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Joubert syndrome

Genetic MONDO:0018772 Neurodevelopmental Disorder Ciliopathy

Joubert syndrome is a rare neurodevelopmental ciliopathy with a characteristic molar tooth sign on brain MRI and multisystem involvement affecting the nervous system, eyes, kidneys, liver, and skeleton.

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Mappings
0
Definitions
2
Inheritance
4
Pathophysiology
0
Histopathology
24
Phenotypes
18
Genes
8
Treatments
38
Subtypes
5
Differentials
2
Datasets
3
Trials
👪

Inheritance

2
Autosomal Recessive
Joubert syndrome is typically inherited in an autosomal recessive pattern, though an X-linked recessive form (Joubert syndrome 10, OFD1 on Xp22.2) exists.
Show evidence (1 reference)
PMID:36803942 SUPPORT Human Clinical
"Joubert syndrome (JS; MIM PS213300) is a rare genetic autosomal recessive disease characterized by cerebellar vermis hypoplasia, a distinctive malformation of the cerebellum and the so-called "molar tooth sign.""
This statement explicitly describes autosomal recessive inheritance.
X-linked recessive
Joubert syndrome 10 is an X-linked recessive form caused by OFD1 mutations on Xp22.2.
Show evidence (2 references)
PMID:31373179 SUPPORT Human Clinical
"pathogenic variants in OFD1 were found to be associated with X-linked intellectual disability, Joubert syndrome type 10 (JBTS10),"
This review links OFD1 pathogenic variants to Joubert syndrome 10 in an X-linked context.
PMID:31373179 SUPPORT Human Clinical
"OFD1, residing on chromosome Xp22.2,"
This provides the OFD1 locus on Xp22.2 supporting X-linked inheritance.
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Subtypes

38
Joubert syndrome 1 Not Yet Curated MONDO:0008944
Joubert syndrome 2 Not Yet Curated MONDO:0011963
Joubert syndrome 3 Not Yet Curated MONDO:0012078
Joubert syndrome with renal defect Not Yet Curated MONDO:0012308
Joubert syndrome 5 Not Yet Curated MONDO:0012432
Joubert syndrome 6 Not Yet Curated MONDO:0012539
Joubert syndrome 7 Not Yet Curated MONDO:0012694
Joubert syndrome 9 Not Yet Curated MONDO:0012849
Joubert syndrome 8 Not Yet Curated MONDO:0012855
Joubert syndrome 13 Not Yet Curated MONDO:0013608
Joubert syndrome 14 Not Yet Curated MONDO:0013745
Joubert syndrome 15 Not Yet Curated MONDO:0013763
Joubert syndrome 16 Not Yet Curated MONDO:0013764
Joubert syndrome 17 Not Yet Curated MONDO:0013824
Joubert syndrome 18 Not Yet Curated MONDO:0013896
Joubert syndrome caused by mutation in TCTN3.
Joubert syndrome 20 Not Yet Curated MONDO:0013994
Joubert syndrome 21 Not Yet Curated MONDO:0014288
Joubert syndrome 22 Not Yet Curated MONDO:0014297
Joubert syndrome 23 Not Yet Curated MONDO:0014664
Joubert syndrome 24 Not Yet Curated MONDO:0014724
Joubert syndrome 25 Not Yet Curated MONDO:0014770
Joubert syndrome 26 Not Yet Curated MONDO:0014771
Joubert syndrome 27 Not Yet Curated MONDO:0014927
Joubert syndrome 28 Not Yet Curated MONDO:0014928
Joubert syndrome 38 Not Yet Curated MONDO:0030353
Joubert syndrome 39 Not Yet Curated MONDO:0030454
Joubert syndrome 40 Not Yet Curated MONDO:0030462
Joubert syndrome 37 Not Yet Curated MONDO:0030933
Joubert syndrome 35 Not Yet Curated MONDO:0032570
Joubert syndrome 36 Not Yet Curated MONDO:0032902
Joubert syndrome 30 Not Yet Curated MONDO:0033308
Joubert syndrome 32 Not Yet Curated MONDO:0033309
Joubert syndrome 31 Not Yet Curated MONDO:0033310
Joubert syndrome 33 Not Yet Curated MONDO:0033311
Joubert syndrome 19 Not Yet Curated MONDO:0800363
Joubert syndrome 29 Not Yet Curated MONDO:0800372
Joubert syndrome 11 Not Yet Curated MONDO:0800382
Joubert syndrome 34 Not Yet Curated MONDO:0800383
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Pathophysiology

4
Ciliary gene mutations disrupt primary cilium assembly
Causative JS genes encode proteins required for primary cilium structure and assembly, disrupting cilium biogenesis in vivo.
cilium assembly link ↕ DYSREGULATED
Show evidence (2 references)
PMID:38502237 SUPPORT In Vitro
"Over 40 causative genes have been reported, all encoding for proteins implicated in the structure or functioning of the primary cilium, a subcellular organelle widely present in embryonic and adult tissues."
JS genes encode primary cilium components, supporting disrupted cilium assembly.
PMID:41165761 SUPPORT In Vitro
"B9 proteins localized to centrioles prior to ciliogenesis, where they facilitated the initiation of ciliogenesis."
This supports impaired ciliogenesis initiation as a core ciliary assembly defect.
Abnormal cilium structure and length
Primary cilia show abnormal number, morphology, and length in JS models, indicating disrupted cilium organization.
cilium organization link ⚠ ABNORMAL
Show evidence (4 references)
PMID:38502237 SUPPORT In Vitro
"In addition, analysis of primary cilium count and morphology showed notable ciliary defects in all differentiating JS patient-derived iPSCs compared to controls."
Patient-derived cells show abnormal primary cilium structure.
PMID:36802443 SUPPORT Model Organism
"Deficiency of the minor spliceosome component U4atac snRNA secondarily results in ciliary defects in human and zebrafish."
Zebrafish models demonstrate in vivo ciliary defects consistent with abnormal cilium organization.
PMID:39400299 SUPPORT Model Organism
"We found that JBTS mutants have altered primary cilia throughout the brain."
Zebrafish JBTS mutants show altered primary cilia in brain tissue.
+ 1 more reference
Impaired intraciliary transport
Disruption of ciliary gene products (e.g., CEP290) impairs intraciliary transport and cilium maintenance.
intraciliary transport link ↕ DYSREGULATED
Show evidence (1 reference)
PMID:33717386 SUPPORT Human Clinical
"Recently, it has been proposed that CEP290 gene product may also play a role in the microtubule-based ciliary transport, in the vesicle transport, the development and maintenance of the cilium"
CEP290 dysfunction is linked to impaired intraciliary transport and cilium maintenance.
Neurodevelopmental defects
Disrupted ciliary biology impairs neurodevelopmental programs, contributing to mid-hindbrain and cerebellar developmental abnormalities.
Show evidence (2 references)
PMID:38502237 SUPPORT In Vitro
"All JS patient-derived iPSCs, regardless of the mutant gene, showed a similar impairment to differentiate into mid-hindbrain and cerebellar granule cells when compared to healthy controls."
Patient-derived cells show impaired neuronal differentiation relevant to neurodevelopmental defects.
PMID:40537162 SUPPORT Human Clinical
"Classic defects include hypoplasia of the cerebellar vermis, thickened cerebellar peduncles, and deepened interpeduncular fossa, which is regarded as a "molar tooth" sign."
This review describes neurodevelopmental malformations characteristic of JS.
●

