Joubert syndrome

Genetic MONDO:0018772 Pathograph 52 Neurodevelopmental Disorder Ciliopathy

Joubert syndrome is a rare, autosomal recessive neurodevelopmental ciliopathy characterized by congenital malformation of the brainstem and agenesis or hypoplasia of the cerebellar vermis producing the characteristic molar tooth sign on brain MRI. Clinical features include abnormal respiratory pattern, nystagmus, hypotonia, ataxia, delay in achieving motor milestones, and multisystem involvement affecting the eyes, kidneys, liver, and skeleton.

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Inheritance

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 (2 references)

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.

ORPHA:475 SUPPORT

"Autosomal recessive"

Orphanet classifies isolated Joubert syndrome as autosomal recessive.

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

Joubert syndrome 1 MONDO:0008944

Joubert syndrome 2 MONDO:0011963

Joubert syndrome 3 MONDO:0012078

Joubert syndrome with renal defect MONDO:0012308

Joubert syndrome 5 MONDO:0012432

Joubert syndrome 6 MONDO:0012539

Joubert syndrome 7 MONDO:0012694

Joubert syndrome 9 MONDO:0012849

Joubert syndrome 8 MONDO:0012855

Joubert syndrome 13 MONDO:0013608

Joubert syndrome 14 MONDO:0013745

Joubert syndrome 15 MONDO:0013763

Joubert syndrome 16 MONDO:0013764

Joubert syndrome 17 MONDO:0013824

Joubert syndrome 18 MONDO:0013896

Joubert syndrome caused by mutation in TCTN3.

Joubert syndrome 20 MONDO:0013994

Joubert syndrome 21 MONDO:0014288

Joubert syndrome 22 MONDO:0014297

Joubert syndrome 23 MONDO:0014664

Joubert syndrome 24 MONDO:0014724

Joubert syndrome 25 MONDO:0014770

Joubert syndrome 26 MONDO:0014771

Joubert syndrome 27 MONDO:0014927

Joubert syndrome 28 MONDO:0014928

Joubert syndrome 38 MONDO:0030353

Joubert syndrome 39 MONDO:0030454

Joubert syndrome 40 MONDO:0030462

Joubert syndrome 37 MONDO:0030933

Joubert syndrome 35 MONDO:0032570

Joubert syndrome 36 MONDO:0032902

Joubert syndrome 30 MONDO:0033308

Joubert syndrome 32 MONDO:0033309

Joubert syndrome 31 MONDO:0033310

Joubert syndrome 33 MONDO:0033311

Joubert syndrome 19 MONDO:0800363

Joubert syndrome 29 MONDO:0800372

Joubert syndrome 11 MONDO:0800382

Joubert syndrome 34 MONDO:0800383

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Pathophysiology

Pathogenic JBTS gene defects

Biallelic (or hemizygous, for X-linked OFD1) pathogenic variants in over 40 ciliary genes initiate Joubert syndrome. The encoded proteins localize to distinct primary cilium subcompartments — basal body, transition zone, axoneme/ciliary tip, and intraflagellar transport machinery — and converge on disrupted primary cilium structure and function.

CPLANE1 hgnc:25801 CEP290 hgnc:29021 TMEM67 hgnc:28396 AHI1 hgnc:21575 ARMC9 hgnc:20730 CSPP1 hgnc:26193 KIAA0586 hgnc:19960 RPGRIP1L hgnc:29168 MKS1 hgnc:7121 CC2D2A hgnc:29253 OFD1 hgnc:2567

Downstream

Ciliary gene mutations disrupt primary cilium assembly Variants in genes encoding basal body, axonemal, and intraflagellar transport components compromise primary cilium biogenesis.

Ciliary transition zone gating defect Variants in transition zone genes (e.g., TMEM67, CC2D2A, MKS1, CEP290, B9D2) disrupt the ciliary gate.

Defective ciliary tip microtubule dynamics Variants in ciliary tip module genes (CEP104, CSPP1, TOGARAM1, ARMC9, CCDC66) disrupt axonemal microtubule growth.

Defective canonical Wnt signaling at the cerebellar midline Loss of AHI1/Jouberin (and CEP290) disrupts cilium-coupled canonical Wnt signaling at the cerebellar dorsal midline.

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."

Defines the genetic architecture of JS as variants in genes encoding primary cilium components.

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."

Anchors a representative list of recurrent JS-causative ciliary genes from a clinical cohort.

Ciliary gene mutations disrupt primary cilium assembly

Causative JS genes encode proteins required for primary cilium structure and assembly, disrupting cilium biogenesis in vivo.

neuron CL:0000540

cilium assembly GO:0060271 ↕ DYSREGULATED

Downstream

Abnormal cilium structure and length Failed cilium assembly produces cilia with abnormal number, morphology, and length.

Impaired intraciliary transport Defective primary cilium biogenesis disrupts the cilium machinery required for intraciliary transport.

Hippocampal neurogenesis defect Loss of basal-body proteins (e.g., KIAA0586/Talpid3) required for cilium assembly disrupts hippocampal progenitor proliferation and migration.

Show evidence (2 references)

PMID:38502237 SUPPORT In Vitro

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 GO:0044782 ⚠ ABNORMAL

Downstream

Defective Sonic hedgehog signaling Abnormal cilium structure compromises the cilium-dependent transduction of Hedgehog signaling.

Photoreceptor outer segment dystrophy Photoreceptor outer segments are modified primary cilia and are particularly sensitive to abnormal cilium structure.

Renal tubular ciliary dysfunction Renal tubular epithelial cilia mediate cilium-dependent homeostasis that is disrupted by abnormal cilium morphology.

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 GO:0042073 ↕ DYSREGULATED

Downstream

Photoreceptor outer segment dystrophy Defective intraciliary cargo transport mislocalizes outer-segment proteins required for photoreceptor function.

Renal tubular ciliary dysfunction Impaired ciliary transport disrupts renal tubular cilium-dependent signaling.

Neurodevelopmental defects Disrupted ciliary trafficking impairs cilium-dependent neurodevelopmental signaling.

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.

neuron CL:0000540 cerebellar granule cell CL:0001031

Downstream

Defective midbrain-hindbrain patterning Disrupted ciliary signaling perturbs mid-hindbrain morphogenesis underlying the JS brain malformation.

Cerebellar vermis hypoplasia Impaired neurodevelopmental programs lead to vermian hypoplasia, the cardinal cerebellar feature of JS.

Intellectual disability Neurodevelopmental disruption manifests as intellectual disability.

Global developmental delay Neurodevelopmental disruption manifests as global developmental delay.

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.

Defective ciliary tip microtubule dynamics

A ciliary tip module composed of CEP104, CSPP1, TOGARAM1, ARMC9 and CCDC66 controls the very slow processive growth of axonemal microtubules. Loss-of-function variants in module members destabilize this assembly and disrupt axonemal microtubule dynamics that are required to build and maintain the primary cilium.

CSPP1 hgnc:26193 ARMC9 hgnc:20730 CEP120 hgnc:26690

axoneme GO:0005930

Downstream

Abnormal cilium structure and length Disrupted ciliary tip microtubule dynamics produce cilia of abnormal length and morphology.

Show evidence (1 reference)

PMID:39856351 SUPPORT In Vitro

"Here we reconstituted in vitro the individual and collective activities of the ciliary tip module proteins CEP104, CSPP1, TOGARAM1, ARMC9 and CCDC66, which interact with each other and with microtubules and, when mutated in humans, cause ciliopathies such as Joubert syndrome."

Defines the ciliary tip module whose members are JBTS-causative and act together to control axonemal microtubule growth.

Ciliary transition zone gating defect

The ciliary transition zone (TZ) is a gatekeeper subdomain that controls passage of signaling proteins into and out of the cilium. The TMEM67/MKS module (TMEM67, MKS1, B9D1, B9D2, CC2D2A) and the NPHP module are anchored at the TZ; pathogenic variants in JS genes encoding TZ components reduce TZ gating, anchoring of TMEM67, and posttranslational tubulin modifications.

TMEM67 hgnc:28396 CC2D2A hgnc:29253 MKS1 hgnc:7121 CEP290 hgnc:29021 B9D1 hgnc:24123 B9D2 hgnc:28636

ciliary transition zone GO:0035869

Downstream

Impaired intraciliary transport A defective TZ gate compromises selective entry and exit of ciliary cargo.

Defective Sonic hedgehog signaling TZ gating is required for ciliary localization of Hedgehog pathway components (SMO, GPR161, TULP3).

Biliary ductal plate malformation via ciliary tight junction defect B9D2 also functions extra-ciliarly in tight junctions; its loss disrupts biliary epithelial polarity.

