Joubert syndrome 20

Summary

Joubert syndrome 20 (MONDO:0013994) is a disease caused by TMEM231 (GenCC Definitive), with 4 cohort genes.

At a glance

• Causal gene: TMEM231 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 452

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Joubert syndrome 20
Mondo ID	MONDO:0013994
OMIM	614970
DOID	DOID:0110989
UMLS	C3554235
MedGen	767149
GARD	0015887
Is cancer (heuristic)	no

Also known as: JBTS20 · Joubert syndrome 20 · Joubert syndrome caused by mutation in TMEM231 · Joubert syndrome type 20 · TMEM231 Joubert syndrome

Data availability: 452 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Joubert syndrome with ocular defect › Joubert syndrome 20

Related subtypes (4): Joubert syndrome 3, Joubert syndrome 14, Joubert syndrome 15, Joubert syndrome 28

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

452 retrieved; paginated sample, class counts are floors:

200 uncertain significance, 156 likely benign, 30 pathogenic, 28 conflicting classifications of pathogenicity, 12 likely pathogenic, 10 benign, 9 pathogenic/likely pathogenic, 7 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2423621	NC_000016.9:g.(?75512539)(75576601_?)del	CHST6	Pathogenic	criteria provided, single submitter
1456039	NM_001077418.3(TMEM231):c.140-3C>G	LOC130059440	Pathogenic	criteria provided, single submitter
2947948	NM_001077418.3(TMEM231):c.140-8dup	LOC130059440	Pathogenic	criteria provided, single submitter
4788994	NM_001077418.3(TMEM231):c.169del (p.Glu57fs)	LOC130059440	Pathogenic	criteria provided, single submitter
1028502	NM_001077418.3(TMEM231):c.248G>A (p.Trp83Ter)	TMEM231	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1192252	NM_001077418.3(TMEM231):c.438+1G>C	TMEM231	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1351746	NC_000016.9:g.(?75573892)(75690509_?)del	TMEM231	Pathogenic	criteria provided, single submitter
1362349	NM_001077418.3(TMEM231):c.284del (p.Asp95fs)	TMEM231	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1368287	NM_001077418.3(TMEM231):c.139+1del	TMEM231	Pathogenic	criteria provided, single submitter
1388711	NM_001077418.3(TMEM231):c.583-1_583delinsAG	TMEM231	Pathogenic	criteria provided, single submitter
1398946	NM_001077418.3(TMEM231):c.354dup (p.His119fs)	TMEM231	Pathogenic	criteria provided, single submitter
1418103	NC_000016.9:g.(?75573892)(75575373_?)del	TMEM231	Pathogenic	criteria provided, single submitter
1430979	NM_001077418.3(TMEM231):c.4G>A (p.Ala2Thr)	TMEM231	Pathogenic	criteria provided, single submitter
1448559	NM_001077418.3(TMEM231):c.535C>T (p.Gln179Ter)	TMEM231	Pathogenic	criteria provided, single submitter
1454613	NM_001077418.3(TMEM231):c.582+1G>A	TMEM231	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1457752	NC_000016.9:g.(?75490611)(75576599_?)del	TMEM231	Pathogenic	criteria provided, single submitter
1458388	NM_001077418.3(TMEM231):c.124G>A (p.Ala42Thr)	TMEM231	Pathogenic	criteria provided, single submitter
1459430	NC_000016.9:g.(?75573892)(75579413_?)del	TMEM231	Pathogenic	criteria provided, single submitter
1802034	NM_001077418.3(TMEM231):c.544C>T (p.Gln182Ter)	TMEM231	Pathogenic	criteria provided, multiple submitters, no conflicts
1960880	NM_001077418.3(TMEM231):c.583-1_593delinsAGTATCTGTGAC	TMEM231	Pathogenic	criteria provided, single submitter
2054331	NM_001077418.3(TMEM231):c.-37G>A	TMEM231	Pathogenic	criteria provided, single submitter
2165068	NM_001077418.3(TMEM231):c.139+39_139+40del	TMEM231	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2423617	NC_000016.9:g.(?75589682)(75590169_?)del	TMEM231	Pathogenic	criteria provided, single submitter
2921947	NM_001077418.3(TMEM231):c.3_4insAGCTCTATGAGCTCATG (p.Ala2fs)	TMEM231	Pathogenic	criteria provided, single submitter
2934525	NM_001077418.3(TMEM231):c.140-9_140-8del	TMEM231	Pathogenic	criteria provided, single submitter
2941997	NM_001077418.3(TMEM231):c.33C>A (p.Val11=)	TMEM231	Pathogenic	criteria provided, single submitter
3243522	NC_000016.9:g.(?75579704)(75579872_?)del	TMEM231	Pathogenic	criteria provided, single submitter
3749689	NM_001077418.3(TMEM231):c.164_176dup (p.Thr60fs)	TMEM231	Pathogenic	criteria provided, single submitter
3756171	NM_001077418.3(TMEM231):c.379C>T (p.Gln127Ter)	TMEM231	Pathogenic	criteria provided, single submitter
3757816	NM_001077418.3(TMEM231):c.208del (p.Val70fs)	TMEM231	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
TMEM231	Definitive	Autosomal recessive	Joubert syndrome 20	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TMEM231	Orphanet:2318	Joubert syndrome with oculorenal defect
TMEM231	Orphanet:2754	Orofaciodigital syndrome type 6
TMEM231	Orphanet:564	Meckel syndrome
GLIS2	Orphanet:329469	Acute megakaryoblastic leukemia in children without Down syndrome
GLIS2	Orphanet:93592	Juvenile nephronophthisis
CHST6	Orphanet:98969	Macular corneal dystrophy

