Lethal congenital contracture syndrome 7

Summary

Lethal congenital contracture syndrome 7 (MONDO:0014569) is a disease caused by CNTNAP1 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: CNTNAP1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 26

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	lethal congenital contracture syndrome 7
Mondo ID	MONDO:0014569
OMIM	616286
DOID	DOID:0061263
UMLS	C4225386
MedGen	894160
GARD	0018564
Is cancer (heuristic)	no

Also known as: CNTNAP1 lethal congenital contracture syndrome · LCCS7 · lethal congenital contracture syndrome 7 · lethal congenital contracture syndrome caused by mutation in CNTNAP1 · lethal congenital contracture syndrome type 7

Data availability: 26 ClinVar variants · 2 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 7

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 8, lethal congenital contracture syndrome 9, NEK9-related lethal skeletal dysplasia, lethal congenital contracture syndrome 11, 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

26 retrieved; paginated sample, class counts are floors:

9 pathogenic, 5 likely pathogenic, 4 conflicting classifications of pathogenicity, 3 uncertain significance, 3 benign, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
427821	NM_003632.2(CNTNAP1):c.[1869G>A];[967T>C]		Pathogenic	no assertion criteria provided
1032140	NM_003632.3(CNTNAP1):c.3657_3660dup (p.Leu1221fs)	CNTNAP1	Pathogenic	criteria provided, single submitter
1219168	NM_003632.3(CNTNAP1):c.3361C>T (p.Arg1121Ter)	CNTNAP1	Pathogenic	criteria provided, multiple submitters, no conflicts
189261	NM_003632.3(CNTNAP1):c.3009dup (p.Glu1004Ter)	CNTNAP1	Pathogenic	no assertion criteria provided
189262	NM_003632.3(CNTNAP1):c.2993-1_2995del	CNTNAP1	Pathogenic	no assertion criteria provided
204313	NM_003632.3(CNTNAP1):c.2901_2902del (p.Cys968fs)	CNTNAP1	Pathogenic	criteria provided, multiple submitters, no conflicts
254173	NM_003632.3(CNTNAP1):c.1561dup (p.Leu521fs)	CNTNAP1	Pathogenic	criteria provided, multiple submitters, no conflicts
692016	NM_003632.3(CNTNAP1):c.2668C>T (p.Arg890Ter)	CNTNAP1	Pathogenic	criteria provided, multiple submitters, no conflicts
984430	GRCh37/hg19 17q21.2(chr17:40842168-40846218)x1	CNTNAP1	Pathogenic	no assertion criteria provided
1679372	NM_003632.3(CNTNAP1):c.1823del (p.Leu608fs)	CNTNAP1	Likely pathogenic	criteria provided, single submitter
1679401	NM_003632.3(CNTNAP1):c.1046G>T (p.Gly349Val)	CNTNAP1	Likely pathogenic	criteria provided, single submitter
266117	NM_003632.3(CNTNAP1):c.2444C>A (p.Thr815Asn)	CNTNAP1	Likely pathogenic	no assertion criteria provided
3251978	NM_003632.3(CNTNAP1):c.3814+1G>C	CNTNAP1	Likely pathogenic	criteria provided, single submitter
3779540	NM_003632.3(CNTNAP1):c.730C>T (p.Gln244Ter)	CNTNAP1	Likely pathogenic	criteria provided, single submitter
1347833	NM_003632.3(CNTNAP1):c.1699G>A (p.Glu567Lys)	CNTNAP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1979310	NM_003632.3(CNTNAP1):c.4066GCCCCA[4] (p.Pro1361_Thr1362insAlaPro)	CNTNAP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2300952	NM_003632.3(CNTNAP1):c.3239C>T (p.Thr1080Met)	CNTNAP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
522842	NM_003632.3(CNTNAP1):c.1163G>C (p.Arg388Pro)	CNTNAP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1031348	NM_003632.3(CNTNAP1):c.2930G>A (p.Arg977His)	CNTNAP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1252013	NM_003632.3(CNTNAP1):c.2515C>T (p.Arg839Trp)	CNTNAP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2664879	NM_003632.3(CNTNAP1):c.2152_2154del (p.Gly718del)	CNTNAP1	Uncertain significance	criteria provided, single submitter
1217319	NM_003632.3(CNTNAP1):c.364-34A>G	CNTNAP1	Benign	criteria provided, multiple submitters, no conflicts
1217320	NM_003632.3(CNTNAP1):c.1736-22G>A	CNTNAP1	Benign	criteria provided, multiple submitters, no conflicts
773317	NM_003632.3(CNTNAP1):c.2340C>A (p.Gly780=)	CNTNAP1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
781302	NM_003632.3(CNTNAP1):c.327C>T (p.Asp109=)	CNTNAP1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
803394	NM_003632.3(CNTNAP1):c.151A>C (p.Arg51=)	CNTNAP1	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
CNTNAP1	Strong	Autosomal recessive	lethal congenital contracture syndrome 7	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CNTNAP1	Orphanet:2680	Hypomyelination neuropathy-arthrogryposis syndrome

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
CNTNAP1	HGNC:8011	ENSG00000108797	P78357	Contactin-associated protein 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CNTNAP1	Contactin-associated protein 1	Required, with CNTNAP2, for radial and longitudinal organization of 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)
CNTNAP1	Other/Unknown	no		FA58C, EGF, Laminin_G

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
CNTNAP1	209	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
CNTNAP1	1,292

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CNTNAP1	P78357	81.51

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Neurofascin interactions	1	1427.5×	7e-04	CNTNAP1

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
neuromuscular junction development, skeletal muscle fiber	1	16852.0×	7e-04	CNTNAP1
postsynaptic density organization	1	8426.0×	7e-04	CNTNAP1
paranodal junction maintenance	1	8426.0×	7e-04	CNTNAP1
protein localization to paranode region of axon	1	4213.0×	9e-04	CNTNAP1
protein localization to juxtaparanode region of axon	1	4213.0×	9e-04	CNTNAP1
paranodal junction assembly	1	2808.7×	0.001	CNTNAP1
neuronal action potential propagation	1	1404.3×	0.002	CNTNAP1
neuromuscular process controlling posture	1	1053.2×	0.002	CNTNAP1
central nervous system myelination	1	991.3×	0.002	CNTNAP1
regulation of synapse maturation	1	936.2×	0.002	CNTNAP1
myelination in peripheral nervous system	1	887.0×	0.002	CNTNAP1
neuromuscular process controlling balance	1	330.4×	0.005	CNTNAP1
neuron projection morphogenesis	1	276.3×	0.005	CNTNAP1
axonogenesis	1	160.5×	0.008	CNTNAP1
mitochondrion organization	1	151.8×	0.008	CNTNAP1
cytoskeleton organization	1	132.7×	0.008	CNTNAP1
cell adhesion	1	37.5×	0.028	CNTNAP1
signal transduction	1	16.1×	0.062	CNTNAP1

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
CNTNAP1	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	CNTNAP1

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)
CNTNAP1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.