cutis laxa, autosomal recessive, type 1B

Summary

cutis laxa, autosomal recessive, type 1B (MONDO:0013754) is a disease caused by EFEMP2 (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: EFEMP2 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 431

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cutis laxa, autosomal recessive, type 1B
Mondo ID	MONDO:0013754
OMIM	614437
DOID	DOID:0070133
UMLS	C3280798
MedGen	482428
GARD	0015804
Is cancer (heuristic)	no

Also known as: ARCL1B · cutis laxa, autosomal recessive, type IB

Data availability: 431 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › autosomal recessive cutis laxa type 1 › cutis laxa, autosomal recessive, type 1B

Related subtypes (2): cutis laxa, autosomal recessive, type 1A, cutis laxa, autosomal recessive, type 1d

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

431 retrieved; paginated sample, class counts are floors:

202 likely benign, 145 uncertain significance, 25 pathogenic, 25 conflicting classifications of pathogenicity, 11 likely pathogenic, 10 benign/likely benign, 9 benign, 4 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1070589	NM_016938.5(EFEMP2):c.919_952dup (p.Pro318fs)	EFEMP2	Pathogenic	criteria provided, single submitter
2067512	NM_016938.5(EFEMP2):c.859dup (p.Cys287fs)	EFEMP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2703407	NM_016938.5(EFEMP2):c.338_339del (p.Gly112_Tyr113insTer)	EFEMP2	Pathogenic	criteria provided, single submitter
2769959	NM_016938.5(EFEMP2):c.917dup (p.Tyr307fs)	EFEMP2	Pathogenic	criteria provided, single submitter
2877716	NM_016938.5(EFEMP2):c.290dup (p.Pro98fs)	EFEMP2	Pathogenic	criteria provided, single submitter
3065562	NM_016938.5(EFEMP2):c.976C>G (p.Arg326Gly)	EFEMP2	Pathogenic	criteria provided, single submitter
3614102	NM_016938.5(EFEMP2):c.229_230dup (p.Tyr78fs)	EFEMP2	Pathogenic	criteria provided, single submitter
3644932	NM_016938.5(EFEMP2):c.1044_1059dup (p.Arg354fs)	EFEMP2	Pathogenic	criteria provided, single submitter
3653395	NM_016938.5(EFEMP2):c.1135del (p.Arg379fs)	EFEMP2	Pathogenic	criteria provided, single submitter
3662053	NM_016938.5(EFEMP2):c.44G>A (p.Trp15Ter)	EFEMP2	Pathogenic	criteria provided, single submitter
39009	NM_016938.5(EFEMP2):c.1189G>A (p.Ala397Thr)	EFEMP2	Pathogenic	criteria provided, single submitter
39011	NM_016938.5(EFEMP2):c.376G>A (p.Glu126Lys)	EFEMP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
39012	NM_016938.5(EFEMP2):c.377A>T (p.Glu126Val)	EFEMP2	Pathogenic	no assertion criteria provided
39013	NM_016938.5(EFEMP2):c.577del (p.Gln193fs)	EFEMP2	Pathogenic	no assertion criteria provided
39014	NM_016938.5(EFEMP2):c.608A>C (p.Asp203Ala)	EFEMP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
39016	NM_016938.5(EFEMP2):c.800G>A (p.Cys267Tyr)	EFEMP2	Pathogenic	no assertion criteria provided
42041	NM_016938.5(EFEMP2):c.679C>T (p.Arg227Cys)	EFEMP2	Pathogenic	criteria provided, single submitter
4727036	NM_016938.5(EFEMP2):c.695_696del (p.Gly231_Tyr232insTer)	EFEMP2	Pathogenic	criteria provided, single submitter
4730985	NM_016938.5(EFEMP2):c.463del (p.Tyr155fs)	EFEMP2	Pathogenic	criteria provided, single submitter
4764644	NM_016938.5(EFEMP2):c.969dup (p.Glu324Ter)	EFEMP2	Pathogenic	criteria provided, single submitter
5423	NM_016938.5(EFEMP2):c.169G>A (p.Glu57Lys)	EFEMP2	Pathogenic	criteria provided, single submitter
5425	NM_016938.5(EFEMP2):c.1070_1073dup (p.Asp359fs)	EFEMP2	Pathogenic	no assertion criteria provided
650648	NM_016938.5(EFEMP2):c.1174del (p.Ile392fs)	EFEMP2	Pathogenic	criteria provided, single submitter
832127	NC_000011.10:g.(?65871960)(65872944_?)del	EFEMP2	Pathogenic	criteria provided, single submitter
915377	NM_016938.5(EFEMP2):c.481G>A (p.Glu161Lys)	EFEMP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
937224	NM_016938.5(EFEMP2):c.861T>A (p.Cys287Ter)	EFEMP2	Pathogenic	criteria provided, single submitter
943459	NM_016938.5(EFEMP2):c.1170+1G>A	EFEMP2	Pathogenic	criteria provided, single submitter
948115	NM_016938.5(EFEMP2):c.499G>T (p.Glu167Ter)	EFEMP2	Pathogenic	criteria provided, multiple submitters, no conflicts
982404	NM_016938.5(EFEMP2):c.379T>C (p.Cys127Arg)	EFEMP2	Pathogenic	criteria provided, single submitter
2020563	NM_016938.5(EFEMP2):c.848-1_850del	EFEMP2	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 11 · 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
EFEMP2	Definitive	Autosomal recessive	cutis laxa, autosomal recessive, type 1B	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
EFEMP2	Orphanet:314718	Lethal arteriopathy syndrome due to fibulin-4 deficiency
EFEMP2	Orphanet:90349	Autosomal recessive cutis laxa type 1
EFEMP2	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
GBE1	Orphanet:206583	Adult polyglucosan body disease
GBE1	Orphanet:308621	Glycogen storage disease due to glycogen branching enzyme deficiency, progressive hepatic form
GBE1	Orphanet:308638	Glycogen storage disease due to glycogen branching enzyme deficiency, non progressive hepatic form
GBE1	Orphanet:308655	Glycogen storage disease due to glycogen branching enzyme deficiency, fatal perinatal neuromuscular form
GBE1	Orphanet:308670	Glycogen storage disease due to glycogen branching enzyme deficiency, congenital neuromuscular form
GBE1	Orphanet:308684	Glycogen storage disease due to glycogen branching enzyme deficiency, childhood combined hepatic and myopathic form
GBE1	Orphanet:308698	Glycogen storage disease due to glycogen branching enzyme deficiency, childhood neuromuscular form
GBE1	Orphanet:308712	Glycogen storage disease due to glycogen branching enzyme deficiency, adult neuromuscular form