Phenotypes

24
Cardiovascular(1) Digestive(3) Eye(4) Genitourinary(2) Limbs(1) Musculoskeletal(2) Nervous System(8) Respiratory(3)
Cardiovascular 1
Portal hypertension RARE Portal hypertension (HP:0001409)
Show evidence (1 reference)
PMID:36580738 SUPPORT Human Clinical
"Portal hypertension and esophageal varices as liver and polycystic kidney disease and nephronophthisis as kidney involvement was encountered in our patients."
Portal hypertension was reported as a liver involvement in this cohort.
Digestive 3
Hepatic fibrosis OCCASIONAL Hepatic fibrosis (HP:0001395)
Show evidence (1 reference)
PMID:36803942 SUPPORT Human Clinical
"Other characteristic features are hypotonia with lateral ataxia, intellectual disability/mental retardation, oculomotor apraxia, retinal dystrophy, abnormalities in the respiratory system, renal cysts, hepatic fibrosis, and skeletal changes."
Hepatic fibrosis is reported among characteristic JS features.
Esophageal varix RARE Esophageal varix (HP:0002040)
Show evidence (1 reference)
PMID:36580738 SUPPORT Human Clinical
"Portal hypertension and esophageal varices as liver and polycystic kidney disease and nephronophthisis as kidney involvement was encountered in our patients."
Esophageal varices were observed in JS patients in this cohort.
Dysphagia VERY_RARE Dysphagia (HP:0002015)
Show evidence (1 reference)
PMID:35602833 SUPPORT Human Clinical
"Here, we present the case of a 20-year-old patient who presented with a new onset of dysphagia that led to a diagnosis of JS."
This adult JS case report highlights dysphagia as a presenting symptom.
Eye 4
Abnormality of eye movement FREQUENT Abnormality of eye movement (HP:0000496)
Show evidence (1 reference)
PMID:38502237 SUPPORT In Vitro
"Joubert syndrome (JS) is a recessively inherited congenital ataxia characterized by hypotonia, psychomotor delay, abnormal ocular movements, intellectual disability, and a peculiar cerebellar and brainstem malformation, the "molar tooth sign.""
Abnormal ocular movements are a defining neurologic-ophthalmologic feature.
Oculomotor apraxia FREQUENT Oculomotor apraxia (HP:0000657)
Show evidence (1 reference)
PMID:36803942 SUPPORT Human Clinical
"Other characteristic features are hypotonia with lateral ataxia, intellectual disability/mental retardation, oculomotor apraxia, retinal dystrophy, abnormalities in the respiratory system, renal cysts, hepatic fibrosis, and skeletal changes."
Oculomotor apraxia is listed among characteristic JS features.
Strabismus VERY_RARE Strabismus (HP:0000486)
Show evidence (1 reference)
PMID:37547106 SUPPORT Human Clinical
"Thirty-four (94.44%) cases had developmental delay, one patient (2.78%) had strabismus, and one patient (2.78%) had intermittent dizziness."
This cohort reports strabismus in a small subset of JS patients.
Retinal dystrophy FREQUENT Retinal dystrophy (HP:0000556)
Show evidence (1 reference)
PMID:36803942 SUPPORT Human Clinical
"Other characteristic features are hypotonia with lateral ataxia, intellectual disability/mental retardation, oculomotor apraxia, retinal dystrophy, abnormalities in the respiratory system, renal cysts, hepatic fibrosis, and skeletal changes."
Retinal dystrophy is cited as a characteristic feature.
Genitourinary 2
Renal cyst OCCASIONAL Renal cyst (HP:0000107)
Show evidence (1 reference)
PMID:36803942 SUPPORT Human Clinical
"Other characteristic features are hypotonia with lateral ataxia, intellectual disability/mental retardation, oculomotor apraxia, retinal dystrophy, abnormalities in the respiratory system, renal cysts, hepatic fibrosis, and skeletal changes."
Renal cysts are reported as part of the JS phenotype spectrum.
Nephronophthisis OCCASIONAL Nephronophthisis (HP:0000090)
Show evidence (1 reference)
PMID:36580738 SUPPORT Human Clinical
"Portal hypertension and esophageal varices as liver and polycystic kidney disease and nephronophthisis as kidney involvement was encountered in our patients."
This cohort reports nephronophthisis as kidney involvement in JS.
Limbs 1
Polydactyly VERY_RARE Polydactyly (HP:0010442)
Show evidence (1 reference)
PMID:38013309 SUPPORT Human Clinical
"Resection was performed to correct the polydactyly."
This JS case report documents polydactyly requiring surgical correction.
Musculoskeletal 2
Hypotonia FREQUENT Hypotonia (HP:0001252)
Show evidence (1 reference)
PMID:36803942 SUPPORT Human Clinical
"Other characteristic features are hypotonia with lateral ataxia, intellectual disability/mental retardation, oculomotor apraxia, retinal dystrophy, abnormalities in the respiratory system, renal cysts, hepatic fibrosis, and skeletal changes."
Hypotonia is listed as a characteristic feature of JS.
Abnormality of the skeletal system OCCASIONAL Abnormality of the skeletal system (HP:0000924)
Show evidence (1 reference)
PMID:36803942 SUPPORT Human Clinical
"Other characteristic features are hypotonia with lateral ataxia, intellectual disability/mental retardation, oculomotor apraxia, retinal dystrophy, abnormalities in the respiratory system, renal cysts, hepatic fibrosis, and skeletal changes."
Skeletal changes are included in the JS phenotype spectrum.
Nervous System 8
Molar tooth sign on MRI VERY_FREQUENT Molar tooth sign on MRI (HP:0002419)
Show evidence (1 reference)
PMID:40537162 SUPPORT Human Clinical
"Classic defects include hypoplasia of the cerebellar vermis, thickened cerebellar peduncles, and deepened interpeduncular fossa, which is regarded as a "molar tooth" sign."
The molar tooth sign is a classic diagnostic feature of JS.
Cerebellar vermis hypoplasia VERY_FREQUENT Cerebellar vermis hypoplasia (HP:0001320)
Show evidence (1 reference)
PMID:40537162 SUPPORT Human Clinical
"Classic defects include hypoplasia of the cerebellar vermis, thickened cerebellar peduncles, and deepened interpeduncular fossa, which is regarded as a "molar tooth" sign."
This review identifies cerebellar vermis hypoplasia as a classic defect in JS.
Ataxia FREQUENT Ataxia (HP:0001251)
Show evidence (1 reference)
PMID:36803942 SUPPORT Human Clinical
"Other characteristic features are hypotonia with lateral ataxia, intellectual disability/mental retardation, oculomotor apraxia, retinal dystrophy, abnormalities in the respiratory system, renal cysts, hepatic fibrosis, and skeletal changes."
Ataxia is described among characteristic features of JS.
Intellectual disability FREQUENT Intellectual disability (HP:0001249)
Show evidence (1 reference)
PMID:36803942 SUPPORT Human Clinical
"Other characteristic features are hypotonia with lateral ataxia, intellectual disability/mental retardation, oculomotor apraxia, retinal dystrophy, abnormalities in the respiratory system, renal cysts, hepatic fibrosis, and skeletal changes."
Intellectual disability is noted as a characteristic feature.
Global developmental delay FREQUENT Global developmental delay (HP:0001263)
Show evidence (1 reference)
PMID:38502237 SUPPORT In Vitro
"Joubert syndrome (JS) is a recessively inherited congenital ataxia characterized by hypotonia, psychomotor delay, abnormal ocular movements, intellectual disability, and a peculiar cerebellar and brainstem malformation, the "molar tooth sign.""
Psychomotor delay supports global developmental delay in JS.
Speech apraxia VERY_RARE Speech apraxia (HP:0011098)
Show evidence (1 reference)
PMID:35860112 SUPPORT Human Clinical
"Clinical features can be noticed shortly after birth that includes hypotonia episodic tachypnea and apnea that may be followed by developmental delays and speech apraxia."
This case report notes speech apraxia in JS.
Seizure VERY_RARE Seizure (HP:0001250)
Show evidence (1 reference)
PMID:33717386 SUPPORT Human Clinical
"presenting with dyspnea, cyanosis, signs of respiratory distress and seizures."
This neonatal case report documents seizures in JS.
Sleep apnea VERY_RARE Sleep apnea (HP:0010535)
Show evidence (1 reference)
PMID:36052101 SUPPORT Human Clinical
"was referred to the Sleep Unit because spells of apnea while sleeping."
This case report describes sleep apnea in a JS patient.
Respiratory 3
Abnormal respiratory system physiology OCCASIONAL Abnormal respiratory system physiology (HP:0002795)
Show evidence (1 reference)
PMID:36803942 SUPPORT Human Clinical
"Other characteristic features are hypotonia with lateral ataxia, intellectual disability/mental retardation, oculomotor apraxia, retinal dystrophy, abnormalities in the respiratory system, renal cysts, hepatic fibrosis, and skeletal changes."
Respiratory system abnormalities are reported among characteristic features.
Episodic tachypnea VERY_RARE Episodic tachypnea (HP:0002876)
Show evidence (1 reference)
PMID:35860112 SUPPORT Human Clinical
"Clinical features can be noticed shortly after birth that includes hypotonia episodic tachypnea and apnea that may be followed by developmental delays and speech apraxia."
This case report describes episodic tachypnea in JS.
Apnea VERY_RARE Apnea (HP:0002104)
Show evidence (1 reference)
PMID:35860112 SUPPORT Human Clinical
"Clinical features can be noticed shortly after birth that includes hypotonia episodic tachypnea and apnea that may be followed by developmental delays and speech apraxia."
This case report describes apnea in JS.
🧬

Genetic Associations

18
CPLANE1 (Causative)
Show evidence (4 references)
PMID:36580738 SUPPORT Human Clinical
"The most common variants were in the CPLANE1, CEP290, and TMEM67 genes, and other causative genes were AHI1, ARMC9, CEP41, CSPP1, HYLS1, KATNIP, KIAA0586, KIF7, RPGRIP1L, including some previously unreported variants in these genes."
This cohort identifies CPLANE1 among the most common JS genes.
PMID:35092359 SUPPORT Human Clinical
"We identified two novel heterozygous variants of CPLANE1 in the proband first, including c.4459del (frameshift variant) and c.7534-14G > A (intronic variant)."
This study reports pathogenic CPLANE1 variants in a JS patient.
PMID:39725884 SUPPORT Human Clinical
"revealing a pair of compound heterozygous CPLANE1 variants"
This prenatal JS case report links CPLANE1 variants to diagnosis.
+ 1 more reference
CEP290 (Causative)
Show evidence (3 references)
PMID:36580738 SUPPORT Human Clinical
"The most common variants were in the CPLANE1, CEP290, and TMEM67 genes, and other causative genes were AHI1, ARMC9, CEP41, CSPP1, HYLS1, KATNIP, KIAA0586, KIF7, RPGRIP1L, including some previously unreported variants in these genes."
This cohort identifies CEP290 as a common JS gene.
PMID:35238134 SUPPORT Human Clinical
"On the other hand, individuals with causal variants in the CEP290 or AHI1 need a closer surveillance for retinal dystrophy and, in case of CEP290, also for chronic kidney disease."
CEP290 variants are linked to retinal dystrophy risk and chronic kidney disease surveillance.
PMID:33717386 SUPPORT Human Clinical
"Genome sequencing revealed a mutation involving the CEP290 gene that ultimately confirmed the diagnosis of Joubert syndrome."
This case report identifies CEP290 mutation as the cause of JS.
TMEM67 (Causative)
Show evidence (4 references)
PMID:36580738 SUPPORT Human Clinical
"The most common variants were in the CPLANE1, CEP290, and TMEM67 genes, and other causative genes were AHI1, ARMC9, CEP41, CSPP1, HYLS1, KATNIP, KIAA0586, KIF7, RPGRIP1L, including some previously unreported variants in these genes."
This cohort identifies TMEM67 as a common JS gene.
PMID:35238134 SUPPORT Human Clinical
"For instance, JS individuals harboring pathogenic variants in TMEM67 have a significantly higher risk of liver fibrosis, while pathogenic variants in NPHP1, RPGRIP1L, and TMEM237 are frequently associated to JS with renal involvement, requiring a closer monitoring of liver parameters, or renal..."
TMEM67 variants are associated with increased liver fibrosis risk in JS.
PMID:39027323 SUPPORT Human Clinical
"The diagnosis of autosomal recessive Joubert syndrome type 6 due to homozygous pathogenic variant c.725A > G p. (Asn242Ser) in TMEM67 gene was confirmed by whole exome sequencing."
This JS type 6 case confirms a pathogenic TMEM67 variant.
+ 1 more reference
AHI1 (Causative)
Show evidence (2 references)
PMID:35238134 SUPPORT Human Clinical
"On the other hand, individuals with causal variants in the CEP290 or AHI1 need a closer surveillance for retinal dystrophy and, in case of CEP290, also for chronic kidney disease."
This review notes AHI1 variants in JS with retinal dystrophy risk.
PMID:33777383 SUPPORT Human Clinical
"Variants in AHI1 account for ∼7% of Joubert syndrome cases and are associated either with ‘pure’ Joubert syndrome, or Joubert syndrome plus renal and/or retinal disease."
This adult JS case report summarizes AHI1 contribution to JS cases.
ARMC9 (Causative)
Show evidence (1 reference)
PMID:36580738 SUPPORT Human Clinical
"The most common variants were in the CPLANE1, CEP290, and TMEM67 genes, and other causative genes were AHI1, ARMC9, CEP41, CSPP1, HYLS1, KATNIP, KIAA0586, KIF7, RPGRIP1L, including some previously unreported variants in these genes."
This cohort reports ARMC9 among causative JS genes.
CEP41 (Causative)
Show evidence (1 reference)
PMID:36580738 SUPPORT Human Clinical
"The most common variants were in the CPLANE1, CEP290, and TMEM67 genes, and other causative genes were AHI1, ARMC9, CEP41, CSPP1, HYLS1, KATNIP, KIAA0586, KIF7, RPGRIP1L, including some previously unreported variants in these genes."
This cohort reports CEP41 among causative JS genes.
CSPP1 (Causative)
Show evidence (2 references)
PMID:36580738 SUPPORT Human Clinical
"The most common variants were in the CPLANE1, CEP290, and TMEM67 genes, and other causative genes were AHI1, ARMC9, CEP41, CSPP1, HYLS1, KATNIP, KIAA0586, KIF7, RPGRIP1L, including some previously unreported variants in these genes."
This cohort reports CSPP1 among causative JS genes.
PMID:40898267 SUPPORT Human Clinical
"Pathogenic CSPP1 variants account for approximately 3% of Joubert syndrome cases."
This case report notes CSPP1 pathogenic variants contribute to JS, supporting CSPP1 as a causative gene.
HYLS1 (Causative)
Show evidence (1 reference)
PMID:36580738 SUPPORT Human Clinical
"The most common variants were in the CPLANE1, CEP290, and TMEM67 genes, and other causative genes were AHI1, ARMC9, CEP41, CSPP1, HYLS1, KATNIP, KIAA0586, KIF7, RPGRIP1L, including some previously unreported variants in these genes."
This cohort reports HYLS1 among causative JS genes.
KATNIP (Causative)
Show evidence (1 reference)
PMID:36580738 SUPPORT Human Clinical
"The most common variants were in the CPLANE1, CEP290, and TMEM67 genes, and other causative genes were AHI1, ARMC9, CEP41, CSPP1, HYLS1, KATNIP, KIAA0586, KIF7, RPGRIP1L, including some previously unreported variants in these genes."
This cohort reports KATNIP among causative JS genes.
KIAA0586 (Causative)
Show evidence (4 references)
PMID:36580738 SUPPORT Human Clinical
"The most common variants were in the CPLANE1, CEP290, and TMEM67 genes, and other causative genes were AHI1, ARMC9, CEP41, CSPP1, HYLS1, KATNIP, KIAA0586, KIF7, RPGRIP1L, including some previously unreported variants in these genes."
This cohort reports KIAA0586 among causative JS genes.
PMID:36788019 SUPPORT Human Clinical
"Two recurrent variants (MKS1 c.1476T>G and KIAA0586 c.428delG), have been detected in homozygosity in unaffected individuals, suggesting they could act as hypomorphic variants."
This study identifies recurrent KIAA0586 variants in JS cohorts.
PMID:40951761 SUPPORT In Vitro
"Variants in KIAA0586/TALPID3 are associated with the ciliopathy Joubert syndrome (JS), which is a genetically heterogeneous disorder."
This study links KIAA0586/TALPID3 variants to JS.
+ 1 more reference
KIF7 (Causative)
Show evidence (1 reference)
PMID:36580738 SUPPORT Human Clinical
"The most common variants were in the CPLANE1, CEP290, and TMEM67 genes, and other causative genes were AHI1, ARMC9, CEP41, CSPP1, HYLS1, KATNIP, KIAA0586, KIF7, RPGRIP1L, including some previously unreported variants in these genes."
This cohort reports KIF7 among causative JS genes.
RPGRIP1L (Causative)
Show evidence (4 references)
PMID:36580738 SUPPORT Human Clinical
"The most common variants were in the CPLANE1, CEP290, and TMEM67 genes, and other causative genes were AHI1, ARMC9, CEP41, CSPP1, HYLS1, KATNIP, KIAA0586, KIF7, RPGRIP1L, including some previously unreported variants in these genes."
This cohort reports RPGRIP1L among causative JS genes.
PMID:38013309 SUPPORT Human Clinical
"Joubert syndrome 7 is caused by mutations in the RPGRIP1L gene."
This case report highlights RPGRIP1L as a JS gene.
PMID:37547106 SUPPORT Human Clinical
"RPGRIP1l: c.1351-11A > G; CEP120: c.214 C > T(p.Arg72Cys)."
This cohort reports RPGRIP1L variants in JS.
+ 1 more reference
MKS1 (Causative)
Show evidence (1 reference)
PMID:36788019 SUPPORT Human Clinical
"Two recurrent variants (MKS1 c.1476T>G and KIAA0586 c.428delG), have been detected in homozygosity in unaffected individuals, suggesting they could act as hypomorphic variants."
This study reports recurrent MKS1 variants in JS cohorts.
CC2D2A (Causative)
Show evidence (1 reference)
PMID:36319078 SUPPORT Human Clinical
"cohort of patients with Joubert syndrome (JS) carrying pathogenic variants on one of the most frequent causative genes, CC2D2A."
This study focuses on CC2D2A-related JS with pathogenic variants.
OFD1 (Causative)
Show evidence (1 reference)
PMID:36704348 SUPPORT Human Clinical
"We identified a novel non-sense variant in the OFD1 gene, OFD1 (NM_003611.3): c.2848A>T (p.Lys950Ter)."
This study reports a pathogenic OFD1 variant in JS.
TCTN1 (Causative)
Show evidence (1 reference)
PMID:34980503 SUPPORT Human Clinical
"Joubert syndrome attributed to variants in the TCTN1 (NM_001082538.2) gene has been only described in two reports."
This case report supports TCTN1 as a JS gene.
CEP120 (Causative)
Show evidence (1 reference)
PMID:37547106 SUPPORT Human Clinical
"RPGRIP1l: c.1351-11A > G; CEP120: c.214 C > T(p.Arg72Cys)."
This cohort reports a CEP120 variant associated with JS.
TOPORS (Causative)
Show evidence (1 reference)
PMID:37227088 SUPPORT Human Clinical
"Our data nominates TOPORS as a novel causal gene for JBTS"
This study identifies TOPORS as a novel JS gene.
💊

