Joubert syndrome 6

Summary

Joubert syndrome 6 (MONDO:0012539) is a disease caused by TMEM67 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: TMEM67 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 314

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Joubert syndrome 6
Mondo ID	MONDO:0012539
MeSH	C537689
OMIM	610688
DOID	DOID:0111001
UMLS	C1853153
MedGen	342805
GARD	0015494
Is cancer (heuristic)	no

Also known as: JBTS6 · Joubert syndrome 6 · Joubert syndrome caused by mutation in TMEM67 · Joubert syndrome type 6 · TMEM67 Joubert syndrome

Data availability: 314 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Joubert syndrome › Joubert syndrome 6

Related subtypes (38): Joubert syndrome 1, Joubert syndrome 10, Joubert syndrome 2, Joubert syndrome 3, Joubert syndrome with renal defect, Joubert syndrome 5, Joubert syndrome 7, Joubert syndrome 9, Joubert syndrome 8, Joubert syndrome 13, Joubert syndrome 14, Joubert syndrome 15, Joubert syndrome 16, Joubert syndrome 17, Joubert syndrome 18, Joubert syndrome 20, Joubert syndrome 21, Joubert syndrome 22, Joubert syndrome 23, Joubert syndrome 24, Joubert syndrome 25, Joubert syndrome 26, Joubert syndrome 27, Joubert syndrome 28, Joubert syndrome 38, Joubert syndrome 39, Joubert syndrome 40, Joubert syndrome 37, Joubert syndrome 35, Joubert syndrome 36, Joubert syndrome 30, Joubert syndrome 32, Joubert syndrome 31, Joubert syndrome 33, Joubert syndrome 19, Joubert syndrome 29, Joubert syndrome 11, Joubert syndrome 34

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

314 retrieved; paginated sample, class counts are floors:

148 uncertain significance, 52 conflicting classifications of pathogenicity, 31 pathogenic, 30 pathogenic/likely pathogenic, 23 likely pathogenic, 17 likely benign, 10 benign/likely benign, 3 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2627377	NM_153704.6(TMEM67):c.[1634G>A;2241G>A]		Pathogenic	no assertion criteria provided
4278970	NM_032485.6(MCM8):c.1866_1867del (p.Ala623fs)	MCM8	Pathogenic	criteria provided, single submitter
1065634	NM_153704.6(TMEM67):c.230C>A (p.Ser77Ter)	TMEM67	Pathogenic	criteria provided, single submitter
1072098	NM_153704.6(TMEM67):c.1975C>T (p.Arg659Ter)	TMEM67	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074275	NM_153704.6(TMEM67):c.1338_1350del (p.Ala447fs)	TMEM67	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
126306	NM_153704.6(TMEM67):c.748G>A (p.Gly250Arg)	TMEM67	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1368	NM_153704.6(TMEM67):c.2315_2322+4delinsG	TMEM67	Pathogenic	no assertion criteria provided
1371	NM_153704.6(TMEM67):c.1538A>G (p.Tyr513Cys)	TMEM67	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1372	NM_153704.6(TMEM67):c.2439+5G>C	TMEM67	Pathogenic	criteria provided, single submitter
1375	NM_153704.6(TMEM67):c.1961-2A>C	TMEM67	Pathogenic	criteria provided, single submitter
1376	NM_153704.6(TMEM67):c.622A>T (p.Arg208Ter)	TMEM67	Pathogenic	criteria provided, multiple submitters, no conflicts
1378	NM_153704.6(TMEM67):c.2498T>C (p.Ile833Thr)	TMEM67	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1379	NM_153704.6(TMEM67):c.2556+1G>T	TMEM67	Pathogenic	criteria provided, single submitter
1380	NM_153704.6(TMEM67):c.312+5G>A	TMEM67	Pathogenic	criteria provided, multiple submitters, no conflicts
1381	NM_153704.6(TMEM67):c.1769T>C (p.Phe590Ser)	TMEM67	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1382	NM_153704.6(TMEM67):c.2461G>A (p.Gly821Ser)	TMEM67	Pathogenic	criteria provided, single submitter
1383	NM_153704.6(TMEM67):c.1843T>C (p.Cys615Arg)	TMEM67	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1385	NM_153704.6(TMEM67):c.2461G>C (p.Gly821Arg)	TMEM67	Pathogenic	no assertion criteria provided
1386	NM_153704.6(TMEM67):c.130C>T (p.Gln44Ter)	TMEM67	Pathogenic	criteria provided, single submitter
1387	NM_153704.6(TMEM67):c.755T>C (p.Met252Thr)	TMEM67	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1411457	NM_153704.6(TMEM67):c.1387C>T (p.Arg463Ter)	TMEM67	Pathogenic	criteria provided, multiple submitters, no conflicts
1454299	NM_153704.6(TMEM67):c.1927C>T (p.Arg643Ter)	TMEM67	Pathogenic	criteria provided, multiple submitters, no conflicts
1691287	NM_153704.6(TMEM67):c.479_480del (p.Phe160fs)	TMEM67	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
191259	NM_153704.6(TMEM67):c.1413-2A>G	TMEM67	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
216826	NM_153704.6(TMEM67):c.725A>G (p.Asn242Ser)	TMEM67	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217708	NM_153704.6(TMEM67):c.1911C>A (p.Phe637Leu)	TMEM67	Pathogenic	criteria provided, single submitter
217709	NM_153704.6(TMEM67):c.389C>G (p.Pro130Arg)	TMEM67	Pathogenic	criteria provided, single submitter
217710	NM_153704.6(TMEM67):c.769A>G (p.Met257Val)	TMEM67	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217712	NM_153704.6(TMEM67):c.300C>A (p.Cys100Ter)	TMEM67	Pathogenic	criteria provided, multiple submitters, no conflicts
217713	NM_153704.6(TMEM67):c.1453C>T (p.Pro485Ser)	TMEM67	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · Orphanet: 5 · 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
TMEM67	Strong	Autosomal recessive	Joubert syndrome 6	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TMEM67	Orphanet:140976	RHYNS syndrome
TMEM67	Orphanet:1454	Joubert syndrome with hepatic defect
TMEM67	Orphanet:475	Isolated Joubert syndrome
TMEM67	Orphanet:564	Meckel syndrome
TMEM67	Orphanet:84081	Senior-Boichis syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TMEM67	HGNC:28396	ENSG00000164953	Q5HYA8	Meckelin	gencc,clinvar
MCM8	HGNC:16147	ENSG00000125885	Q9UJA3	DNA helicase MCM8	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TMEM67	Meckelin	Required for ciliary structure and function.
MCM8	DNA helicase MCM8	Component of the MCM8-MCM9 complex, which is involved in the repair of double-stranded DNA breaks (DBSs) and DNA interstrand cross-links (ICLs) by homologous recombination (HR).

