Lethal congenital contracture syndrome 9

Summary

Lethal congenital contracture syndrome 9 (MONDO:0014670) is a disease caused by ADGRG6 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: ADGRG6 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 14

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	lethal congenital contracture syndrome 9
Mondo ID	MONDO:0014670
OMIM	616503
DOID	DOID:0061265
UMLS	C4225303
MedGen	903881
GARD	0025011
Is cancer (heuristic)	no

Also known as: ADGRG6 lethal congenital contracture syndrome · LCCS9 · lethal congenital contracture syndrome 9 · lethal congenital contracture syndrome caused by mutation in ADGRG6 · lethal congenital contracture syndrome type 9

Data availability: 14 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 9

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, 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

14 retrieved; paginated sample, class counts are floors:

4 uncertain significance, 3 pathogenic, 3 likely pathogenic, 2 benign, 1 pathogenic/likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1342704	NM_198569.3(ADGRG6):c.2219T>A (p.Leu740Ter)	ADGRG6	Pathogenic	criteria provided, single submitter
192347	NM_198569.3(ADGRG6):c.19C>T (p.Arg7Ter)	ADGRG6	Pathogenic	criteria provided, single submitter
192348	NM_198569.3(ADGRG6):c.2144dup (p.Gln716fs)	ADGRG6	Pathogenic	criteria provided, single submitter
192349	NM_198569.3(ADGRG6):c.2306T>A (p.Val769Glu)	ADGRG6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3064408	NM_198569.3(ADGRG6):c.672_681del (p.Ser225fs)	ADGRG6	Likely pathogenic	criteria provided, single submitter
3233964	NM_198569.3(ADGRG6):c.1424+2T>A	ADGRG6	Likely pathogenic	criteria provided, single submitter
4081094	NM_198569.3(ADGRG6):c.931C>T (p.Arg311Ter)	ADGRG6	Likely pathogenic	criteria provided, single submitter
1029348	NM_198569.3(ADGRG6):c.2470G>C (p.Ala824Pro)	ADGRG6	Uncertain significance	criteria provided, single submitter
2438877	NM_198569.3(ADGRG6):c.2180C>G (p.Pro727Arg)	ADGRG6	Uncertain significance	criteria provided, single submitter
4077845	NM_198569.3(ADGRG6):c.829T>C (p.Cys277Arg)	ADGRG6	Uncertain significance	criteria provided, single submitter
4845271	NM_198569.3(ADGRG6):c.1955+4_1955+7del	ADGRG6	Uncertain significance	criteria provided, single submitter
791451	NM_198569.3(ADGRG6):c.354A>G (p.Leu118=)	ADGRG6	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
802278	NM_198569.3(ADGRG6):c.1476G>A (p.Leu492=)	ADGRG6	Benign	criteria provided, single submitter
802279	NM_198569.3(ADGRG6):c.3380A>G (p.Gln1127Arg)	ADGRG6	Benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 0 · 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
ADGRG6	Definitive	Autosomal recessive	lethal congenital contracture syndrome 9	5

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
ADGRG6	HGNC:13841	ENSG00000112414	Q86SQ4	Adhesion G-protein coupled receptor G6	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ADGRG6	Adhesion G-protein coupled receptor G6	Adhesion G-protein coupled receptor (aGPCR) for steroid hormones, such as progesterone and 17alpha-hydroxyprogesterone (17OHP).

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
GPCR	1	23.9×	0.042

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ADGRG6	GPCR	yes		GPS, GPCR_2_secretin-like, CUB_dom

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
amniotic fluid	1
endometrium epithelium	1
placenta	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ADGRG6	247	ubiquitous	marker	endometrium epithelium, amniotic fluid, placenta

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ADGRG6	1,079

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ADGRG6	Q86SQ4	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
EGR2 and SOX10-mediated initiation of Schwann cell myelination	1	368.4×	0.008	ADGRG6
Nervous system development	1	42.9×	0.035	ADGRG6
Developmental Biology	1	14.5×	0.069	ADGRG6

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
Schwann cell differentiation	1	2407.4×	0.003	ADGRG6
regulation of sprouting angiogenesis	1	2407.4×	0.003	ADGRG6
establishment of blood-brain barrier	1	1404.3×	0.003	ADGRG6
heart trabecula formation	1	1123.5×	0.003	ADGRG6
myelination in peripheral nervous system	1	887.0×	0.003	ADGRG6
regulation of bone mineralization	1	732.7×	0.003	ADGRG6
placenta development	1	443.5×	0.005	ADGRG6
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1	337.0×	0.006	ADGRG6
myelination	1	251.5×	0.006	ADGRG6
cartilage development	1	251.5×	0.006	ADGRG6
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	1	218.9×	0.006	ADGRG6
adenylate cyclase-activating G protein-coupled receptor signaling pathway	1	113.1×	0.011	ADGRG6
cell surface receptor signaling pathway	1	64.1×	0.018	ADGRG6
nervous system development	1	45.9×	0.023	ADGRG6
G protein-coupled receptor signaling pathway	1	36.2×	0.028	ADGRG6

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
ADGRG6	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
ADGRG6	2	Binding: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	1	ADGRG6
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
ADGRG6	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.