Treatments

8
Supportive care MAXO:0000950
Conservative symptomatic management for neurodevelopmental features.
Show evidence (1 reference)
PMID:36484066 SUPPORT Human Clinical
"Patient was managed conservatively with symptomatic treatment."
This case report indicates conservative symptomatic management in JS.
Physical therapy MAXO:0000011
Physical therapy to promote psychomotor development.
Show evidence (1 reference)
PMID:37288221 SUPPORT Human Clinical
"All patients received physical, occupational, and speech-language-hearing therapy, depending on their symptoms and conditions."
This case series describes physical therapy in JS rehabilitation.
Occupational therapy MAXO:0001351
Occupational therapy to support functional independence.
Show evidence (1 reference)
PMID:37288221 SUPPORT Human Clinical
"All patients received physical, occupational, and speech-language-hearing therapy, depending on their symptoms and conditions."
This case series describes occupational therapy in JS rehabilitation.
Speech therapy MAXO:0000930
Speech-language therapy for communication and swallowing support.
Show evidence (1 reference)
PMID:37288221 SUPPORT Human Clinical
"All patients received physical, occupational, and speech-language-hearing therapy, depending on their symptoms and conditions."
This case series describes speech-language therapy in JS rehabilitation.
Orthotic device usage MAXO:0000482
Orthotic intervention for hypotonia and ataxia.
Show evidence (1 reference)
PMID:37288221 SUPPORT Human Clinical
"For hypotonia and ataxia, an orthotic intervention was considered in all three cases, and foot or ankle-foot orthoses were used in two cases."
This case series reports orthotic device usage to address hypotonia and ataxia.
Genetic counseling MAXO:0000079
Counseling for families to support management planning and recurrence risk discussion.
Show evidence (1 reference)
PMID:37490694 SUPPORT Human Clinical
"The early diagnosis of Joubert syndrome is reflected in better pediatric follow-up, which impacts its prognosis and the possibility of improving the patient's quality of life with a multidisciplinary management and genetic counseling."
The case report highlights genetic counseling as part of care that improves quality of life.
Liver transplantation MAXO:0001175
Treatment for severe portal hypertension in COACH syndrome (Joubert syndrome with congenital hepatic fibrosis).
Show evidence (1 reference)
PMID:37965976 SUPPORT Human Clinical
"LT should be considered an effective treatment for COACH syndrome in patients with severe portal hypertension."
The review concludes that liver transplantation is effective for JS patients with congenital hepatic fibrosis and portal hypertension.
Nasobiliary drainage
Procedural management for refractory cholestatic pruritus in JS with hepatic involvement.
Show evidence (1 reference)
PMID:37799488 SUPPORT Human Clinical
"Nasobiliary drainage is a relatively safe and effective method for treating intractable cholestatic pruritus."
This case report describes nasobiliary drainage for refractory cholestatic pruritus in JS.
🔬

Biochemical Markers

4
Urea (Elevated)
Context: Renal involvement with elevated urea in a neonatal JS case.
Show evidence (1 reference)
PMID:33717386 SUPPORT Human Clinical
"elevated levels of urea and creatinine were detected"
This neonatal JS case report documents elevated urea.
Creatinine (Elevated)
Context: Renal involvement with elevated creatinine in a neonatal JS case.
Show evidence (2 references)
PMID:33717386 SUPPORT Human Clinical
"elevated levels of urea and creatinine were detected"
This neonatal JS case report documents elevated creatinine.
PMID:33777383 SUPPORT Human Clinical
"Her eGFR at the age of 51 years was 57 mL/min/1.73 m2"
This adult JS case report provides serum creatinine levels with reduced eGFR.
Estimated glomerular filtration rate (Decreased)
Context: Progressive renal dysfunction in an adult JS case.
Show evidence (1 reference)
PMID:33777383 SUPPORT Human Clinical
"This had steadily declined to 24 mL/min/1.73 m2 (S creatinine 189 µmol/L) at first nephrology assessment."
The reported eGFR indicates decreased renal function in JS.
Urine protein-to-creatinine ratio (Elevated)
Context: Renal involvement with proteinuria in an adult JS case.
Show evidence (1 reference)
PMID:33777383 SUPPORT Human Clinical
"urine protein–creatinine ratio was 67 mg/mmol."
This indicates proteinuria in a JS case with renal disease.
🔀

Differential Diagnoses

5

Conditions with similar clinical presentations that must be differentiated from Joubert syndrome:

Nephronophthisis MONDO:0019005
Overlapping Features Ciliopathy with overlapping features that can resemble Joubert syndrome.
Distinguishing Features
  • Predominant renal involvement without the classic molar tooth sign on MRI.
  • Progressive tubulointerstitial kidney disease is the primary presentation.
Show evidence (1 reference)
PMID:36803942 SUPPORT Human Clinical
"Such pleiotropic characteristics are typical of many disorders involving primary cilium aberrations, providing a significant overlap between JS and other ciliopathies such as nephronophthisis, Meckel syndrome, and Bardet-Biedl syndrome."
The review notes overlap between JS and nephronophthisis, supporting it as a differential diagnosis.
Meckel syndrome MONDO:0018921
Overlapping Features Ciliopathy with overlapping features that can resemble Joubert syndrome.
Distinguishing Features
  • Severe, typically lethal ciliopathy with encephalocele and renal cystic dysplasia.
  • Presents prenatally with multiple congenital anomalies.
Show evidence (1 reference)
PMID:36803942 SUPPORT Human Clinical
"Such pleiotropic characteristics are typical of many disorders involving primary cilium aberrations, providing a significant overlap between JS and other ciliopathies such as nephronophthisis, Meckel syndrome, and Bardet-Biedl syndrome."
The review notes overlap between JS and Meckel syndrome, supporting it as a differential diagnosis.
Bardet-Biedl syndrome MONDO:0015229
Overlapping Features Ciliopathy with overlapping features that can resemble Joubert syndrome.
Distinguishing Features
  • Postaxial polydactyly, obesity, and retinal dystrophy without molar tooth sign.
  • Cognitive impairment and renal anomalies may occur but brainstem malformation is not typical.
Show evidence (1 reference)
PMID:36803942 SUPPORT Human Clinical
"Such pleiotropic characteristics are typical of many disorders involving primary cilium aberrations, providing a significant overlap between JS and other ciliopathies such as nephronophthisis, Meckel syndrome, and Bardet-Biedl syndrome."
The review notes overlap between JS and Bardet-Biedl syndrome, supporting it as a differential diagnosis.
Senior-Loken syndrome Not Yet Curated MONDO:0017842
Overlapping Features Ciliopathy with renal and retinal involvement that can overlap with JS.
Distinguishing Features
  • Predominant nephronophthisis with retinal dystrophy.
  • Lacks the molar tooth sign typical of JS.
Show evidence (1 reference)
PMID:33717386 SUPPORT Human Clinical
"This would explain the frequent association between CEP290 mutations and Joubert syndrome with renal involvement, as well as other syndromes such as Senior-Loken, Meckel, Bardet-Biedl with overlapping clinical features"
This case report notes overlapping features between JS and Senior-Loken syndrome.
Dandy-Walker syndrome Not Yet Curated MONDO:0009072
Overlapping Features Posterior fossa malformation that can mimic JS on initial imaging.
Distinguishing Features
  • Cystic dilation of the fourth ventricle and enlarged posterior fossa.
  • Absence of the molar tooth sign differentiates it from JS.
Show evidence (1 reference)
PMID:33717386 SUPPORT Human Clinical
"Initially a diagnosis of Dandy Walker malformation with no clear signs of obstruction of the foramen magnum was suspected"
This case report shows Dandy-Walker considered in the differential before JS was confirmed.
📊

Related Datasets

2
Joubert Syndrome-derived induced pluripotent stem cells show altered neuronal differentiation in vitro GEO:GSE254556
Transcriptomic profiling of JS patient-derived iPSC neuronal differentiation (mid-hindbrain precursors and cerebellar granule cells) compared with controls.
human BULK RNA SEQ GEO
Conditions: Joubert syndrome iPSC-derived neuronal differentiation
PMID:38502237
Show evidence (1 reference)
GEO:GSE254556 SUPPORT In Vitro
"Differentiation was monitored over 31 days through the detection of lineage-specific marker expression by qRT-PCR, immunofluorescence, and transcriptomics analysis."
This GEO dataset contains transcriptomic analysis of JS iPSC differentiation.
Variable phenotypes and penetrance between and within different zebrafish transition zone mutants GEO:GSE217001
Transcriptomic profiling of zebrafish transition zone mutants used to model ciliopathy phenotypes relevant to Joubert syndrome.
zebrafish BULK RNA SEQ GEO
Conditions: Joubert syndrome zebrafish transition zone mutants
PMID:36533556
Show evidence (1 reference)
GEO:GSE217001 SUPPORT Model Organism
"Meckel Syndrome, Nephronophthisis, Joubert Syndrome, and Bardet-Biedl Syndrome have mutations in proteins that localize to the ciliary transition zone (TZ)."
This GEO series centers on transition zone mutants relevant to Joubert syndrome and other ciliopathies.
🔬

