Joubert syndrome with Jeune asphyxiating thoracic dystrophy

Summary

Joubert syndrome with Jeune asphyxiating thoracic dystrophy (MONDO:0018342) is a disease with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 3
• ClinVar variants: 4
• Phenotypes (HPO): 73

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		8	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

73 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000657	Oculomotor apraxia	Frequent (30-79%)
HP:0001290	Generalized hypotonia	Frequent (30-79%)
HP:0001321	Cerebellar hypoplasia	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0002007	Frontal bossing	Frequent (30-79%)
HP:0002119	Ventriculomegaly	Frequent (30-79%)
HP:0002419	Molar tooth sign on MRI	Frequent (30-79%)
HP:0002789	Tachypnea	Frequent (30-79%)
HP:0004719	Hyperechogenic kidneys	Frequent (30-79%)
HP:0011933	Elongated superior cerebellar peduncle	Frequent (30-79%)
HP:0000047	Hypospadias	Occasional (5-29%)
HP:0000083	Renal insufficiency	Occasional (5-29%)
HP:0000110	Renal dysplasia	Occasional (5-29%)
HP:0000286	Epicanthus	Occasional (5-29%)
HP:0000316	Hypertelorism	Occasional (5-29%)
HP:0000347	Micrognathia	Occasional (5-29%)
HP:0000358	Posteriorly rotated ears	Occasional (5-29%)
HP:0000369	Low-set ears	Occasional (5-29%)
HP:0000396	Overfolded helix	Occasional (5-29%)
HP:0000545	Myopia	Occasional (5-29%)
HP:0000556	Retinal dystrophy	Occasional (5-29%)
HP:0000572	Visual loss	Occasional (5-29%)
HP:0000773	Short ribs	Occasional (5-29%)
HP:0000803	Renal cortical cysts	Occasional (5-29%)
HP:0000890	Long clavicles	Occasional (5-29%)
HP:0001156	Brachydactyly	Occasional (5-29%)
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0001273	Abnormal corpus callosum morphology	Occasional (5-29%)
HP:0001305	Dandy-Walker malformation	Occasional (5-29%)
HP:0001317	Abnormal cerebellum morphology	Occasional (5-29%)
HP:0001320	Cerebellar vermis hypoplasia	Occasional (5-29%)
HP:0001331	Absent septum pellucidum	Occasional (5-29%)
HP:0001344	Absent speech	Occasional (5-29%)
HP:0001591	Bell-shaped thorax	Occasional (5-29%)
HP:0002020	Gastroesophageal reflux	Occasional (5-29%)
HP:0002085	Occipital encephalocele	Occasional (5-29%)
HP:0002100	Recurrent aspiration pneumonia	Occasional (5-29%)
HP:0002104	Apnea	Occasional (5-29%)
HP:0002134	Abnormality of the basal ganglia	Occasional (5-29%)
HP:0002195	Dysgenesis of the cerebellar vermis	Occasional (5-29%)
HP:0002205	Recurrent respiratory infections	Occasional (5-29%)
HP:0002280	Enlarged cisterna magna	Occasional (5-29%)
HP:0002435	Meningocele	Occasional (5-29%)
HP:0002516	Increased intracranial pressure	Occasional (5-29%)
HP:0002558	Supernumerary nipple	Occasional (5-29%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Occasional (5-29%)
HP:0003170	Abnormality of the acetabulum	Occasional (5-29%)
HP:0003411	Proximal femoral metaphyseal irregularity	Occasional (5-29%)
HP:0004322	Short stature	Occasional (5-29%)
HP:0004629	Small cervical vertebral bodies	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Joubert syndrome with Jeune asphyxiating thoracic dystrophy
Mondo ID	MONDO:0018342
Orphanet	397715
SNOMED CT	733418003
UMLS	C4518774
MedGen	1371401
GARD	0017637
Is cancer (heuristic)	no

Also known as: JBTS with JATD · Joubert syndrome with JATD

Data availability: 4 ClinVar variants · 2 GenCC gene-disease records.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › autosomal recessive cerebellar ataxia › autosomal recessive congenital cerebellar ataxia › Joubert syndrome and related disorders › Joubert syndrome with Jeune asphyxiating thoracic dystrophy

Related subtypes (3): Joubert syndrome with oculorenal defect, Joubert syndrome with ocular defect, COACH syndrome

Subtypes (2): Joubert syndrome 21, short-rib thoracic dysplasia 14 with 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