Show evidence (2 references)

PMID:35137054 SUPPORT Human Clinical

"We identified biallelic missense and nonsense mutations in the gene encoding the transmembrane protein TMEM218 in unrelated patients with features related to Bardet-Biedl, Joubert and Meckel-Gruber syndrome (MKS) and characterized TMEM218 as a major component of the ciliary TZ module."

Establishes that JBTS-spectrum disease arises from variants in genes encoding ciliary transition zone module components.

PMID:41165761 SUPPORT In Vitro

"The B9 complex interacted with and anchored TMEM67 to the TZ membrane."

Defines a direct molecular interaction at the transition zone whose disruption is a JBTS mechanism.

Defective Sonic hedgehog signaling

Hedgehog signal transduction depends on regulated trafficking of Smoothened and other Hh components through the primary cilium. Disrupted ciliary structure or transition zone gating in JS reduces Hh signaling, perturbing Hh-dependent neural patterning and limb development.

neural progenitor cell CL:0011020

smoothened signaling pathway GO:0007224 ↓ DECREASED

Downstream

Defective midbrain-hindbrain patterning Reduced cilium-dependent Hedgehog signaling disrupts mid-hindbrain morphogenesis.

Polydactyly Cilium-dependent Hedgehog signaling is required for limb-bud patterning; its disruption causes preaxial/postaxial digit duplication.

Show evidence (1 reference)

PMID:39385469 SUPPORT Model Organism

"We show that Togaram1 is expressed in the neural tube and Togaram1 knockout mice have abnormal cilia, reduced sonic hedgehog (Shh) signaling, abnormal neural tube patterning, and display neural tube closure defects."

Demonstrates that loss of a JBTS gene reduces ciliary Shh signaling and perturbs cilium-dependent patterning.

Defective canonical Wnt signaling at the cerebellar midline

AHI1 (Jouberin) participates in canonical Wnt signal transduction. In Ahi1-mutant mouse cerebellum, Wnt reporter activity is reduced at the site of cerebellar hemisphere fusion, producing a vermis-midline fusion defect that recapitulates the human cerebellar vermis hypoplasia of JS. The defect is partially rescued by lithium, a Wnt pathway agonist.

neural progenitor cell CL:0011020 cerebellar granule cell precursor CL:0002362

AHI1 hgnc:21575 CEP290 hgnc:29021

canonical Wnt signaling pathway GO:0060070 ↓ DECREASED

cerebellar vermis UBERON:0004720

Downstream

Cerebellar vermis hypoplasia Reduced Wnt-dependent proliferation at the dorsal midline produces vermis hypoplasia.

Molar tooth sign on MRI Vermis hypoplasia is the dominant component of the molar tooth sign.

Show evidence (2 references)

PMID:21623382 SUPPORT Model Organism

"Our findings implicate a defect in Wnt signaling in the cerebellar midline phenotype seen in Joubert syndrome that can be overcome with Wnt stimulation."

Directly links AHI1/Jouberin loss to defective canonical Wnt signaling at the developing cerebellar midline.

PMID:21623382 SUPPORT Model Organism

"These mice show cerebellar hypoplasia with a vermis-midline fusion defect early in development."

Shows that AHI1 loss in mice produces a cerebellar vermis-midline fusion defect that parallels human JS.

Defective midbrain-hindbrain patterning

Disrupted ciliary signaling perturbs morphogenesis of the midbrain-hindbrain boundary, producing the characteristic JS malformation: hypoplasia of the cerebellar vermis, thickened/elongated superior cerebellar peduncles, and a deepened interpeduncular fossa.

midbrain-hindbrain boundary morphogenesis GO:0021555 ↕ DYSREGULATED

Downstream

Defective superior cerebellar peduncle decussation Mid-hindbrain patterning defects underlie the failure of axonal decussation across the brainstem midline.

Cerebellar vermis hypoplasia Failed midline morphogenesis produces vermian hypoplasia.

Brainstem control center dysfunction Mid-hindbrain malformation disrupts brainstem nuclei controlling respiratory rhythm and ocular motor pathways.

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."

Documents the mid-hindbrain malformation pattern that defines the JS molar tooth sign.

Defective superior cerebellar peduncle decussation

A defining feature of JS is failure of axons to cross the midline at the superior cerebellar peduncles, the central pontine tracts, and the corticospinal tracts. This points to a defective axon-guidance program at the mid-hindbrain junction and contributes directly to the molar tooth sign and the cerebellar/motor phenotypes.

axon guidance GO:0007411 ↕ DYSREGULATED

superior cerebellar peduncle UBERON:0002150 decussation of superior cerebellar peduncle UBERON:0002588

Downstream

Molar tooth sign on MRI Elongated, non-decussating superior cerebellar peduncles plus deep interpeduncular fossa produce the molar tooth radiographic sign.

Hypotonia Disrupted brainstem motor pathways contribute to early hypotonia.

Ataxia Loss of cerebellar output decussation contributes to ataxia.

Show evidence (1 reference)

PMID:24592023 SUPPORT Human Clinical

"JSRD is characterized by lack of decussation of the superior cerebellar peduncles, central pontine tracts and corticospinal tracts suggesting defective axon guidance."

Establishes failed midline decussation in JS as a defective axon-guidance phenotype at the mid-hindbrain junction.

Hippocampal neurogenesis defect

KIAA0586/Talpid3 is a basal-body protein required for primary cilium assembly. Talpid3 mutant mice show reduced proliferation in the dentate gyrus, a disrupted glial scaffold, and mis-localized progenitors in the granule cell layer — defective hippocampal neurogenesis that links ciliary dysfunction to learning and memory deficits seen in JS patients.

neural progenitor cell CL:0011020

KIAA0586 hgnc:19960

Downstream

Intellectual disability Hippocampal neurogenesis defects contribute to learning/memory impairment.

Global developmental delay Hippocampal and other ciliary neurogenesis defects manifest as global developmental delay.

Show evidence (2 references)

PMID:35470378 SUPPORT Model Organism

"At early postnatal stages, the Talpid3 mutants exhibit a reduction in proliferation in the dentate gyrus and a disrupted glial scaffold."

Demonstrates a hippocampal neurogenesis defect in a Talpid3 (KIAA0586) JS model.

PMID:35470378 SUPPORT Model Organism

"Our findings suggest a link between the hippocampal defects and the learning/memory deficits seen in JS patients."

Connects the model-organism hippocampal phenotype to human JS cognitive features.

Photoreceptor outer segment dystrophy

Photoreceptor outer segments are highly modified primary cilia. Pathogenic JS variants affecting transition zone gating (CEP290) or its interactors (NPHP5/IQCB1) produce aberrantly elongated ciliary axonemes, impaired outer segment development, and mislocalization of visual pigments to photoreceptor cell soma — the cellular basis of JS-associated retinal dystrophy.

photoreceptor cell CL:0000210

CEP290 hgnc:29021 AHI1 hgnc:21575

photoreceptor outer segment GO:0001750

Downstream

Retinal dystrophy Outer segment dystrophy and visual pigment mislocalization produce progressive retinal dystrophy.

Show evidence (2 references)

PMID:36084637 SUPPORT In Vitro

"Organoids revealed impaired development of outer segment structures, which are modified primary cilia, and mislocalization of visual pigments to photoreceptor cell soma."

Patient-derived retinal organoids show outer segment defects and visual pigment mislocalization driven by transition zone disruption.

PMID:36084637 SUPPORT In Vitro

"All patient-derived cells showed reduced levels of CEP290 protein, a critical cilia transition zone component interacting with NPHP5, providing a plausible mechanism for aberrant ciliary gating and cargo transport."

Mechanistically links transition zone (CEP290/NPHP5) dysfunction to photoreceptor cilium failure.

Renal tubular ciliary dysfunction

Renal tubular epithelial cells require functional primary cilia for homeostasis. Variants in JS genes encoding transition zone (CEP290) and NPHP-module components disrupt tubular ciliary signaling and drive nephronophthisis-type tubulointerstitial disease and renal cyst formation. CEP290 variants in particular confer chronic kidney disease risk that warrants surveillance.

kidney tubule cell CL:1000507

CEP290 hgnc:29021 RPGRIP1L hgnc:29168

Downstream

Nephronophthisis Tubular ciliopathy drives the nephronophthisis-type tubulointerstitial kidney disease in JS.

Renal cyst Disrupted cilium-dependent tubular signaling produces renal cysts.

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."

Genotype-phenotype review identifies CEP290 as a JS subtype with elevated chronic kidney disease risk.

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..."

Defines the JS gene subset whose variants converge on renal tubular ciliopathy.

