Lethal congenital contracture syndrome 3

Summary

Lethal congenital contracture syndrome 3 (MONDO:0012656) is a disease caused by PIP5K1C (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PIP5K1C (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 10

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		14	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	lethal congenital contracture syndrome 3
Mondo ID	MONDO:0012656
MeSH	C566961
OMIM	611369
Orphanet	137783
DOID	DOID:0060653
SNOMED CT	715420005
UMLS	C1969655
MedGen	369555
GARD	0012644
Is cancer (heuristic)	no

Also known as: LCCS3 · lethal congenital contractural syndrome 3 · lethal congenital contracture syndrome 3 · lethal congenital contracture syndrome caused by mutation in PIP5K1C · lethal congenital contracture syndrome type 3 · PIP5K1C lethal congenital contracture syndrome

Data availability: 10 ClinVar variants · 5 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 3

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, lethal congenital contracture syndrome 2, craniolenticulosutural dysplasia, 8q22.1 microdeletion syndrome, Braddock syndrome, choanal atresia-hearing loss-cardiac defects-craniofacial dysmorphism syndrome, BNAR syndrome, Frias syndrome, 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

10 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
4615	NM_012398.3(PIP5K1C):c.757G>A (p.Asp253Asn)	PIP5K1C	Pathogenic	no assertion criteria provided
3377275	NM_012398.3(PIP5K1C):c.777_778dup (p.Lys260fs)	PIP5K1C	Likely pathogenic	criteria provided, single submitter
694416	NM_012398.3(PIP5K1C):c.1148T>C (p.Val383Ala)	PIP5K1C	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2411479	NM_012398.3(PIP5K1C):c.136A>G (p.Met46Val)	PIP5K1C	Uncertain significance	criteria provided, multiple submitters, no conflicts
2434867	NM_012398.3(PIP5K1C):c.991C>T (p.Arg331Cys)	PIP5K1C	Uncertain significance	criteria provided, single submitter
3359143	NM_012398.3(PIP5K1C):c.1640_1641insCTCC (p.Arg548fs)	PIP5K1C	Uncertain significance	criteria provided, single submitter
1221119	NM_012398.3(PIP5K1C):c.1345+25C>T	PIP5K1C	Benign	criteria provided, multiple submitters, no conflicts
1253793	NM_012398.3(PIP5K1C):c.684G>A (p.Ser228=)	PIP5K1C	Benign	criteria provided, multiple submitters, no conflicts
1258350	NM_012398.3(PIP5K1C):c.1787+31G>A	PIP5K1C	Benign	criteria provided, multiple submitters, no conflicts
1293116	NM_012398.3(PIP5K1C):c.468+20C>T	PIP5K1C	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 18 · Orphanet: 4 · 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
MYBPC1	Strong	Autosomal recessive	lethal congenital contracture syndrome 4	11
PIP5K1C	Strong	Autosomal recessive	lethal congenital contracture syndrome 3	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PIP5K1C	Orphanet:137783	Lethal congenital contracture syndrome type 3
MYBPC1	Orphanet:1146	Distal arthrogryposis type 1
MYBPC1	Orphanet:137783	Lethal congenital contracture syndrome type 3
MYBPC1	Orphanet:498693	MYBPC1-related autosomal recessive non-lethal arthrogryposis multiplex congenita syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PIP5K1C	HGNC:8996	ENSG00000186111	O60331	Phosphatidylinositol 4-phosphate 5-kinase type-1 gamma	gencc,clinvar
MYBPC1	HGNC:7549	ENSG00000196091	Q00872	Myosin-binding protein C, slow-type	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PIP5K1C	Phosphatidylinositol 4-phosphate 5-kinase type-1 gamma	Catalyzes the phosphorylation of phosphatidylinositol 4-phosphate (PtdIns(4)P/PI4P) to form phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2/PIP2), a lipid second messenger that regulates several cellular processes such as signal trans…
MYBPC1	Myosin-binding protein C, slow-type	Thick filament-associated protein located in the crossbridge region of vertebrate striated muscle a bands.

