Asphyxiating thoracic dystrophy 1

Summary

Asphyxiating thoracic dystrophy 1 (MONDO:0008831) is a disease with 6 cohort genes. The dominant Reactome pathway is Intraflagellar transport (4 cohort genes).

At a glance

• Cohort genes: 6
• ClinVar variants: 11

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	asphyxiating thoracic dystrophy 1
Mondo ID	MONDO:0008831
OMIM	208500
DOID	DOID:0110085
UMLS	C4551856
MedGen	1648057
GARD	0015140
Is cancer (heuristic)	no

Also known as: asphyxiating thoracic dystrophy 1 · asphyxiating thoracic dystrophy type 1 · ATD1 · short-rib thoracic dysplasia 1 with or without polydactyly · SRTD1

Data availability: 11 ClinVar variants.

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 1

Related subtypes (23): 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 2, 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

11 retrieved; paginated sample, class counts are floors:

4 pathogenic, 3 uncertain significance, 2 pathogenic/likely pathogenic, 2 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
212767	NM_016008.4(DYNC2LI1):c.1000G>T (p.Glu334Ter)	ABCG5	Pathogenic	no assertion criteria provided
212764	NM_016008.4(DYNC2LI1):c.993+1G>A	DYNC2LI1	Pathogenic	criteria provided, single submitter
212765	NM_016008.4(DYNC2LI1):c.349C>G (p.Leu117Val)	DYNC2LI1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
212766	NM_016008.4(DYNC2LI1):c.372G>A (p.Trp124Ter)	DYNC2LI1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
212768	NM_016008.4(DYNC2LI1):c.993+3A>G	DYNC2LI1	Pathogenic	no assertion criteria provided
1451353	NM_014714.4(IFT140):c.490G>T (p.Glu164Ter)	IFT140	Pathogenic	criteria provided, multiple submitters, no conflicts
266103	NM_014714.4(IFT140):c.3943GCCAAG[2] (p.1315AK[2])	IFT140	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
837274	NM_015662.3(IFT172):c.3674G>A (p.Arg1225Gln)	IFT172	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
459279	NM_001377.3(DYNC2H1):c.466T>A (p.Leu156Ile)	DYNC2H1	Uncertain significance	criteria provided, single submitter
548623	NM_001199397.3(NEK1):c.3410T>C (p.Leu1137Pro)	NEK1	Uncertain significance	criteria provided, single submitter
634600	NM_001199397.3(NEK1):c.2974+1G>T	NEK1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 20 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ABCG5	Orphanet:2882	Sitosterolemia
ABCG5	Orphanet:391665	Homozygous familial hypercholesterolemia
DYNC2LI1	Orphanet:289	Ellis Van Creveld syndrome
DYNC2LI1	Orphanet:474	Jeune syndrome
IFT140	Orphanet:140969	Saldino-Mainzer syndrome
IFT140	Orphanet:474	Jeune syndrome
IFT140	Orphanet:65	Leber congenital amaurosis
IFT140	Orphanet:730	Autosomal dominant polycystic kidney disease
IFT140	Orphanet:791	Retinitis pigmentosa
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
IFT172	Orphanet:110	Bardet-Biedl syndrome
IFT172	Orphanet:140969	Saldino-Mainzer syndrome
IFT172	Orphanet:474	Jeune syndrome
IFT172	Orphanet:791	Retinitis pigmentosa
NEK1	Orphanet:2751	Orofaciodigital syndrome type 2
NEK1	Orphanet:803	Amyotrophic lateral sclerosis
NEK1	Orphanet:93269	Short rib-polydactyly syndrome, Majewski type