Biliary ductal plate malformation via ciliary tight junction defect

TMEM67 variants confer the highest risk of liver fibrosis among JS genotypes. Mechanistically, B9D2 — a TMEM67 partner at the ciliary transition zone — also acts before ciliogenesis to mature and maintain epithelial tight junctions, ensuring biliary lumen formation. Loss of B9D2 function disrupts cholangiocyte tight junctions and biliary lumen formation, producing the ductal plate malformation that underlies congenital hepatic fibrosis and portal hypertension in JS.

cholangiocyte CL:1000488

TMEM67 hgnc:28396 B9D2 hgnc:28636

tight junction assembly GO:0120192 ↕ DYSREGULATED

Downstream

Hepatic fibrosis Ductal plate malformation drives congenital hepatic fibrosis.

Portal hypertension Progressive hepatic fibrosis raises portal venous pressure.

Esophageal varix Portal hypertension produces porto-systemic collaterals including esophageal varices.

Show evidence (2 references)

PMID:39455645 SUPPORT In Vitro

"Our work demonstrates that before ciliogenesis occurs, B9D2 is crucial for the maturation and maintenance of tight junctions ensuring epithelial barrier tightness and appropriate biliary lumen formation."

Establishes a non-ciliary B9D2 function in tight junctions and biliary lumen formation as the mechanism of biliary dysgenesis in JS.

PMID:35238134 SUPPORT Human Clinical

Identifies TMEM67 as the JS genotype most strongly associated with liver fibrosis, downstream of the biliary ductal plate defect.

Brainstem control center dysfunction

The same mid-hindbrain malformation that produces the molar tooth sign disrupts brainstem nuclei controlling respiratory rhythm and ocular motor pathways, manifesting in neonates as episodic tachypnea and apnea and as oculomotor apraxia and other abnormal eye movements.

Downstream

Episodic tachypnea Brainstem respiratory control dysfunction drives episodic tachypnea.

Apnea Brainstem respiratory control dysfunction drives apneic episodes.

Sleep apnea Persistent brainstem control dysfunction contributes to sleep apnea later in life.

Oculomotor apraxia Brainstem ocular motor pathway disruption contributes to oculomotor apraxia.

Abnormality of eye movement Brainstem ocular motor pathway disruption produces abnormal eye movements.

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."

Documents the early-onset brainstem-mediated respiratory dysrhythmias characteristic of JS.

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Pathograph

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Referential integrity issues (1):

Target 'Polydactyly' (from 'Defective Sonic hedgehog signaling') not found in named elements

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Phenotypes

Cardiovascular 2

Portal hypertension VERY_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.

Situs inversus totalis OCCASIONAL Situs inversus totalis HP:0001696

Show evidence (1 reference)

ORPHA:475 SUPPORT

"HP:0001696 | Situs inversus totalis | Occasional (29-5%)"

Orphanet classifies situs inversus totalis as occasional (29-5%) in isolated Joubert syndrome.

Digestive 4

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 VERY_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.

Feeding difficulties in infancy FREQUENT Feeding difficulties in infancy HP:0008872

Show evidence (1 reference)

ORPHA:475 SUPPORT

"HP:0008872 | Feeding difficulties in infancy | Frequent (79-30%)"

Orphanet classifies feeding difficulties in infancy as frequent (79-30%) in isolated Joubert syndrome.

Ear 1

Hearing impairment OCCASIONAL Hearing impairment HP:0000365

Show evidence (1 reference)

PMID:37547106 SUPPORT Human Clinical

"Three-quarters of cases had one or more other organ or system involvement, with a greater predilection for vision and hearing impairment."

A 36-child JS cohort reports vision and hearing impairment as common multi-organ features.

Eye 6

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 VERY_FREQUENT Oculomotor apraxia HP:0000657

Show evidence (2 references)

PMID:36803942 SUPPORT Human Clinical

Oculomotor apraxia is listed among characteristic JS features.

ORPHA:475 SUPPORT

"HP:0000657 | Oculomotor apraxia | Very frequent (99-80%)"

Orphanet classifies oculomotor apraxia as very frequent (99-80%) in isolated Joubert syndrome.

Strabismus OCCASIONAL Strabismus HP:0000486

Show evidence (2 references)

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.

ORPHA:475 SUPPORT

"HP:0000486 | Strabismus | Occasional (29-5%)"

Orphanet classifies strabismus as occasional (29-5%) in isolated Joubert syndrome.

Retinal dystrophy FREQUENT Retinal dystrophy HP:0000556

Show evidence (1 reference)

PMID:36803942 SUPPORT Human Clinical

Retinal dystrophy is cited as a characteristic feature.

Nystagmus FREQUENT Nystagmus HP:0000639

Show evidence (1 reference)

ORPHA:475 SUPPORT

"HP:0000639 | Nystagmus | Frequent (79-30%)"

Orphanet classifies nystagmus as frequent (79-30%) in isolated Joubert syndrome.

Ptosis OCCASIONAL Ptosis HP:0000508

Show evidence (1 reference)

ORPHA:475 SUPPORT

"HP:0000508 | Ptosis | Occasional (29-5%)"

Orphanet classifies ptosis as occasional (29-5%) in isolated Joubert syndrome.

Genitourinary 2

Renal cyst OCCASIONAL Renal cyst HP:0000107

Show evidence (1 reference)

PMID:36803942 SUPPORT Human Clinical

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.

Head and Neck 2

Long face FREQUENT Long face HP:0000276

Show evidence (1 reference)

ORPHA:475 SUPPORT

"HP:0000276 | Long face | Frequent (79-30%)"

Orphanet classifies long face as frequent (79-30%) in isolated Joubert syndrome.

Orofacial cleft OCCASIONAL Orofacial cleft HP:0000202

Show evidence (1 reference)

ORPHA:475 SUPPORT

"HP:0000202 | Orofacial cleft | Occasional (29-5%)"

Orphanet classifies orofacial cleft as occasional (29-5%) in isolated Joubert syndrome.

Musculoskeletal 3

Hypotonia VERY_FREQUENT Hypotonia HP:0001252

Show evidence (2 references)

PMID:36803942 SUPPORT Human Clinical

Hypotonia is listed as a characteristic feature of JS.

ORPHA:475 SUPPORT

"HP:0001252 | Hypotonia | Very frequent (99-80%)"

Orphanet classifies hypotonia as very frequent (99-80%) in isolated Joubert syndrome.

Abnormality of the skeletal system OCCASIONAL Abnormality of the skeletal system HP:0000924

Show evidence (1 reference)

PMID:36803942 SUPPORT Human Clinical

Skeletal changes are included in the JS phenotype spectrum.

Scoliosis OCCASIONAL Scoliosis HP:0002650

Show evidence (1 reference)

ORPHA:475 SUPPORT

"HP:0002650 | Scoliosis | Occasional (29-5%)"

Orphanet classifies scoliosis as occasional (29-5%) in isolated Joubert syndrome.

Nervous System 11

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 VERY_FREQUENT Ataxia HP:0001251

Show evidence (2 references)

PMID:36803942 SUPPORT Human Clinical

Ataxia is described among characteristic features of JS.

ORPHA:475 SUPPORT

"HP:0001251 | Ataxia | Very frequent (99-80%)"

Orphanet classifies ataxia as very frequent (99-80%) in isolated Joubert syndrome.

Intellectual disability VERY_FREQUENT Intellectual disability HP:0001249

Show evidence (2 references)

PMID:36803942 SUPPORT Human Clinical

Intellectual disability is noted as a characteristic feature.

ORPHA:475 SUPPORT

"HP:0001249 | Intellectual disability | Very frequent (99-80%)"

Orphanet classifies intellectual disability as very frequent (99-80%) in isolated Joubert syndrome.

Global developmental delay VERY_FREQUENT Global developmental delay HP:0001263

Show evidence (2 references)

PMID:38502237 SUPPORT In Vitro

Psychomotor delay supports global developmental delay in JS.

ORPHA:475 SUPPORT

"HP:0001263 | Global developmental delay | Very frequent (99-80%)"

Orphanet classifies global developmental delay as very frequent (99-80%) in isolated Joubert syndrome.

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.

Gait disturbance FREQUENT Gait disturbance HP:0001288

Show evidence (1 reference)

ORPHA:475 SUPPORT

"HP:0001288 | Gait disturbance | Frequent (79-30%)"

Orphanet classifies gait disturbance as frequent (79-30%) in isolated Joubert syndrome.

Hydrocephalus OCCASIONAL Hydrocephalus HP:0000238

Show evidence (1 reference)

ORPHA:475 SUPPORT

"HP:0000238 | Hydrocephalus | Occasional (29-5%)"

Orphanet classifies hydrocephalus as occasional (29-5%) in isolated Joubert syndrome.

