Lethal congenital contracture syndrome 8

Summary

Lethal congenital contracture syndrome 8 (MONDO:0014570) is a disease caused by ADCY6 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: ADCY6 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 8

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	lethal congenital contracture syndrome 8
Mondo ID	MONDO:0014570
OMIM	616287
DOID	DOID:0061264
UMLS	C4225385
MedGen	896058
GARD	0018565
Is cancer (heuristic)	no

Also known as: ADCY6 lethal congenital contracture syndrome · LCCS8 · lethal congenital contracture syndrome 8 · lethal congenital contracture syndrome caused by mutation in ADCY6 · lethal congenital contracture syndrome type 8

Data availability: 8 ClinVar variants · 3 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 8

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 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

8 retrieved; paginated sample, class counts are floors:

3 pathogenic, 3 uncertain significance, 2 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
189260	NM_015270.5(ADCY6):c.3346C>T (p.Arg1116Cys)	ADCY6	Pathogenic	no assertion criteria provided
995839	NM_015270.5(ADCY6):c.1535+1G>A	ADCY6	Pathogenic	no assertion criteria provided
995840	NM_015270.5(ADCY6):c.3007G>A (p.Glu1003Lys)	ADCY6	Pathogenic	no assertion criteria provided
243078	NM_015270.5(ADCY6):c.2975A>G (p.Tyr992Cys)	ADCY6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2690847	NM_015270.5(ADCY6):c.520G>A (p.Ala174Thr)	ADCY6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2263121	NM_015270.5(ADCY6):c.1613G>A (p.Arg538His)	ADCY6	Uncertain significance	criteria provided, multiple submitters, no conflicts
2690848	NM_015270.5(ADCY6):c.583_585del (p.Met195del)	ADCY6	Uncertain significance	criteria provided, single submitter
931553	NM_015270.5(ADCY6):c.1027C>G (p.Leu343Val)	ADCY6	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
ADCY6	Strong	Autosomal recessive	lethal congenital contracture syndrome 8	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ADCY6	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
ADCY6	HGNC:237	ENSG00000174233	O43306	Adenylate cyclase type 6	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ADCY6	Adenylate cyclase type 6	Catalyzes the formation of the signaling molecule cAMP downstream of G protein-coupled receptors.

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)
ADCY6	Other/Unknown	no		A/G_cyclase, Adcy_conserved_dom, A/G_cyclase_CS

Expression context

Cohort genes with no expression data: 0.

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
apex of heart	1
heart left ventricle	1
right atrium auricular region	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ADCY6	212	ubiquitous	yes	apex of heart, heart left ventricle, right atrium auricular region

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ADCY6	1,379

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ADCY6	O43306	76.33

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 49. 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
Adenylate cyclase activating pathway	1	1142.0×	0.007	ADCY6
Adenylate cyclase inhibitory pathway	1	761.3×	0.007	ADCY6
PKA activation in glucagon signalling	1	671.8×	0.007	ADCY6
PKA activation	1	634.4×	0.007	ADCY6
Activation of GABAB receptors	1	601.0×	0.007	ADCY6
PKA-mediated phosphorylation of CREB	1	571.0×	0.007	ADCY6
GABA B receptor activation	1	543.8×	0.007	ADCY6
Adrenaline,noradrenaline inhibits insulin secretion	1	393.8×	0.007	ADCY6
Anti-inflammatory response favouring Leishmania parasite infection	1	393.8×	0.007	ADCY6
Leishmania parasite growth and survival	1	393.8×	0.007	ADCY6
Calmodulin induced events	1	380.7×	0.007	ADCY6
CaM pathway	1	380.7×	0.007	ADCY6
Ca-dependent events	1	368.4×	0.007	ADCY6
Aquaporin-mediated transport	1	368.4×	0.007	ADCY6
Glucagon signaling in metabolic regulation	1	346.1×	0.007	ADCY6
G-protein mediated events	1	326.3×	0.007	ADCY6
DAG and IP3 signaling	1	317.2×	0.007	ADCY6
GABA receptor activation	1	317.2×	0.007	ADCY6
Response of endothelial cells to shear stress	1	300.5×	0.007	ADCY6
FCGR3A-mediated IL10 synthesis	1	292.8×	0.007	ADCY6
Opioid Signalling	1	265.6×	0.007	ADCY6
PLC beta mediated events	1	265.6×	0.007	ADCY6
Glucagon-like Peptide-1 (GLP1) regulates insulin secretion	1	265.6×	0.007	ADCY6
Vasopressin regulates renal water homeostasis via Aquaporins	1	265.6×	0.007	ADCY6
Cellular responses to mechanical stimuli	1	259.6×	0.007	ADCY6
ADORA2B mediated anti-inflammatory cytokines production	1	253.8×	0.007	ADCY6
GPER1 signaling	1	248.3×	0.007	ADCY6
G alpha (z) signalling events	1	233.1×	0.008	ADCY6
Regulation of insulin secretion	1	219.6×	0.008	ADCY6
Signaling by Hedgehog	1	184.2×	0.009	ADCY6

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
negative regulation of urine volume	1	4213.0×	0.002	ADCY6
adenylate cyclase-activating serotonin receptor signaling pathway	1	3370.4×	0.002	ADCY6
cellular response to catecholamine stimulus	1	2407.4×	0.002	ADCY6
cellular response to vasopressin	1	2106.5×	0.002	ADCY6
adenylate cyclase-inhibiting serotonin receptor signaling pathway	1	1685.2×	0.002	ADCY6
adenylate cyclase-activating dopamine receptor signaling pathway	1	1532.0×	0.002	ADCY6
cAMP biosynthetic process	1	1404.3×	0.002	ADCY6
cellular response to forskolin	1	1123.5×	0.002	ADCY6
cellular response to glucagon stimulus	1	842.6×	0.002	ADCY6
cellular response to prostaglandin E stimulus	1	842.6×	0.002	ADCY6
vascular endothelial cell response to laminar fluid shear stress	1	732.7×	0.002	ADCY6
blood vessel diameter maintenance	1	624.1×	0.002	ADCY6
renal water homeostasis	1	510.7×	0.003	ADCY6
negative regulation of neuron projection development	1	237.3×	0.005	ADCY6
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	1	218.9×	0.005	ADCY6
adenylate cyclase-activating G protein-coupled receptor signaling pathway	1	113.1×	0.009	ADCY6
intracellular signal transduction	1	38.1×	0.026	ADCY6

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ADCY6	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
ADCY6	16	Binding:14, Functional:2

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	ADCY6

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)
ADCY6	16	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.