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ABCG5	HGNC:13886	ENSG00000138075	Q9H222	ATP-binding cassette sub-family G member 5	clinvar
DYNC2LI1	HGNC:24595	ENSG00000138036	Q8TCX1	Cytoplasmic dynein 2 light intermediate chain 1	clinvar
IFT140	HGNC:29077	ENSG00000187535	Q96RY7	Intraflagellar transport protein 140 homolog	clinvar
DYNC2H1	HGNC:2962	ENSG00000187240	Q8NCM8	Cytoplasmic dynein 2 heavy chain 1	clinvar
IFT172	HGNC:30391	ENSG00000138002	Q9UG01	Intraflagellar transport protein 172 homolog	clinvar
NEK1	HGNC:7744	ENSG00000137601	Q96PY6	Serine/threonine-protein kinase Nek1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ABCG5	ATP-binding cassette sub-family G member 5	ABCG5 and ABCG8 form an obligate heterodimer that mediates Mg(2+)- and ATP-dependent sterol transport across the cell membrane.
DYNC2LI1	Cytoplasmic dynein 2 light intermediate chain 1	Acts as one of several non-catalytic accessory components of the cytoplasmic dynein 2 complex (dynein-2 complex), a motor protein complex that drives the movement of cargos along microtubules within cilia and flagella in concert with the i…
IFT140	Intraflagellar transport protein 140 homolog	Component of the IFT complex A (IFT-A), a complex required for retrograde ciliary transport and entry into cilia of G protein-coupled receptors (GPCRs).
DYNC2H1	Cytoplasmic dynein 2 heavy chain 1	May function as a motor for intraflagellar retrograde transport.
IFT172	Intraflagellar transport protein 172 homolog	Required for the maintenance and formation of cilia.
NEK1	Serine/threonine-protein kinase Nek1	Phosphorylates serines and threonines, but also appears to possess tyrosine kinase activity.

Protein-family classification

Druggable: 2 · Difficult: 2 · Unknown: 2 · Druggable fraction: 0.33

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
Transporter	1	13.0×	0.149
Scaffold/PPI	2	5.8×	0.149
Kinase	1	4.6×	0.264
Other/Unknown	2	0.6×	0.936

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ABCG5	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABC2_TM
DYNC2LI1	Other/Unknown	no		Dynein_light_int_chain, P-loop_NTPase, DYNC2LI1
IFT140	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
IFT172	Scaffold/PPI	no		WD40_rpt, TPR-like_helical_dom_sf, WD40/YVTN_repeat-like_dom_sf
NEK1	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf

Expression context

Cohort genes with no expression data: 0.

6 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)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right uterine tube	4
bronchial epithelial cell	3
secondary oocyte	2
duodenum	1
jejunal mucosa	1
right lobe of liver	1
mucosa of paranasal sinus	1
left lobe of thyroid gland	1
right lobe of thyroid gland	1
left testis	1
oocyte	1
trigeminal ganglion	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ABCG5	61	tissue_specific	marker	jejunal mucosa, right lobe of liver, duodenum
DYNC2LI1	293	ubiquitous	marker	right uterine tube, bronchial epithelial cell, mucosa of paranasal sinus
IFT140	214	ubiquitous	marker	right uterine tube, right lobe of thyroid gland, left lobe of thyroid gland
DYNC2H1	230	ubiquitous	marker	secondary oocyte, bronchial epithelial cell, right uterine tube
IFT172	236	ubiquitous	marker	right uterine tube, bronchial epithelial cell, left testis
NEK1	288	ubiquitous	marker	secondary oocyte, trigeminal ganglion, oocyte

Protein interactions among cohort

Intra-cohort edges: 7.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ABCG5	1,996
IFT172	1,922
DYNC2H1	1,885
IFT140	1,602
NEK1	1,512
DYNC2LI1	852

Intra-cohort edges

A	B	Sources
DYNC2H1	DYNC2LI1	biogrid_interaction, intact, string_interaction
DYNC2H1	IFT140	string_interaction
DYNC2H1	IFT172	string_interaction
DYNC2H1	NEK1	string_interaction
DYNC2LI1	IFT140	string_interaction
DYNC2LI1	IFT172	string_interaction
IFT140	IFT172	string_interaction

Structural data

PDB: 6 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ABCG5	Q9H222	8
IFT140	Q96RY7	4
DYNC2H1	Q8NCM8	4
DYNC2LI1	Q8TCX1	3
NEK1	Q96PY6	2
IFT172	Q9UG01	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 18. Enrichment computed across 6 evidence-associated genes (6 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 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Intraflagellar transport	4	133.6×	1e-07	DYNC2LI1, IFT140, DYNC2H1, IFT172
Hedgehog ‘off’ state	3	89.2×	3e-05	IFT140, DYNC2H1, IFT172
Defective ABCG8 causes GBD4 and sitosterolemia	1	951.7×	0.005	ABCG5
Defective ABCG5 causes sitosterolemia	1	951.7×	0.005	ABCG5
ABC transporters in lipid homeostasis	1	100.2×	0.030	ABCG5
Regulation of pyruvate metabolism	1	95.2×	0.030	NEK1
ABC transporter disorders	1	73.2×	0.030	ABCG5
Pyruvate metabolism	1	68.0×	0.030	NEK1
NR1H2 and NR1H3-mediated signaling	1	65.6×	0.030	ABCG5
NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux	1	51.4×	0.035	ABCG5
Disorders of transmembrane transporters	1	23.2×	0.069	ABCG5
ABC-family protein mediated transport	1	20.2×	0.073	ABCG5
Signaling by Nuclear Receptors	1	17.0×	0.080	ABCG5
Aerobic respiration and respiratory electron transport	1	14.8×	0.085	NEK1
Transport of small molecules	1	4.2×	0.259	ABCG5
Disease	1	2.2×	0.427	ABCG5
Metabolism	1	1.9×	0.442	NEK1
Signal Transduction	1	1.7×	0.463	ABCG5