Tremor OCCASIONAL Tremor HP:0001337

Show evidence (1 reference)

ORPHA:475 SUPPORT

"HP:0001337 | Tremor | Occasional (29-5%)"

Orphanet classifies tremor as occasional (29-5%) in isolated Joubert syndrome.

Seizure OCCASIONAL Seizure HP:0001250

Show evidence (2 references)

PMID:33717386 SUPPORT Human Clinical

"presenting with dyspnea, cyanosis, signs of respiratory distress and seizures."

This neonatal case report documents seizures in JS.

ORPHA:475 SUPPORT

"HP:0001250 | Seizure | Occasional (29-5%)"

Orphanet classifies seizures as occasional (29-5%) in isolated Joubert syndrome.

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

Respiratory system abnormalities are reported among characteristic features.

Episodic tachypnea VERY_FREQUENT Episodic tachypnea HP:0002876

Show evidence (2 references)

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.

ORPHA:475 SUPPORT

"HP:0002876 | Episodic tachypnea | Very frequent (99-80%)"

Orphanet classifies episodic tachypnea as very frequent (99-80%) in isolated Joubert syndrome, upgrading from single case report evidence.

Apnea VERY_FREQUENT Apnea HP:0002104

Show evidence (2 references)

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.

ORPHA:475 SUPPORT

"HP:0002104 | Apnea | Very frequent (99-80%)"

Orphanet classifies apnea as very frequent (99-80%) in isolated Joubert syndrome.

Other 9

Biparietal narrowing FREQUENT Biparietal narrowing HP:0004422

Show evidence (1 reference)

ORPHA:475 SUPPORT

"HP:0004422 | Biparietal narrowing | Frequent (79-30%)"

Orphanet classifies biparietal narrowing as frequent (79-30%) in isolated Joubert syndrome.

Abnormal pattern of respiration VERY_FREQUENT Abnormal pattern of respiration HP:0002793

Show evidence (1 reference)

ORPHA:475 SUPPORT

"HP:0002793 | Abnormal pattern of respiration | Very frequent (99-80%)"

Orphanet classifies abnormal pattern of respiration as very frequent (99-80%) in isolated Joubert syndrome.

Iris coloboma OCCASIONAL Iris coloboma HP:0000612

Show evidence (1 reference)

ORPHA:475 SUPPORT

"HP:0000612 | Iris coloboma | Occasional (29-5%)"

Orphanet classifies iris coloboma as occasional (29-5%) in isolated Joubert syndrome.

Encephalocele OCCASIONAL Encephalocele HP:0002084

Show evidence (1 reference)

ORPHA:475 SUPPORT

"HP:0002084 | Encephalocele | Occasional (29-5%)"

Orphanet classifies encephalocele as occasional (29-5%) in isolated Joubert syndrome.

Hand polydactyly OCCASIONAL Hand polydactyly HP:0001161

Show evidence (1 reference)

ORPHA:475 SUPPORT

"HP:0001161 | Hand polydactyly | Occasional (29-5%)"

Orphanet classifies hand polydactyly as occasional (29-5%) in isolated Joubert syndrome.

Foot polydactyly OCCASIONAL Foot polydactyly HP:0001829

Show evidence (1 reference)

ORPHA:475 SUPPORT

"HP:0001829 | Foot polydactyly | Occasional (29-5%)"

Orphanet classifies foot polydactyly as occasional (29-5%) in isolated Joubert syndrome.

Aplasia/Hypoplasia of the corpus callosum OCCASIONAL Aplasia/Hypoplasia of the corpus callosum HP:0007370

Show evidence (1 reference)

ORPHA:475 SUPPORT

"HP:0007370 | Aplasia/Hypoplasia of the corpus callosum | Occasional (29-5%)"

Orphanet classifies corpus callosum anomalies as occasional (29-5%) in isolated Joubert syndrome.

Aganglionic megacolon OCCASIONAL Aganglionic megacolon HP:0002251

Show evidence (1 reference)

ORPHA:475 SUPPORT

"HP:0002251 | Aganglionic megacolon | Occasional (29-5%)"

Orphanet classifies aganglionic megacolon as occasional (29-5%) in isolated Joubert syndrome.

Abnormal cardiovascular system morphology OCCASIONAL Abnormal cardiovascular system morphology HP:0030680

Show evidence (1 reference)

ORPHA:475 SUPPORT

"HP:0030680 | Abnormal cardiovascular system morphology | Occasional (29-5%)"

Orphanet classifies abnormal cardiovascular system morphology as occasional (29-5%) in isolated Joubert syndrome.

🧬

Genetic Associations

CPLANE1 (Causative)

Gene: CPLANE1 hgnc:25801

Show evidence (4 references)

PMID:36580738 SUPPORT Human Clinical

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)

Gene: CEP290 hgnc:29021

Show evidence (3 references)

PMID:36580738 SUPPORT Human Clinical

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)

Gene: TMEM67 hgnc:28396

Show evidence (4 references)

PMID:36580738 SUPPORT Human Clinical

This cohort identifies TMEM67 as a common JS gene.

PMID:35238134 SUPPORT Human Clinical

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)

Gene: AHI1 hgnc:21575

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)

Gene: ARMC9 hgnc:20730

Show evidence (1 reference)

PMID:36580738 SUPPORT Human Clinical

This cohort reports ARMC9 among causative JS genes.

CEP41 (Causative)

Gene: CEP41 hgnc:12370

Show evidence (1 reference)

PMID:36580738 SUPPORT Human Clinical

This cohort reports CEP41 among causative JS genes.

CSPP1 (Causative)

Gene: CSPP1 hgnc:26193

Show evidence (2 references)

PMID:36580738 SUPPORT Human Clinical

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)

Gene: HYLS1 hgnc:26558

Show evidence (1 reference)

PMID:36580738 SUPPORT Human Clinical

This cohort reports HYLS1 among causative JS genes.

KATNIP (Causative)

Gene: KATNIP hgnc:29068

Show evidence (1 reference)

PMID:36580738 SUPPORT Human Clinical

This cohort reports KATNIP among causative JS genes.

KIAA0586 (Causative)

Gene: KIAA0586 hgnc:19960

Show evidence (4 references)

PMID:36580738 SUPPORT Human Clinical

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 Human Clinical

"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)

Gene: KIF7 hgnc:30497

Show evidence (1 reference)

PMID:36580738 SUPPORT Human Clinical

This cohort reports KIF7 among causative JS genes.

RPGRIP1L (Causative)

Gene: RPGRIP1L hgnc:29168

Show evidence (4 references)

PMID:36580738 SUPPORT Human Clinical

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)

Gene: MKS1 hgnc:7121

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)

Gene: CC2D2A hgnc:29253

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)

Gene: OFD1 hgnc:2567

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)

Gene: TCTN1 hgnc:26113

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)

Gene: CEP120 hgnc:26690

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)

Gene: TOPORS hgnc:21653

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.

INPP5E (Causative)

Gene: INPP5E hgnc:21474

Show evidence (1 reference)

ORPHA:475 SUPPORT

"INPP5E | inositol polyphosphate-5-phosphatase E | hgnc:21474 | Disease-causing germline mutation(s) in"

Orphanet lists INPP5E as a disease-causing gene for isolated Joubert syndrome.

ARL13B (Causative)

Gene: ARL13B hgnc:25419

Show evidence (2 references)

ORPHA:475 SUPPORT

"ARL13B | ARF like GTPase 13B | hgnc:25419 | Disease-causing germline mutation(s) in"

Orphanet lists ARL13B as a disease-causing gene for isolated Joubert syndrome.

CGGV:assertion_f6c474c9-4035-498c-a902-03be50d36205-2020-06-03T210114.719Z SUPPORT Other

ClinGen classifies the ARL13B-Joubert syndrome gene-disease relationship as definitive with autosomal recessive inheritance.

TCTN2 (Causative)

Gene: TCTN2 hgnc:25774

Show evidence (1 reference)

ORPHA:475 SUPPORT

"TCTN2 | tectonic family member 2 | hgnc:25774 | Disease-causing germline mutation(s) in"

Orphanet lists TCTN2 as a disease-causing gene for isolated Joubert syndrome.

TCTN3 (Causative)

Gene: TCTN3 hgnc:24519

Show evidence (1 reference)

ORPHA:475 SUPPORT

"TCTN3 | tectonic family member 3 | hgnc:24519 | Disease-causing germline mutation(s) in"

Orphanet lists TCTN3 as a disease-causing gene for isolated Joubert syndrome.

