Asphyxiating thoracic dystrophy 2

Summary

Asphyxiating thoracic dystrophy 2 (MONDO:0012644) is a disease caused by IFT80 (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: IFT80 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 196

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	asphyxiating thoracic dystrophy 2
Mondo ID	MONDO:0012644
MeSH	C566982
OMIM	611263
DOID	DOID:0110086
UMLS	C1970005
MedGen	370804
GARD	0015511
Is cancer (heuristic)	no

Also known as: asphyxiating thoracic dystrophy 2 · asphyxiating thoracic dystrophy type 2 · ATD2 · IFT80 Jeune syndrome · Jeune syndrome caused by mutation in IFT80 · short-rib thoracic dysplasia 2 with or without polydactyly · SRTD2

Data availability: 196 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › ciliopathy › Jeune syndrome › asphyxiating thoracic dystrophy 2

Related subtypes (23): asphyxiating thoracic dystrophy 1, Ellis-van Creveld syndrome, short-rib thoracic dysplasia 6 with or without polydactyly, short-rib thoracic dysplasia 9 with or without polydactyly, Beemer-Langer syndrome, asphyxiating thoracic dystrophy 3, asphyxiating thoracic dystrophy 4, short-rib thoracic dysplasia 7 with or without polydactyly, asphyxiating thoracic dystrophy 5, short-rib thoracic dysplasia 8 with or without polydactyly, short-rib thoracic dysplasia 10 with or without polydactyly, short-rib thoracic dysplasia 11 with or without polydactyly, short-rib thoracic dysplasia 13 with or without polydactyly, short-rib thoracic dysplasia 14 with polydactyly, short-rib thoracic dysplasia 15 with polydactyly, short-rib thoracic dysplasia 16 with or without polydactyly, short-rib thoracic dysplasia 21 without polydactyly, short-rib thoracic dysplasia 19 with or without polydactyly, short-rib thoracic dysplasia 18 with polydactyly, short-rib thoracic dysplasia 20 with polydactyly, short-rib thoracic dysplasia 17 with or without polydactyly, Jeune syndrome - GRK2-related, short-rib thoracic dysplasia 22 without polydactyly

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

196 retrieved; paginated sample, class counts are floors:

127 uncertain significance, 28 conflicting classifications of pathogenicity, 13 likely pathogenic, 10 benign, 6 pathogenic/likely pathogenic, 5 likely benign, 4 benign/likely benign, 3 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
100665	NM_020800.3(IFT80):c.721G>A (p.Gly241Arg)	IFT80	Pathogenic	no assertion criteria provided
2181200	NM_020800.3(IFT80):c.1483C>T (p.Arg495Ter)	IFT80	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4531879	NM_020800.3(IFT80):c.1198G>T (p.Glu400Ter)	IFT80	Pathogenic	criteria provided, single submitter
1330851	NM_020800.3(IFT80):c.411dup (p.Met138fs)	TRIM59-IFT80	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2187694	NM_020800.3(IFT80):c.1961dup (p.Asn654fs)	TRIM59-IFT80	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2910537	NM_020800.3(IFT80):c.701C>G (p.Ser234Ter)	TRIM59-IFT80	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
956602	NM_020800.3(IFT80):c.958-1G>T	TRIM59-IFT80	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
989	NM_020800.3(IFT80):c.315C>G (p.His105Gln)	TRIM59-IFT80	Pathogenic	no assertion criteria provided
992480	NM_020800.3(IFT80):c.401C>G (p.Ser134Ter)	TRIM59-IFT80	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3588718	NM_020800.3(IFT80):c.1994del (p.Ile665fs)	IFT80	Likely pathogenic	criteria provided, single submitter
3588722	NM_020800.3(IFT80):c.1380+1G>T	IFT80	Likely pathogenic	criteria provided, single submitter
3588727	NM_020800.3(IFT80):c.1095del (p.Pro366fs)	IFT80	Likely pathogenic	criteria provided, single submitter
3588733	NM_020800.3(IFT80):c.755dup (p.Leu252fs)	IFT80	Likely pathogenic	criteria provided, single submitter
3588741	NM_020800.3(IFT80):c.544_545dup (p.Leu182fs)	IFT80	Likely pathogenic	criteria provided, single submitter
3588743	NM_020800.3(IFT80):c.370+2T>G	IFT80	Likely pathogenic	criteria provided, single submitter
3588745	NM_020800.3(IFT80):c.259+1G>T	IFT80	Likely pathogenic	criteria provided, single submitter
3588746	NM_020800.3(IFT80):c.248_249del (p.Thr83fs)	IFT80	Likely pathogenic	criteria provided, single submitter
3588753	NM_020800.3(IFT80):c.1A>G (p.Met1Val)	IFT80	Likely pathogenic	criteria provided, single submitter
429428	NM_020800.3(IFT80):c.1646_1648del (p.Leu549del)	IFT80	Likely pathogenic	criteria provided, single submitter
983305	NM_020800.3(IFT80):c.2048G>T (p.Gly683Val)	IFT80	Likely pathogenic	criteria provided, single submitter
1067006	NM_020800.3(IFT80):c.440-2A>G	TRIM59-IFT80	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2440874	NM_020800.3(IFT80):c.1665-1del	TRIM59-IFT80	Likely pathogenic	criteria provided, single submitter
1167003	NM_020800.3(IFT80):c.1381-14dup	IFT80	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1652659	NM_020800.3(IFT80):c.371-19T>G	IFT80	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
196501	NM_020800.3(IFT80):c.60G>A (p.Val20=)	IFT80	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2911142	NM_020800.3(IFT80):c.1689T>A (p.Ile563=)	IFT80	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
343967	NM_020800.3(IFT80):c.1678A>G (p.Asn560Asp)	IFT80	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
343968	NM_020800.3(IFT80):c.1326C>T (p.Leu442=)	IFT80	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
343974	NM_020800.3(IFT80):c.897G>A (p.Val299=)	IFT80	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
343975	NM_020800.3(IFT80):c.807T>C (p.Thr269=)	IFT80	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 7 · 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
IFT80	Definitive	Autosomal recessive	asphyxiating thoracic dystrophy 2	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
IFT80	Orphanet:474	Jeune syndrome
IFT80	Orphanet:93268	Short rib-polydactyly syndrome, Beemer-Langer type
IFT80	Orphanet:93271	Short rib-polydactyly syndrome, Verma-Naumoff type
DYNC2H1	Orphanet:474	Jeune syndrome
DYNC2H1	Orphanet:93269	Short rib-polydactyly syndrome, Majewski type
DYNC2H1	Orphanet:93270	Short rib-polydactyly syndrome, Saldino-Noonan type
DYNC2H1	Orphanet:93271	Short rib-polydactyly syndrome, Verma-Naumoff type

