achondrogenesis type IA

Summary

achondrogenesis type IA (MONDO:0008701) is a disease caused by TRIP11 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: TRIP11 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 698
• Phenotypes (HPO): 27

Clinical features

Signs & symptoms

Clinical features (HPO)

27 HPO clinical features (Orphanet curated; top 27 by frequency):

HPO ID	Term	Frequency
HP:0000256	Macrocephaly	Very frequent (80-99%)
HP:0000343	Long philtrum	Very frequent (80-99%)
HP:0000347	Micrognathia	Very frequent (80-99%)
HP:0000463	Anteverted nares	Very frequent (80-99%)
HP:0000470	Short neck	Very frequent (80-99%)
HP:0000474	Thickened nuchal skin fold	Very frequent (80-99%)
HP:0000774	Narrow chest	Very frequent (80-99%)
HP:0001789	Hydrops fetalis	Very frequent (80-99%)
HP:0002007	Frontal bossing	Very frequent (80-99%)
HP:0002983	Micromelia	Very frequent (80-99%)
HP:0003196	Short nose	Very frequent (80-99%)
HP:0003270	Abdominal distention	Very frequent (80-99%)
HP:0003336	Abnormal enchondral ossification	Very frequent (80-99%)
HP:0003510	Severe short stature	Very frequent (80-99%)
HP:0005716	Lethal skeletal dysplasia	Very frequent (80-99%)
HP:0006703	Aplasia/Hypoplasia of the lungs	Very frequent (80-99%)
HP:0010306	Short thorax	Very frequent (80-99%)
HP:0012368	Flat face	Very frequent (80-99%)
HP:0001537	Umbilical hernia	Frequent (30-79%)
HP:0001561	Polyhydramnios	Frequent (30-79%)
HP:0001773	Short foot	Frequent (30-79%)
HP:0002757	Recurrent fractures	Frequent (30-79%)
HP:0004279	Short palm	Frequent (30-79%)
HP:0006640	Multiple ribs fractures	Frequent (30-79%)
HP:0100541	Femoral hernia	Frequent (30-79%)
HP:0000476	Cystic hygroma	Occasional (5-29%)
HP:0030680	Abnormal cardiovascular system morphology	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	achondrogenesis type IA
Mondo ID	MONDO:0008701
MeSH	C536015
OMIM	200600
Orphanet	93299
DOID	DOID:0080054
SNOMED CT	42725006
UMLS	C0265273
MedGen	78546
GARD	0000459
Is cancer (heuristic)	no

Also known as: ACG1A · achondrogenesis, Houston-Harris type · achondrogenesis, type IA · Houston-Harris achondrogenesis

Data availability: 698 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › bone development disease › osteochondrodysplasia › achondrogenesis › achondrogenesis type IA

Related subtypes (4): achondrogenesis type II, acromesomelic dysplasia 2A, achondrogenesis type IB, hypochondrogenesis

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

600 retrieved; paginated sample, class counts are floors:

243 uncertain significance, 198 likely benign, 45 benign, 41 pathogenic, 41 conflicting classifications of pathogenicity, 16 likely pathogenic, 15 benign/likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1028711	NM_004239.4(TRIP11):c.2611C>T (p.Arg871Ter)	TRIP11	Pathogenic	criteria provided, multiple submitters, no conflicts
1098269	NM_004239.4(TRIP11):c.5457+81T>A	TRIP11	Pathogenic	criteria provided, single submitter
1120079	NM_004239.4(TRIP11):c.3082C>T (p.Arg1028Ter)	TRIP11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1251989	NM_004239.4(TRIP11):c.4459_4460del (p.Met1487fs)	TRIP11	Pathogenic	no assertion criteria provided
1251991	NM_004239.4(TRIP11):c.763C>T (p.Arg255Ter)	TRIP11	Pathogenic	criteria provided, single submitter
1338763	NM_004239.4(TRIP11):c.526C>T (p.Arg176Ter)	TRIP11	Pathogenic	criteria provided, single submitter
1351407	NM_004239.4(TRIP11):c.2123dup (p.Asn708fs)	TRIP11	Pathogenic	criteria provided, single submitter
1390930	NM_004239.4(TRIP11):c.2123del (p.Asn708fs)	TRIP11	Pathogenic	criteria provided, single submitter
1415474	NM_004239.4(TRIP11):c.2782C>T (p.Gln928Ter)	TRIP11	Pathogenic	criteria provided, single submitter
1419547	NM_004239.4(TRIP11):c.774_777del (p.Ser259fs)	TRIP11	Pathogenic	criteria provided, single submitter
1451176	NM_004239.4(TRIP11):c.1987dup (p.Gln663fs)	TRIP11	Pathogenic	criteria provided, single submitter
1460090	NM_004239.4(TRIP11):c.922del (p.Met308fs)	TRIP11	Pathogenic	criteria provided, single submitter
1727207	NM_004239.4(TRIP11):c.581_582insA (p.Ala195fs)	TRIP11	Pathogenic	criteria provided, single submitter
1804974	NM_004239.4(TRIP11):c.5269C>T (p.Arg1757Ter)	TRIP11	Pathogenic	criteria provided, single submitter
1895654	NM_004239.4(TRIP11):c.2448dup (p.Ile817fs)	TRIP11	Pathogenic	criteria provided, single submitter
1917995	NM_004239.4(TRIP11):c.4508_4511del (p.Met1503fs)	TRIP11	Pathogenic	criteria provided, single submitter
2017964	NM_004239.4(TRIP11):c.5392C>T (p.Gln1798Ter)	TRIP11	Pathogenic	criteria provided, single submitter
2096778	NM_004239.4(TRIP11):c.3641del (p.Lys1213_Leu1214insTer)	TRIP11	Pathogenic	criteria provided, single submitter
2416088	NM_004239.4(TRIP11):c.877dup (p.Thr293fs)	TRIP11	Pathogenic	criteria provided, single submitter
2635180	NM_004239.4(TRIP11):c.757C>T (p.Arg253Ter)	TRIP11	Pathogenic	criteria provided, single submitter
2702312	NM_004239.4(TRIP11):c.3173del (p.Thr1058fs)	TRIP11	Pathogenic	criteria provided, single submitter
2766007	NM_004239.4(TRIP11):c.1622dup (p.Arg542fs)	TRIP11	Pathogenic	criteria provided, single submitter
2768141	NM_004239.4(TRIP11):c.944_948del (p.Ile315fs)	TRIP11	Pathogenic	criteria provided, single submitter
2768462	NM_004239.4(TRIP11):c.5519C>G (p.Ser1840Ter)	TRIP11	Pathogenic	criteria provided, single submitter
2791084	NM_004239.4(TRIP11):c.3507del (p.Asp1170fs)	TRIP11	Pathogenic	criteria provided, single submitter
2814011	NM_004239.4(TRIP11):c.2911dup (p.Thr971fs)	TRIP11	Pathogenic	criteria provided, single submitter
2833369	NM_004239.4(TRIP11):c.3104_3105insTTTTTTTTTTTTTTTTTTTTNNNNNNNNNNATCCACCCGCCTCGGCCTCCCAAAGTGCTGGGATTACAGGCGTGAGCCACCGCGCCCGGCCGAGATTAAACTTCT (p.Leu1035_Asn1036insPhePhePhePhePhePheXaaXaaXaaXaaSerThrArgLeuGlyLeuProLysCysTrpAspTyrArgArgGluProProArgProAlaGluIleLysLeuLeu)	TRIP11	Pathogenic	criteria provided, single submitter
2843452	NM_004239.4(TRIP11):c.3268C>T (p.Gln1090Ter)	TRIP11	Pathogenic	criteria provided, single submitter
2904253	NM_004239.4(TRIP11):c.4432_4433del (p.Glu1478fs)	TRIP11	Pathogenic	criteria provided, single submitter
2991772	NM_004239.4(TRIP11):c.4551_4554del (p.Lys1517fs)	TRIP11	Pathogenic	criteria provided, single submitter