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
EFEMP2	HGNC:3219	ENSG00000172638	O95967	EGF-containing fibulin-like extracellular matrix protein 2	gencc,clinvar
MUS81	HGNC:29814	ENSG00000172732	Q96NY9	Structure-specific endonuclease subunit MUS81	clinvar
GBE1	HGNC:4180	ENSG00000114480	Q04446	1,4-alpha-glucan-branching enzyme	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
EFEMP2	EGF-containing fibulin-like extracellular matrix protein 2	Plays a crucial role in elastic fiber formation in tissue, and in the formation of ultrastructural connections between elastic laminae and smooth muscle cells in the aorta, therefore participates in terminal differentiation and maturation…
MUS81	Structure-specific endonuclease subunit MUS81	Catalytic subunit of two functionally distinct, structure-specific, heterodimeric DNA endonucleases MUS81-EME1 and MUS81-EME2 that are involved in the maintenance of genome stability.
GBE1	1,4-alpha-glucan-branching enzyme	Glycogen-branching enzyme participates in the glycogen biosynthetic process along with glycogenin and glycogen synthase.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

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
Antibody/Immunoglobulin	1	9.7×	0.298
Enzyme (other)	1	4.0×	0.345
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
EFEMP2	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom
MUS81	Enzyme (other)	yes	3.1.21.10	ERCC4_domain, HHH_MUS81, Restrct_endonuc-II-like
GBE1	Antibody/Immunoglobulin	yes		Glyco_hydro_13_N, GH13_cat_dom, A-amylase/branching_C

Expression context

Cohort genes with no expression data: 0.

