Marbach-Rustad progeroid syndrome

Summary

Marbach-Rustad progeroid syndrome (MONDO:0859147) is a disease caused by LEMD2 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: LEMD2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		3	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	Marbach-Rustad progeroid syndrome
Mondo ID	MONDO:0859147
OMIM	619322
Orphanet	659873
UMLS	C5543388
MedGen	1784907
GARD	0026658
Is cancer (heuristic)	no

Also known as: LEMD2-associated nuclear envelopathy with early progeroid appearance · Marbach-Rustad progeroid syndrome · Wormian bones-micrognathia-abnormal dentition-progeroid syndrome

Data availability: 1 ClinVar variant · 4 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 › Marbach-Rustad 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, mandibuloacral dysplasia progeroid syndrome, achalasia-progeroid syndrome, Fischer-Zirnsak 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

1 retrieved; paginated sample, class counts are floors:

1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
917488	NM_181336.4(LEMD2):c.1436C>T (p.Ser479Phe)	LEMD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 3 · 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
LEMD2	Strong	Autosomal dominant	Marbach-Rustad progeroid syndrome	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LEMD2	Orphanet:441447	Early-onset posterior subcapsular cataract
LEMD2	Orphanet:659873	Wormian bones-micrognathia-abnormal dentition-progeroid syndrome
LEMD2	Orphanet:98994	Total early-onset cataract

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
LEMD2	HGNC:21244	ENSG00000161904	Q8NC56	LEM domain-containing protein 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LEMD2	LEM domain-containing protein 2	Nuclear lamina-associated inner nuclear membrane protein that is involved in nuclear structure organization, maintenance of nuclear envelope (NE) integrity and NE reformation after mitosis.

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)
LEMD2	Other/Unknown	no		LEM_dom, LEM/LEM-like_dom_sf, Man1/Src1-like_C

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
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LEMD2	186	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LEMD2	2,340

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LEMD2	Q8NC56	71.49

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. 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
Depolymerization of the Nuclear Lamina	1	761.3×	0.006	LEMD2
Initiation of Nuclear Envelope (NE) Reformation	1	601.0×	0.006	LEMD2
Nuclear Envelope Breakdown	1	456.8×	0.006	LEMD2
Mitotic Prophase	1	368.4×	0.006	LEMD2
Sealing of the nuclear envelope (NE) by ESCRT-III	1	346.1×	0.006	LEMD2
Nuclear Envelope (NE) Reassembly	1	292.8×	0.006	LEMD2
Mitotic Metaphase and Anaphase	1	96.8×	0.014	LEMD2
Mitotic Anaphase	1	96.8×	0.014	LEMD2
M Phase	1	66.0×	0.019	LEMD2
Cell Cycle, Mitotic	1	48.2×	0.023	LEMD2
Cell Cycle	1	36.0×	0.028	LEMD2

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
heart formation	1	3370.4×	0.002	LEMD2
nuclear membrane organization	1	2407.4×	0.002	LEMD2
nuclear envelope organization	1	991.3×	0.003	LEMD2
protein localization to chromatin	1	581.1×	0.003	LEMD2
skeletal muscle cell differentiation	1	343.9×	0.004	LEMD2
negative regulation of MAPK cascade	1	300.9×	0.004	LEMD2
negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	263.3×	0.004	LEMD2
neurogenesis	1	208.1×	0.005	LEMD2

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
LEMD2	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	LEMD2

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)
LEMD2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.