import	1	167.9×	0.006	PAM16

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 ATP-dependent activity	1	1685.2×	0.002	PAM16
protein import into mitochondrial matrix	1	702.2×	0.003	PAM16
ossification	1	227.7×	0.006	PAM16
intracellular protein transport	1	64.8×	0.015	PAM16

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 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
PAM16	0	0
CORO7-PAM16	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	2	PAM16, CORO7-PAM16

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)
PAM16	0	—
CORO7-PAM16	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.