Clinical Trials

3
NCT01401998 NOT_APPLICABLE RECRUITING
Registry and biospecimen resource for hepato-renal fibrocystic diseases including Joubert syndrome to support clinical and genetic data sharing.
Show evidence (1 reference)
clinicaltrials:NCT01401998 SUPPORT Human Clinical
"Hepato-renal fibrocystic diseases (HRFD) is a term developed that encompasses rare diseases such as Autosomal Recessive Polycystic Kidney Disease (ARPKD), and other diseases with common features (Joubert syndrome, Bardet Biedl syndrome, Meckel-Gruber syndrome, congenital hepatic fibrosis (CHF),..."
This registry explicitly includes Joubert syndrome among HRFD conditions.
NCT00873678 NOT_APPLICABLE COMPLETED
Genetic prevalence study of AHI1, NPHP1, and CEP290 in Joubert syndrome and cerebello-oculo-renal syndromes.
Show evidence (1 reference)
clinicaltrials:NCT00873678 SUPPORT Human Clinical
"assessment of the prevalence of AHI1 mutations in Joubert syndrome and cerebello-oculo-renal syndromes (JS/CORS)"
This study targets Joubert syndrome genetic prevalence.
NCT04874909 NOT_APPLICABLE UNKNOWN
Ciliopathy stratification study aimed at developing diagnostic and prognostic biomarkers for renal outcomes.
Show evidence (1 reference)
clinicaltrials:NCT04874909 SUPPORT Human Clinical
"The purpose of the C'IL-LICO RICM study is to develop innovative and transformative diagnostic and prognostic for patients suffering from ciliopathies leading to renal failure."
This study focuses on ciliopathy-related renal prognosis and biomarker development.
{ }