Protein-family classification

Druggable: 2 · 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
Antibody/Immunoglobulin	1	14.6×	0.071
Kinase	1	13.9×	0.071

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PIP5K1C	Kinase	yes	2.7.1.68	PInositol-4-P-4/5-kinase_core, PInositol-4/5-P-5/4-kinase, PInositol-4-P-4/5-kinase_C_sf
MYBPC1	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, FN3_dom

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
biceps brachii	1
skeletal muscle tissue of biceps brachii	1
skeletal muscle tissue of rectus abdominis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PIP5K1C	279	ubiquitous	marker	right hemisphere of cerebellum, cerebellar cortex, cerebellar hemisphere
MYBPC1	225	broad	marker	biceps brachii, skeletal muscle tissue of rectus abdominis, skeletal muscle tissue of biceps brachii

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PIP5K1C	1,853
MYBPC1	1,816

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MYBPC1	Q00872	8
PIP5K1C	O60331	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
SEMA3A-Plexin repulsion signaling by inhibiting Integrin adhesion	1	380.7×	0.015	PIP5K1C
Regulation of CDH1 posttranslational processing and trafficking to plasma membrane	1	167.9×	0.015	PIP5K1C
Striated Muscle Contraction	1	154.3×	0.015	MYBPC1
Synthesis of PIPs at the plasma membrane	1	105.7×	0.017	PIP5K1C
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	1	48.4×	0.026	PIP5K1C
Clathrin-mediated endocytosis	1	42.6×	0.026	PIP5K1C
Muscle contraction	1	38.6×	0.026	MYBPC1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
adherens junction assembly	1	648.1×	0.008	PIP5K1C
synaptic vesicle exocytosis	1	383.0×	0.008	PIP5K1C
regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	351.1×	0.008	PIP5K1C
clathrin-dependent endocytosis	1	290.6×	0.008	PIP5K1C
membrane organization	1	255.3×	0.008	PIP5K1C
phosphatidylinositol phosphate biosynthetic process	1	240.7×	0.008	PIP5K1C
synaptic vesicle endocytosis	1	216.1×	0.008	PIP5K1C
sarcomere organization	1	191.5×	0.008	MYBPC1
phosphatidylinositol biosynthetic process	1	183.2×	0.008	PIP5K1C
neutrophil chemotaxis	1	142.8×	0.010	PIP5K1C
phagocytosis	1	120.4×	0.011	PIP5K1C
cell-cell adhesion	1	50.8×	0.023	PIP5K1C
actin cytoskeleton organization	1	39.6×	0.027	PIP5K1C
cell adhesion	1	18.7×	0.053	MYBPC1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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
PIP5K1C	PAZOPANIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PIP5K1C	10	4
MYBPC1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PAZOPANIB	4	PIP5K1C
ENZASTAURIN	3	PIP5K1C
ALVOCIDIB	3	PIP5K1C
DOVITINIB	3	PIP5K1C
RUBOXISTAURIN	3	PIP5K1C
TG100-115	2	PIP5K1C
R-406	2	PIP5K1C
BIIB-091	2	PIP5K1C
GSK-461364	1	PIP5K1C
GSK-690693	1	PIP5K1C

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PIP5K1C	116	Binding:116

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PIP5K1C	2.7.1.68	1-phosphatidylinositol-4-phosphate 5-kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
PIP5K1C	116

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

10 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)
PAZOPANIB	4	PIP5K1C
ENZASTAURIN	3	PIP5K1C
ALVOCIDIB	3	PIP5K1C
DOVITINIB	3	PIP5K1C
RUBOXISTAURIN	3	PIP5K1C
TG100-115	2	PIP5K1C
R-406	2	PIP5K1C
BIIB-091	2	PIP5K1C
GSK-461364	1	PIP5K1C
GSK-690693	1	PIP5K1C

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PIP5K1C
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	MYBPC1
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)
MYBPC1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.