Lethal congenital contracture syndrome 2

Summary

Lethal congenital contracture syndrome 2 (MONDO:0011868) is a disease caused by ERBB3 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ERBB3 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 17

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		1	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	lethal congenital contracture syndrome 2
Mondo ID	MONDO:0011868
MeSH	C564369
OMIM	607598
Orphanet	137776
DOID	DOID:0060560
SNOMED CT	715419004
UMLS	C1843478
MedGen	334413
GARD	0009177
Is cancer (heuristic)	no

Also known as: ERBB3 lethal congenital contracture syndrome · LCCS2 · lethal congenital contractural syndrome 2 · lethal congenital contracture syndrome 2 · lethal congenital contracture syndrome caused by mutation in ERBB3 · lethal congenital contracture syndrome type 2 · multiple contracture syndrome, Israeli Bedouin type · multiple contracture syndrome, Israeli-Bedouin type

Data availability: 17 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › disorder of development or morphogenesis › developmental defect during embryogenesis › multiple congenital anomalies/dysmorphic syndrome › multiple congenital anomalies/dysmorphic syndrome without intellectual disability › lethal congenital contracture syndrome 2

Related subtypes (167): Treacher-Collins syndrome, branchio-oto-renal syndrome, acrorenal syndrome, Townes-Brocks syndrome, Ascher syndrome, brachytelephalangy-dysmorphism-Kallmann syndrome, branchiooculofacial syndrome, Gordon syndrome, cataract-aberrant oral frenula-growth delay syndrome, cherubism, Alagille syndrome, cleft palate-lateral synechia syndrome, blepharocheilodontic syndrome, craniofacial-deafness-hand syndrome, cryptomicrotia-brachydactyly-excess fingertip arch syndrome, Beare-Stevenson cutis gyrata syndrome, Cyprus facial-neuromusculoskeletal syndrome, deafness-craniofacial syndrome, short stature-valvular heart disease-characteristic facies syndrome, 3-M syndrome, external auditory canal atresia-vertical talus-hypertelorism syndrome, femoral-facial syndrome, multinodular goiter-cystic kidney-polydactyly syndrome, hand-foot-genital syndrome, Bencze syndrome, oculoauriculovertebral spectrum with radial defects, Holt-Oram syndrome, mullerian duct anomalies-limb anomalies syndrome, Aase-Smith syndrome, LADD syndrome, Noonan syndrome with multiple lentigines, median nodule of the upper lip, Nager acrofacial dysostosis, Marshall syndrome, Binder syndrome, Schilbach-Rott syndrome, nasopalpebral lipoma-coloboma syndrome, autosomal dominant prognathism, short stature-craniofacial anomalies-genital hypoplasia syndrome, radial hypoplasia-triphalangeal thumbs-hypospadias-maxillary diastema syndrome, scalp-ear-nipple syndrome, flat face-microstomia-ear anomaly syndrome, Czeizel-Losonci syndrome, otospondylomegaepiphyseal dysplasia, autosomal dominant, ventricular extrasystoles with syncopal episodes-perodactyly-robin sequence syndrome, posterior fusion of lumbosacral vertebrae-blepharoptosis syndrome, acrofacial dysostosis, Weyers type, Freeman-Sheldon syndrome, Ackerman syndrome, acro-renal-mandibular syndrome, acrocraniofacial dysostosis, PAGOD syndrome, alar cartilages hypoplasia-coloboma-telecanthus syndrome, microcephaly-albinism-digital anomalies syndrome, fetal akinesia deformation sequence, Cooper-Jabs syndrome, Barber-Say syndrome, Beemer-Ertbruggen syndrome, blepharophimosis-ptosis-esotropia-syndactyly-short stature syndrome, camptodactyly syndrome, Guadalajara type 1, camptodactyly syndrome, Guadalajara type 2, heart defects-limb shortening syndrome, Verloove Vanhorick-Brubakk syndrome, Juberg-Hayward syndrome, heart defect - tongue hamartoma - polysyndactyly syndrome, Fraser syndrome, split hand-foot malformation 1 with sensorineural hearing loss, von Voss-Cherstvoy syndrome, autosomal recessive faciodigitogenital syndrome, gingival fibromatosis-facial dysmorphism syndrome, Fibulo-ulnar