Joubert syndrome 22

Summary

Joubert syndrome 22 (MONDO:0014297) is a disease caused by PDE6D (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: PDE6D (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 71

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Joubert syndrome 22
Mondo ID	MONDO:0014297
OMIM	615665
DOID	DOID:0110991
UMLS	C3810278
MedGen	816608
GARD	0015999
Is cancer (heuristic)	no

Also known as: JBTS22 · Joubert syndrome 22 · Joubert syndrome caused by mutation in PDE6D · Joubert syndrome type 22 · PDE6D Joubert syndrome

Data availability: 71 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Joubert syndrome › Joubert syndrome 22

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 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

71 retrieved; paginated sample, class counts are floors:

35 likely benign, 25 uncertain significance, 7 pathogenic, 2 benign/likely benign, 1 pathogenic/likely pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
100773	NM_002601.4(PDE6D):c.140-1G>A	PDE6D	Pathogenic	no assertion criteria provided
1382726	NM_002601.4(PDE6D):c.114del (p.Ser39fs)	PDE6D	Pathogenic	criteria provided, single submitter
1414071	NM_002601.4(PDE6D):c.66del (p.Arg23fs)	PDE6D	Pathogenic	criteria provided, single submitter
1683781	NM_002601.4(PDE6D):c.46A>T (p.Lys16Ter)	PDE6D	Pathogenic	no assertion criteria provided
2001656	NM_002601.4(PDE6D):c.342del (p.Glu114fs)	PDE6D	Pathogenic	criteria provided, single submitter
2181645	NM_002601.4(PDE6D):c.181C>T (p.Arg61Ter)	PDE6D	Pathogenic	criteria provided, single submitter
2424497	NC_000002.11:g.(?232645755)(232645824_?)del	PDE6D	Pathogenic	criteria provided, single submitter
590801	NM_002601.4(PDE6D):c.367_368insG (p.Leu123fs)	PDE6D	Pathogenic/Likely pathogenic	no assertion criteria provided
917951	NM_002601.4(PDE6D):c.257del (p.Cys86fs)	PDE6D	Likely pathogenic	criteria provided, single submitter
1374168	NC_000002.11:g.(?231033840)(234978657_?)dup	COPS7B	Uncertain significance	criteria provided, single submitter
2187766	NM_002601.4(PDE6D):c.30G>C (p.Glu10Asp)	LOC129935846	Uncertain significance	criteria provided, single submitter
1056121	NC_000002.11:g.(?232597662)(232603918_?)dup	PDE6D	Uncertain significance	criteria provided, single submitter
1354430	NM_002601.4(PDE6D):c.266-3C>T	PDE6D	Uncertain significance	criteria provided, single submitter
1360750	NM_002601.4(PDE6D):c.364G>A (p.Val122Ile)	PDE6D	Uncertain significance	criteria provided, single submitter
1371082	NM_002601.4(PDE6D):c.359C>A (p.Ala120Glu)	PDE6D	Uncertain significance	criteria provided, single submitter
1392287	NM_002601.4(PDE6D):c.328G>A (p.Glu110Lys)	PDE6D	Uncertain significance	criteria provided, single submitter
1410663	NC_000002.11:g.(?232597662)(232597763_?)del	PDE6D	Uncertain significance	criteria provided, single submitter
1410677	NM_002601.4(PDE6D):c.103A>G (p.Thr35Ala)	PDE6D	Uncertain significance	criteria provided, single submitter
1441438	NM_002601.4(PDE6D):c.67C>T (p.Arg23Trp)	PDE6D	Uncertain significance	criteria provided, multiple submitters, no conflicts
1441633	NM_002601.4(PDE6D):c.40G>A (p.Gly14Ser)	PDE6D	Uncertain significance	criteria provided, single submitter
1485922	NM_002601.4(PDE6D):c.51A>C (p.Leu17=)	PDE6D	Uncertain significance	criteria provided, single submitter
1508371	NM_002601.4(PDE6D):c.304A>C (p.Thr102Pro)	PDE6D	Uncertain significance	criteria provided, single submitter
1525951	NM_002601.4(PDE6D):c.390A>T (p.Glu130Asp)	PDE6D	Uncertain significance	criteria provided, single submitter
1912702	NM_002601.4(PDE6D):c.182G>A (p.Arg61Gln)	PDE6D	Uncertain significance	criteria provided, single submitter
2026306	NM_002601.4(PDE6D):c.298A>G (p.Asn100Asp)	PDE6D	Uncertain significance	criteria provided, single submitter
2131348	NM_002601.4(PDE6D):c.227T>C (p.Leu76Pro)	PDE6D	Uncertain significance	criteria provided, single submitter
2151819	NM_002601.4(PDE6D):c.224G>A (p.Arg75His)	PDE6D	Uncertain significance	criteria provided, multiple submitters, no conflicts
2158118	NM_002601.4(PDE6D):c.68G>A (p.Arg23Gln)	PDE6D	Uncertain significance	criteria provided, single submitter
2159721	NM_002601.4(PDE6D):c.424A>G (p.Thr142Ala)	PDE6D	Uncertain significance	criteria provided, single submitter
2424498	NC_000002.11:g.(?232597662)(232597763_?)dup	PDE6D	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
PDE6D	Strong	Autosomal recessive	Joubert syndrome 22	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PDE6D	Orphanet:2754	Orofaciodigital syndrome type 6
PDE6D	Orphanet:475	Isolated Joubert 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
PDE6D	HGNC:8788	ENSG00000156973	O43924	Retinal rod rhodopsin-sensitive cGMP 3’,5’-cyclic phosphodiesterase subunit delta	gencc,clinvar
COPS7B	HGNC:16760	ENSG00000144524	Q9H9Q2	COP9 signalosome complex subunit 7b	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PDE6D	Retinal rod rhodopsin-sensitive cGMP 3’,5’-cyclic phosphodiesterase subunit delta	Promotes the release of prenylated target proteins from cellular membranes.
COPS7B	COP9 signalosome complex subunit 7b	Component of the COP9 signalosome complex (CSN), a complex involved in various cellular and developmental processes.

