Congenital muscular dystrophy-respiratory failure-skin abnormalities-joint hyperlaxity syndrome

Summary

Congenital muscular dystrophy-respiratory failure-skin abnormalities-joint hyperlaxity syndrome (MONDO:0014896) is a disease caused by TRIP4 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: TRIP4 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 8
• Phenotypes (HPO): 30

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		4	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

30 HPO clinical features (Orphanet curated; top 30 by frequency):

HPO ID	Term	Frequency
HP:0002747	Respiratory insufficiency due to muscle weakness	Very frequent (80-99%)
HP:0003458	EMG: myopathic abnormalities	Very frequent (80-99%)
HP:0007502	Follicular hyperkeratosis	Very frequent (80-99%)
HP:0001382	Joint hypermobility	Very frequent (80-99%)
HP:0000218	High palate	Frequent (30-79%)
HP:0000467	Neck muscle weakness	Frequent (30-79%)
HP:0000767	Pectus excavatum	Frequent (30-79%)
HP:0000958	Dry skin	Frequent (30-79%)
HP:0001270	Motor delay	Frequent (30-79%)
HP:0001290	Generalized hypotonia	Frequent (30-79%)
HP:0002020	Gastroesophageal reflux	Frequent (30-79%)
HP:0002205	Recurrent respiratory infections	Frequent (30-79%)
HP:0002421	Poor head control	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0003306	Spinal rigidity	Frequent (30-79%)
HP:0003557	Increased variability in muscle fiber diameter	Frequent (30-79%)
HP:0003687	Centrally nucleated skeletal muscle fibers	Frequent (30-79%)
HP:0003690	Limb muscle weakness	Frequent (30-79%)
HP:0003789	Minicore myopathy	Frequent (30-79%)
HP:0010647	Abnormal elasticity of skin	Frequent (30-79%)
HP:0011471	Gastrostomy tube feeding in infancy	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0000028	Cryptorchidism	Occasional (5-29%)
HP:0000750	Delayed speech and language development	Occasional (5-29%)
HP:0000823	Delayed puberty	Occasional (5-29%)
HP:0001612	Weak cry	Occasional (5-29%)
HP:0002828	Multiple joint contractures	Occasional (5-29%)
HP:0008081	Pes valgus	Occasional (5-29%)
HP:0008180	Mildly elevated creatine kinase	Occasional (5-29%)
HP:0025502	Overweight	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital muscular dystrophy-respiratory failure-skin abnormalities-joint hyperlaxity syndrome
Mondo ID	MONDO:0014896
OMIM	617066
Orphanet	486815
UMLS	C4310736
MedGen	934703
GARD	0017883
Is cancer (heuristic)	no

Also known as: congenital muscular dystrophy, Davignon-Chauveau type · MDCDC · muscular dystrophy, congenital, Davignon-Chauveau type

Data availability: 8 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › congenital muscular dystrophy › congenital muscular dystrophy-respiratory failure-skin abnormalities-joint hyperlaxity syndrome

Related subtypes (22): Ullrich congenital muscular dystrophy, Bethlem myopathy, arthrogryposis due to muscular dystrophy, congenital muscular dystrophy-infantile cataract-hypogonadism syndrome, muscular dystrophy, congenital, with rapid progression, congenital myasthenic syndrome 10, megaconial type congenital muscular dystrophy, congenital muscular dystrophy 1B, congenital merosin-deficient muscular dystrophy 1A, congenital muscular dystrophy due to integrin alpha-7 deficiency, congenital muscular dystrophy due to LMNA mutation, congenital myopathy, Paradas type, autosomal recessive myogenic arthrogryposis multiplex congenita, muscular dystrophy-dystroglycanopathy, congenital muscular dystrophy with hyperlaxity, muscle-eye-brain disease, rigid spine syndrome, congenital muscular dystrophy with cataracts and intellectual disability, SNUPN-related muscular dystrophy with or without multi-system involvement, congenital muscular dystrophy caused by variation in POMGNT2, collagen 6-related congenital muscular dystrophy, congenital muscular dystrophy without intellectual disability

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
1934244	NM_016213.5(TRIP4):c.135dup (p.Arg46fs)	TRIP4	Pathogenic	criteria provided, multiple submitters, no conflicts
253117	NM_016213.5(TRIP4):c.950G>A (p.Arg317Gln)	TRIP4	Pathogenic	no assertion criteria provided
1327919	NM_016213.5(TRIP4):c.1678+1_1678+2insC	LOC126862156	Uncertain significance	criteria provided, single submitter
1030539	NM_016213.5(TRIP4):c.1465C>T (p.Arg489Cys)	TRIP4	Uncertain significance	criteria provided, multiple submitters, no conflicts
977162	NM_016213.5(TRIP4):c.1065del (p.Ile356fs)	TRIP4	Uncertain significance	criteria provided, single submitter
1287307	NM_016213.5(TRIP4):c.1596G>A (p.Glu532=)	LOC126862156	Benign	criteria provided, multiple submitters, no conflicts
1282717	NM_016213.5(TRIP4):c.1044-25G>A	TRIP4	Benign	criteria provided, multiple submitters, no conflicts
710055	NM_016213.5(TRIP4):c.981C>T (p.Thr327=)	TRIP4	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
TRIP4	Strong	Autosomal recessive	prenatal-onset spinal muscular atrophy with congenital bone fractures	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TRIP4	Orphanet:486811	Prenatal-onset spinal muscular atrophy with congenital bone fractures
TRIP4	Orphanet:486815	Congenital muscular dystrophy-respiratory failure-skin abnormalities-joint hyperlaxity 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
TRIP4	HGNC:12310	ENSG00000103671	Q15650	Activating signal cointegrator 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TRIP4	Activating signal cointegrator 1	Transcription coactivator which associates with nuclear receptors, transcriptional coactivators including EP300, CREBBP and NCOA1, and basal transcription factors like TBP and TFIIA to facilitate nuclear receptors-mediated transcription.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TRIP4	Transcription factor	no		ASCH_domain, TRIP4/RQT4_C2HC5_Znf, PUA-like_sf

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
lower esophagus mucosa	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TRIP4	282	ubiquitous	marker	sural nerve, lower esophagus mucosa, amniotic fluid

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TRIP4	1,541

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TRIP4	Q15650	10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
ZNF598 and the Ribosome-associated Quality Trigger (RQT) complex dissociate a ribosome stalled on a no-go mRNA	1	117.7×	0.008	TRIP4

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
regulation of myoblast differentiation	1	2407.4×	0.001	TRIP4
ribosome-associated ubiquitin-dependent protein catabolic process	1	2407.4×	0.001	TRIP4
ribosome disassembly	1	991.3×	0.002	TRIP4
estrogen receptor signaling pathway	1	732.7×	0.002	TRIP4
rescue of stalled cytosolic ribosome	1	481.5×	0.003	TRIP4
regulation of DNA-templated transcription	1	31.6×	0.036	TRIP4
positive regulation of DNA-templated transcription	1	27.9×	0.036	TRIP4

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TRIP4	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	TRIP4

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)
TRIP4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.