Joubert syndrome 25

Summary

Joubert syndrome 25 (MONDO:0014770) is a disease caused by CEP104 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: CEP104 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 311

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Joubert syndrome 25
Mondo ID	MONDO:0014770
OMIM	616781
DOID	DOID:0110994
UMLS	C4084842
MedGen	895764
GARD	0016159
Is cancer (heuristic)	no

Also known as: CEP104 Joubert syndrome · JBTS25 · Joubert syndrome 25 · Joubert syndrome caused by mutation in CEP104 · Joubert syndrome type 25

Data availability: 311 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Joubert syndrome › Joubert syndrome 25

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 6, 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 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

311 retrieved; paginated sample, class counts are floors:

134 likely benign, 81 uncertain significance, 25 benign, 20 benign/likely benign, 18 conflicting classifications of pathogenicity, 13 pathogenic, 13 likely pathogenic, 7 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1412663	NC_000001.10:g.(?861322)(3768971_?)del	ARHGEF16	Pathogenic	criteria provided, single submitter
1322057	NM_014704.4(CEP104):c.2081_2084del (p.Gln694fs)	CEP104	Pathogenic	criteria provided, multiple submitters, no conflicts
1343654	NM_014704.4(CEP104):c.1051_1054del (p.Thr351fs)	CEP104	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1691031	NM_014704.4(CEP104):c.1879G>T (p.Glu627Ter)	CEP104	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2072188	NM_014704.4(CEP104):c.163C>T (p.Arg55Ter)	CEP104	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
221274	NM_014704.4(CEP104):c.735+2T>C	CEP104	Pathogenic	criteria provided, single submitter
221275	NM_014704.4(CEP104):c.1328_1329insT (p.Tyr444fs)	CEP104	Pathogenic	no assertion criteria provided
221276	NM_014704.4(CEP104):c.496C>T (p.Arg166Ter)	CEP104	Pathogenic	no assertion criteria provided
221277	NM_014704.4(CEP104):c.2572-2A>G	CEP104	Pathogenic	no assertion criteria provided
2634864	NM_014704.4(CEP104):c.895C>T (p.Arg299Ter)	CEP104	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2893140	NC_000001.11:g.3823227_3823243del	CEP104	Pathogenic	criteria provided, single submitter
3004548	NM_014704.4(CEP104):c.1745del (p.His582fs)	CEP104	Pathogenic	criteria provided, single submitter
3583724	NM_014704.4(CEP104):c.808A>T (p.Lys270Ter)	CEP104	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3646990	NM_014704.4(CEP104):c.157A>T (p.Arg53Ter)	CEP104	Pathogenic	criteria provided, single submitter
4700540	NM_014704.4(CEP104):c.1351C>T (p.Arg451Ter)	CEP104	Pathogenic	criteria provided, single submitter
4812090	NM_014704.4(CEP104):c.1031del (p.Lys344fs)	CEP104	Pathogenic	criteria provided, single submitter
542192	NM_014704.4(CEP104):c.759T>G (p.Tyr253Ter)	CEP104	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
542193	NM_014704.4(CEP104):c.1082_1091del (p.Pro361fs)	CEP104	Pathogenic	criteria provided, single submitter
665628	NC_000001.11:g.(?3815382)(3852427_?)del	CEP104	Pathogenic	criteria provided, single submitter
800522	NM_014704.4(CEP104):c.300_301del (p.Leu100_Cys101insTer)	CEP104	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1704568	NM_014704.4(CEP104):c.2286del (p.Glu762fs)	CEP104	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1878385	NM_014704.4(CEP104):c.1485+1G>A	CEP104	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3583673	NM_014704.4(CEP104):c.2365-2A>G	CEP104	Likely pathogenic	criteria provided, single submitter
3583677	NM_014704.4(CEP104):c.2361del (p.Lys787fs)	CEP104	Likely pathogenic	criteria provided, single submitter
3583685	NM_014704.4(CEP104):c.2188+1G>T	CEP104	Likely pathogenic	criteria provided, single submitter
3583691	NM_014704.4(CEP104):c.2151+2T>C	CEP104	Likely pathogenic	criteria provided, single submitter
3583701	NM_014704.4(CEP104):c.2088_2091del (p.Glu697fs)	CEP104	Likely pathogenic	criteria provided, single submitter
3583713	NM_014704.4(CEP104):c.968C>G (p.Ser323Ter)	CEP104	Likely pathogenic	criteria provided, single submitter
3583731	NM_014704.4(CEP104):c.735+1G>T	CEP104	Likely pathogenic	criteria provided, single submitter
434718	NM_014704.4(CEP104):c.49del (p.Asp17fs)	CEP104	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 2 · 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
CEP104	Definitive	Autosomal recessive	Joubert syndrome 25	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CEP104	Orphanet:475	Isolated Joubert syndrome
CEP104	Orphanet:88616	Autosomal recessive non-syndromic intellectual disability

