Asphyxiating thoracic dystrophy 4

Summary

Asphyxiating thoracic dystrophy 4 (MONDO:0013441) is a disease caused by TTC21B (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: TTC21B (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 383

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	asphyxiating thoracic dystrophy 4
Mondo ID	MONDO:0013441
OMIM	613819
DOID	DOID:0110088
UMLS	C3151185
MedGen	462535
GARD	0015718
Is cancer (heuristic)	no

Also known as: asphyxiating thoracic dystrophy 4 · asphyxiating thoracic dystrophy type 4 · ATD4 · short-rib thoracic dysplasia 4 with or without polydactyly · SRTD4

Data availability: 383 ClinVar variants · 3 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 4

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 2, asphyxiating thoracic dystrophy 3, 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

383 retrieved; paginated sample, class counts are floors:

216 uncertain significance, 68 conflicting classifications of pathogenicity, 27 likely benign, 19 likely pathogenic, 19 benign, 18 pathogenic/likely pathogenic, 10 benign/likely benign, 6 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
225033	NM_001377.3(DYNC2H1):c.10648T>C (p.Ser3550Pro)	DYNC2H1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070283	NM_024753.5(TTC21B):c.1546C>T (p.Gln516Ter)	TTC21B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1077012	NM_024753.5(TTC21B):c.497del (p.Lys166fs)	TTC21B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1179040	NM_024753.5(TTC21B):c.3087del (p.Gly1030fs)	TTC21B	Pathogenic	criteria provided, single submitter
1179137	NM_024753.5(TTC21B):c.264_267dupTAGA	TTC21B	Pathogenic	criteria provided, multiple submitters, no conflicts
1224329	NM_024753.5(TTC21B):c.2741del (p.Cys914fs)	TTC21B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1328343	NM_024753.5(TTC21B):c.1656_1659del (p.Leu551_Cys552insTer)	TTC21B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1344652	NM_024753.5(TTC21B):c.1038G>A (p.Trp346Ter)	TTC21B	Pathogenic	criteria provided, single submitter
1363746	NM_024753.5(TTC21B):c.1377T>A (p.Cys459Ter)	TTC21B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1451834	NM_024753.5(TTC21B):c.172C>T (p.Arg58Ter)	TTC21B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1453748	NM_024753.5(TTC21B):c.2482dup (p.Met828fs)	TTC21B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1944012	NM_024753.5(TTC21B):c.431del	TTC21B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1983220	NM_024753.5(TTC21B):c.3130C>T (p.Arg1044Ter)	TTC21B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2927399	NM_024753.5(TTC21B):c.1479_1482del (p.Thr494fs)	TTC21B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2934957	NM_024753.5(TTC21B):c.1088-1G>A	TTC21B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30935	NM_024753.5(TTC21B):c.626C>T (p.Pro209Leu)	TTC21B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30937	NM_024753.5(TTC21B):c.2758-2A>G	TTC21B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30938	NM_024753.5(TTC21B):c.1231C>T (p.Arg411Ter)	TTC21B	Pathogenic	criteria provided, multiple submitters, no conflicts
30939	NM_024753.5(TTC21B):c.2384T>C (p.Leu795Pro)	TTC21B	Pathogenic	no assertion criteria provided
446649	NM_024753.5(TTC21B):c.2500C>T (p.Gln834Ter)	TTC21B	Pathogenic	criteria provided, multiple submitters, no conflicts
446650	NM_024753.5(TTC21B):c.1320del (p.Phe440fs)	TTC21B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
446651	NM_024753.5(TTC21B):c.3605T>C (p.Leu1202Pro)	TTC21B	Pathogenic/Likely pathogenic	no assertion criteria provided
449860	NM_024753.5(TTC21B):c.1088-1G>C	TTC21B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
591254	NM_024753.5(TTC21B):c.2913dup (p.Val972fs)	TTC21B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2498130	NM_024753.5(TTC21B):c.[2569G>A;3130_3131dup]		Likely pathogenic	criteria provided, single submitter
1179039	NM_024753.5(TTC21B):c.3102-2A>G	TTC21B	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1179100	NM_024753.5(TTC21B):c.1386+1G>T	TTC21B	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1179185	NM_024753.5(TTC21B):c.3340C>T (p.Gln1114Ter)	TTC21B	Likely pathogenic	criteria provided, single submitter
1473506	NM_024753.5(TTC21B):c.1087+1G>A	TTC21B	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2498129	NM_024753.5(TTC21B):c.3130_3131dup (p.His1045fs)	TTC21B	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 6 · 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
TTC21B	Definitive	Autosomal recessive	asphyxiating thoracic dystrophy 4	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TTC21B	Orphanet:474	Jeune syndrome
TTC21B	Orphanet:93591	Infantile nephronophthisis
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
TTC21B	HGNC:25660	ENSG00000123607	Q7Z4L5	Tetratricopeptide repeat protein 21B	gencc,clinvar
DYNC2H1	HGNC:2962	ENSG00000187240	Q8NCM8	Cytoplasmic dynein 2 heavy chain 1	clinvar
TTC21B-AS1	HGNC:41115	ENSG00000224490		TTC21B antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TTC21B	Tetratricopeptide repeat protein 21B	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.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · 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
Other/Unknown	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TTC21B	Other/Unknown	no		TPR-like_helical_dom_sf, TPR_rpt, TTC21A/TTC21B
DYNC2H1	Other/Unknown	no		AAA+_ATPase, Dhc_D6_P-loop, Dynein_heavy_tail
TTC21B-AS1	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
right uterine tube	2
calcaneal tendon	1
cerebellar hemisphere	1
bronchial epithelial cell	1
secondary oocyte	1
bone marrow cell	1
male germ line stem cell (sensu Vertebrata) in testis	1
skeletal muscle tissue	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TTC21B	179	ubiquitous	marker	right uterine tube, calcaneal tendon, cerebellar hemisphere
DYNC2H1	230	ubiquitous	marker	secondary oocyte, bronchial epithelial cell, right uterine tube
TTC21B-AS1	119	tissue_specific	yes	male germ line stem cell (sensu Vertebrata) in testis, bone marrow cell, skeletal muscle tissue

