Joubert syndrome 14

Summary

Joubert syndrome 14 (MONDO:0013745) is a disease caused by TMEM237 (GenCC Definitive), with 4 cohort genes.

At a glance

• Causal gene: TMEM237 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 443

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Joubert syndrome 14
Mondo ID	MONDO:0013745
OMIM	614424
DOID	DOID:0110983
UMLS	C3280766
MedGen	482396
GARD	0015801
Is cancer (heuristic)	no

Also known as: JBTS14 · Joubert syndrome 14 · Joubert syndrome caused by mutation in TMEM237 · Joubert syndrome type 14 · TMEM237 Joubert syndrome

Data availability: 443 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Joubert syndrome with oculorenal defect › Joubert syndrome 14

Related subtypes (4): Joubert syndrome 2, Joubert syndrome 5, Joubert syndrome 9, Joubert syndrome 16

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

443 retrieved; paginated sample, class counts are floors:

229 uncertain significance, 132 likely benign, 24 pathogenic, 20 conflicting classifications of pathogenicity, 13 benign, 10 likely pathogenic, 9 benign/likely benign, 6 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
584058	NC_000002.12:g.(?201618900)(201647825_?)del	LOC129935417	Pathogenic	criteria provided, single submitter
2423585	NC_000002.11:g.(?202501451)(202633608_?)del	MPP4	Pathogenic	criteria provided, single submitter
1065465	NM_001044385.3(TMEM237):c.869+1del	TMEM237	Pathogenic	criteria provided, multiple submitters, no conflicts
1069606	NM_001044385.3(TMEM237):c.605_606del (p.Ile202fs)	TMEM237	Pathogenic	criteria provided, single submitter
1072229	NC_000002.11:g.(?202466462)(202508123_?)del	TMEM237	Pathogenic	criteria provided, single submitter
1075598	NM_001044385.3(TMEM237):c.890C>G (p.Ser297Ter)	TMEM237	Pathogenic	criteria provided, single submitter
1403232	NM_001044385.3(TMEM237):c.325C>T (p.Arg109Ter)	TMEM237	Pathogenic	criteria provided, single submitter
1430872	NM_001044385.3(TMEM237):c.278T>A (p.Leu93Ter)	TMEM237	Pathogenic	criteria provided, single submitter
1451775	NM_001044385.3(TMEM237):c.175C>T (p.Arg59Ter)	TMEM237	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1452907	NM_001044385.3(TMEM237):c.606_609dup (p.Val204fs)	TMEM237	Pathogenic	criteria provided, single submitter
1455230	NM_001044385.3(TMEM237):c.314C>G (p.Ser105Ter)	TMEM237	Pathogenic	criteria provided, single submitter
1456904	NM_001044385.3(TMEM237):c.470_473dup (p.Thr159fs)	TMEM237	Pathogenic	criteria provided, single submitter
183328	NM_001044385.3(TMEM237):c.869+1G>A	TMEM237	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2120213	NM_001044385.3(TMEM237):c.128dup (p.Asn43fs)	TMEM237	Pathogenic	criteria provided, single submitter
2120625	NM_001044385.3(TMEM237):c.694dup (p.Ser232fs)	TMEM237	Pathogenic	criteria provided, single submitter
2147441	NM_001044385.3(TMEM237):c.725G>A (p.Trp242Ter)	TMEM237	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2188320	NM_001044385.3(TMEM237):c.413_420del (p.Glu138fs)	TMEM237	Pathogenic	criteria provided, single submitter
2423584	NC_000002.11:g.(?202508062)(202508123_?)del	TMEM237	Pathogenic	criteria provided, single submitter
31180	NM_001044385.3(TMEM237):c.52C>T (p.Arg18Ter)	TMEM237	Pathogenic	criteria provided, multiple submitters, no conflicts
31181	NM_001044385.3(TMEM237):c.677+1G>T	TMEM237	Pathogenic	no assertion criteria provided
31183	NM_001044385.3(TMEM237):c.76C>T (p.Gln26Ter)	TMEM237	Pathogenic	criteria provided, single submitter
31184	NM_001044385.3(TMEM237):c.943+1G>T	TMEM237	Pathogenic	criteria provided, multiple submitters, no conflicts
3236134	NM_001044385.3(TMEM237):c.487C>T (p.Gln163Ter)	TMEM237	Pathogenic	criteria provided, single submitter
4720598	NM_001044385.3(TMEM237):c.869+1G>T	TMEM237	Pathogenic	criteria provided, single submitter
4732547	NM_001044385.3(TMEM237):c.658dup (p.Thr220fs)	TMEM237	Pathogenic	criteria provided, single submitter
647195	NM_001044385.3(TMEM237):c.901C>T (p.Arg301Ter)	TMEM237	Pathogenic	criteria provided, single submitter
654117	NM_001044385.3(TMEM237):c.677+1G>A	TMEM237	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
666987	NM_001044385.3(TMEM237):c.62del (p.Pro21fs)	TMEM237	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
692024	NM_001044385.3(TMEM237):c.275-2A>G	TMEM237	Pathogenic	criteria provided, single submitter
841287	NM_001044385.3(TMEM237):c.553+1G>A	TMEM237	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 4 · 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
TMEM237	Definitive	Autosomal recessive	Joubert syndrome 14	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TMEM237	Orphanet:220497	Joubert syndrome with renal defect
TMEM237	Orphanet:2318	Joubert syndrome with oculorenal defect
TMEM237	Orphanet:475	Isolated Joubert syndrome
TMEM237	Orphanet:564	Meckel syndrome