B9D1 (Causative)

Gene: B9D1 hgnc:24123

Show evidence (1 reference)

ORPHA:475 SUPPORT

"B9D1 | B9 domain containing 1 | hgnc:24123 | Disease-causing germline mutation(s) in"

Orphanet lists B9D1 as a disease-causing gene for isolated Joubert syndrome.

B9D2 (Causative)

Gene: B9D2 hgnc:28636

Show evidence (1 reference)

ORPHA:475 SUPPORT

"B9D2 | B9 domain containing 2 | hgnc:28636 | Disease-causing germline mutation(s) in"

Orphanet lists B9D2 as a disease-causing gene for isolated Joubert syndrome.

TMEM237 (Causative)

Gene: TMEM237 hgnc:14432

Show evidence (1 reference)

ORPHA:475 SUPPORT

"TMEM237 | transmembrane protein 237 | hgnc:14432 | Disease-causing germline mutation(s) in"

Orphanet lists TMEM237 as a disease-causing gene for isolated Joubert syndrome.

TOGARAM1 (Causative)

Gene: TOGARAM1 hgnc:19959

Show evidence (1 reference)

ORPHA:475 SUPPORT

"TOGARAM1 | TOG array regulator of axonemal microtubules 1 | hgnc:19959 | Disease-causing germline mutation(s) in"

Orphanet lists TOGARAM1 as a disease-causing gene for isolated Joubert syndrome.

SUFU (Causative)

Gene: SUFU hgnc:16466

Show evidence (1 reference)

ORPHA:475 SUPPORT

"SUFU | SUFU negative regulator of hedgehog signaling | hgnc:16466 | Disease-causing germline mutation(s) in"

Orphanet lists SUFU as a disease-causing gene for isolated Joubert syndrome.

IFT74 (Causative)

Gene: IFT74 hgnc:21424

Show evidence (1 reference)

ORPHA:475 SUPPORT

"IFT74 | intraflagellar transport 74 | hgnc:21424 | Disease-causing germline mutation(s) in"

Orphanet lists IFT74 as a disease-causing gene for isolated Joubert syndrome.

PDE6D (Causative)

Gene: PDE6D hgnc:8788

Show evidence (1 reference)

ORPHA:475 SUPPORT

"PDE6D | phosphodiesterase 6D | hgnc:8788 | Disease-causing germline mutation(s) in"

Orphanet lists PDE6D as a disease-causing gene for isolated Joubert syndrome.

PIBF1 (Causative)

Gene: PIBF1 hgnc:23352

Show evidence (1 reference)

ORPHA:475 SUPPORT

"PIBF1 | progesterone immunomodulatory binding factor 1 | hgnc:23352 | Disease-causing germline mutation(s) in"

Orphanet lists PIBF1 as a disease-causing gene for isolated Joubert syndrome.

CBY1 (Causative)

Gene: CBY1 hgnc:1307

Show evidence (1 reference)

ORPHA:475 SUPPORT

"CBY1 | chibby 1, beta catenin antagonist | hgnc:1307 | Disease-causing germline mutation(s) (loss of function) in"

Orphanet lists CBY1 loss-of-function as disease-causing for isolated Joubert syndrome.

TMEM218 (Causative)

Gene: TMEM218 hgnc:27344

Show evidence (1 reference)

ORPHA:475 SUPPORT

"TMEM218 | transmembrane protein 218 | hgnc:27344 | Disease-causing germline mutation(s) (loss of function) in"

Orphanet lists TMEM218 loss-of-function as disease-causing for isolated Joubert syndrome.

CEP104 (Causative)

Gene: CEP104 hgnc:24866

Show evidence (1 reference)

ORPHA:475 SUPPORT

"CEP104 | centrosomal protein 104 | hgnc:24866 | Disease-causing germline mutation(s) in"

Orphanet lists CEP104 as a disease-causing gene for isolated Joubert syndrome.

ARL3 (Causative)

Gene: ARL3 hgnc:694

Show evidence (1 reference)

ORPHA:475 SUPPORT

"ARL3 | ARF like GTPase 3 | hgnc:694 | Disease-causing germline mutation(s) in"

Orphanet lists ARL3 as a disease-causing gene for isolated Joubert syndrome.

KIAA0753 (Causative)

Gene: KIAA0753 hgnc:29110

Show evidence (1 reference)

ORPHA:475 SUPPORT

"KIAA0753 | KIAA0753 | hgnc:29110 | Disease-causing germline mutation(s) in"

Orphanet lists KIAA0753 as a disease-causing gene for isolated Joubert syndrome.

💊

Medical Actions

Supportive care

Action: 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

Action: 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

Action: 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

Action: 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

Action: 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

Action: 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

Action: liver transplantation MAXO:0001175

Treatment for severe portal hypertension in COACH syndrome (Joubert syndrome with congenital hepatic fibrosis).

Mechanism Target:

MODULATES Biliary ductal plate malformation via ciliary tight junction defect — Liver transplantation addresses end-stage portal hypertension caused by congenital hepatic fibrosis from ciliary tight-junction defects in bile duct morphogenesis; it does not correct the underlying ciliopathy.

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.

Kidney transplantation

Action: kidney transplantation Ontology label: Kidney Transplantation NCIT:C15265

Treatment for end-stage kidney disease in JS patients with progressive renal ciliopathy. Pre-emptive and post-dialysis kidney transplantation are both feasible.

Mechanism Target:

MODULATES Renal tubular ciliary dysfunction — Kidney transplantation replaces end-stage renal tissue lost to ciliopathy- driven tubular dysfunction; the transplanted organ has normal ciliary function, bypassing the JS renal defect.

Show evidence (2 references)

PMID:33432080 SUPPORT Human Clinical

"Hemodialysis was performed using arteriovenous fistula in two cases, and kidney transplantation was performed 9 times in eight cases."

This Japanese cohort of 11 JS patients with ESKD documents kidney transplantation as a feasible RRT modality.

PMID:33432080 SUPPORT Human Clinical

"Any type of RRT modality can be a treatment option for patients with JS and ESKD."

The cohort's overall conclusion supports any RRT modality, including transplantation, as effective in JS-ESKD.

Renal dialysis

Action: renal dialysis MAXO:0000601

Peritoneal dialysis or hemodialysis for JS patients with end-stage kidney disease, often as a bridge to transplantation.

Mechanism Target:

MODULATES Renal tubular ciliary dysfunction — Renal dialysis provides renal replacement for end-stage kidney disease caused by JS ciliopathy-driven tubular dysfunction, serving as bridge therapy or long-term substitute when transplantation is not feasible.

Show evidence (1 reference)

PMID:33432080 SUPPORT Human Clinical

"Peritoneal dialysis (PD) was introduced in seven cases, with a median treatment duration of 5.4 (3.4-10.7) years."

Documents peritoneal dialysis as a long-duration RRT modality used in JS patients with ESKD.

Caffeine for neonatal apnea

Action: Pharmacotherapy NCIT:C15986

Agent: caffeine CHEBI:27732

Caffeine citrate to ameliorate central apneic episodes in neonates with Joubert syndrome.

Mechanism Target:

MODULATES Brainstem control center dysfunction — Caffeine is a non-selective adenosine receptor antagonist that stimulates central respiratory drive, compensating for the brainstem rhythmogenesis impairment arising from ciliopathy-driven midbrain-hindbrain patterning defects.

Show evidence (1 reference)

PMID:15385018 SUPPORT Human Clinical

"suggest consideration of the use of caffeine to ameliorate the apneic episodes seen in early infancy in this syndrome."

Case report recommends caffeine for neonatal apneic episodes in JS.

