Lethal congenital contracture syndrome 11

Summary

Lethal congenital contracture syndrome 11 (MONDO:0014965) is a disease caused by GLDN (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: GLDN (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 33

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	lethal congenital contracture syndrome 11
Mondo ID	MONDO:0014965
OMIM	617194
DOID	DOID:0061267
UMLS	C4310670
MedGen	934637
GARD	0013220
Is cancer (heuristic)	no

Also known as: GLDN lethal congenital contracture syndrome · LCCS11 · lethal congenital contracture arthrogryposis-11 · lethal congenital contracture syndrome 11 · lethal congenital contracture syndrome 11; LCCS11 · lethal congenital contracture syndrome caused by mutation in GLDN · lethal congenital contracture syndrome type 11

Data availability: 33 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 › lethal congenital contracture syndrome › lethal congenital contracture syndrome 11

Related subtypes (11): lethal congenital contracture syndrome 1, lethal congenital contracture syndrome 2, lethal congenital contracture syndrome 3, lethal congenital contracture syndrome 4, fetal akinesia-cerebral and retinal hemorrhage syndrome, lethal congenital contracture syndrome 6, lethal congenital contracture syndrome 7, lethal congenital contracture syndrome 8, lethal congenital contracture syndrome 9, NEK9-related lethal skeletal dysplasia, lethal congenital contracture syndrome 12

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

33 retrieved; paginated sample, class counts are floors:

14 likely pathogenic, 8 uncertain significance, 4 pathogenic, 3 conflicting classifications of pathogenicity, 3 pathogenic/likely pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
268104	NM_181789.4(GLDN):c.758del (p.Pro253fs)	GLDN	Pathogenic	no assertion criteria provided
268107	NM_181789.4(GLDN):c.1240C>T (p.Arg414Ter)	GLDN	Pathogenic	criteria provided, single submitter
268108	NM_181789.4(GLDN):c.541+1G>A	GLDN	Pathogenic	no assertion criteria provided
3382965	NM_181789.4(GLDN):c.139dup (p.Ala47fs)	GLDN	Pathogenic	criteria provided, single submitter
452116	NM_181789.4(GLDN):c.1428C>A (p.Phe476Leu)	GLDN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
488521	NM_181789.4(GLDN):c.1305G>A (p.Trp435Ter)	GLDN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
870381	NM_181789.4(GLDN):c.980_981del (p.Ser327fs)	GLDN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1175345	NM_181789.4(GLDN):c.82G>C (p.Ala28Pro)	GLDN	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2663883	NM_181789.4(GLDN):c.817+1G>A	GLDN	Likely pathogenic	criteria provided, single submitter
268105	NM_181789.4(GLDN):c.1423G>C (p.Ala475Pro)	GLDN	Likely pathogenic	criteria provided, multiple submitters, no conflicts
268106	NM_181789.4(GLDN):c.95C>A (p.Ala32Glu)	GLDN	Likely pathogenic	criteria provided, single submitter
268109	NM_181789.4(GLDN):c.1435C>T (p.Arg479Ter)	GLDN	Likely pathogenic	criteria provided, single submitter
2690612	NM_181789.4(GLDN):c.1347dup (p.Ala450fs)	GLDN	Likely pathogenic	criteria provided, single submitter
3254992	NM_181789.4(GLDN):c.1507C>T (p.Gln503Ter)	GLDN	Likely pathogenic	criteria provided, single submitter
3336674	NM_181789.4(GLDN):c.1525_1529del (p.Asp509fs)	GLDN	Likely pathogenic	criteria provided, single submitter
3382964	NM_181789.4(GLDN):c.1143_1144del (p.Tyr382fs)	GLDN	Likely pathogenic	criteria provided, single submitter
4845823	NM_181789.4(GLDN):c.1423G>A (p.Ala475Thr)	GLDN	Likely pathogenic	criteria provided, single submitter
807423	NM_181789.4(GLDN):c.86T>C (p.Leu29Pro)	GLDN	Likely pathogenic	criteria provided, single submitter
813924	NM_181789.4(GLDN):c.59T>C (p.Leu20Pro)	GLDN	Likely pathogenic	criteria provided, single submitter
916579	NM_181789.4(GLDN):c.385_392del (p.Cys129fs)	GLDN	Likely pathogenic	criteria provided, single submitter
974889	NM_181789.4(GLDN):c.1028-2A>T	GLDN	Likely pathogenic	criteria provided, single submitter
1711382	NM_181789.4(GLDN):c.1494G>C (p.Leu498Phe)	GLDN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3075712	NM_181789.4(GLDN):c.1282G>C (p.Ala428Pro)	GLDN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
807260	NM_181789.4(GLDN):c.95C>G (p.Ala32Gly)	GLDN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1027905	NM_181789.4(GLDN):c.314G>A (p.Arg105His)	GLDN	Uncertain significance	criteria provided, multiple submitters, no conflicts
2212657	NM_181789.4(GLDN):c.314G>C (p.Arg105Pro)	GLDN	Uncertain significance	criteria provided, multiple submitters, no conflicts
2314538	NM_181789.4(GLDN):c.1160G>A (p.Gly387Asp)	GLDN	Uncertain significance	criteria provided, multiple submitters, no conflicts
2691006	NM_181789.4(GLDN):c.79T>C (p.Ser27Pro)	GLDN	Uncertain significance	criteria provided, single submitter
3779700	NM_181789.4(GLDN):c.818-2A>G	GLDN	Uncertain significance	criteria provided, single submitter
4078782	NM_181789.4(GLDN):c.452G>A (p.Gly151Glu)	GLDN	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
GLDN	Strong	Autosomal recessive	lethal congenital contracture syndrome 11	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GLDN	Orphanet:994	Fetal akinesia deformation sequence

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
GLDN	HGNC:29514	ENSG00000186417	Q6ZMI3	Gliomedin	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GLDN	Gliomedin	Ligand for NRCAM and NFASC/neurofascin that plays a role in the formation and maintenance of the nodes of Ranvier on myelinated axons.

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)
GLDN	Other/Unknown	no		Olfac-like_dom, Collagen, Olfactomedin-like_domain

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
inferior vagus X ganglion	1
pons	1
trigeminal ganglion	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GLDN	226	broad	marker	inferior vagus X ganglion, trigeminal ganglion, pons

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GLDN	866

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GLDN	Q6ZMI3	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

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
microvillus organization	1	8426.0×	4e-04	GLDN
clustering of voltage-gated sodium channels	1	2407.4×	6e-04	GLDN
signal transduction	1	16.1×	0.062	GLDN

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
GLDN	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	GLDN

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)
GLDN	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.