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)
PDE6D	Other/Unknown	no		PDED_dom, Ig_E-set, Rhodop-sen_GMP-Pdiesterase_dsu
COPS7B	Other/Unknown	no		PCI_dom, CSN7_helixI, COPS7/eIF3m

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
left testis	2
right testis	2
testis	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PDE6D	284	ubiquitous	marker	left testis, right testis, testis
COPS7B	243	ubiquitous	marker	right uterine tube, right testis, left testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COPS7B	1,561
PDE6D	1,307

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PDE6D	O43924	40
COPS7B	Q9H9Q2	25

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. 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
ARL13B-mediated ciliary trafficking of INPP5E	1	1903.3×	0.003	PDE6D
RAS processing	1	237.9×	0.013	PDE6D
DNA Damage Recognition in GG-NER	1	142.8×	0.014	COPS7B
Formation of TC-NER Pre-Incision Complex	1	105.7×	0.014	COPS7B
Cargo recognition for clathrin-mediated endocytosis	1	52.4×	0.023	COPS7B
Neddylation	1	23.7×	0.042	COPS7B

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
COP9 signalosome assembly	1	1685.2×	0.002	COPS7B
protein deneddylation	1	648.1×	0.003	COPS7B
regulation of protein neddylation	1	468.1×	0.003	COPS7B
visual perception	1	39.8×	0.025	PDE6D

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
PDE6D	VARDENAFIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PDE6D	8	4
COPS7B	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VARDENAFIL	4	PDE6D
SILDENAFIL	4	PDE6D
TADALAFIL	4	PDE6D
DIPYRIDAMOLE	4	PDE6D
SORAFENIB	4	PDE6D
ROSUVASTATIN	4	PDE6D
ZAPRINAST	2	PDE6D
TBA-7371	2	PDE6D

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
PDE6D	147	Binding:145, ADMET:2
COPS7B	1	Binding:1

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
PDE6D	147

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

8 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)
VARDENAFIL	4	PDE6D
SILDENAFIL	4	PDE6D
TADALAFIL	4	PDE6D
DIPYRIDAMOLE	4	PDE6D
SORAFENIB	4	PDE6D
ROSUVASTATIN	4	PDE6D
ZAPRINAST	2	PDE6D
TBA-7371	2	PDE6D

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PDE6D
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	1	COPS7B

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
COPS7B	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.