Protein-family classification

Druggable: 0 · Difficult: 0 · 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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TMEM67	Other/Unknown	no		Growth_fac_rcpt_cys_sf, Meckelin
MCM8	Other/Unknown	no		MCM_dom, AAA+_ATPase, NA-bd_OB-fold

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	2
calcaneal tendon	1
right uterine tube	1
oocyte	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TMEM67	203	ubiquitous	marker	buccal mucosa cell, right uterine tube, calcaneal tendon
MCM8	226	ubiquitous	marker	primordial germ cell in gonad, buccal mucosa cell, oocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MCM8	1,952
TMEM67	1,194

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MCM8	Q9UJA3	7
TMEM67	Q5HYA8	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 23. Enrichment computed across 2 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
E2F mediated regulation of DNA replication	1	815.7×	0.010	MCM8
CDC6 association with the ORC:origin complex	1	713.8×	0.010	MCM8
E2F-enabled inhibition of pre-replication complex formation	1	634.4×	0.010	MCM8
DNA strand elongation	1	571.0×	0.010	MCM8
Unwinding of DNA	1	439.2×	0.010	MCM8
Activation of the pre-replicative complex	1	163.1×	0.015	MCM8
DNA Replication Pre-Initiation	1	158.6×	0.015	MCM8
Activation of ATR in response to replication stress	1	150.3×	0.015	MCM8
Switching of origins to a post-replicative state	1	150.3×	0.015	MCM8
Synthesis of DNA	1	150.3×	0.015	MCM8
DNA Replication	1	119.0×	0.016	MCM8
G1/S Transition	1	116.5×	0.016	MCM8
Mitotic G1 phase and G1/S transition	1	92.1×	0.017	MCM8
S Phase	1	90.6×	0.017	MCM8
Orc1 removal from chromatin	1	89.2×	0.017	MCM8
Assembly of the pre-replicative complex	1	69.6×	0.020	MCM8
G2/M Checkpoints	1	67.2×	0.020	MCM8
Anchoring of the basal body to the plasma membrane	1	56.5×	0.022	TMEM67
Cilium Assembly	1	54.4×	0.022	TMEM67
Cell Cycle Checkpoints	1	44.3×	0.026	MCM8
Organelle biogenesis and maintenance	1	33.0×	0.033	TMEM67
Cell Cycle, Mitotic	1	24.1×	0.043	MCM8
Cell Cycle	1	18.0×	0.055	MCM8

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
recombinational interstrand cross-link repair	1	4213.0×	0.001	MCM8
mismatch repair involved in maintenance of fidelity involved in DNA-dependent DNA replication	1	4213.0×	0.001	MCM8
male gamete generation	1	2106.5×	0.002	MCM8
negative regulation of centrosome duplication	1	1685.2×	0.002	TMEM67
female gamete generation	1	401.2×	0.006	MCM8
non-canonical Wnt signaling pathway	1	290.6×	0.006	TMEM67
protein localization to chromatin	1	290.6×	0.006	MCM8
ERAD pathway	1	90.6×	0.017	TMEM67
double-strand break repair via homologous recombination	1	78.0×	0.017	MCM8
cilium assembly	1	36.8×	0.032	TMEM67
protein stabilization	1	33.4×	0.032	MCM8
DNA damage response	1	26.8×	0.037	MCM8

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 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
TMEM67	0	0
MCM8	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	2	TMEM67, MCM8

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TMEM67	0	—
MCM8	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.