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DYNC2H1	1,885
TTC21B	1,588
TTC21B-AS1	0

Intra-cohort edges

A	B	Sources
DYNC2H1	TTC21B	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DYNC2H1	Q8NCM8	4
TTC21B	Q7Z4L5	3

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×	3e-05	TTC21B, DYNC2H1
Hedgehog ‘off’ state	2	178.4×	3e-05	TTC21B, 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
intraciliary retrograde transport	2	1123.5×	2e-05	TTC21B, DYNC2H1
protein localization to cilium	2	401.2×	8e-05	TTC21B, DYNC2H1
regulation of intraciliary retrograde transport	1	4213.0×	0.002	TTC21B
cilium assembly	2	73.6×	0.002	TTC21B, DYNC2H1
protein localization to non-motile cilium	1	2106.5×	0.003	TTC21B
negative regulation of eating behavior	1	1404.3×	0.003	TTC21B
forebrain dorsal/ventral pattern formation	1	1053.2×	0.004	TTC21B
Bergmann glial cell differentiation	1	766.0×	0.004	TTC21B
cerebellar Purkinje cell differentiation	1	526.6×	0.006	TTC21B
spinal cord motor neuron differentiation	1	468.1×	0.006	DYNC2H1
ventricular system development	1	421.3×	0.006	TTC21B
cilium movement involved in cell motility	1	337.0×	0.006	DYNC2H1
regulation of smoothened signaling pathway	1	312.1×	0.006	TTC21B
coronary vasculature development	1	312.1×	0.006	DYNC2H1
dorsal/ventral pattern formation	1	210.7×	0.008	DYNC2H1
positive regulation of smoothened signaling pathway	1	210.7×	0.008	DYNC2H1
embryonic limb morphogenesis	1	200.6×	0.008	DYNC2H1
forebrain development	1	175.5×	0.009	DYNC2H1
non-motile cilium assembly	1	145.3×	0.010	DYNC2H1
determination of left/right symmetry	1	127.7×	0.011	DYNC2H1
smoothened signaling pathway	1	90.6×	0.014	TTC21B
protein processing	1	85.1×	0.014	DYNC2H1
positive regulation of canonical Wnt signaling pathway	1	77.3×	0.015	TTC21B
kidney development	1	70.2×	0.016	DYNC2H1
Golgi organization	1	66.9×	0.016	DYNC2H1
positive regulation of gene expression	1	19.4×	0.053	TTC21B
regulation of transcription by RNA polymerase II	1	5.8×	0.164	TTC21B

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
TTC21B	0	0
DYNC2H1	0	0
TTC21B-AS1	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	TTC21B, DYNC2H1, TTC21B-AS1

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)
TTC21B	0	—
DYNC2H1	0	—
TTC21B-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.