4 retrieved; paginated sample, class counts are floors:

3 pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
523177	NM_014714.4(IFT140):c.3454-488_4182+2588dup	IFT140	Pathogenic	criteria provided, single submitter
523180	NM_014714.4(IFT140):c.3141+1G>T	IFT140	Pathogenic	criteria provided, multiple submitters, no conflicts
523185	NM_014714.4(IFT140):c.3454-1003_4040+737delinsC	IFT140	Pathogenic	criteria provided, single submitter
97053	NM_014714.4(IFT140):c.874G>A (p.Val292Met)	IFT140	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 16 · Orphanet: 10 · 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
CSPP1	Definitive	Autosomal recessive	Joubert syndrome 21	6
KIAA0586	Definitive	Autosomal recessive	Joubert syndrome 23	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KIAA0586	Orphanet:397715	Joubert syndrome with Jeune asphyxiating thoracic dystrophy
KIAA0586	Orphanet:475	Isolated Joubert syndrome
CSPP1	Orphanet:397715	Joubert syndrome with Jeune asphyxiating thoracic dystrophy
CSPP1	Orphanet:475	Isolated Joubert syndrome
CSPP1	Orphanet:564	Meckel 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

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KIAA0586	HGNC:19960	ENSG00000100578	Q9BVV6	Protein TALPID3	gencc
CSPP1	HGNC:26193	ENSG00000104218	Q1MSJ5	Centrosome and spindle pole-associated protein 1	gencc
IFT140	HGNC:29077	ENSG00000187535	Q96RY7	Intraflagellar transport protein 140 homolog	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KIAA0586	Protein TALPID3	Required for ciliogenesis and sonic hedgehog/SHH signaling.
CSPP1	Centrosome and spindle pole-associated protein 1	May play a role in cell-cycle-dependent microtubule organization.
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).

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)
KIAA0586	Other/Unknown	no		TALPID3
CSPP1	Other/Unknown	no		CSPP1, CSPP1_C
IFT140	Scaffold/PPI	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, WD40_repeat_dom_sf

Expression context

Cohort genes with no expression data: 0.

3 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
left testis	1
male germ line stem cell (sensu Vertebrata) in testis	1
right testis	1
bronchial epithelial cell	1
sperm	1
left lobe of thyroid gland	1
right lobe of thyroid gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KIAA0586	247	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, right testis, left testis
CSPP1	275	ubiquitous	marker	bronchial epithelial cell, sperm, right uterine tube
IFT140	214	ubiquitous	marker	right uterine tube, right lobe of thyroid gland, left lobe of thyroid gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CSPP1	2,300
IFT140	1,602
KIAA0586	1,405

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
IFT140	Q96RY7	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CSPP1	Q1MSJ5	57.34
KIAA0586	Q9BVV6	47.61

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 3 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
Intraflagellar transport	1	200.3×	0.006	IFT140
Hedgehog ‘off’ state	1	178.4×	0.006	IFT140

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
neural tube patterning	1	936.2×	0.007	IFT140
regulation of establishment of protein localization	1	802.5×	0.007	KIAA0586
cilium assembly	2	49.1×	0.007	KIAA0586, IFT140
embryonic camera-type eye development	1	401.2×	0.009	IFT140
intraciliary retrograde transport	1	374.5×	0.009	IFT140
photoreceptor cell outer segment organization	1	351.1×	0.009	IFT140
embryonic brain development	1	267.5×	0.009	IFT140
regulation of smoothened signaling pathway	1	208.1×	0.009	IFT140
regulation of cilium assembly	1	200.6×	0.009	IFT140
embryonic cranial skeleton morphogenesis	1	193.7×	0.009	IFT140
positive regulation of cytokinesis	1	133.8×	0.011	CSPP1
protein localization to cilium	1	133.8×	0.011	IFT140
positive regulation of cell division	1	112.3×	0.012	CSPP1
embryonic digit morphogenesis	1	100.3×	0.012	IFT140
non-motile cilium assembly	1	96.8×	0.012	IFT140
determination of left/right symmetry	1	85.1×	0.013	IFT140
smoothened signaling pathway	1	60.4×	0.017	KIAA0586
heart development	1	26.2×	0.038	IFT140

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KIAA0586	0	0
CSPP1	0	0
IFT140	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
CSPP1	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	KIAA0586, CSPP1, IFT140

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)
KIAA0586	0	—
CSPP1	1	—
IFT140	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.