Source YAML

click to show 
name: Joubert syndrome
creation_date: '2026-01-28T21:44:07Z'
updated_date: '2026-02-02T19:28:32Z'
description: >-
  Joubert syndrome is a rare neurodevelopmental ciliopathy with a characteristic
  molar tooth sign on brain MRI and multisystem involvement affecting the
  nervous system, eyes, kidneys, liver, and skeleton.
category: Genetic
parents:
- Neurodevelopmental Disorder
- Ciliopathy
disease_term:
  term:
    id: MONDO:0018772
    label: Joubert syndrome
  preferred_term: Joubert syndrome
has_subtypes:
- name: Joubert syndrome 1
  subtype_term:
    preferred_term: Joubert syndrome 1
    term:
      id: MONDO:0008944
      label: Joubert syndrome 1
- name: Joubert syndrome 2
  subtype_term:
    preferred_term: Joubert syndrome 2
    term:
      id: MONDO:0011963
      label: Joubert syndrome 2
- name: Joubert syndrome 3
  subtype_term:
    preferred_term: Joubert syndrome 3
    term:
      id: MONDO:0012078
      label: Joubert syndrome 3
- name: Joubert syndrome with renal defect
  subtype_term:
    preferred_term: Joubert syndrome with renal defect
    term:
      id: MONDO:0012308
      label: Joubert syndrome with renal defect
- name: Joubert syndrome 5
  subtype_term:
    preferred_term: Joubert syndrome 5
    term:
      id: MONDO:0012432
      label: Joubert syndrome 5
- name: Joubert syndrome 6
  subtype_term:
    preferred_term: Joubert syndrome 6
    term:
      id: MONDO:0012539
      label: Joubert syndrome 6
- name: Joubert syndrome 7
  subtype_term:
    preferred_term: Joubert syndrome 7
    term:
      id: MONDO:0012694
      label: Joubert syndrome 7
- name: Joubert syndrome 9
  subtype_term:
    preferred_term: Joubert syndrome 9
    term:
      id: MONDO:0012849
      label: Joubert syndrome 9
- name: Joubert syndrome 8
  subtype_term:
    preferred_term: Joubert syndrome 8
    term:
      id: MONDO:0012855
      label: Joubert syndrome 8
- name: Joubert syndrome 13
  subtype_term:
    preferred_term: Joubert syndrome 13
    term:
      id: MONDO:0013608
      label: Joubert syndrome 13
- name: Joubert syndrome 14
  subtype_term:
    preferred_term: Joubert syndrome 14
    term:
      id: MONDO:0013745
      label: Joubert syndrome 14
- name: Joubert syndrome 15
  subtype_term:
    preferred_term: Joubert syndrome 15
    term:
      id: MONDO:0013763
      label: Joubert syndrome 15
- name: Joubert syndrome 16
  subtype_term:
    preferred_term: Joubert syndrome 16
    term:
      id: MONDO:0013764
      label: Joubert syndrome 16
- name: Joubert syndrome 17
  subtype_term:
    preferred_term: Joubert syndrome 17
    term:
      id: MONDO:0013824
      label: Joubert syndrome 17
- name: Joubert syndrome 18
  subtype_term:
    preferred_term: Joubert syndrome 18
    term:
      id: MONDO:0013896
      label: Joubert syndrome 18
  description: Joubert syndrome caused by mutation in TCTN3.
- name: Joubert syndrome 20
  subtype_term:
    preferred_term: Joubert syndrome 20
    term:
      id: MONDO:0013994
      label: Joubert syndrome 20
- name: Joubert syndrome 21
  subtype_term:
    preferred_term: Joubert syndrome 21
    term:
      id: MONDO:0014288
      label: Joubert syndrome 21
- name: Joubert syndrome 22
  subtype_term:
    preferred_term: Joubert syndrome 22
    term:
      id: MONDO:0014297
      label: Joubert syndrome 22
- name: Joubert syndrome 23
  subtype_term:
    preferred_term: Joubert syndrome 23
    term:
      id: MONDO:0014664
      label: Joubert syndrome 23
- name: Joubert syndrome 24
  subtype_term:
    preferred_term: Joubert syndrome 24
    term:
      id: MONDO:0014724
      label: Joubert syndrome 24
- name: Joubert syndrome 25
  subtype_term:
    preferred_term: Joubert syndrome 25
    term:
      id: MONDO:0014770
      label: Joubert syndrome 25
- name: Joubert syndrome 26
  subtype_term:
    preferred_term: Joubert syndrome 26
    term:
      id: MONDO:0014771
      label: Joubert syndrome 26
- name: Joubert syndrome 27
  subtype_term:
    preferred_term: Joubert syndrome 27
    term:
      id: MONDO:0014927
      label: Joubert syndrome 27
- name: Joubert syndrome 28
  subtype_term:
    preferred_term: Joubert syndrome 28
    term:
      id: MONDO:0014928
      label: Joubert syndrome 28
- name: Joubert syndrome 38
  subtype_term:
    preferred_term: Joubert syndrome 38
    term:
      id: MONDO:0030353
      label: Joubert syndrome 38
- name: Joubert syndrome 39
  subtype_term:
    preferred_term: Joubert syndrome 39
    term:
      id: MONDO:0030454
      label: Joubert syndrome 39
- name: Joubert syndrome 40
  subtype_term:
    preferred_term: Joubert syndrome 40
    term:
      id: MONDO:0030462
      label: Joubert syndrome 40
- name: Joubert syndrome 37
  subtype_term:
    preferred_term: Joubert syndrome 37
    term:
      id: MONDO:0030933
      label: Joubert syndrome 37
- name: Joubert syndrome 35
  subtype_term:
    preferred_term: Joubert syndrome 35
    term:
      id: MONDO:0032570
      label: Joubert syndrome 35
- name: Joubert syndrome 36
  subtype_term:
    preferred_term: Joubert syndrome 36
    term:
      id: MONDO:0032902
      label: Joubert syndrome 36
- name: Joubert syndrome 30
  subtype_term:
    preferred_term: Joubert syndrome 30
    term:
      id: MONDO:0033308
      label: Joubert syndrome 30
- name: Joubert syndrome 32
  subtype_term:
    preferred_term: Joubert syndrome 32
    term:
      id: MONDO:0033309
      label: Joubert syndrome 32
- name: Joubert syndrome 31
  subtype_term:
    preferred_term: Joubert syndrome 31
    term:
      id: MONDO:0033310
      label: Joubert syndrome 31
- name: Joubert syndrome 33
  subtype_term:
    preferred_term: Joubert syndrome 33
    term:
      id: MONDO:0033311
      label: Joubert syndrome 33
- name: Joubert syndrome 19
  subtype_term:
    preferred_term: Joubert syndrome 19
    term:
      id: MONDO:0800363
      label: Joubert syndrome 19
- name: Joubert syndrome 29
  subtype_term:
    preferred_term: Joubert syndrome 29
    term:
      id: MONDO:0800372
      label: Joubert syndrome 29
- name: Joubert syndrome 11
  subtype_term:
    preferred_term: Joubert syndrome 11
    term:
      id: MONDO:0800382
      label: Joubert syndrome 11
- name: Joubert syndrome 34
  subtype_term:
    preferred_term: Joubert syndrome 34
    term:
      id: MONDO:0800383
      label: Joubert syndrome 34
prevalence:
- population: Global infants
  percentage: 1 in 80,000-100,000 infants per year
  evidence:
  - reference: PMID:40537162
    supports: SUPPORT
    snippet: "Joubert syndrome (JS) is a rare neurodevelopmental and multisystem ciliopathy that affects 1 in 80,000-10,0000 infants globally per year."
    explanation: This review provides a global prevalence estimate for JS.
    evidence_source: HUMAN_CLINICAL
- population: Reported prevalence
  percentage: 1:80,000-1:100,000
  evidence:
  - reference: PMID:37490694
    supports: SUPPORT
    snippet: "Joubert syndrome is a rare genetic condition with a prevalence of 1:80,000-1:100,000."
    explanation: This case report reiterates the commonly cited prevalence range.
    evidence_source: HUMAN_CLINICAL
epidemiology:
- name: Growth cohort size
  description: >-
    The largest published growth cohort in JS includes 170 individuals, which
    provides a benchmark for phenotypic and growth data but is not population
    prevalence.
  evidence:
  - reference: PMID:34951506
    supports: SUPPORT
    snippet: "Prospective growth and measurement data on 170 individuals with JS were collected, including parental measurements, birth measurements, and serial measures when available."
    explanation: This large cohort size helps contextualize epidemiologic descriptions but does not represent population prevalence.
    evidence_source: HUMAN_CLINICAL
- name: Consanguinity and family impact cohort
  description: >-
    Cross-sectional study of 49 parents of children with JS in Turkey reported
    high consanguinity rates and limited genetic screening uptake.
  evidence:
  - reference: PMID:40750754
    supports: SUPPORT
    snippet: "A descriptive, cross-sectional study was conducted with 49 parents of children with JS in Turkey."
    explanation: This provides the cohort context for family impact measures in JS.
    evidence_source: HUMAN_CLINICAL
  - reference: PMID:40750754
    supports: SUPPORT
    snippet: "Consanguineous marriage was reported by 61.2% of families, yet only 8.2% underwent genetic screening, emphasizing the importance of genetic counseling."
    explanation: This quantifies consanguinity and genetic screening uptake in a JS cohort.
    evidence_source: HUMAN_CLINICAL
inheritance:
- name: Autosomal Recessive
  description: >-
    Joubert syndrome is typically inherited in an autosomal recessive pattern,
    though an X-linked recessive form (Joubert syndrome 10, OFD1 on Xp22.2)
    exists.
  evidence:
  - reference: PMID:36803942
    supports: SUPPORT
    snippet: "Joubert syndrome (JS; MIM PS213300) is a rare genetic autosomal recessive disease characterized by cerebellar vermis hypoplasia, a distinctive malformation of the cerebellum and the so-called \"molar tooth sign.\""
    explanation: This statement explicitly describes autosomal recessive inheritance.
    evidence_source: HUMAN_CLINICAL
- name: X-linked recessive
  description: >-
    Joubert syndrome 10 is an X-linked recessive form caused by OFD1 mutations
    on Xp22.2.
  evidence:
  - reference: PMID:31373179
    supports: SUPPORT
    snippet: "pathogenic variants in OFD1 were found to be associated with X-linked intellectual disability, Joubert syndrome type 10 (JBTS10),"
    explanation: This review links OFD1 pathogenic variants to Joubert syndrome 10 in an X-linked context.
    evidence_source: HUMAN_CLINICAL
  - reference: PMID:31373179
    supports: SUPPORT
    snippet: "OFD1, residing on chromosome Xp22.2,"
    explanation: This provides the OFD1 locus on Xp22.2 supporting X-linked inheritance.
    evidence_source: HUMAN_CLINICAL
pathophysiology:
- name: Ciliary gene mutations disrupt primary cilium assembly
  description: >-
    Causative JS genes encode proteins required for primary cilium structure
    and assembly, disrupting cilium biogenesis in vivo.
  biological_processes:
  - preferred_term: cilium assembly
    term:
      id: GO:0060271
      label: cilium assembly
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:38502237
    supports: SUPPORT
    snippet: "Over 40 causative genes have been reported, all encoding for proteins implicated in the structure or functioning of the primary cilium, a subcellular organelle widely present in embryonic and adult tissues."
    explanation: JS genes encode primary cilium components, supporting disrupted cilium assembly.
    evidence_source: IN_VITRO
  - reference: PMID:41165761
    supports: SUPPORT
    snippet: "B9 proteins localized to centrioles prior to ciliogenesis, where they facilitated the initiation of ciliogenesis."
    explanation: This supports impaired ciliogenesis initiation as a core ciliary assembly defect.
    evidence_source: IN_VITRO
- name: Abnormal cilium structure and length
  description: >-
    Primary cilia show abnormal number, morphology, and length in JS models,
    indicating disrupted cilium organization.
  biological_processes:
  - preferred_term: cilium organization
    term:
      id: GO:0044782
      label: cilium organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:38502237
    supports: SUPPORT
    snippet: "In addition, analysis of primary cilium count and morphology showed notable ciliary defects in all differentiating JS patient-derived iPSCs compared to controls."
    explanation: Patient-derived cells show abnormal primary cilium structure.
    evidence_source: IN_VITRO
  - reference: PMID:36802443
    supports: SUPPORT
    snippet: "Deficiency of the minor spliceosome component U4atac snRNA secondarily results in ciliary defects in human and zebrafish."
    explanation: Zebrafish models demonstrate in vivo ciliary defects consistent with abnormal cilium organization.
    evidence_source: MODEL_ORGANISM
  - reference: PMID:39400299
    supports: SUPPORT
    snippet: "We found that JBTS mutants have altered primary cilia throughout the brain."
    explanation: Zebrafish JBTS mutants show altered primary cilia in brain tissue.
    evidence_source: MODEL_ORGANISM
  - reference: PMID:40951761
    supports: SUPPORT
    snippet: "The patient-derived fibroblasts exhibited reduced primary cilia length and altered distribution of PCM1."
    explanation: KIAA0586/TALPID3 variants are associated with reduced cilia length.
    evidence_source: IN_VITRO
- name: Impaired intraciliary transport
  description: >-
    Disruption of ciliary gene products (e.g., CEP290) impairs intraciliary transport
    and cilium maintenance.
  biological_processes:
  - preferred_term: intraciliary transport
    term:
      id: GO:0042073
      label: intraciliary transport
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:33717386
    supports: SUPPORT
    snippet: "Recently, it has been proposed that CEP290 gene product may also play a role in the microtubule-based ciliary transport, in the vesicle transport, the development and maintenance of the cilium"
    explanation: CEP290 dysfunction is linked to impaired intraciliary transport and cilium maintenance.
    evidence_source: HUMAN_CLINICAL
- name: Neurodevelopmental defects
  description: >-
    Disrupted ciliary biology impairs neurodevelopmental programs, contributing
    to mid-hindbrain and cerebellar developmental abnormalities.
  evidence:
  - reference: PMID:38502237
    supports: SUPPORT
    snippet: "All JS patient-derived iPSCs, regardless of the mutant gene, showed a similar impairment to differentiate into mid-hindbrain and cerebellar granule cells when compared to healthy controls."
    explanation: Patient-derived cells show impaired neuronal differentiation relevant to neurodevelopmental defects.
    evidence_source: IN_VITRO
  - reference: PMID:40537162
    supports: SUPPORT
    snippet: "Classic defects include hypoplasia of the cerebellar vermis, thickened cerebellar peduncles, and deepened interpeduncular fossa, which is regarded as a \"molar tooth\" sign."
    explanation: This review describes neurodevelopmental malformations characteristic of JS.
    evidence_source: HUMAN_CLINICAL
phenotypes:
- name: Molar tooth sign on MRI
  category: Neurologic
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Molar tooth sign on MRI
    term:
      id: HP:0002419
      label: Molar tooth sign on MRI
  evidence:
  - reference: PMID:40537162
    supports: SUPPORT
