Bartsocas-Papas syndrome 1

Summary

Bartsocas-Papas syndrome 1 (MONDO:0009901) is a disease caused by RIPK4 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: RIPK4 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 131
• Phenotypes (HPO): 26

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		24	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated
Prevalence at birth	1-9 / 1 000 000	0.15	Spain	Validated

Signs & symptoms

Clinical features (HPO)

26 HPO clinical features (Orphanet curated; top 26 by frequency):

HPO ID	Term	Frequency
HP:0000050	Hypoplastic male external genitalia	Very frequent (80-99%)
HP:0000062	Ambiguous genitalia	Very frequent (80-99%)
HP:0000161	Median cleft lip	Very frequent (80-99%)
HP:0000175	Cleft palate	Very frequent (80-99%)
HP:0000252	Microcephaly	Very frequent (80-99%)
HP:0001770	Toe syndactyly	Very frequent (80-99%)
HP:0001800	Hypoplastic toenails	Very frequent (80-99%)
HP:0001883	Talipes	Very frequent (80-99%)
HP:0006101	Finger syndactyly	Very frequent (80-99%)
HP:0007418	Alopecia totalis	Very frequent (80-99%)
HP:0009755	Ankyloblepharon	Very frequent (80-99%)
HP:0009756	Popliteal pterygium	Very frequent (80-99%)
HP:0010185	Aplasia/Hypoplasia of the distal phalanges of the toes	Very frequent (80-99%)
HP:0100240	Synostosis of joints	Very frequent (80-99%)
HP:0100840	Aplasia/Hypoplasia of the eyebrow	Very frequent (80-99%)
HP:0200102	Sparse or absent eyelashes	Very frequent (80-99%)
HP:0000160	Narrow mouth	Frequent (30-79%)
HP:0000347	Micrognathia	Frequent (30-79%)
HP:0000430	Underdeveloped nasal alae	Frequent (30-79%)
HP:0000625	Eyelid coloboma	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0003196	Short nose	Frequent (30-79%)
HP:0007957	Corneal opacity	Frequent (30-79%)
HP:0009777	Absent thumb	Frequent (30-79%)
HP:0008678	Renal hypoplasia/aplasia	Occasional (5-29%)
HP:0030680	Abnormal cardiovascular system morphology	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Bartsocas-Papas syndrome 1
Mondo ID	MONDO:0009901
MeSH	C564874
OMIM	263650
Orphanet	1234
NCIT	C168990
SNOMED CT	722376008
UMLS	C1849718
MedGen	337894
GARD	0004436
Is cancer (heuristic)	no

Also known as: autosomal recessive popliteal pterygium syndrome · Bartsocas Papas syndrome · Bartsocas-Papas syndrome · BPS · lethal popliteal pterygium syndrome · popliteal pterygium syndrome lethal type · popliteal pterygium syndrome, Bartsocas-Papas type · popliteal pterygium syndrome, Bartsocas-Papas type 1 · popliteal pterygium syndrome, lethal type · pterygium popliteal lethal type

Data availability: 131 ClinVar variants · 3 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › disorder of development or morphogenesis › developmental defect during embryogenesis › congenital limb malformation › arthrogryposis syndrome › popliteal pterygium syndrome › Bartsocas-Papas syndrome 1

Related subtypes (2): autosomal dominant popliteal pterygium syndrome, Bartsocas-Papas syndrome 2

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

131 retrieved; paginated sample, class counts are floors:

71 uncertain significance, 23 benign, 16 benign/likely benign, 8 conflicting classifications of pathogenicity, 7 likely benign, 5 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
30511	NM_020639.3(RIPK4):c.1127C>A (p.Ser376Ter)	RIPK4	Pathogenic	no assertion criteria provided
30512	NM_020639.3(RIPK4):c.242T>A (p.Ile81Asn)	RIPK4	Pathogenic	no assertion criteria provided
30513	NM_020639.3(RIPK4):c.362T>A (p.Ile121Asn)	RIPK4	Pathogenic	no assertion criteria provided
30514	NM_020639.3(RIPK4):c.777dup (p.Arg260fs)	RIPK4	Pathogenic	no assertion criteria provided
585265	NM_020639.3(RIPK4):c.1074dup (p.Glu359Ter)	RIPK4	Pathogenic	no assertion criteria provided
1285557	NM_020639.3(RIPK4):c.722G>A (p.Arg241His)	RIPK4	Likely pathogenic	criteria provided, single submitter
340012	NM_020639.3(RIPK4):c.2145C>T (p.His715=)	RIPK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
340022	NM_020639.3(RIPK4):c.1243G>A (p.Val415Met)	RIPK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
340035	NM_020639.3(RIPK4):c.267C>T (p.Arg89=)	RIPK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
716721	NM_020639.3(RIPK4):c.832+2T>C	RIPK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
734574	NM_020639.3(RIPK4):c.252G>A (p.Val84=)	RIPK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
746355	NM_020639.3(RIPK4):c.1137C>T (p.Ser379=)	RIPK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
748316	NM_020639.3(RIPK4):c.1344C>T (p.Ala448=)	RIPK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
781521	NM_020639.3(RIPK4):c.2277C>T (p.Ala759=)	RIPK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1033541	NM_020639.3(RIPK4):c.1511A>G (p.Gln504Arg)	RIPK4	Uncertain significance	criteria provided, single submitter
1187860	NM_020639.3(RIPK4):c.721C>T (p.Arg241Cys)	RIPK4	Uncertain significance	criteria provided, multiple submitters, no conflicts
2506358	NM_020639.3(RIPK4):c.467A>C (p.His156Pro)	RIPK4	Uncertain significance	criteria provided, single submitter
339985	NM_020639.3(RIPK4):c.*1361T>A	RIPK4	Uncertain significance	criteria provided, multiple submitters, no conflicts
339986	NM_020639.3(RIPK4):c.*1248C>T	RIPK4	Uncertain significance	criteria provided, single submitter
339987	NM_020639.3(RIPK4):c.*1234G>A	RIPK4	Uncertain significance	criteria provided, single submitter
339988	NM_020639.3(RIPK4):c.*1081C>T	RIPK4	Uncertain significance	criteria provided, single submitter
339991	NM_020639.3(RIPK4):c.*978C>G	RIPK4	Uncertain significance	criteria provided, single submitter
339995	NM_020639.3(RIPK4):c.*729C>T	RIPK4	Uncertain significance	criteria provided, single submitter
340000	NM_020639.3(RIPK4):c.*281G>A	RIPK4	Uncertain significance	criteria provided, single submitter
340003	NM_020639.3(RIPK4):c.*215G>T	RIPK4	Uncertain significance	criteria provided, single submitter
340004	NM_020639.3(RIPK4):c.*201C>T	RIPK4	Uncertain significance	criteria provided, single submitter
340005	NM_020639.3(RIPK4):c.*142G>A	RIPK4	Uncertain significance	criteria provided, single submitter
340007	NM_020639.3(RIPK4):c.*73G>A	RIPK4	Uncertain significance	criteria provided, single submitter
340008	NM_020639.3(RIPK4):c.*60G>A	RIPK4	Uncertain significance	criteria provided, single submitter
340009	NM_020639.3(RIPK4):c.*59C>T	RIPK4	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
RIPK4	Definitive	Autosomal recessive	Bartsocas-Papas syndrome 1	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RIPK4	Orphanet:1234	Bartsocas-Papas syndrome
RIPK4	Orphanet:1401	CHAND 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
RIPK4	HGNC:496	ENSG00000183421	P57078	Receptor-interacting serine/threonine-protein kinase 4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RIPK4	Receptor-interacting serine/threonine-protein kinase 4	Serine/threonine protein kinase.

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)
RIPK4	Kinase	yes		Prot_kinase_dom, Ankyrin_rpt, Ser/Thr_kinase_AS

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
epithelium of esophagus	1
esophagus squamous epithelium	1
tongue squamous epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RIPK4	182	broad	marker	esophagus squamous epithelium, tongue squamous epithelium, epithelium of esophagus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RIPK4	5,738

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RIPK4	P57078	75.41

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

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
skin development	1	443.5×	0.004	RIPK4
morphogenesis of an epithelium	1	343.9×	0.004	RIPK4
obsolete positive regulation of NF-kappaB transcription factor activity	1	205.5×	0.005	RIPK4

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
RIPK4	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RIPK4	15	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	RIPK4
AXITINIB	4	RIPK4
RUXOLITINIB	4	RIPK4
VANDETANIB	4	RIPK4
NINTEDANIB	4	RIPK4
SUNITINIB	4	RIPK4
ERLOTINIB	4	RIPK4
CRIZOTINIB	4	RIPK4
LESTAURTINIB	3	RIPK4
FORETINIB	2	RIPK4
TG100-115	2	RIPK4
R-406	2	RIPK4
TOZASERTIB	2	RIPK4
KW-2449	1	RIPK4
AST-487	1	RIPK4

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
RIPK4	91	Binding:91

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

15 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)
FEDRATINIB	4	RIPK4
AXITINIB	4	RIPK4
RUXOLITINIB	4	RIPK4
VANDETANIB	4	RIPK4
NINTEDANIB	4	RIPK4
SUNITINIB	4	RIPK4
ERLOTINIB	4	RIPK4
CRIZOTINIB	4	RIPK4
LESTAURTINIB	3	RIPK4
FORETINIB	2	RIPK4
TG100-115	2	RIPK4
R-406	2	RIPK4
TOZASERTIB	2	RIPK4
KW-2449	1	RIPK4
AST-487	1	RIPK4

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	RIPK4
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.