3 cohort genes 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ascending aorta	1
stromal cell of endometrium	1
tendon of biceps brachii	1
body of uterus	1
left uterine tube	1
muscle layer of sigmoid colon	1
biceps brachii	1
gluteal muscle	1
tibialis anterior	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
EFEMP2	289	ubiquitous	marker	stromal cell of endometrium, tendon of biceps brachii, ascending aorta
MUS81	284	ubiquitous	marker	body of uterus, left uterine tube, muscle layer of sigmoid colon
GBE1	293	ubiquitous	marker	gluteal muscle, tibialis anterior, biceps brachii

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GBE1	3,402
MUS81	2,423
EFEMP2	2,219

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MUS81	Q96NY9	15
GBE1	Q04446	3
EFEMP2	O95967	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Glycogen storage disease type IV (GBE1)	1	1268.9×	0.009	GBE1
Glycogen synthesis	1	271.9×	0.015	GBE1
Resolution of D-Loop Structures	1	211.5×	0.015	MUS81
Molecules associated with elastic fibres	1	102.9×	0.015	EFEMP2
Homology Directed Repair	1	102.9×	0.015	MUS81
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1	102.9×	0.015	MUS81
Resolution of D-loop Structures through Holliday Junction Intermediates	1	100.2×	0.015	MUS81
Fanconi Anemia Pathway	1	92.8×	0.015	MUS81
DNA Double-Strand Break Repair	1	82.8×	0.015	MUS81
HDR through Homologous Recombination (HRR)	1	63.4×	0.017	MUS81
DNA Repair	1	32.8×	0.030	MUS81

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of smooth muscle cell-matrix adhesion	1	5617.3×	0.002	EFEMP2
positive regulation of aortic smooth muscle cell differentiation	1	2808.7×	0.002	EFEMP2
regulation of collagen fibril organization	1	1872.4×	0.002	EFEMP2
aorta smooth muscle tissue morphogenesis	1	1404.3×	0.002	EFEMP2
resolution of mitotic recombination intermediates	1	1404.3×	0.002	MUS81
response to intra-S DNA damage checkpoint signaling	1	1404.3×	0.002	MUS81
positive regulation of collagen fibril organization	1	1404.3×	0.002	EFEMP2
vascular associated smooth muscle cell development	1	561.7×	0.005	EFEMP2
elastic fiber assembly	1	510.7×	0.005	EFEMP2
osteoblast proliferation	1	468.1×	0.005	MUS81
double-strand break repair via break-induced replication	1	432.1×	0.005	MUS81
resolution of meiotic recombination intermediates	1	312.1×	0.005	MUS81
glycogen biosynthetic process	1	312.1×	0.005	GBE1
DNA catabolic process	1	312.1×	0.005	MUS81
mitotic intra-S DNA damage checkpoint signaling	1	312.1×	0.005	MUS81
negative regulation of vascular associated smooth muscle cell proliferation	1	224.7×	0.007	EFEMP2
aorta development	1	187.2×	0.008	EFEMP2
glycogen metabolic process	1	175.5×	0.008	GBE1
replication fork processing	1	140.4×	0.009	MUS81
generation of precursor metabolites and energy	1	114.6×	0.010	GBE1
telomere maintenance	1	89.2×	0.013	MUS81
double-strand break repair	1	67.7×	0.016	MUS81
negative regulation of neuron apoptotic process	1	37.0×	0.028	GBE1
DNA repair	1	21.3×	0.046	MUS81

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
MUS81	IDARUBICIN HYDROCHLORIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MUS81	3	4
EFEMP2	0	0
GBE1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
IDARUBICIN HYDROCHLORIDE	4	MUS81
LIRAGLUTIDE	4	MUS81
PIRARUBICIN	3	MUS81

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
MUS81	17	Binding:17

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MUS81	3.1.21.10	crossover junction endodeoxyribonuclease

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

3 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)
IDARUBICIN HYDROCHLORIDE	4	MUS81
LIRAGLUTIDE	4	MUS81
PIRARUBICIN	3	MUS81

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	MUS81
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	GBE1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	EFEMP2

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)
EFEMP2	0	—
GBE1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.