🔬

Biochemical Markers

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

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

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

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

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

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: '2026-04-28T12:00:00Z'
description: >-
  Joubert syndrome is a rare, autosomal recessive neurodevelopmental ciliopathy
  characterized by congenital malformation of the brainstem and agenesis or
  hypoplasia of the cerebellar vermis producing the characteristic molar tooth
  sign on brain MRI. Clinical features include abnormal respiratory pattern,
  nystagmus, hypotonia, ataxia, delay in achieving motor milestones, and
  multisystem involvement affecting the 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
    reference_title: "Genetics Review: Joubert Syndrome."
    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
    reference_title: "Joubert syndrome: a case report of neonatal presentation and early diagnosis."
    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
- population: Italy
  percentage: 0.47 per 100,000 (overall); 1.7 per 100,000 in 0-19 year olds
  evidence:
  - reference: ORPHA:475
    supports: SUPPORT
    snippet: "1-9 / 1 000 000 | Italy | Point prevalence | PMID:31969461"
    explanation: Orphanet cites Italian point prevalence from a population-based study.
  - reference: PMID:31969461
    supports: SUPPORT
    snippet: "We identified 284 patients with JS"
    explanation: First population-based prevalence estimate of JS in Italy, identifying 284 patients with an overall rate of 0.47 per 100,000.
    evidence_source: HUMAN_CLINICAL
- population: Spain
  percentage: At least 1 in 20,000 newborns per year
  evidence:
  - reference: ORPHA:475
    supports: SUPPORT
    snippet: "1-9 / 100 000 | Spain | Prevalence at birth | PMID:34308544"
    explanation: Orphanet cites Spanish birth prevalence from a regional cohort study.
  - reference: PMID:34308544
    supports: SUPPORT
    snippet: "The incidence of Joubert syndrome was at least 1 / 20,000 newborns / year."
    explanation: Spanish regional cohort reports JS birth incidence higher than prior global estimates.
    evidence_source: HUMAN_CLINICAL
- population: Worldwide (estimated)
  percentage: 1:80,000-1:100,000 newborns
  evidence:
  - reference: ORPHA:475
    supports: SUPPORT
    snippet: "1-9 / 100 000 | Worldwide | Prevalence at birth | PMID:35860112"
    explanation: Orphanet cites worldwide birth prevalence from case report literature.
  - reference: PMID:35860112
    supports: SUPPORT
    snippet: "The incidence of estimated to be from 1:80,000 to 1:100,000."
    explanation: Case report cites the commonly reported global incidence 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
    reference_title: "Growth in Joubert syndrome: Growth curves and physical measurements with correlation to genotype and hepatorenal disease in 170 individuals."
    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
    reference_title: "Joubert Syndrome in Children-A Comprehensive Analysis of Quality of Life, Functional Independence and Family Impact."
    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
    reference_title: "Joubert Syndrome in Children-A Comprehensive Analysis of Quality of Life, Functional Independence and Family Impact."
    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
    reference_title: "Joubert syndrome: Molecular basis and treatment."
    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
  - reference: ORPHA:475
    supports: SUPPORT
    snippet: "Autosomal recessive"
    explanation: Orphanet classifies isolated Joubert syndrome as autosomal recessive.
- 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
    reference_title: "The expanding phenotype of OFD1-related disorders: Hemizygous loss-of-function variants in three patients with primary ciliary dyskinesia."
    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
    reference_title: "The expanding phenotype of OFD1-related disorders: Hemizygous loss-of-function variants in three patients with primary ciliary dyskinesia."
    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: Pathogenic JBTS gene defects
  description: >-
    Biallelic (or hemizygous, for X-linked OFD1) pathogenic variants in
    over 40 ciliary genes initiate Joubert syndrome. The encoded proteins
    localize to distinct primary cilium subcompartments — basal body,
    transition zone, axoneme/ciliary tip, and intraflagellar transport
    machinery — and converge on disrupted primary cilium structure and
    function.
  genes:
  - preferred_term: CPLANE1
    term:
      id: hgnc:25801
      label: CPLANE1
  - preferred_term: CEP290
    term:
      id: hgnc:29021
      label: CEP290
  - preferred_term: TMEM67
    term:
      id: hgnc:28396
      label: TMEM67
  - preferred_term: AHI1
    term:
      id: hgnc:21575
      label: AHI1
  - preferred_term: ARMC9
    term:
      id: hgnc:20730
      label: ARMC9
  - preferred_term: CSPP1
    term:
      id: hgnc:26193
      label: CSPP1
  - preferred_term: KIAA0586
    term:
      id: hgnc:19960
      label: KIAA0586
  - preferred_term: RPGRIP1L
    term:
      id: hgnc:29168
      label: RPGRIP1L
  - preferred_term: MKS1
    term:
      id: hgnc:7121
      label: MKS1
  - preferred_term: CC2D2A
    term:
      id: hgnc:29253
      label: CC2D2A
  - preferred_term: OFD1
    term:
      id: hgnc:2567
      label: OFD1
  evidence:
  - reference: PMID:38502237
    reference_title: "Joubert syndrome-derived induced pluripotent stem cells show altered neuronal differentiation in vitro."
    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: Defines the genetic architecture of JS as variants in genes encoding primary cilium components.
    evidence_source: IN_VITRO
  - reference: PMID:36580738
    reference_title: "Clinical and genetic spectrum from a prototype of ciliopathy: Joubert syndrome."
    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: Anchors a representative list of recurrent JS-causative ciliary genes from a clinical cohort.
    evidence_source: HUMAN_CLINICAL
  downstream:
  - target: Ciliary gene mutations disrupt primary cilium assembly
    description: Variants in genes encoding basal body, axonemal, and intraflagellar transport components compromise primary cilium biogenesis.
  - target: Ciliary transition zone gating defect
    description: Variants in transition zone genes (e.g., TMEM67, CC2D2A, MKS1, CEP290, B9D2) disrupt the ciliary gate.
  - target: Defective ciliary tip microtubule dynamics
    description: Variants in ciliary tip module genes (CEP104, CSPP1, TOGARAM1, ARMC9, CCDC66) disrupt axonemal microtubule growth.
  - target: Defective canonical Wnt signaling at the cerebellar midline
    description: Loss of AHI1/Jouberin (and CEP290) disrupts cilium-coupled canonical Wnt signaling at the cerebellar dorsal midline.
- 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.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: cilium assembly
    term:
      id: GO:0060271
      label: cilium assembly
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:38502237
    reference_title: "Joubert syndrome-derived induced pluripotent stem cells show altered neuronal differentiation in vitro."
    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
    reference_title: "Ciliopathy-related B9 protein complex regulates ciliary axonemal microtubule posttranslational modifications and initiation of ciliogenesis."
    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
  downstream:
  - target: Abnormal cilium structure and length
    description: Failed cilium assembly produces cilia with abnormal number, morphology, and length.
  - target: Impaired intraciliary transport
    description: Defective primary cilium biogenesis disrupts the cilium machinery required for intraciliary transport.
  - target: Hippocampal neurogenesis defect
    description: Loss of basal-body proteins (e.g., KIAA0586/Talpid3) required for cilium assembly disrupts hippocampal progenitor proliferation and migration.
- 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
    reference_title: "Joubert syndrome-derived induced pluripotent stem cells show altered neuronal differentiation in vitro."
    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
    reference_title: "Deficiency of the minor spliceosome component U4atac snRNA secondarily results in ciliary defects in human and zebrafish."
    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
    reference_title: "Shared and unique consequences of Joubert Syndrome gene dysfunction on the zebrafish central nervous system."
    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
    reference_title: "Molecular treatment options for patients carrying KIAA0586/TALPID3 variants."
    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
  downstream:
  - target: Defective Sonic hedgehog signaling
    description: Abnormal cilium structure compromises the cilium-dependent transduction of Hedgehog signaling.
  - target: Photoreceptor outer segment dystrophy
    description: Photoreceptor outer segments are modified primary cilia and are particularly sensitive to abnormal cilium structure.
  - target: Renal tubular ciliary dysfunction
    description: Renal tubular epithelial cilia mediate cilium-dependent homeostasis that is disrupted by abnormal cilium morphology.
- 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
    reference_title: "A case report of Joubert syndrome with renal involvement and seizures in a neonate."
