Joubert syndrome 23

Summary

Joubert syndrome 23 (MONDO:0014664) is a disease caused by KIAA0586 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: KIAA0586 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 1,341

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Joubert syndrome 23
Mondo ID	MONDO:0014664
OMIM	616490
DOID	DOID:0110992
UMLS	C4084822
MedGen	900119
GARD	0016124
Is cancer (heuristic)	no

Also known as: JBTS23 · Joubert syndrome 23 · Joubert syndrome caused by mutation in KIAA0586 · Joubert syndrome type 23 · KIAA0586 Joubert syndrome

Data availability: 1,341 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 23

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 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

600 retrieved; paginated sample, class counts are floors:

358 uncertain significance, 167 likely benign, 27 pathogenic, 19 benign, 11 conflicting classifications of pathogenicity, 10 likely pathogenic, 4 benign/likely benign, 3 pathogenic/likely pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1458692	NC_000014.8:g.(?58711639)(59014694_?)del	ARID4A	Pathogenic	criteria provided, single submitter
1068589	NM_001329943.3(KIAA0586):c.1466_1476del (p.Lys489fs)	KIAA0586	Pathogenic	criteria provided, single submitter
1070138	NM_001329943.3(KIAA0586):c.1935del (p.Val646fs)	KIAA0586	Pathogenic	criteria provided, single submitter
1070838	NM_001329943.3(KIAA0586):c.4495+3755del	KIAA0586	Pathogenic	criteria provided, single submitter
1072185	NM_001329943.3(KIAA0586):c.1667dup (p.Arg557fs)	KIAA0586	Pathogenic	criteria provided, single submitter
1073545	NM_001329943.3(KIAA0586):c.1075_1076del (p.Lys359fs)	KIAA0586	Pathogenic	criteria provided, single submitter
1175094	NM_001329943.3(KIAA0586):c.2536del (p.Val846fs)	KIAA0586	Pathogenic	criteria provided, single submitter
1175854	NM_001329943.3(KIAA0586):c.38del (p.Lys13fs)	KIAA0586	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1350774	NM_001329943.3(KIAA0586):c.25G>T (p.Glu9Ter)	KIAA0586	Pathogenic	criteria provided, single submitter
1357141	NM_001329943.3(KIAA0586):c.4456C>T (p.Gln1486Ter)	KIAA0586	Pathogenic	criteria provided, single submitter
1359882	NM_001329943.3(KIAA0586):c.622dup (p.Thr208fs)	KIAA0586	Pathogenic	criteria provided, single submitter
1369714	NM_001329943.3(KIAA0586):c.3353del (p.Pro1118fs)	KIAA0586	Pathogenic	criteria provided, single submitter
1379251	NM_001329943.3(KIAA0586):c.126T>A (p.Cys42Ter)	KIAA0586	Pathogenic	criteria provided, single submitter
1406363	NM_001329943.3(KIAA0586):c.2050C>T (p.Arg684Ter)	KIAA0586	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1429932	NM_001329943.3(KIAA0586):c.3700del (p.Val1234fs)	KIAA0586	Pathogenic	criteria provided, single submitter
1435532	NM_001329943.3(KIAA0586):c.1872del (p.Glu625fs)	KIAA0586	Pathogenic	criteria provided, single submitter
1435732	NM_001329943.3(KIAA0586):c.411-1371G>A	KIAA0586	Pathogenic	criteria provided, single submitter
1452576	NM_001329943.3(KIAA0586):c.3638del (p.Pro1213fs)	KIAA0586	Pathogenic	criteria provided, single submitter
1453326	NM_001329943.3(KIAA0586):c.938del (p.Tyr313fs)	KIAA0586	Pathogenic	criteria provided, single submitter
1453478	NM_001329943.3(KIAA0586):c.4495+3777del	KIAA0586	Pathogenic	criteria provided, single submitter
1453784	NM_001329943.3(KIAA0586):c.4225del (p.Glu1409fs)	KIAA0586	Pathogenic	criteria provided, single submitter
1453816	NM_001329943.3(KIAA0586):c.4495+3785A>T	KIAA0586	Pathogenic	criteria provided, single submitter
1456969	NM_001329943.3(KIAA0586):c.3580C>T (p.Gln1194Ter)	KIAA0586	Pathogenic	criteria provided, multiple submitters, no conflicts
1457512	NM_001329943.3(KIAA0586):c.4495+3767A>T	KIAA0586	Pathogenic	criteria provided, single submitter
1457530	NM_001329943.3(KIAA0586):c.2047_2048del (p.Glu683fs)	KIAA0586	Pathogenic	criteria provided, single submitter
1457538	NM_001329943.3(KIAA0586):c.1093del (p.Glu365fs)	KIAA0586	Pathogenic	criteria provided, single submitter
1517797	NM_001329943.3(KIAA0586):c.3142_3144+5del	KIAA0586	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1683813	NM_001329943.3(KIAA0586):c.3097dup (p.Ala1033fs)	KIAA0586	Pathogenic	criteria provided, multiple submitters, no conflicts
1899465	NM_001329943.3(KIAA0586):c.653_663del (p.Asp218fs)	KIAA0586	Pathogenic	criteria provided, single submitter
1938645	NM_001329943.3(KIAA0586):c.3718_3719del (p.Leu1240fs)	KIAA0586	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · 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
KIAA0586	Definitive	Autosomal recessive	Joubert syndrome 23	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KIAA0586	Orphanet:397715	Joubert syndrome with Jeune asphyxiating thoracic dystrophy
KIAA0586	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
KIAA0586	HGNC:19960	ENSG00000100578	Q9BVV6	Protein TALPID3	gencc,clinvar
ARID4A	HGNC:9885	ENSG00000032219	P29374	AT-rich interactive domain-containing protein 4A	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KIAA0586	Protein TALPID3	Required for ciliogenesis and sonic hedgehog/SHH signaling.
ARID4A	AT-rich interactive domain-containing protein 4A	DNA-binding protein which modulates activity of several transcription factors including RB1 (retinoblastoma-associated protein) and AR (androgen receptor).