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
IFT80	HGNC:29262	ENSG00000068885	Q9P2H3	Intraflagellar transport protein 80 homolog	gencc,clinvar
DYNC2H1	HGNC:2962	ENSG00000187240	Q8NCM8	Cytoplasmic dynein 2 heavy chain 1	clinvar
TRIM59-IFT80	HGNC:56756	ENSG00000248710		TRIM59-IFT80 readthrough (NMD candidate)	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
IFT80	Intraflagellar transport protein 80 homolog	Component of the intraflagellar transport (IFT) complex B, which is essential for the development and maintenance of motile and sensory cilia.
DYNC2H1	Cytoplasmic dynein 2 heavy chain 1	May function as a motor for intraflagellar retrograde transport.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 2 · 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
Scaffold/PPI	1	5.8×	0.327
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
IFT80	Scaffold/PPI	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, WD40_repeat_dom_sf
DYNC2H1	Other/Unknown	no		AAA+_ATPase, Dhc_D6_P-loop, Dynein_heavy_tail
TRIM59-IFT80	Other/Unknown	no

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
colonic epithelium	1
endothelial cell	1
oviduct epithelium	1
bronchial epithelial cell	1
right uterine tube	1
secondary oocyte	1
corpus callosum	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IFT80	256	ubiquitous	marker	colonic epithelium, oviduct epithelium, endothelial cell
DYNC2H1	230	ubiquitous	marker	secondary oocyte, bronchial epithelial cell, right uterine tube
TRIM59-IFT80	68	tissue_specific	yes	corpus callosum, male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IFT80	2,582
DYNC2H1	1,885
TRIM59-IFT80	0

Intra-cohort edges

A	B	Sources
DYNC2H1	IFT80	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DYNC2H1	Q8NCM8	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
IFT80	Q9P2H3	92.50

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 3 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
Intraflagellar transport	2	200.3×	5e-05	IFT80, DYNC2H1
Hedgehog ‘off’ state	1	89.2×	0.011	DYNC2H1

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
non-motile cilium assembly	2	290.6×	5e-04	IFT80, DYNC2H1
growth plate cartilage chondrocyte differentiation	1	2106.5×	0.003	IFT80
response to inositol	1	2106.5×	0.003	IFT80
tooth eruption	1	1685.2×	0.003	IFT80
receptor localization to non-motile cilium	1	1685.2×	0.003	IFT80
cartilage homeostasis	1	1685.2×	0.003	IFT80
negative regulation of non-canonical Wnt signaling pathway	1	1685.2×	0.003	IFT80
cilium assembly	2	73.6×	0.003	IFT80, DYNC2H1
bone mineralization involved in bone maturation	1	1404.3×	0.004	IFT80
articular cartilage development	1	1203.7×	0.004	IFT80
odontoblast differentiation	1	1053.2×	0.004	IFT80
osteoblast proliferation	1	702.2×	0.006	IFT80
intraciliary retrograde transport	1	561.7×	0.006	DYNC2H1
spinal cord motor neuron differentiation	1	468.1×	0.007	DYNC2H1
intraciliary anterograde transport	1	443.5×	0.007	IFT80
proteasomal protein catabolic process	1	383.0×	0.008	IFT80
negative regulation of keratinocyte proliferation	1	351.1×	0.008	IFT80
cilium movement involved in cell motility	1	337.0×	0.008	DYNC2H1
coronary vasculature development	1	312.1×	0.008	DYNC2H1
non-canonical Wnt signaling pathway	1	290.6×	0.008	IFT80
keratinocyte proliferation	1	290.6×	0.008	IFT80
endochondral ossification	1	271.8×	0.008	IFT80
spinal cord development	1	255.3×	0.008	IFT80
dorsal/ventral pattern formation	1	210.7×	0.008	DYNC2H1
positive regulation of smoothened signaling pathway	1	210.7×	0.008	DYNC2H1
limb development	1	205.5×	0.008	IFT80
establishment or maintenance of cell polarity	1	200.6×	0.008	IFT80
embryonic limb morphogenesis	1	200.6×	0.008	DYNC2H1
protein localization to cilium	1	200.6×	0.008	DYNC2H1
canonical NF-kappaB signal transduction	1	183.2×	0.009	IFT80

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 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
IFT80	0	0
DYNC2H1	0	0
TRIM59-IFT80	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	IFT80, DYNC2H1, TRIM59-IFT80

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
IFT80	0	—
DYNC2H1	0	—
TRIM59-IFT80	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.