    snippet: "Classic defects include hypoplasia of the cerebellar vermis, thickened cerebellar peduncles, and deepened interpeduncular fossa, which is regarded as a \"molar tooth\" sign."
    explanation: The molar tooth sign is a classic diagnostic feature of JS.
    evidence_source: HUMAN_CLINICAL
- name: Cerebellar vermis hypoplasia
  category: Neurologic
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Cerebellar vermis hypoplasia
    term:
      id: HP:0001320
      label: Cerebellar vermis hypoplasia
  evidence:
  - reference: PMID:40537162
    supports: SUPPORT
    snippet: "Classic defects include hypoplasia of the cerebellar vermis, thickened cerebellar peduncles, and deepened interpeduncular fossa, which is regarded as a \"molar tooth\" sign."
    explanation: This review identifies cerebellar vermis hypoplasia as a classic defect in JS.
    evidence_source: HUMAN_CLINICAL
- name: Hypotonia
  category: Neuromuscular
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:36803942
    supports: SUPPORT
    snippet: "Other characteristic features are hypotonia with lateral ataxia, intellectual disability/mental retardation, oculomotor apraxia, retinal dystrophy, abnormalities in the respiratory system, renal cysts, hepatic fibrosis, and skeletal changes."
    explanation: Hypotonia is listed as a characteristic feature of JS.
    evidence_source: HUMAN_CLINICAL
- name: Ataxia
  category: Neurologic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:36803942
    supports: SUPPORT
    snippet: "Other characteristic features are hypotonia with lateral ataxia, intellectual disability/mental retardation, oculomotor apraxia, retinal dystrophy, abnormalities in the respiratory system, renal cysts, hepatic fibrosis, and skeletal changes."
    explanation: Ataxia is described among characteristic features of JS.
    evidence_source: HUMAN_CLINICAL
- name: Intellectual disability
  category: Neurodevelopmental
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:36803942
    supports: SUPPORT
    snippet: "Other characteristic features are hypotonia with lateral ataxia, intellectual disability/mental retardation, oculomotor apraxia, retinal dystrophy, abnormalities in the respiratory system, renal cysts, hepatic fibrosis, and skeletal changes."
    explanation: Intellectual disability is noted as a characteristic feature.
    evidence_source: HUMAN_CLINICAL
- name: Global developmental delay
  category: Neurodevelopmental
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:38502237
    supports: SUPPORT
    snippet: "Joubert syndrome (JS) is a recessively inherited congenital ataxia characterized by hypotonia, psychomotor delay, abnormal ocular movements, intellectual disability, and a peculiar cerebellar and brainstem malformation, the \"molar tooth sign.\""
    explanation: Psychomotor delay supports global developmental delay in JS.
    evidence_source: IN_VITRO
- name: Speech apraxia
  category: Neurodevelopmental
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: Speech apraxia
    term:
      id: HP:0011098
      label: Speech apraxia
  evidence:
  - reference: PMID:35860112
    supports: SUPPORT
    snippet: "Clinical features can be noticed shortly after birth that includes hypotonia episodic tachypnea and apnea that may be followed by developmental delays and speech apraxia."
    explanation: This case report notes speech apraxia in JS.
    evidence_source: HUMAN_CLINICAL
- name: Abnormality of eye movement
  category: Ophthalmologic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Abnormality of eye movement
    term:
      id: HP:0000496
      label: Abnormality of eye movement
  evidence:
  - reference: PMID:38502237
    supports: SUPPORT
    snippet: "Joubert syndrome (JS) is a recessively inherited congenital ataxia characterized by hypotonia, psychomotor delay, abnormal ocular movements, intellectual disability, and a peculiar cerebellar and brainstem malformation, the \"molar tooth sign.\""
    explanation: Abnormal ocular movements are a defining neurologic-ophthalmologic feature.
    evidence_source: IN_VITRO
- name: Oculomotor apraxia
  category: Ophthalmologic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Oculomotor apraxia
    term:
      id: HP:0000657
      label: Oculomotor apraxia
  evidence:
  - reference: PMID:36803942
    supports: SUPPORT
    snippet: "Other characteristic features are hypotonia with lateral ataxia, intellectual disability/mental retardation, oculomotor apraxia, retinal dystrophy, abnormalities in the respiratory system, renal cysts, hepatic fibrosis, and skeletal changes."
    explanation: Oculomotor apraxia is listed among characteristic JS features.
    evidence_source: HUMAN_CLINICAL
- name: Strabismus
  category: Ophthalmologic
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: PMID:37547106
    supports: SUPPORT
    snippet: "Thirty-four (94.44%) cases had developmental delay, one patient (2.78%) had strabismus, and one patient (2.78%) had intermittent dizziness."
    explanation: This cohort reports strabismus in a small subset of JS patients.
    evidence_source: HUMAN_CLINICAL
- name: Retinal dystrophy
  category: Ophthalmologic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Retinal dystrophy
    term:
      id: HP:0000556
      label: Retinal dystrophy
  evidence:
  - reference: PMID:36803942
    supports: SUPPORT
    snippet: "Other characteristic features are hypotonia with lateral ataxia, intellectual disability/mental retardation, oculomotor apraxia, retinal dystrophy, abnormalities in the respiratory system, renal cysts, hepatic fibrosis, and skeletal changes."
    explanation: Retinal dystrophy is cited as a characteristic feature.
    evidence_source: HUMAN_CLINICAL
- name: Abnormal respiratory system physiology
  category: Respiratory
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Abnormal respiratory system physiology
    term:
      id: HP:0002795
      label: Abnormal respiratory system physiology
  evidence:
  - reference: PMID:36803942
    supports: SUPPORT
    snippet: "Other characteristic features are hypotonia with lateral ataxia, intellectual disability/mental retardation, oculomotor apraxia, retinal dystrophy, abnormalities in the respiratory system, renal cysts, hepatic fibrosis, and skeletal changes."
    explanation: Respiratory system abnormalities are reported among characteristic features.
    evidence_source: HUMAN_CLINICAL
- name: Episodic tachypnea
  category: Respiratory
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: Episodic tachypnea
    term:
      id: HP:0002876
      label: Episodic tachypnea
  evidence:
  - reference: PMID:35860112
    supports: SUPPORT
    snippet: "Clinical features can be noticed shortly after birth that includes hypotonia episodic tachypnea and apnea that may be followed by developmental delays and speech apraxia."
    explanation: This case report describes episodic tachypnea in JS.
    evidence_source: HUMAN_CLINICAL
- name: Apnea
  category: Respiratory
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: Apnea
    term:
      id: HP:0002104
      label: Apnea
  evidence:
  - reference: PMID:35860112
    supports: SUPPORT
    snippet: "Clinical features can be noticed shortly after birth that includes hypotonia episodic tachypnea and apnea that may be followed by developmental delays and speech apraxia."
    explanation: This case report describes apnea in JS.
    evidence_source: HUMAN_CLINICAL
- name: Renal cyst
  category: Renal
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Renal cyst
    term:
      id: HP:0000107
      label: Renal cyst
  evidence:
  - reference: PMID:36803942
    supports: SUPPORT
    snippet: "Other characteristic features are hypotonia with lateral ataxia, intellectual disability/mental retardation, oculomotor apraxia, retinal dystrophy, abnormalities in the respiratory system, renal cysts, hepatic fibrosis, and skeletal changes."
    explanation: Renal cysts are reported as part of the JS phenotype spectrum.
    evidence_source: HUMAN_CLINICAL
- name: Nephronophthisis
  category: Renal
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Nephronophthisis
    term:
      id: HP:0000090
      label: Nephronophthisis
  evidence:
  - reference: PMID:36580738
    supports: SUPPORT
    snippet: "Portal hypertension and esophageal varices as liver and polycystic kidney disease and nephronophthisis as kidney involvement was encountered in our patients."
    explanation: This cohort reports nephronophthisis as kidney involvement in JS.
    evidence_source: HUMAN_CLINICAL
- name: Hepatic fibrosis
  category: Hepatic
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Hepatic fibrosis
    term:
      id: HP:0001395
      label: Hepatic fibrosis
  evidence:
  - reference: PMID:36803942
    supports: SUPPORT
    snippet: "Other characteristic features are hypotonia with lateral ataxia, intellectual disability/mental retardation, oculomotor apraxia, retinal dystrophy, abnormalities in the respiratory system, renal cysts, hepatic fibrosis, and skeletal changes."
    explanation: Hepatic fibrosis is reported among characteristic JS features.
    evidence_source: HUMAN_CLINICAL
- name: Portal hypertension
  category: Hepatic
  frequency: RARE
  phenotype_term:
    preferred_term: Portal hypertension
    term:
      id: HP:0001409
      label: Portal hypertension
  evidence:
  - reference: PMID:36580738
    supports: SUPPORT
    snippet: "Portal hypertension and esophageal varices as liver and polycystic kidney disease and nephronophthisis as kidney involvement was encountered in our patients."
    explanation: Portal hypertension was reported as a liver involvement in this cohort.
    evidence_source: HUMAN_CLINICAL
- name: Esophageal varix
  category: Gastrointestinal
  frequency: RARE
  phenotype_term:
    preferred_term: Esophageal varix
    term:
      id: HP:0002040
      label: Esophageal varix
  evidence:
  - reference: PMID:36580738
    supports: SUPPORT
    snippet: "Portal hypertension and esophageal varices as liver and polycystic kidney disease and nephronophthisis as kidney involvement was encountered in our patients."
    explanation: Esophageal varices were observed in JS patients in this cohort.
    evidence_source: HUMAN_CLINICAL
- name: Abnormality of the skeletal system
  category: Skeletal
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Abnormality of the skeletal system
    term:
      id: HP:0000924
      label: Abnormality of the skeletal system
  evidence:
  - reference: PMID:36803942
    supports: SUPPORT
    snippet: "Other characteristic features are hypotonia with lateral ataxia, intellectual disability/mental retardation, oculomotor apraxia, retinal dystrophy, abnormalities in the respiratory system, renal cysts, hepatic fibrosis, and skeletal changes."
    explanation: Skeletal changes are included in the JS phenotype spectrum.
    evidence_source: HUMAN_CLINICAL
- name: Dysphagia
  category: Gastrointestinal
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: PMID:35602833
    supports: SUPPORT
    snippet: "Here, we present the case of a 20-year-old patient who presented with a new onset of dysphagia that led to a diagnosis of JS."
    explanation: This adult JS case report highlights dysphagia as a presenting symptom.
    evidence_source: HUMAN_CLINICAL
- name: Seizure
  category: Neurologic
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:33717386
    supports: SUPPORT
    snippet: "presenting with dyspnea, cyanosis, signs of respiratory distress and seizures."
    explanation: This neonatal case report documents seizures in JS.
    evidence_source: HUMAN_CLINICAL
- name: Sleep apnea
  category: Respiratory
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: Sleep apnea
    term:
      id: HP:0010535
      label: Sleep apnea
  evidence:
  - reference: PMID:36052101
    supports: SUPPORT
    snippet: "was referred to the Sleep Unit because spells of apnea while sleeping."
    explanation: This case report describes sleep apnea in a JS patient.
    evidence_source: HUMAN_CLINICAL
- name: Polydactyly
  category: Skeletal
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: Polydactyly
    term:
      id: HP:0010442
      label: Polydactyly
  evidence:
  - reference: PMID:38013309
    supports: SUPPORT
    snippet: "Resection was performed to correct the polydactyly."
    explanation: This JS case report documents polydactyly requiring surgical correction.
    evidence_source: HUMAN_CLINICAL
biochemical:
- name: Urea
  presence: Elevated
  context: Renal involvement with elevated urea in a neonatal JS case.
  biomarker_term:
    preferred_term: urea
    term:
      id: CHEBI:16199
      label: urea
  evidence:
  - reference: PMID:33717386
    supports: SUPPORT
    snippet: "elevated levels of urea and creatinine were detected"
    explanation: This neonatal JS case report documents elevated urea.
    evidence_source: HUMAN_CLINICAL
- name: Creatinine
  presence: Elevated
  context: Renal involvement with elevated creatinine in a neonatal JS case.
  biomarker_term:
    preferred_term: creatinine
    term:
      id: CHEBI:16737
      label: creatinine
  evidence:
  - reference: PMID:33717386
    supports: SUPPORT
    snippet: "elevated levels of urea and creatinine were detected"
    explanation: This neonatal JS case report documents elevated creatinine.
    evidence_source: HUMAN_CLINICAL
  - reference: PMID:33777383
    supports: SUPPORT
    snippet: "Her eGFR at the age of 51 years was 57 mL/min/1.73 m2"
    explanation: This adult JS case report provides serum creatinine levels with reduced eGFR.
    evidence_source: HUMAN_CLINICAL
- name: Estimated glomerular filtration rate
  presence: Decreased
  context: Progressive renal dysfunction in an adult JS case.
  evidence:
  - reference: PMID:33777383
    supports: SUPPORT
    snippet: "This had steadily declined to 24 mL/min/1.73 m2 (S creatinine 189 µmol/L) at first nephrology assessment."
    explanation: The reported eGFR indicates decreased renal function in JS.
    evidence_source: HUMAN_CLINICAL
- name: Urine protein-to-creatinine ratio
  presence: Elevated
  context: Renal involvement with proteinuria in an adult JS case.
  evidence:
  - reference: PMID:33777383
    supports: SUPPORT
    snippet: "urine protein–creatinine ratio was 67 mg/mmol."
    explanation: This indicates proteinuria in a JS case with renal disease.
    evidence_source: HUMAN_CLINICAL
genetic:
- name: CPLANE1
  association: Causative
  evidence:
  - reference: PMID:36580738
    supports: SUPPORT