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TMEM237	HGNC:14432	ENSG00000155755	Q96Q45	Transmembrane protein 237	gencc,clinvar
STRADB	HGNC:13205	ENSG00000082146	Q9C0K7	STE20-related kinase adapter protein beta	clinvar
MPP4	HGNC:13680	ENSG00000082126	Q96JB8	MAGUK p55 subfamily member 4	clinvar
ILF3	HGNC:6038	ENSG00000129351	Q12906	Interleukin enhancer-binding factor 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TMEM237	Transmembrane protein 237	Component of the transition zone in primary cilia.
STRADB	STE20-related kinase adapter protein beta	Pseudokinase which, in complex with CAB39/MO25 (CAB39/MO25alpha or CAB39L/MO25beta), binds to and activates STK11/LKB1.
MPP4	MAGUK p55 subfamily member 4	May play a role in retinal photoreceptors development.
ILF3	Interleukin enhancer-binding factor 3	RNA-binding protein that plays an essential role in the biogenesis of circular RNAs (circRNAs) which are produced by back-splicing circularization of pre-mRNAs.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 2 · 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
Kinase	2	13.9×	0.015
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TMEM237	Other/Unknown	no		TMEM237
STRADB	Kinase	yes		Prot_kinase_dom, Kinase-like_dom_sf, STRAD_A/B-like
MPP4	Kinase	yes		SH3_domain, PDZ, L27_dom
ILF3	Other/Unknown	no		DZF_dom, dsRBD_dom, DSRM1_ILF3

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adrenal tissue	2
ventricular zone	2
calcaneal tendon	1
right adrenal gland	1
right adrenal gland cortex	1
cerebellar hemisphere	1
oocyte	1
secondary oocyte	1
cortical plate	1
ganglionic eminence	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TMEM237	250	ubiquitous	marker	calcaneal tendon, adrenal tissue, ventricular zone
STRADB	140	ubiquitous	marker	adrenal tissue, right adrenal gland cortex, right adrenal gland
MPP4	122	broad	marker	secondary oocyte, oocyte, cerebellar hemisphere
ILF3	303	ubiquitous	marker	ganglionic eminence, ventricular zone, cortical plate

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ILF3	4,787
TMEM237	2,169
MPP4	1,139
STRADB	882

Structural data

PDB: 1 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ILF3	Q12906	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MPP4	Q96JB8	76.39
STRADB	Q9C0K7	74.39
TMEM237	Q96Q45	63.79

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 4 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
Regulation of CDH11 gene transcription	1	519.1×	0.010	ILF3
Energy dependent regulation of mTOR by LKB1-AMPK	1	196.9×	0.013	STRADB
MTOR signalling	1	132.8×	0.013	STRADB
PKR-mediated signaling	1	70.5×	0.018	ILF3
Signal Transduction	1	5.1×	0.187	STRADB

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
spliceosome-depend formation of circular RNA	1	842.6×	0.018	ILF3
activation of protein kinase activity	1	383.0×	0.020	STRADB
regulation of Wnt signaling pathway	1	221.7×	0.020	TMEM237
protein localization to synapse	1	191.5×	0.020	MPP4
protein export from nucleus	1	127.7×	0.023	STRADB
negative regulation of extrinsic apoptotic signaling pathway in absence of ligand	1	102.8×	0.023	STRADB
negative regulation of viral genome replication	1	93.6×	0.023	ILF3
JNK cascade	1	68.0×	0.027	STRADB
negative regulation of translation	1	49.0×	0.034	ILF3
cell morphogenesis	1	39.4×	0.038	STRADB
cilium assembly	1	18.4×	0.066	TMEM237
defense response to virus	1	17.3×	0.066	ILF3
protein phosphorylation	1	17.0×	0.066	ILF3
negative regulation of DNA-templated transcription	1	7.9×	0.129	ILF3
positive regulation of DNA-templated transcription	1	7.0×	0.136	ILF3

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 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
ILF3	1	2
TMEM237	0	0
STRADB	0	0
MPP4	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SEPANTRONIUM BROMIDE	2	ILF3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
STRADB	20	Binding:20
ILF3	4	Binding:4

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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)
SEPANTRONIUM BROMIDE	2	ILF3

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	1	ILF3
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	2	STRADB, MPP4
E	Difficult family or no structure, no drug	1	TMEM237

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)
TMEM237	0	—
STRADB	20	—
MPP4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.