    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
  downstream:
  - target: Photoreceptor outer segment dystrophy
    description: Defective intraciliary cargo transport mislocalizes outer-segment proteins required for photoreceptor function.
  - target: Renal tubular ciliary dysfunction
    description: Impaired ciliary transport disrupts renal tubular cilium-dependent signaling.
  - target: Neurodevelopmental defects
    description: Disrupted ciliary trafficking impairs cilium-dependent neurodevelopmental signaling.
- name: Neurodevelopmental defects
  description: >-
    Disrupted ciliary biology impairs neurodevelopmental programs, contributing
    to mid-hindbrain and cerebellar developmental abnormalities.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  - preferred_term: cerebellar granule cell
    term:
      id: CL:0001031
      label: cerebellar granule cell
  evidence:
  - reference: PMID:38502237
    reference_title: "Joubert syndrome-derived induced pluripotent stem cells show altered neuronal differentiation in vitro."
    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
    reference_title: "Genetics Review: Joubert Syndrome."
    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
  downstream:
  - target: Defective midbrain-hindbrain patterning
    description: Disrupted ciliary signaling perturbs mid-hindbrain morphogenesis underlying the JS brain malformation.
  - target: Cerebellar vermis hypoplasia
    description: Impaired neurodevelopmental programs lead to vermian hypoplasia, the cardinal cerebellar feature of JS.
  - target: Intellectual disability
    description: Neurodevelopmental disruption manifests as intellectual disability.
  - target: Global developmental delay
    description: Neurodevelopmental disruption manifests as global developmental delay.
- name: Defective ciliary tip microtubule dynamics
  description: >-
    A ciliary tip module composed of CEP104, CSPP1, TOGARAM1, ARMC9 and
    CCDC66 controls the very slow processive growth of axonemal
    microtubules. Loss-of-function variants in module members destabilize
    this assembly and disrupt axonemal microtubule dynamics that are
    required to build and maintain the primary cilium.
  genes:
  - preferred_term: CSPP1
    term:
      id: hgnc:26193
      label: CSPP1
  - preferred_term: ARMC9
    term:
      id: hgnc:20730
      label: ARMC9
  - preferred_term: CEP120
    term:
      id: hgnc:26690
      label: CEP120
  cellular_components:
  - preferred_term: axoneme
    term:
      id: GO:0005930
      label: axoneme
  evidence:
  - reference: PMID:39856351
    reference_title: "A network of interacting ciliary tip proteins with opposing activities imparts slow and processive microtubule growth."
    supports: SUPPORT
    snippet: "Here we reconstituted in vitro the individual and collective activities of the ciliary tip module proteins CEP104, CSPP1, TOGARAM1, ARMC9 and CCDC66, which interact with each other and with microtubules and, when mutated in humans, cause ciliopathies such as Joubert syndrome."
    explanation: Defines the ciliary tip module whose members are JBTS-causative and act together to control axonemal microtubule growth.
    evidence_source: IN_VITRO
  downstream:
  - target: Abnormal cilium structure and length
    description: Disrupted ciliary tip microtubule dynamics produce cilia of abnormal length and morphology.
- name: Ciliary transition zone gating defect
  conforms_to: "ciliopathy_dysfunction#Basal Body and Transition Zone Dysfunction"
  description: >-
    The ciliary transition zone (TZ) is a gatekeeper subdomain that
    controls passage of signaling proteins into and out of the cilium.
    The TMEM67/MKS module (TMEM67, MKS1, B9D1, B9D2, CC2D2A) and the
    NPHP module are anchored at the TZ; pathogenic variants in JS genes
    encoding TZ components reduce TZ gating, anchoring of TMEM67, and
    posttranslational tubulin modifications.
  genes:
  - preferred_term: TMEM67
    term:
      id: hgnc:28396
      label: TMEM67
  - preferred_term: CC2D2A
    term:
      id: hgnc:29253
      label: CC2D2A
  - preferred_term: MKS1
    term:
      id: hgnc:7121
      label: MKS1
  - preferred_term: CEP290
    term:
      id: hgnc:29021
      label: CEP290
  - preferred_term: B9D1
    term:
      id: hgnc:24123
      label: B9D1
  - preferred_term: B9D2
    term:
      id: hgnc:28636
      label: B9D2
  cellular_components:
  - preferred_term: ciliary transition zone
    term:
      id: GO:0035869
      label: ciliary transition zone
  evidence:
  - reference: PMID:35137054
    reference_title: "The ciliary transition zone protein TMEM218 synergistically interacts with the NPHP module and its reduced dosage leads to a wide range of syndromic ciliopathies."
    supports: SUPPORT
    snippet: "We identified biallelic missense and nonsense mutations in the gene encoding the transmembrane protein TMEM218 in unrelated patients with features related to Bardet-Biedl, Joubert and Meckel-Gruber syndrome (MKS) and characterized TMEM218 as a major component of the ciliary TZ module."
    explanation: Establishes that JBTS-spectrum disease arises from variants in genes encoding ciliary transition zone module components.
    evidence_source: HUMAN_CLINICAL
  - reference: PMID:41165761
    reference_title: "Ciliopathy-related B9 protein complex regulates ciliary axonemal microtubule posttranslational modifications and initiation of ciliogenesis."
    supports: SUPPORT
    snippet: "The B9 complex interacted with and anchored TMEM67 to the TZ membrane."
    explanation: Defines a direct molecular interaction at the transition zone whose disruption is a JBTS mechanism.
    evidence_source: IN_VITRO
  downstream:
  - target: Impaired intraciliary transport
    description: A defective TZ gate compromises selective entry and exit of ciliary cargo.
  - target: Defective Sonic hedgehog signaling
    description: TZ gating is required for ciliary localization of Hedgehog pathway components (SMO, GPR161, TULP3).
  - target: Biliary ductal plate malformation via ciliary tight junction defect
    description: B9D2 also functions extra-ciliarly in tight junctions; its loss disrupts biliary epithelial polarity.
- name: Defective Sonic hedgehog signaling
  conforms_to: "ciliopathy_dysfunction#Impaired Hedgehog Signal Transduction"
  description: >-
    Hedgehog signal transduction depends on regulated trafficking of
    Smoothened and other Hh components through the primary cilium.
    Disrupted ciliary structure or transition zone gating in JS reduces
    Hh signaling, perturbing Hh-dependent neural patterning and limb
    development.
  cell_types:
  - preferred_term: neural progenitor cell
    term:
      id: CL:0011020
      label: neural progenitor cell
  biological_processes:
  - preferred_term: smoothened signaling pathway
    term:
      id: GO:0007224
      label: smoothened signaling pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:39385469
    reference_title: "Togaram1 is expressed in the neural tube and its absence causes neural tube closure defects."
    supports: SUPPORT
    snippet: "We show that Togaram1 is expressed in the neural tube and Togaram1 knockout mice have abnormal cilia, reduced sonic hedgehog (Shh) signaling, abnormal neural tube patterning, and display neural tube closure defects."
    explanation: Demonstrates that loss of a JBTS gene reduces ciliary Shh signaling and perturbs cilium-dependent patterning.
    evidence_source: MODEL_ORGANISM
  downstream:
  - target: Defective midbrain-hindbrain patterning
    description: Reduced cilium-dependent Hedgehog signaling disrupts mid-hindbrain morphogenesis.
  - target: Polydactyly
    description: Cilium-dependent Hedgehog signaling is required for limb-bud patterning; its disruption causes preaxial/postaxial digit duplication.
- name: Defective canonical Wnt signaling at the cerebellar midline
  description: >-
    AHI1 (Jouberin) participates in canonical Wnt signal transduction.
    In Ahi1-mutant mouse cerebellum, Wnt reporter activity is reduced at
    the site of cerebellar hemisphere fusion, producing a vermis-midline
    fusion defect that recapitulates the human cerebellar vermis
    hypoplasia of JS. The defect is partially rescued by lithium, a Wnt
    pathway agonist.
  cell_types:
  - preferred_term: neural progenitor cell
    term:
      id: CL:0011020
      label: neural progenitor cell
  - preferred_term: cerebellar granule cell precursor
    term:
      id: CL:0002362
      label: cerebellar granule cell precursor
  genes:
  - preferred_term: AHI1
    term:
      id: hgnc:21575
      label: AHI1
  - preferred_term: CEP290
    term:
      id: hgnc:29021
      label: CEP290
  biological_processes:
  - preferred_term: canonical Wnt signaling pathway
    term:
      id: GO:0060070
      label: canonical Wnt signaling pathway
    modifier: DECREASED
  locations:
  - preferred_term: cerebellar vermis
    term:
      id: UBERON:0004720
      label: cerebellar vermis
  evidence:
  - reference: PMID:21623382
    reference_title: "Defective Wnt-dependent cerebellar midline fusion in a mouse model of Joubert syndrome."
    supports: SUPPORT
    snippet: "Our findings implicate a defect in Wnt signaling in the cerebellar midline phenotype seen in Joubert syndrome that can be overcome with Wnt stimulation."
    explanation: Directly links AHI1/Jouberin loss to defective canonical Wnt signaling at the developing cerebellar midline.
    evidence_source: MODEL_ORGANISM
  - reference: PMID:21623382
    reference_title: "Defective Wnt-dependent cerebellar midline fusion in a mouse model of Joubert syndrome."