    snippet: "The most common variants were in the CPLANE1, CEP290, and TMEM67 genes, and other causative genes were AHI1, ARMC9, CEP41, CSPP1, HYLS1, KATNIP, KIAA0586, KIF7, RPGRIP1L, including some previously unreported variants in these genes."
    explanation: This cohort identifies CPLANE1 among the most common JS genes.
    evidence_source: HUMAN_CLINICAL
  - reference: PMID:35092359
    supports: SUPPORT
    snippet: "We identified two novel heterozygous variants of CPLANE1 in the proband first, including c.4459del (frameshift variant) and c.7534-14G > A (intronic variant)."
    explanation: This study reports pathogenic CPLANE1 variants in a JS patient.
    evidence_source: HUMAN_CLINICAL
  - reference: PMID:39725884
    supports: SUPPORT
    snippet: "revealing a pair of compound heterozygous CPLANE1 variants"
    explanation: This prenatal JS case report links CPLANE1 variants to diagnosis.
    evidence_source: HUMAN_CLINICAL
  - reference: PMID:33794348
    supports: SUPPORT
    snippet: "The whole exome sequencing identified a novel compound heterozygous variation in the CPLANE1 gene related with Joubert syndrome"
    explanation: This prenatal case report identifies CPLANE1 variants causing JS.
    evidence_source: HUMAN_CLINICAL
  gene_term:
    preferred_term: CPLANE1
    term:
      id: hgnc:25801
      label: CPLANE1
- name: CEP290
  association: Causative
  evidence:
  - reference: PMID:36580738
    supports: SUPPORT
    snippet: "The most common variants were in the CPLANE1, CEP290, and TMEM67 genes, and other causative genes were AHI1, ARMC9, CEP41, CSPP1, HYLS1, KATNIP, KIAA0586, KIF7, RPGRIP1L, including some previously unreported variants in these genes."
    explanation: This cohort identifies CEP290 as a common JS gene.
    evidence_source: HUMAN_CLINICAL
  - reference: PMID:35238134
    supports: SUPPORT
    snippet: "On the other hand, individuals with causal variants in the CEP290 or AHI1 need a closer surveillance for retinal dystrophy and, in case of CEP290, also for chronic kidney disease."
    explanation: CEP290 variants are linked to retinal dystrophy risk and chronic kidney disease surveillance.
    evidence_source: HUMAN_CLINICAL
  - reference: PMID:33717386
    supports: SUPPORT
    snippet: "Genome sequencing revealed a mutation involving the CEP290 gene that ultimately confirmed the diagnosis of Joubert syndrome."
    explanation: This case report identifies CEP290 mutation as the cause of JS.
    evidence_source: HUMAN_CLINICAL
  gene_term:
    preferred_term: CEP290
    term:
      id: hgnc:29021
      label: CEP290
- name: TMEM67
  association: Causative
  evidence:
  - reference: PMID:36580738
    supports: SUPPORT
    snippet: "The most common variants were in the CPLANE1, CEP290, and TMEM67 genes, and other causative genes were AHI1, ARMC9, CEP41, CSPP1, HYLS1, KATNIP, KIAA0586, KIF7, RPGRIP1L, including some previously unreported variants in these genes."
    explanation: This cohort identifies TMEM67 as a common JS gene.
    evidence_source: HUMAN_CLINICAL
  - reference: PMID:35238134
    supports: SUPPORT
    snippet: "For instance, JS individuals harboring pathogenic variants in TMEM67 have a significantly higher risk of liver fibrosis, while pathogenic variants in NPHP1, RPGRIP1L, and TMEM237 are frequently associated to JS with renal involvement, requiring a closer monitoring of liver parameters, or renal functioning."
    explanation: TMEM67 variants are associated with increased liver fibrosis risk in JS.
    evidence_source: HUMAN_CLINICAL
  - reference: PMID:39027323
    supports: SUPPORT
    snippet: "The diagnosis of autosomal recessive Joubert syndrome type 6 due to homozygous pathogenic variant c.725A > G p. (Asn242Ser) in TMEM67 gene was confirmed by whole exome sequencing."
    explanation: This JS type 6 case confirms a pathogenic TMEM67 variant.
    evidence_source: HUMAN_CLINICAL
  - reference: PMID:39849212
    supports: SUPPORT
    snippet: "Whole Exome Sequencing (WES), performed via buccal swab, showed biallelic pathogenic variants at NM_153704.6:c.2086 C > T (NP_714915.3:p.Leu696Phe) and NM_153704.6:c.431del (NP_714915.3:p.Leu144CysfsTer19) in TMEM67, which are associated with Joubert Syndrome 6 (OMIM:610688) in a compound heterozygous state."
    explanation: This case report identifies biallelic TMEM67 variants associated with Joubert syndrome 6.
    evidence_source: HUMAN_CLINICAL
  gene_term:
    preferred_term: TMEM67
    term:
      id: hgnc:28396
      label: TMEM67
- name: AHI1
  association: Causative
  evidence:
  - reference: PMID:35238134
    supports: SUPPORT
    snippet: "On the other hand, individuals with causal variants in the CEP290 or AHI1 need a closer surveillance for retinal dystrophy and, in case of CEP290, also for chronic kidney disease."
    explanation: This review notes AHI1 variants in JS with retinal dystrophy risk.
    evidence_source: HUMAN_CLINICAL
  - reference: PMID:33777383
    supports: SUPPORT
    snippet: "Variants in AHI1 account for ∼7% of Joubert syndrome cases and are associated either with ‘pure’ Joubert syndrome, or Joubert syndrome plus renal and/or retinal disease."
    explanation: This adult JS case report summarizes AHI1 contribution to JS cases.
    evidence_source: HUMAN_CLINICAL
  gene_term:
    preferred_term: AHI1
    term:
      id: hgnc:21575
      label: AHI1
- name: ARMC9
  association: Causative
  evidence:
  - reference: PMID:36580738
    supports: SUPPORT
    snippet: "The most common variants were in the CPLANE1, CEP290, and TMEM67 genes, and other causative genes were AHI1, ARMC9, CEP41, CSPP1, HYLS1, KATNIP, KIAA0586, KIF7, RPGRIP1L, including some previously unreported variants in these genes."
    explanation: This cohort reports ARMC9 among causative JS genes.
    evidence_source: HUMAN_CLINICAL
  gene_term:
    preferred_term: ARMC9
    term:
      id: hgnc:20730
      label: ARMC9
- name: CEP41
  association: Causative
  evidence:
  - reference: PMID:36580738
    supports: SUPPORT
    snippet: "The most common variants were in the CPLANE1, CEP290, and TMEM67 genes, and other causative genes were AHI1, ARMC9, CEP41, CSPP1, HYLS1, KATNIP, KIAA0586, KIF7, RPGRIP1L, including some previously unreported variants in these genes."
    explanation: This cohort reports CEP41 among causative JS genes.
    evidence_source: HUMAN_CLINICAL
  gene_term:
    preferred_term: CEP41
    term:
      id: hgnc:12370
      label: CEP41
- name: CSPP1
  association: Causative
  evidence:
  - reference: PMID:36580738
    supports: SUPPORT
    snippet: "The most common variants were in the CPLANE1, CEP290, and TMEM67 genes, and other causative genes were AHI1, ARMC9, CEP41, CSPP1, HYLS1, KATNIP, KIAA0586, KIF7, RPGRIP1L, including some previously unreported variants in these genes."
    explanation: This cohort reports CSPP1 among causative JS genes.
    evidence_source: HUMAN_CLINICAL
  - reference: PMID:40898267
    supports: SUPPORT
    snippet: "Pathogenic CSPP1 variants account for approximately 3% of Joubert syndrome cases."
    explanation: This case report notes CSPP1 pathogenic variants contribute to JS, supporting CSPP1 as a causative gene.
    evidence_source: HUMAN_CLINICAL
  gene_term:
    preferred_term: CSPP1
    term:
      id: hgnc:26193
      label: CSPP1
- name: HYLS1
  association: Causative
  evidence:
  - reference: PMID:36580738
    supports: SUPPORT
    snippet: "The most common variants were in the CPLANE1, CEP290, and TMEM67 genes, and other causative genes were AHI1, ARMC9, CEP41, CSPP1, HYLS1, KATNIP, KIAA0586, KIF7, RPGRIP1L, including some previously unreported variants in these genes."
    explanation: This cohort reports HYLS1 among causative JS genes.
    evidence_source: HUMAN_CLINICAL
  gene_term:
    preferred_term: HYLS1
    term:
      id: hgnc:26558
      label: HYLS1
- name: KATNIP
  association: Causative
  evidence:
  - reference: PMID:36580738
    supports: SUPPORT
    snippet: "The most common variants were in the CPLANE1, CEP290, and TMEM67 genes, and other causative genes were AHI1, ARMC9, CEP41, CSPP1, HYLS1, KATNIP, KIAA0586, KIF7, RPGRIP1L, including some previously unreported variants in these genes."
    explanation: This cohort reports KATNIP among causative JS genes.
    evidence_source: HUMAN_CLINICAL
  gene_term:
    preferred_term: KATNIP
    term:
      id: hgnc:29068
      label: KATNIP
- name: KIAA0586
  association: Causative
  evidence:
  - reference: PMID:36580738
    supports: SUPPORT
    snippet: "The most common variants were in the CPLANE1, CEP290, and TMEM67 genes, and other causative genes were AHI1, ARMC9, CEP41, CSPP1, HYLS1, KATNIP, KIAA0586, KIF7, RPGRIP1L, including some previously unreported variants in these genes."
    explanation: This cohort reports KIAA0586 among causative JS genes.
    evidence_source: HUMAN_CLINICAL
  - reference: PMID:36788019
    supports: SUPPORT
    snippet: "Two recurrent variants (MKS1 c.1476T>G and KIAA0586 c.428delG), have been detected in homozygosity in unaffected individuals, suggesting they could act as hypomorphic variants."
    explanation: This study identifies recurrent KIAA0586 variants in JS cohorts.
    evidence_source: HUMAN_CLINICAL
  - reference: PMID:40951761
    supports: SUPPORT
    snippet: "Variants in KIAA0586/TALPID3 are associated with the ciliopathy Joubert syndrome (JS), which is a genetically heterogeneous disorder."
    explanation: This study links KIAA0586/TALPID3 variants to JS.
    evidence_source: IN_VITRO
  - reference: PMID:41020477
    supports: SUPPORT
    snippet: "JBTS23, a subtype of Joubert syndrome, is caused by variations in the KIAA0586 gene."
    explanation: This report identifies pathogenic KIAA0586 variants in a JS subtype, supporting causative association.
    evidence_source: HUMAN_CLINICAL
  gene_term:
    preferred_term: KIAA0586
    term:
      id: hgnc:19960
      label: KIAA0586
- name: KIF7
  association: Causative
  evidence:
  - reference: PMID:36580738
    supports: SUPPORT
    snippet: "The most common variants were in the CPLANE1, CEP290, and TMEM67 genes, and other causative genes were AHI1, ARMC9, CEP41, CSPP1, HYLS1, KATNIP, KIAA0586, KIF7, RPGRIP1L, including some previously unreported variants in these genes."
    explanation: This cohort reports KIF7 among causative JS genes.
    evidence_source: HUMAN_CLINICAL
  gene_term:
    preferred_term: KIF7
    term:
      id: hgnc:30497
      label: KIF7
- name: RPGRIP1L
  association: Causative
  evidence:
  - reference: PMID:36580738
    supports: SUPPORT
    snippet: "The most common variants were in the CPLANE1, CEP290, and TMEM67 genes, and other causative genes were AHI1, ARMC9, CEP41, CSPP1, HYLS1, KATNIP, KIAA0586, KIF7, RPGRIP1L, including some previously unreported variants in these genes."
    explanation: This cohort reports RPGRIP1L among causative JS genes.
    evidence_source: HUMAN_CLINICAL
  - reference: PMID:38013309
    supports: SUPPORT
    snippet: "Joubert syndrome 7 is caused by mutations in the RPGRIP1L gene."
    explanation: This case report highlights RPGRIP1L as a JS gene.
    evidence_source: HUMAN_CLINICAL
  - reference: PMID:37547106
    supports: SUPPORT
    snippet: "RPGRIP1l: c.1351-11A > G; CEP120: c.214 C > T(p.Arg72Cys)."
    explanation: This cohort reports RPGRIP1L variants in JS.
    evidence_source: HUMAN_CLINICAL
  - reference: PMID:37993833
    supports: SUPPORT
    snippet: "Genetic analysis showed novel compound heterozygous mutations in the RPGRIP1L gene [p.L447fs*7(p.Leu447fsTer7) and p.G908V (p.Gly908Val)]."
    explanation: This case report identifies RPGRIP1L mutations in JS with oculorenal involvement.
    evidence_source: HUMAN_CLINICAL
  gene_term:
    preferred_term: RPGRIP1L
    term:
      id: hgnc:29168
      label: RPGRIP1L
- name: MKS1
  association: Causative
  evidence:
  - reference: PMID:36788019
    supports: SUPPORT
    snippet: "Two recurrent variants (MKS1 c.1476T>G and KIAA0586 c.428delG), have been detected in homozygosity in unaffected individuals, suggesting they could act as hypomorphic variants."
    explanation: This study reports recurrent MKS1 variants in JS cohorts.
    evidence_source: HUMAN_CLINICAL
  gene_term:
    preferred_term: MKS1
    term:
      id: hgnc:7121
      label: MKS1
- name: CC2D2A
  association: Causative
  evidence:
  - reference: PMID:36319078
    supports: SUPPORT
    snippet: "cohort of patients with Joubert syndrome (JS) carrying pathogenic variants on one of the most frequent causative genes, CC2D2A."
    explanation: This study focuses on CC2D2A-related JS with pathogenic variants.
    evidence_source: HUMAN_CLINICAL
  gene_term:
    preferred_term: CC2D2A
    term:
      id: hgnc:29253
      label: CC2D2A
- name: OFD1
  association: Causative
  evidence:
  - reference: PMID:36704348
    supports: SUPPORT
    snippet: "We identified a novel non-sense variant in the OFD1 gene, OFD1 (NM_003611.3): c.2848A>T (p.Lys950Ter)."
    explanation: This study reports a pathogenic OFD1 variant in JS.
    evidence_source: HUMAN_CLINICAL
  gene_term:
    preferred_term: OFD1
    term:
      id: hgnc:2567
      label: OFD1
- name: TCTN1
  association: Causative
  evidence:
  - reference: PMID:34980503
    supports: SUPPORT
    snippet: "Joubert syndrome attributed to variants in the TCTN1 (NM_001082538.2) gene has been only described in two reports."
    explanation: This case report supports TCTN1 as a JS gene.
    evidence_source: HUMAN_CLINICAL
  gene_term:
    preferred_term: TCTN1
    term:
      id: hgnc:26113
      label: TCTN1
- name: CEP120
  association: Causative
  evidence:
  - reference: PMID:37547106
    supports: SUPPORT
    snippet: "RPGRIP1l: c.1351-11A > G; CEP120: c.214 C > T(p.Arg72Cys)."
    explanation: This cohort reports a CEP120 variant associated with JS.
    evidence_source: HUMAN_CLINICAL
  gene_term:
    preferred_term: CEP120
    term:
      id: hgnc:26690
      label: CEP120
- name: TOPORS
  association: Causative
  evidence:
  - reference: PMID:37227088
    supports: SUPPORT
    snippet: "Our data nominates TOPORS as a novel causal gene for JBTS"
    explanation: This study identifies TOPORS as a novel JS gene.
    evidence_source: HUMAN_CLINICAL
  gene_term:
    preferred_term: TOPORS
    term:
      id: hgnc:21653
      label: TOPORS
environmental: []
treatments:
- name: Supportive care
  description: Conservative symptomatic management for neurodevelopmental features.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:36484066
    supports: SUPPORT
    snippet: "Patient was managed conservatively with symptomatic treatment."
    explanation: This case report indicates conservative symptomatic management in JS.