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
intraciliary retrograde transport	3	561.7×	6e-07	DYNC2LI1, IFT140, DYNC2H1
cilium assembly	4	49.1×	1e-05	IFT140, DYNC2H1, IFT172, NEK1
non-motile cilium assembly	3	145.3×	1e-05	IFT140, DYNC2H1, IFT172
determination of left/right symmetry	3	127.7×	2e-05	DYNC2LI1, IFT140, DYNC2H1
spinal cord motor neuron differentiation	2	312.1×	2e-04	DYNC2H1, IFT172
regulation of cilium assembly	2	200.6×	4e-04	DYNC2LI1, IFT140
dorsal/ventral pattern formation	2	140.4×	6e-04	DYNC2H1, IFT172
positive regulation of smoothened signaling pathway	2	140.4×	6e-04	DYNC2H1, IFT172
protein localization to cilium	2	133.8×	6e-04	IFT140, DYNC2H1
hindgut development	1	2808.7×	0.002	IFT172
protein processing	2	56.7×	0.003	DYNC2H1, IFT172
negative regulation of intestinal phytosterol absorption	1	1404.3×	0.003	ABCG5
negative regulation of intestinal cholesterol absorption	1	1404.3×	0.003	ABCG5
sterol transport	1	468.1×	0.008	ABCG5
neural tube patterning	1	468.1×	0.008	IFT140
intraciliary transport involved in cilium assembly	1	401.2×	0.009	DYNC2LI1
intestinal cholesterol absorption	1	234.1×	0.014	ABCG5
embryonic camera-type eye development	1	200.6×	0.015	IFT140
left/right axis specification	1	200.6×	0.015	IFT172
embryonic camera-type eye morphogenesis	1	187.2×	0.015	IFT172
photoreceptor cell outer segment organization	1	175.5×	0.015	IFT140
intraciliary anterograde transport	1	147.8×	0.017	IFT172
embryonic brain development	1	133.8×	0.018	IFT140
negative regulation of keratinocyte proliferation	1	117.0×	0.020	IFT172
cilium movement involved in cell motility	1	112.3×	0.020	DYNC2H1
regulation of smoothened signaling pathway	1	104.0×	0.020	IFT140
coronary vasculature development	1	104.0×	0.020	DYNC2H1
response to muscle activity	1	96.8×	0.020	ABCG5
keratinocyte proliferation	1	96.8×	0.020	IFT172
embryonic cranial skeleton morphogenesis	1	96.8×	0.020	IFT140

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 5

Druggability breadth: 1 of 6 evidence-associated genes (17%) 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
NEK1	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NEK1	12	4
ABCG5	0	0
DYNC2LI1	0	0
IFT140	0	0
DYNC2H1	0	0
IFT172	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	NEK1
DABRAFENIB	4	NEK1
LESTAURTINIB	3	NEK1
TG100-115	2	NEK1
R-406	2	NEK1
PELITINIB	2	NEK1
GSK-461364	1	NEK1
KW-2449	1	NEK1
AMG-900	1	NEK1
TAK-593	1	NEK1
CYC-116	1	NEK1
AST-487	1	NEK1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
NEK1	288	Binding:288

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
NEK1	288

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

12 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	NEK1
DABRAFENIB	4	NEK1
LESTAURTINIB	3	NEK1
TG100-115	2	NEK1
R-406	2	NEK1
PELITINIB	2	NEK1
GSK-461364	1	NEK1
KW-2449	1	NEK1
AMG-900	1	NEK1
TAK-593	1	NEK1
CYC-116	1	NEK1
AST-487	1	NEK1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	NEK1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	ABCG5
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	DYNC2LI1, IFT140, DYNC2H1, IFT172

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
DYNC2H1	0	NEK1
ABCG5	0	—
DYNC2LI1	0	—
IFT140	0	—
IFT172	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.