hypoplasia-renal anomalies syndrome, frontofacionasal dysplasia, genito-palato-cardiac syndrome, Hirschsprung disease-hearing loss-polydactyly syndrome, Holzgreve-Wagner-Rehder syndrome, hydrocephaly-tall stature-joint laxity syndrome, McKusick-Kaufman syndrome, acrofrontofacionasal dysostosis 2, Vici syndrome, Donohue syndrome, Dahlberg-Borer-Newcomer syndrome, macrosomia-microphthalmia-cleft palate syndrome, mesomelic dwarfism-cleft palate-camptodactyly syndrome, Nijmegen breakage syndrome, lethal congenital contracture syndrome 1, Richieri Costa-da Silva syndrome, Keipert syndrome, nephrosis-deafness-urinary tract-digital malformations syndrome, ichthyosis-oral and digital anomalies syndrome, otoonychoperoneal syndrome, PHAVER syndrome, polysyndactyly-cardiac malformation syndrome, postaxial acrofacial dysostosis, autosomal recessive multiple pterygium syndrome, rapadilino syndrome, renal-genital-middle ear anomalies, Richieri Costa-Pereira syndrome, SHORT syndrome, tetraamelia-multiple malformations syndrome, thymic-renal-anal-lung dysplasia, trigonocephaly-bifid nose-acral anomalies syndrome, white forelock with malformations, syndactyly-telecanthus-anogenital and renal malformations syndrome, Abruzzo-Erickson syndrome, CHILD syndrome, pentalogy of Cantrell, atrioventricular defect-blepharophimosis-radial and anal defect syndrome, short tarsus-absence of lower eyelashes syndrome, PARC syndrome, CODAS syndrome, pectus excavatum-macrocephaly-dysplastic nails syndrome, velo-facial-skeletal syndrome, anophthalmia plus syndrome, van den Ende-Gupta syndrome, absent tibia-polydactyly-arachnoid cyst syndrome, diaphragmatic defect-limb deficiency-skull defect syndrome, cleft lip/palate-intestinal malrotation-cardiopathy syndrome, Matthew-Wood syndrome, microcephaly-cardiac defect-lung malsegmentation syndrome, dislocation of the hip-dysmorphism syndrome, short stature-auditory canal atresia-mandibular hypoplasia-skeletal anomalies syndrome, grange syndrome, camptodactyly, myopia, and fibrosis of the medial rectus muscle of eye, arhinia, choanal atresia, and microphthalmia, anonychia-microcephaly syndrome, developmental malformations-deafness-dystonia syndrome, craniolenticulosutural dysplasia, 8q22.1 microdeletion syndrome, Braddock syndrome, choanal atresia-hearing loss-cardiac defects-craniofacial dysmorphism syndrome, BNAR syndrome, Frias syndrome, lethal congenital contracture syndrome 3, Fontaine progeroid syndrome, microcephaly-facio-cardio-skeletal syndrome, Hadziselimovic type, Nijmegen breakage syndrome-like disorder, Warsaw breakage syndrome, even-plus syndrome, split-foot malformation-mesoaxial polydactyly syndrome, anophthalmia-megalocornea-cardiopathy-skeletal anomalies syndrome, digitotalar dysmorphism, heart-hand syndrome type 2, night blindness-skeletal anomalies-dysmorphism syndrome, Charlie M syndrome, facial dysmorphism-anorexia-cachexia-eye and skin anomalies syndrome, cleft lip-retinopathy syndrome, Cole-Carpenter syndrome, progressive non-infectious anterior vertebral fusion, dysmorphism-pectus carinatum-joint laxity syndrome, Hirschsprung disease-type D brachydactyly syndrome, mandibuloacral dysplasia, contractures - webbed neck - micrognathia - hypoplastic nipples syndrome, Thomas syndrome, Waardenburg syndrome, Weill-Marchesani syndrome, branchiootic syndrome, auricular abnormalities-cleft lip with or without cleft palate-ocular abnormalities syndrome, Axenfeld-Rieger syndrome, macrostomia-preauricular tags-external ophthalmoplegia syndrome, pelvis syndrome, Fanconi anemia, van der Woude syndrome, hypertrichosis-acromegaloid facial appearance syndrome, 49,XYYYY syndrome, congenital vertebral-cardiac-renal anomalies syndrome, structural heart defects and renal anomalies syndrome, Greig cephalopolysyndactyly-contiguous gene syndrome

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

17 retrieved; paginated sample, class counts are floors:

7 likely pathogenic, 4 uncertain significance, 3 benign, 2 conflicting classifications of pathogenicity, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
12572	NM_001982.4(ERBB3):c.1184-9A>G	ERBB3	Likely pathogenic	criteria provided, single submitter
2627242	NM_001982.4(ERBB3):c.3202-2A>G	ERBB3	Likely pathogenic	criteria provided, single submitter
3574998	NM_001982.4(ERBB3):c.83-2A>G	ERBB3	Likely pathogenic	criteria provided, single submitter
3574999	NM_001982.4(ERBB3):c.237G>A (p.Trp79Ter)	ERBB3	Likely pathogenic	criteria provided, single submitter
3575000	NM_001982.4(ERBB3):c.3223del (p.Ser1075fs)	ERBB3	Likely pathogenic	criteria provided, single submitter
4845779	NM_001982.4(ERBB3):c.2442G>A (p.Trp814Ter)	ERBB3	Likely pathogenic	criteria provided, single submitter
978710	NM_001982.4(ERBB3):c.1253T>C (p.Ile418Thr)	ERBB3	Likely pathogenic	criteria provided, single submitter
1163537	NM_001982.4(ERBB3):c.2993A>G (p.Lys998Arg)	ERBB3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
806898	NM_001982.4(ERBB3):c.89C>T (p.Pro30Leu)	ERBB3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1992381	NM_001982.4(ERBB3):c.2615A>T (p.Lys872Met)	ERBB3	Uncertain significance	criteria provided, single submitter
2585366	NM_001982.4(ERBB3):c.650A>C (p.His217Pro)	ERBB3	Uncertain significance	criteria provided, single submitter
634469	NM_001982.4(ERBB3):c.2241G>C (p.Lys747Asn)	ERBB3	Uncertain significance	criteria provided, multiple submitters, no conflicts
800957	NM_001982.4(ERBB3):c.3425C>T (p.Pro1142Leu)	ERBB3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1226099	NM_001982.4(ERBB3):c.3129+9A>C	ERBB3	Benign	criteria provided, multiple submitters, no conflicts
1248586	NM_001982.4(ERBB3):c.3348G>A (p.Arg1116=)	ERBB3	Benign	criteria provided, multiple submitters, no conflicts
1255390	NM_001982.4(ERBB3):c.234+8A>T	ERBB3	Benign	criteria provided, multiple submitters, no conflicts
1255391	NM_001982.4(ERBB3):c.2616+16G>C	ERBB3	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 2 · 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
ERBB3	Strong	Autosomal recessive	lethal congenital contracture syndrome 2	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ERBB3	Orphanet:137776	Lethal congenital contracture syndrome type 2
ERBB3	Orphanet:388	Hirschsprung disease

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
ERBB3	HGNC:3431	ENSG00000065361	P21860	Receptor tyrosine-protein kinase erbB-3	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ERBB3	Receptor tyrosine-protein kinase erbB-3	Tyrosine-protein kinase that plays an essential role as cell surface receptor for neuregulins.

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
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ERBB3	Kinase	yes	2.7.10.1	Rcpt_L-dom, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_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
dorsal root ganglion	1
jejunal mucosa	1
trigeminal ganglion	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ERBB3	274	broad	marker	trigeminal ganglion, jejunal mucosa, dorsal root ganglion

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ERBB3	4,511

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ERBB3	P21860	23

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. 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
GRB7 events in ERBB2 signaling	1	1903.3×	0.004	ERBB3
Downregulation of ERBB2:ERBB3 signaling	1	815.7×	0.004	ERBB3
ERBB2 Activates PTK6 Signaling	1	815.7×	0.004	ERBB3
ERBB2 Regulates Cell Motility	1	713.8×	0.004	ERBB3
PI3K events in ERBB2 signaling	1	671.8×	0.004	ERBB3
SHC1 events in ERBB2 signaling	1	475.8×	0.004	ERBB3
Signaling by ERBB2 TMD/JMD mutants	1	475.8×	0.004	ERBB3
Signaling by ERBB2 KD Mutants	1	423.0×	0.004	ERBB3
Downregulation of ERBB2 signaling	1	380.7×	0.004	ERBB3
Signaling by ERBB2	1	346.1×	0.004	ERBB3
Signaling by ERBB4	1	271.9×	0.005	ERBB3
Constitutive Signaling by Aberrant PI3K in Cancer	1	126.9×	0.010	ERBB3
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	1	96.8×	0.012	ERBB3
PIP3 activates AKT signaling	1	66.8×	0.016	ERBB3
RAF/MAP kinase cascade	1	61.1×	0.016	ERBB3