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)
KIAA0586	Other/Unknown	no		TALPID3
ARID4A	Other/Unknown	no		Chromo/chromo_shadow_dom, ARID_dom, Tudor

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	1
male germ line stem cell (sensu Vertebrata) in testis	1
right testis	1
buccal mucosa cell	1
calcaneal tendon	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KIAA0586	247	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, right testis, left testis
ARID4A	277	ubiquitous	marker	calcaneal tendon, sural nerve, buccal mucosa cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ARID4A	3,311
KIAA0586	1,405

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ARID4A	P29374	7

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KIAA0586	Q9BVV6	47.61

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. 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
HDACs deacetylate histones	1	120.2×	0.028	ARID4A
Potential therapeutics for SARS	1	114.2×	0.028	ARID4A
Chromatin organization	1	81.6×	0.028	ARID4A
Chromatin modifying enzymes	1	72.3×	0.028	ARID4A
SARS-CoV Infections	1	55.4×	0.029	ARID4A
Viral Infection Pathways	1	30.8×	0.043	ARID4A
Infectious disease	1	24.8×	0.046	ARID4A
Disease	1	13.1×	0.076	ARID4A

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
establishment of Sertoli cell barrier	1	1685.2×	0.007	ARID4A
regulation of establishment of protein localization	1	1203.7×	0.007	KIAA0586
genomic imprinting	1	495.6×	0.010	ARID4A
negative regulation of stem cell population maintenance	1	383.0×	0.010	ARID4A
erythrocyte development	1	263.3×	0.012	ARID4A
positive regulation of stem cell population maintenance	1	172.0×	0.015	ARID4A
smoothened signaling pathway	1	90.6×	0.023	KIAA0586
negative regulation of transforming growth factor beta receptor signaling pathway	1	86.9×	0.023	ARID4A
negative regulation of cell migration	1	55.8×	0.032	ARID4A
cilium assembly	1	36.8×	0.041	KIAA0586
transcription by RNA polymerase II	1	35.3×	0.041	ARID4A
spermatogenesis	1	17.6×	0.075	ARID4A
negative regulation of DNA-templated transcription	1	15.8×	0.077	ARID4A
negative regulation of transcription by RNA polymerase II	1	8.9×	0.125	ARID4A
positive regulation of transcription by RNA polymerase II	1	7.4×	0.139	ARID4A
regulation of transcription by RNA polymerase II	1	5.8×	0.164	ARID4A

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 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
KIAA0586	0	0
ARID4A	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
ARID4A	5	Binding:5

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	KIAA0586, ARID4A

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)
KIAA0586	0	—
ARID4A	5	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.