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
TMEM231	HGNC:37234	ENSG00000205084	Q9H6L2	Transmembrane protein 231	gencc,clinvar
ADAT1	HGNC:228	ENSG00000065457	Q9BUB4	tRNA-specific adenosine deaminase 1	clinvar
GLIS2	HGNC:29450	ENSG00000126603	Q9BZE0	Zinc finger protein GLIS2	clinvar
CHST6	HGNC:6938	ENSG00000183196	Q9GZX3	Carbohydrate sulfotransferase 6	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TMEM231	Transmembrane protein 231	Transmembrane component of the tectonic-like complex, a complex localized at the transition zone of primary cilia and acting as a barrier that prevents diffusion of transmembrane proteins between the cilia and plasma membranes.
ADAT1	tRNA-specific adenosine deaminase 1	Specifically deaminates adenosine-37 to inosine in tRNA-Ala.
GLIS2	Zinc finger protein GLIS2	Can act either as a transcriptional repressor or as a transcriptional activator, depending on the cell context.
CHST6	Carbohydrate sulfotransferase 6	Sulfotransferase that utilizes 3’-phospho-5’-adenylyl sulfate (PAPS) as sulfonate donor to catalyze the transfer of sulfate to position 6 of non-reducing N-acetylglucosamine (GlcNAc) residues of keratan.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.25

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
Enzyme (other)	1	3.0×	0.605
Transcription factor	1	2.1×	0.605
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TMEM231	Other/Unknown	no		TMEM231
ADAT1	Enzyme (other)	yes	3.5.4.34	A_deamin
GLIS2	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, GLI-like
CHST6	Other/Unknown	no		Sulfotransferase_dom, Carbohydrate_sulfotransferase, P-loop_NTPase

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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
bronchial epithelial cell	2
bronchus	2
epithelium of bronchus	1
left testis	1
oocyte	1
secondary oocyte	1
ascending aorta	1
metanephros cortex	1
right coronary artery	1
nasal cavity epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TMEM231	257	ubiquitous	marker	bronchial epithelial cell, epithelium of bronchus, bronchus
ADAT1	255	ubiquitous	marker	oocyte, secondary oocyte, left testis
GLIS2	134	ubiquitous	yes	right coronary artery, metanephros cortex, ascending aorta
CHST6	162	broad	marker	bronchial epithelial cell, bronchus, nasal cavity epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GLIS2	1,690
TMEM231	858
ADAT1	596
CHST6	523

Structural data

PDB: 0 · AlphaFold-only: 4 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CHST6	Q9GZX3	90.66
TMEM231	Q9H6L2	88.65
ADAT1	Q9BUB4	82.40
GLIS2	Q9BZE0	55.47

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
Defective CHST6 causes MCDC1	1	713.8×	0.007	CHST6
Keratan sulfate biosynthesis	1	190.3×	0.009	CHST6
tRNA processing	1	178.4×	0.009	ADAT1
tRNA modification in the nucleus and cytosol	1	146.4×	0.009	ADAT1
Metabolism of RNA	1	20.8×	0.047	ADAT1

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
cell differentiation involved in kidney development	1	1404.3×	0.015	GLIS2
neuroepithelial cell differentiation	1	383.0×	0.015	TMEM231
N-acetylglucosamine metabolic process	1	300.9×	0.015	CHST6
vasculature development	1	280.9×	0.015	TMEM231
sulfur compound metabolic process	1	280.9×	0.015	CHST6
keratan sulfate proteoglycan biosynthetic process	1	247.8×	0.015	CHST6
tRNA processing	1	210.7×	0.015	ADAT1
hematopoietic stem cell homeostasis	1	140.4×	0.020	GLIS2
negative regulation of smoothened signaling pathway	1	113.9×	0.021	GLIS2
positive regulation of protein localization to nucleus	1	98.0×	0.022	GLIS2
camera-type eye development	1	89.6×	0.022	TMEM231
embryonic digit morphogenesis	1	75.2×	0.024	TMEM231
regulation of protein localization	1	51.4×	0.033	TMEM231
smoothened signaling pathway	1	45.3×	0.034	TMEM231
carbohydrate metabolic process	1	34.0×	0.043	CHST6
central nervous system development	1	28.9×	0.047	GLIS2
cilium assembly	1	18.4×	0.066	TMEM231
in utero embryonic development	1	18.0×	0.066	TMEM231
negative regulation of DNA-templated transcription	1	7.9×	0.140	GLIS2
positive regulation of DNA-templated transcription	1	7.0×	0.149	GLIS2
negative regulation of transcription by RNA polymerase II	1	4.4×	0.217	GLIS2
positive regulation of transcription by RNA polymerase II	1	3.7×	0.243	GLIS2

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 4 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
TMEM231	0	0
ADAT1	0	0
GLIS2	0	0
CHST6	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ADAT1	3.5.4.34	tRNAAla(adenine37) deaminase

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

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	1	ADAT1
E	Difficult family or no structure, no drug	3	TMEM231, GLIS2, CHST6

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TMEM231	0	—
ADAT1	0	—
GLIS2	0	—
CHST6	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.