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
positive regulation of cardiac muscle tissue development	1	8426.0×	0.003	ERBB3
cranial nerve development	1	5617.3×	0.003	ERBB3
negative regulation of secretion	1	3370.4×	0.003	ERBB3
Schwann cell differentiation	1	2407.4×	0.003	ERBB3
ERBB2-ERBB3 signaling pathway	1	1685.2×	0.003	ERBB3
negative regulation of motor neuron apoptotic process	1	1532.0×	0.003	ERBB3
endocardial cushion development	1	1404.3×	0.003	ERBB3
motor neuron apoptotic process	1	1123.5×	0.003	ERBB3
Schwann cell development	1	1053.2×	0.003	ERBB3
positive regulation of calcineurin-NFAT signaling cascade	1	802.5×	0.004	ERBB3
peripheral nervous system development	1	581.1×	0.005	ERBB3
extrinsic apoptotic signaling pathway in absence of ligand	1	468.1×	0.005	ERBB3
negative regulation of cell adhesion	1	383.0×	0.006	ERBB3
negative regulation of signal transduction	1	374.5×	0.006	ERBB3
myelination	1	251.5×	0.007	ERBB3
epidermal growth factor receptor signaling pathway	1	247.8×	0.007	ERBB3
positive regulation of epithelial cell proliferation	1	244.2×	0.007	ERBB3
wound healing	1	227.7×	0.007	ERBB3
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	210.7×	0.007	ERBB3
neuron apoptotic process	1	185.2×	0.008	ERBB3
cell surface receptor protein tyrosine kinase signaling pathway	1	173.7×	0.008	ERBB3
regulation of cell population proliferation	1	115.4×	0.012	ERBB3
negative regulation of neuron apoptotic process	1	110.9×	0.012	ERBB3
neuron differentiation	1	100.3×	0.012	ERBB3
positive regulation of MAPK cascade	1	80.6×	0.014	ERBB3
heart development	1	78.8×	0.014	ERBB3
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	78.4×	0.014	ERBB3
positive regulation of gene expression	1	38.7×	0.028	ERBB3
negative regulation of apoptotic process	1	34.8×	0.030	ERBB3
signal transduction	1	16.1×	0.062	ERBB3

Therapeutics

Drug target analysis

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

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

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
ERBB3	MOBOCERTINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ERBB3	23	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOBOCERTINIB	4	ERBB3
AFATINIB	4	ERBB3
NERATINIB	4	ERBB3
VANDETANIB	4	ERBB3
BOSUTINIB	4	ERBB3
OSIMERTINIB	4	ERBB3
DASATINIB	4	ERBB3
ERLOTINIB	4	ERBB3
LAPATINIB	4	ERBB3
GEFITINIB	4	ERBB3
CANERTINIB	3	ERBB3
ROCILETINIB	3	ERBB3
ALVOCIDIB	3	ERBB3
CEDIRANIB	3	ERBB3
CANERTINIB DIHYDROCHLORIDE	3	ERBB3
LESTAURTINIB	3	ERBB3
AEE-788	2	ERBB3
FORETINIB	2	ERBB3
SAPITINIB	2	ERBB3
PF-06459988	2	ERBB3
MAVELERTINIB	2	ERBB3
TOZASERTIB	2	ERBB3
TAK-285	1	ERBB3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ERBB3	169	Binding:169

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ERBB3	2.7.10.1	receptor protein-tyrosine kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
ERBB3	169

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

23 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.

Compound	Max phase	Cohort target (bioactivity)
MOBOCERTINIB	4	ERBB3
AFATINIB	4	ERBB3
NERATINIB	4	ERBB3
VANDETANIB	4	ERBB3
BOSUTINIB	4	ERBB3
OSIMERTINIB	4	ERBB3
DASATINIB	4	ERBB3
ERLOTINIB	4	ERBB3
LAPATINIB	4	ERBB3
GEFITINIB	4	ERBB3
CANERTINIB	3	ERBB3
ROCILETINIB	3	ERBB3
ALVOCIDIB	3	ERBB3
CEDIRANIB	3	ERBB3
CANERTINIB DIHYDROCHLORIDE	3	ERBB3
LESTAURTINIB	3	ERBB3
AEE-788	2	ERBB3
FORETINIB	2	ERBB3
SAPITINIB	2	ERBB3
PF-06459988	2	ERBB3
MAVELERTINIB	2	ERBB3
TOZASERTIB	2	ERBB3
TAK-285	1	ERBB3

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ERBB3
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	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 0.