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
CEP104	HGNC:24866	ENSG00000116198	O60308	Centrosomal protein of 104 kDa	gencc,clinvar
ARHGEF16	HGNC:15515	ENSG00000130762	Q5VV41	Rho guanine nucleotide exchange factor 16	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CEP104	Centrosomal protein of 104 kDa	Required for ciliogenesis and for structural integrity at the ciliary tip.
ARHGEF16	Rho guanine nucleotide exchange factor 16	Guanyl-nucleotide exchange factor of the RHOG GTPase stimulating the exchange of RHOG-associated GDP for GTP.

Protein-family classification

Druggable: 0 · Difficult: 2 · Unknown: 0 · 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	8.6×	0.225
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CEP104	Transcription factor	no		Galactose-bd-like_sf, ARM-like, ARM-type_fold
ARHGEF16	Scaffold/PPI	no		DH_dom, SH3_domain, PH_domain

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	1
secondary oocyte	1
sperm	1
ileal mucosa	1
metanephros cortex	1
mucosa of transverse colon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CEP104	284	ubiquitous	marker	secondary oocyte, buccal mucosa cell, sperm
ARHGEF16	199	broad	marker	mucosa of transverse colon, metanephros cortex, ileal mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ARHGEF16	1,269
CEP104	1,199

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CEP104	O60308	2
ARHGEF16	Q5VV41	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 2 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
Cell death signalling via NRAGE, NRIF and NADE	1	219.6×	0.016	ARHGEF16
p75 NTR receptor-mediated signalling	1	187.2×	0.016	ARHGEF16
NRAGE signals death through JNK	1	184.2×	0.016	ARHGEF16
RHOG GTPase cycle	1	148.3×	0.016	ARHGEF16
Death Receptor Signaling	1	139.3×	0.016	ARHGEF16
G alpha (12/13) signalling events	1	137.6×	0.016	ARHGEF16
CDC42 GTPase cycle	1	72.3×	0.026	ARHGEF16
RHO GTPase cycle	1	60.1×	0.027	ARHGEF16
GPCR downstream signalling	1	43.4×	0.032	ARHGEF16
Signaling by GPCR	1	40.1×	0.032	ARHGEF16
Signaling by Rho GTPases	1	34.2×	0.032	ARHGEF16
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	33.5×	0.032	ARHGEF16
Signal Transduction	1	10.2×	0.098	ARHGEF16

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of Cdc42 protein signal transduction	1	1404.3×	0.003	ARHGEF16
activation of GTPase activity	1	732.7×	0.003	ARHGEF16
positive regulation of protein localization to plasma membrane	1	271.8×	0.006	ARHGEF16
cell chemotaxis	1	185.2×	0.006	ARHGEF16
regulation of actin cytoskeleton organization	1	157.5×	0.006	ARHGEF16

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
CEP104	0	0
ARHGEF16	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	CEP104, ARHGEF16

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)
CEP104	0	—
ARHGEF16	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.