    evidence_source: HUMAN_CLINICAL
- name: Physical therapy
  description: Physical therapy to promote psychomotor development.
  treatment_term:
    preferred_term: physical therapy
    term:
      id: MAXO:0000011
      label: physical therapy
  evidence:
  - reference: PMID:37288221
    supports: SUPPORT
    snippet: "All patients received physical, occupational, and speech-language-hearing therapy, depending on their symptoms and conditions."
    explanation: This case series describes physical therapy in JS rehabilitation.
    evidence_source: HUMAN_CLINICAL
- name: Occupational therapy
  description: Occupational therapy to support functional independence.
  treatment_term:
    preferred_term: occupational therapy
    term:
      id: MAXO:0001351
      label: occupational therapy
  evidence:
  - reference: PMID:37288221
    supports: SUPPORT
    snippet: "All patients received physical, occupational, and speech-language-hearing therapy, depending on their symptoms and conditions."
    explanation: This case series describes occupational therapy in JS rehabilitation.
    evidence_source: HUMAN_CLINICAL
- name: Speech therapy
  description: Speech-language therapy for communication and swallowing support.
  treatment_term:
    preferred_term: speech therapy
    term:
      id: MAXO:0000930
      label: speech therapy
  evidence:
  - reference: PMID:37288221
    supports: SUPPORT
    snippet: "All patients received physical, occupational, and speech-language-hearing therapy, depending on their symptoms and conditions."
    explanation: This case series describes speech-language therapy in JS rehabilitation.
    evidence_source: HUMAN_CLINICAL
- name: Orthotic device usage
  description: Orthotic intervention for hypotonia and ataxia.
  treatment_term:
    preferred_term: orthotic device usage
    term:
      id: MAXO:0000482
      label: orthotic device usage
  evidence:
  - reference: PMID:37288221
    supports: SUPPORT
    snippet: "For hypotonia and ataxia, an orthotic intervention was considered in all three cases, and foot or ankle-foot orthoses were used in two cases."
    explanation: This case series reports orthotic device usage to address hypotonia and ataxia.
    evidence_source: HUMAN_CLINICAL
- name: Genetic counseling
  description: Counseling for families to support management planning and recurrence risk discussion.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: PMID:37490694
    supports: SUPPORT
    snippet: "The early diagnosis of Joubert syndrome is reflected in better pediatric follow-up, which impacts its prognosis and the possibility of improving the patient's quality of life with a multidisciplinary management and genetic counseling."
    explanation: The case report highlights genetic counseling as part of care that improves quality of life.
    evidence_source: HUMAN_CLINICAL
- name: Liver transplantation
  description: Treatment for severe portal hypertension in COACH syndrome (Joubert syndrome with congenital hepatic fibrosis).
  treatment_term:
    preferred_term: liver transplantation
    term:
      id: MAXO:0001175
      label: liver transplantation
  evidence:
  - reference: PMID:37965976
    supports: SUPPORT
    snippet: "LT should be considered an effective treatment for COACH syndrome in patients with severe portal hypertension."
    explanation: The review concludes that liver transplantation is effective for JS patients with congenital hepatic fibrosis and portal hypertension.
    evidence_source: HUMAN_CLINICAL
- name: Nasobiliary drainage
  description: Procedural management for refractory cholestatic pruritus in JS with hepatic involvement.
  evidence:
  - reference: PMID:37799488
    supports: SUPPORT
    snippet: "Nasobiliary drainage is a relatively safe and effective method for treating intractable cholestatic pruritus."
    explanation: This case report describes nasobiliary drainage for refractory cholestatic pruritus in JS.
    evidence_source: HUMAN_CLINICAL
clinical_trials:
- name: NCT01401998
  phase: NOT_APPLICABLE
  status: RECRUITING
  description: Registry and biospecimen resource for hepato-renal fibrocystic diseases including Joubert syndrome to support clinical and genetic data sharing.
  evidence:
  - reference: clinicaltrials:NCT01401998
    supports: SUPPORT
    snippet: "Hepato-renal fibrocystic diseases (HRFD) is a term developed that encompasses rare diseases such as Autosomal Recessive Polycystic Kidney Disease (ARPKD), and other diseases with common features (Joubert syndrome, Bardet Biedl syndrome, Meckel-Gruber syndrome, congenital hepatic fibrosis (CHF), Caroli syndrome (CS), polycystic liver disease, oro-facial-digital syndrome, nephronophithisis (NPHP), and glomerulocystic Kidney Disease)."
    explanation: This registry explicitly includes Joubert syndrome among HRFD conditions.
    evidence_source: HUMAN_CLINICAL
- name: NCT00873678
  phase: NOT_APPLICABLE
  status: COMPLETED
  description: Genetic prevalence study of AHI1, NPHP1, and CEP290 in Joubert syndrome and cerebello-oculo-renal syndromes.
  evidence:
  - reference: clinicaltrials:NCT00873678
    supports: SUPPORT
    snippet: "assessment of the prevalence of AHI1 mutations in Joubert syndrome and cerebello-oculo-renal syndromes (JS/CORS)"
    explanation: This study targets Joubert syndrome genetic prevalence.
    evidence_source: HUMAN_CLINICAL
- name: NCT04874909
  phase: NOT_APPLICABLE
  status: UNKNOWN
  description: Ciliopathy stratification study aimed at developing diagnostic and prognostic biomarkers for renal outcomes.
  evidence:
  - reference: clinicaltrials:NCT04874909
    supports: SUPPORT
    snippet: "The purpose of the C'IL-LICO RICM study is to develop innovative and transformative diagnostic and prognostic for patients suffering from ciliopathies leading to renal failure."
    explanation: This study focuses on ciliopathy-related renal prognosis and biomarker development.
    evidence_source: HUMAN_CLINICAL
datasets:
- accession: GEO:GSE254556
  title: Joubert Syndrome-derived induced pluripotent stem cells show altered neuronal differentiation in vitro
  description: >-
    Transcriptomic profiling of JS patient-derived iPSC neuronal differentiation
    (mid-hindbrain precursors and cerebellar granule cells) compared with controls.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  conditions:
  - Joubert syndrome
  - iPSC-derived neuronal differentiation
  platform: GEO
  publication: PMID:38502237
  evidence:
  - reference: GEO:GSE254556
    supports: SUPPORT
    snippet: "Differentiation was monitored over 31 days through the detection of lineage-specific marker expression by qRT-PCR, immunofluorescence, and transcriptomics analysis."
    explanation: This GEO dataset contains transcriptomic analysis of JS iPSC differentiation.
    evidence_source: IN_VITRO
- accession: GEO:GSE217001
  title: Variable phenotypes and penetrance between and within different zebrafish transition zone mutants
  description: >-
    Transcriptomic profiling of zebrafish transition zone mutants used to model
    ciliopathy phenotypes relevant to Joubert syndrome.
  organism:
    preferred_term: zebrafish
    term:
      id: NCBITaxon:7955
      label: Danio rerio
  data_type: BULK_RNA_SEQ
  conditions:
  - Joubert syndrome
  - zebrafish transition zone mutants
  platform: GEO
  publication: PMID:36533556
  evidence:
  - reference: GEO:GSE217001
    supports: SUPPORT
    snippet: "Meckel Syndrome, Nephronophthisis, Joubert Syndrome, and Bardet-Biedl Syndrome have mutations in proteins that localize to the ciliary transition zone (TZ)."
    explanation: This GEO series centers on transition zone mutants relevant to Joubert syndrome and other ciliopathies.
    evidence_source: MODEL_ORGANISM
diagnosis:
- name: Brain MRI for molar tooth sign
  description: Brain MRI identifying the molar tooth sign supports the diagnosis of Joubert syndrome.
  diagnosis_term:
    preferred_term: magnetic resonance imaging procedure
    term:
      id: MAXO:0000424
      label: magnetic resonance imaging procedure
  evidence:
  - reference: PMID:36484066
    supports: SUPPORT
    snippet: "Identification of molar tooth sign on magnetic resonance imaging studies assisted to make a definitive diagnosis."
    explanation: MRI identification of the molar tooth sign supports diagnosis.
    evidence_source: HUMAN_CLINICAL
  - reference: PMID:37490694
    supports: SUPPORT
    snippet: "conducted a magnetic resonance of the brain and identified the \"molar tooth sign,\""
    explanation: Brain MRI showing the molar tooth sign is pathognomonic for JS.
    evidence_source: HUMAN_CLINICAL
- name: Molecular genetic testing
  description: Molecular genetic testing confirms Joubert syndrome diagnosis.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: MAXO:0000533
      label: molecular genetic testing
  evidence:
  - reference: PMID:33717386
    supports: SUPPORT
    snippet: "The definitive diagnosis was established through molecular genetic testing."
    explanation: Molecular genetic testing confirms JS diagnosis.
    evidence_source: HUMAN_CLINICAL
- name: Clinical whole-exome sequencing
  description: Whole-exome sequencing supports diagnosis and can increase diagnostic yield in JS.
  diagnosis_term:
    preferred_term: clinical whole-exome sequencing
    term:
      id: MAXO:0009004
      label: clinical whole-exome sequencing
  evidence:
  - reference: PMID:34846692
    supports: SUPPORT
    snippet: "whole-exome sequencing (WES) disclosed pathogenic variants in other genes causative of distinct brain malformative conditions"
    explanation: WES helps clarify diagnosis when initial JS genetic testing is inconclusive.
    evidence_source: HUMAN_CLINICAL
  - reference: PMID:39394465
    supports: SUPPORT
    snippet: "We show that CNVs and intronic splicing variants are a common mutational mechanism in JS; more importantly, we demonstrate that a significant proportion of such variants can be disclosed simply through a focused reanalysis of available ES data"
    explanation: Exome sequencing and reanalysis improve diagnostic yield in JS.
    evidence_source: HUMAN_CLINICAL
  - reference: PMID:34821546
    supports: SUPPORT
    snippet: "this case was confirmed by fetal exome sequencing (Joubert syndrome)."
    explanation: Fetal exome sequencing can confirm JS diagnosis prenatally.
    evidence_source: HUMAN_CLINICAL
differential_diagnoses:
- name: Nephronophthisis
  description: Ciliopathy with overlapping features that can resemble Joubert syndrome.
  distinguishing_features:
  - Predominant renal involvement without the classic molar tooth sign on MRI.
  - Progressive tubulointerstitial kidney disease is the primary presentation.
  disease_term:
    preferred_term: nephronophthisis
    term:
      id: MONDO:0019005
      label: nephronophthisis
  evidence:
  - reference: PMID:36803942
    supports: SUPPORT
    snippet: "Such pleiotropic characteristics are typical of many disorders involving primary cilium aberrations, providing a significant overlap between JS and other ciliopathies such as nephronophthisis, Meckel syndrome, and Bardet-Biedl syndrome."
    explanation: The review notes overlap between JS and nephronophthisis, supporting it as a differential diagnosis.
    evidence_source: HUMAN_CLINICAL
- name: Meckel syndrome
  description: Ciliopathy with overlapping features that can resemble Joubert syndrome.
  distinguishing_features:
  - Severe, typically lethal ciliopathy with encephalocele and renal cystic dysplasia.
  - Presents prenatally with multiple congenital anomalies.
  disease_term:
    preferred_term: Meckel syndrome
    term:
      id: MONDO:0018921
      label: Meckel syndrome
  evidence:
  - reference: PMID:36803942
    supports: SUPPORT
    snippet: "Such pleiotropic characteristics are typical of many disorders involving primary cilium aberrations, providing a significant overlap between JS and other ciliopathies such as nephronophthisis, Meckel syndrome, and Bardet-Biedl syndrome."
    explanation: The review notes overlap between JS and Meckel syndrome, supporting it as a differential diagnosis.
    evidence_source: HUMAN_CLINICAL
- name: Bardet-Biedl syndrome
  description: Ciliopathy with overlapping features that can resemble Joubert syndrome.
  distinguishing_features:
  - Postaxial polydactyly, obesity, and retinal dystrophy without molar tooth sign.
  - Cognitive impairment and renal anomalies may occur but brainstem malformation is not typical.
  disease_term:
    preferred_term: Bardet-Biedl syndrome
    term:
      id: MONDO:0015229
      label: Bardet-Biedl syndrome
  evidence:
  - reference: PMID:36803942
    supports: SUPPORT
    snippet: "Such pleiotropic characteristics are typical of many disorders involving primary cilium aberrations, providing a significant overlap between JS and other ciliopathies such as nephronophthisis, Meckel syndrome, and Bardet-Biedl syndrome."
    explanation: The review notes overlap between JS and Bardet-Biedl syndrome, supporting it as a differential diagnosis.
    evidence_source: HUMAN_CLINICAL
- name: Senior-Loken syndrome
  description: Ciliopathy with renal and retinal involvement that can overlap with JS.
  distinguishing_features:
  - Predominant nephronophthisis with retinal dystrophy.
  - Lacks the molar tooth sign typical of JS.
  disease_term:
    preferred_term: Senior-Loken syndrome
    term:
      id: MONDO:0017842
      label: Senior-Loken syndrome
  evidence:
  - reference: PMID:33717386
    supports: SUPPORT
    snippet: "This would explain the frequent association between CEP290 mutations and Joubert syndrome with renal involvement, as well as other syndromes such as Senior-Loken, Meckel, Bardet-Biedl with overlapping clinical features"
    explanation: This case report notes overlapping features between JS and Senior-Loken syndrome.
    evidence_source: HUMAN_CLINICAL
- name: Dandy-Walker syndrome
  description: Posterior fossa malformation that can mimic JS on initial imaging.
  distinguishing_features:
  - Cystic dilation of the fourth ventricle and enlarged posterior fossa.
  - Absence of the molar tooth sign differentiates it from JS.
  disease_term:
    preferred_term: Dandy-Walker syndrome
    term:
      id: MONDO:0009072
      label: Dandy-Walker syndrome
  evidence:
  - reference: PMID:33717386
    supports: SUPPORT
    snippet: "Initially a diagnosis of Dandy Walker malformation with no clear signs of obstruction of the foramen magnum was suspected"
    explanation: This case report shows Dandy-Walker considered in the differential before JS was confirmed.
    evidence_source: HUMAN_CLINICAL