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
TRIP11	Definitive	Autosomal recessive	achondrogenesis type IA	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TRIP11	Orphanet:166272	Odontochondrodysplasia
TRIP11	Orphanet:93299	Achondrogenesis type 1A

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
TRIP11	HGNC:12305	ENSG00000100815	Q15643	Thyroid receptor-interacting protein 11	gencc,clinvar
KCNK13	HGNC:6275	ENSG00000152315	Q9HB14	Potassium channel subfamily K member 13	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TRIP11	Thyroid receptor-interacting protein 11	Is a membrane tether required for vesicle tethering to Golgi.
KCNK13	Potassium channel subfamily K member 13	K(+) channel that conducts outward rectifying tonic currents potentiated by purinergic signals.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Ion channel	1	55.8×	0.036
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TRIP11	Other/Unknown	no		GRIP_dom
KCNK13	Ion channel	yes		2pore_dom_K_chnl, 2pore_dom_K_chnl_THIK, K_chnl_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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adrenal tissue	1
calcaneal tendon	1
male germ line stem cell (sensu Vertebrata) in testis	1
left testis	1
monocyte	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TRIP11	270	ubiquitous	marker	calcaneal tendon, male germ line stem cell (sensu Vertebrata) in testis, adrenal tissue
KCNK13	133	tissue_specific	yes	right testis, left testis, monocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TRIP11	2,991
KCNK13	474

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KCNK13	Q9HB14	14

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TRIP11	Q15643	66.78

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. 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
Tandem pore domain halothane-inhibited K+ channel (THIK)	1	5710.0×	0.002	KCNK13
Tandem pore domain potassium channels	1	475.8×	0.009	KCNK13
Phase 4 - resting membrane potential	1	300.5×	0.009	KCNK13
Signaling by FLT3 fusion proteins	1	285.5×	0.009	TRIP11
Intra-Golgi traffic	1	129.8×	0.015	TRIP11
Intraflagellar transport	1	100.2×	0.017	TRIP11
Potassium Channels	1	67.2×	0.021	KCNK13
Cardiac conduction	1	54.4×	0.023	KCNK13
Muscle contraction	1	38.6×	0.029	KCNK13
Neuronal System	1	22.1×	0.045	KCNK13

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
regulation of excitatory synapse pruning	1	8426.0×	0.002	KCNK13
regulation of NLRP3 inflammasome complex assembly	1	4213.0×	0.002	KCNK13
obsolete vesicle tethering to Golgi	1	1685.2×	0.002	TRIP11
chondrocyte differentiation involved in endochondral bone morphogenesis	1	1404.3×	0.002	TRIP11
Golgi ribbon formation	1	766.0×	0.003	TRIP11
regulation of resting membrane potential	1	648.1×	0.003	KCNK13
protein transmembrane transport	1	648.1×	0.003	TRIP11
inner ear receptor cell stereocilium organization	1	421.3×	0.004	TRIP11
ventricular septum development	1	247.8×	0.006	TRIP11
cartilage development	1	125.8×	0.011	TRIP11
endoplasmic reticulum to Golgi vesicle-mediated transport	1	68.0×	0.016	TRIP11
potassium ion transmembrane transport	1	68.0×	0.016	KCNK13
Golgi organization	1	66.9×	0.016	TRIP11
transcription by RNA polymerase II	1	35.3×	0.028	TRIP11

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TRIP11	0	0
KCNK13	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
KCNK13	5	Binding:5

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

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	KCNK13
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	TRIP11

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TRIP11	0	—
KCNK13	5	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.