cutis laxa, autosomal recessive, type 1A

Summary

cutis laxa, autosomal recessive, type 1A (MONDO:0009052) is a disease caused by FBLN5 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: FBLN5 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 31

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cutis laxa, autosomal recessive, type 1A
Mondo ID	MONDO:0009052
MeSH	C562628
OMIM	219100
DOID	DOID:0070135
SNOMED CT	59451000
UMLS	C5848058
MedGen	1846304
GARD	0015157
Is cancer (heuristic)	no

Also known as: ARCL1 · ARCL1A · cutis laxa, autosomal recessive, type IA

Data availability: 31 ClinVar variants · 5 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 1A

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

31 retrieved; paginated sample, class counts are floors:

9 uncertain significance, 9 pathogenic, 6 conflicting classifications of pathogenicity, 2 benign, 2 not provided, 2 pathogenic/likely pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
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
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
2882131	NM_006329.4(FBLN5):c.479G>A (p.Trp160Ter)	FBLN5	Pathogenic	criteria provided, single submitter
689758	NM_006329.4(FBLN5):c.1201_1202del (p.Ser401fs)	FBLN5	Pathogenic	criteria provided, single submitter
995864	NM_006329.4(FBLN5):c.1134T>G (p.Tyr378Ter)	FBLN5	Pathogenic	criteria provided, single submitter
5424	NM_016938.5(EFEMP2):c.835C>T (p.Arg279Cys)	EFEMP2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
21451	NM_006329.4(FBLN5):c.1171G>T (p.Glu391Ter)	FBLN5	Conflicting classifications of pathogenicity	no assertion criteria provided
21453	NM_006329.4(FBLN5):c.604G>A (p.Gly202Arg)	FBLN5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
21454	NM_006329.4(FBLN5):c.649T>C (p.Cys217Arg)	FBLN5	Conflicting classifications of pathogenicity	no assertion criteria provided
218359	NM_006329.4(FBLN5):c.268G>A (p.Gly90Ser)	FBLN5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
218360	NM_006329.4(FBLN5):c.376G>A (p.Val126Met)	FBLN5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
5475	NM_006329.4(FBLN5):c.679T>C (p.Ser227Pro)	FBLN5	Conflicting classifications of pathogenicity	no assertion criteria provided
39010	NM_016938.5(EFEMP2):c.1226G>A (p.Arg409Gln)	EFEMP2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1172837	NM_006329.4(FBLN5):c.245A>C (p.Asn82Thr)	FBLN5	Uncertain significance	criteria provided, multiple submitters, no conflicts
1463161	NM_006329.4(FBLN5):c.1076G>A (p.Arg359His)	FBLN5	Uncertain significance	criteria provided, multiple submitters, no conflicts
1519738	NM_006329.4(FBLN5):c.834C>G (p.Ile278Met)	FBLN5	Uncertain significance	criteria provided, multiple submitters, no conflicts
1804877	NM_006329.4(FBLN5):c.432C>G (p.Cys144Trp)	FBLN5	Uncertain significance	no assertion criteria provided
3775653	NM_006329.4(FBLN5):c.662G>A (p.Cys221Tyr)	FBLN5	Uncertain significance	criteria provided, single submitter
417872	NM_006329.4(FBLN5):c.1183C>T (p.Arg395Trp)	FBLN5	Uncertain significance	criteria provided, single submitter
502499	NM_006329.4(FBLN5):c.799G>A (p.Gly267Ser)	FBLN5	Uncertain significance	criteria provided, multiple submitters, no conflicts
5481	NM_006329.4(FBLN5):c.1051C>T (p.Arg351Trp)	FBLN5	Uncertain significance	criteria provided, multiple submitters, no conflicts
39015	NM_016938.5(EFEMP2):c.775A>G (p.Ile259Val)	EFEMP2	Benign	criteria provided, multiple submitters, no conflicts
163450	NM_006329.4(FBLN5):c.945T>C (p.Ile315=)	FBLN5	Benign	criteria provided, multiple submitters, no conflicts
21450	NM_006329.4(FBLN5):c.1090G>T (p.Asp364Tyr)	FBLN5	not provided	no classification provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · Orphanet: 6 · 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
FBLN5	Definitive	Autosomal recessive	cutis laxa, autosomal recessive, type 1A	14

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FBLN5	Orphanet:280598	Hereditary sensorimotor neuropathy with hyperelastic skin
FBLN5	Orphanet:90348	Autosomal dominant cutis laxa
FBLN5	Orphanet:90349	Autosomal recessive cutis laxa type 1
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

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FBLN5	HGNC:3602	ENSG00000140092	Q9UBX5	Fibulin-5	gencc,clinvar
EFEMP2	HGNC:3219	ENSG00000172638	O95967	EGF-containing fibulin-like extracellular matrix protein 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FBLN5	Fibulin-5	Essential for elastic fiber formation, is involved in the assembly of continuous elastin (ELN) polymer and promotes the interaction of microfibrils and ELN.
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…

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)
FBLN5	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom
EFEMP2	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ascending aorta	2
descending thoracic aorta	1
thoracic aorta	1
stromal cell of endometrium	1
tendon of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FBLN5	261	ubiquitous	marker	thoracic aorta, ascending aorta, descending thoracic aorta
EFEMP2	289	ubiquitous	marker	stromal cell of endometrium, tendon of biceps brachii, ascending aorta

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FBLN5	2,301
EFEMP2	2,219

Intra-cohort edges

A	B	Sources
EFEMP2	FBLN5	intact

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EFEMP2	O95967	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FBLN5	Q9UBX5	83.69

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Molecules associated with elastic fibres	2	308.6×	2e-05	FBLN5, EFEMP2
Elastic fibre formation	1	167.9×	0.006	FBLN5

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
elastic fiber assembly	2	1532.0×	7e-06	FBLN5, EFEMP2
intramembranous bone growth	1	8426.0×	7e-04	FBLN5
positive regulation of smooth muscle cell-matrix adhesion	1	8426.0×	7e-04	EFEMP2
positive regulation of aortic smooth muscle cell differentiation	1	4213.0×	0.001	EFEMP2
regulation of collagen fibril organization	1	2808.7×	0.001	EFEMP2
aorta smooth muscle tissue morphogenesis	1	2106.5×	0.001	EFEMP2
positive regulation of collagen fibril organization	1	2106.5×	0.001	EFEMP2
regulation of removal of superoxide radicals	1	1404.3×	0.002	FBLN5
secretion	1	1053.2×	0.002	FBLN5
vascular associated smooth muscle cell development	1	842.6×	0.002	EFEMP2
positive regulation of osteoblast proliferation	1	601.9×	0.003	FBLN5
negative regulation of vascular associated smooth muscle cell proliferation	1	337.0×	0.004	EFEMP2
aorta development	1	280.9×	0.005	EFEMP2
protein localization to cell surface	1	247.8×	0.005	FBLN5
negative regulation of angiogenesis	1	84.3×	0.014	FBLN5
cell-matrix adhesion	1	81.8×	0.014	FBLN5
negative regulation of transcription by RNA polymerase II	1	8.9×	0.116	FBLN5
positive regulation of transcription by RNA polymerase II	1	7.4×	0.130	FBLN5

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
FBLN5	0	0
EFEMP2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	FBLN5, 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)
FBLN5	0	—
EFEMP2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.