    supports: SUPPORT
    snippet: "These mice show cerebellar hypoplasia with a vermis-midline fusion defect early in development."
    explanation: Shows that AHI1 loss in mice produces a cerebellar vermis-midline fusion defect that parallels human JS.
    evidence_source: MODEL_ORGANISM
  downstream:
  - target: Cerebellar vermis hypoplasia
    description: Reduced Wnt-dependent proliferation at the dorsal midline produces vermis hypoplasia.
  - target: Molar tooth sign on MRI
    description: Vermis hypoplasia is the dominant component of the molar tooth sign.
- name: Defective midbrain-hindbrain patterning
  conforms_to: "ciliopathy_dysfunction#Cerebellar and CNS Malformation"
  description: >-
    Disrupted ciliary signaling perturbs morphogenesis of the
    midbrain-hindbrain boundary, producing the characteristic JS
    malformation: hypoplasia of the cerebellar vermis, thickened/elongated
    superior cerebellar peduncles, and a deepened interpeduncular fossa.
  biological_processes:
  - preferred_term: midbrain-hindbrain boundary morphogenesis
    term:
      id: GO:0021555
      label: midbrain-hindbrain boundary morphogenesis
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:40537162
    reference_title: "Genetics Review: Joubert Syndrome."
    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: Documents the mid-hindbrain malformation pattern that defines the JS molar tooth sign.
    evidence_source: HUMAN_CLINICAL
  downstream:
  - target: Defective superior cerebellar peduncle decussation
    description: Mid-hindbrain patterning defects underlie the failure of axonal decussation across the brainstem midline.
  - target: Cerebellar vermis hypoplasia
    description: Failed midline morphogenesis produces vermian hypoplasia.
  - target: Brainstem control center dysfunction
    description: Mid-hindbrain malformation disrupts brainstem nuclei controlling respiratory rhythm and ocular motor pathways.
- name: Defective superior cerebellar peduncle decussation
  description: >-
    A defining feature of JS is failure of axons to cross the midline at
    the superior cerebellar peduncles, the central pontine tracts, and
    the corticospinal tracts. This points to a defective axon-guidance
    program at the mid-hindbrain junction and contributes directly to
    the molar tooth sign and the cerebellar/motor phenotypes.
  biological_processes:
  - preferred_term: axon guidance
    term:
      id: GO:0007411
      label: axon guidance
    modifier: DYSREGULATED
  locations:
  - preferred_term: superior cerebellar peduncle
    term:
      id: UBERON:0002150
      label: superior cerebellar peduncle
  - preferred_term: decussation of superior cerebellar peduncle
    term:
      id: UBERON:0002588
      label: decussation of superior cerebellar peduncle
  evidence:
  - reference: PMID:24592023
    reference_title: "Joubert syndrome and related disorders, prenatal diagnosis with ultrasound and magnetic resonance imaging."
    supports: SUPPORT
    snippet: "JSRD is characterized by lack of decussation of the superior cerebellar peduncles, central pontine tracts and corticospinal tracts suggesting defective axon guidance."
    explanation: Establishes failed midline decussation in JS as a defective axon-guidance phenotype at the mid-hindbrain junction.
    evidence_source: HUMAN_CLINICAL
  downstream:
  - target: Molar tooth sign on MRI
    description: Elongated, non-decussating superior cerebellar peduncles plus deep interpeduncular fossa produce the molar tooth radiographic sign.
  - target: Hypotonia
    description: Disrupted brainstem motor pathways contribute to early hypotonia.
  - target: Ataxia
    description: Loss of cerebellar output decussation contributes to ataxia.
- name: Hippocampal neurogenesis defect
  description: >-
    KIAA0586/Talpid3 is a basal-body protein required for primary cilium
    assembly. Talpid3 mutant mice show reduced proliferation in the
    dentate gyrus, a disrupted glial scaffold, and mis-localized
    progenitors in the granule cell layer — defective hippocampal
    neurogenesis that links ciliary dysfunction to learning and memory
    deficits seen in JS patients.
  genes:
  - preferred_term: KIAA0586
    term:
      id: hgnc:19960
      label: KIAA0586
  cell_types:
  - preferred_term: neural progenitor cell
    term:
      id: CL:0011020
      label: neural progenitor cell
  evidence:
  - reference: PMID:35470378
    reference_title: "Hippocampals neurogenesis is impaired in mice with a deletion in the coiled coil domain of Talpid3-implications for Joubert syndrome."
    supports: SUPPORT
    snippet: "At early postnatal stages, the Talpid3 mutants exhibit a reduction in proliferation in the dentate gyrus and a disrupted glial scaffold."
    explanation: Demonstrates a hippocampal neurogenesis defect in a Talpid3 (KIAA0586) JS model.
    evidence_source: MODEL_ORGANISM
  - reference: PMID:35470378
    reference_title: "Hippocampals neurogenesis is impaired in mice with a deletion in the coiled coil domain of Talpid3-implications for Joubert syndrome."
    supports: SUPPORT
    snippet: "Our findings suggest a link between the hippocampal defects and the learning/memory deficits seen in JS patients."
    explanation: Connects the model-organism hippocampal phenotype to human JS cognitive features.
    evidence_source: MODEL_ORGANISM
  downstream:
  - target: Intellectual disability
    description: Hippocampal neurogenesis defects contribute to learning/memory impairment.
  - target: Global developmental delay
    description: Hippocampal and other ciliary neurogenesis defects manifest as global developmental delay.
- name: Photoreceptor outer segment dystrophy
  conforms_to: "ciliopathy_dysfunction#Photoreceptor Connecting Cilium Degeneration"
  description: >-
    Photoreceptor outer segments are highly modified primary cilia.
    Pathogenic JS variants affecting transition zone gating (CEP290) or
    its interactors (NPHP5/IQCB1) produce aberrantly elongated ciliary
    axonemes, impaired outer segment development, and mislocalization of
    visual pigments to photoreceptor cell soma — the cellular basis of
    JS-associated retinal dystrophy.
  genes:
  - preferred_term: CEP290
    term:
      id: hgnc:29021
      label: CEP290
  - preferred_term: AHI1
    term:
      id: hgnc:21575
      label: AHI1
  cell_types:
  - preferred_term: photoreceptor cell
    term:
      id: CL:0000210
      label: photoreceptor cell
  cellular_components:
  - preferred_term: photoreceptor outer segment
    term:
      id: GO:0001750
      label: photoreceptor outer segment
  evidence:
  - reference: PMID:36084637
    reference_title: "In vitro modeling and rescue of ciliopathy associated with IQCB1/NPHP5 mutations using patient-derived cells."
    supports: SUPPORT
    snippet: "Organoids revealed impaired development of outer segment structures, which are modified primary cilia, and mislocalization of visual pigments to photoreceptor cell soma."
    explanation: Patient-derived retinal organoids show outer segment defects and visual pigment mislocalization driven by transition zone disruption.
    evidence_source: IN_VITRO
  - reference: PMID:36084637
    reference_title: "In vitro modeling and rescue of ciliopathy associated with IQCB1/NPHP5 mutations using patient-derived cells."
    supports: SUPPORT
    snippet: "All patient-derived cells showed reduced levels of CEP290 protein, a critical cilia transition zone component interacting with NPHP5, providing a plausible mechanism for aberrant ciliary gating and cargo transport."
    explanation: Mechanistically links transition zone (CEP290/NPHP5) dysfunction to photoreceptor cilium failure.
    evidence_source: IN_VITRO
  downstream:
  - target: Retinal dystrophy
    description: Outer segment dystrophy and visual pigment mislocalization produce progressive retinal dystrophy.
- name: Renal tubular ciliary dysfunction
  conforms_to: "ciliopathy_dysfunction#Renal Tubular Cystic and Fibrotic Disease"
  description: >-
    Renal tubular epithelial cells require functional primary cilia for
    homeostasis. Variants in JS genes encoding transition zone (CEP290)
    and NPHP-module components disrupt tubular ciliary signaling and
    drive nephronophthisis-type tubulointerstitial disease and renal
    cyst formation. CEP290 variants in particular confer chronic kidney
    disease risk that warrants surveillance.
  genes:
  - preferred_term: CEP290
    term:
      id: hgnc:29021
      label: CEP290
  - preferred_term: RPGRIP1L
    term:
      id: hgnc:29168
      label: RPGRIP1L
  cell_types:
  - preferred_term: kidney tubule cell
    term:
      id: CL:1000507
      label: kidney tubule cell
  evidence:
  - reference: PMID:35238134
    reference_title: "Genotype-phenotype correlates in Joubert syndrome: A review."
    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: Genotype-phenotype review identifies CEP290 as a JS subtype with elevated chronic kidney disease risk.
    evidence_source: HUMAN_CLINICAL
  - reference: PMID:35238134
    reference_title: "Genotype-phenotype correlates in Joubert syndrome: A review."
    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: Defines the JS gene subset whose variants converge on renal tubular ciliopathy.
    evidence_source: HUMAN_CLINICAL
  downstream:
  - target: Nephronophthisis
    description: Tubular ciliopathy drives the nephronophthisis-type tubulointerstitial kidney disease in JS.
  - target: Renal cyst
    description: Disrupted cilium-dependent tubular signaling produces renal cysts.
- name: Biliary ductal plate malformation via ciliary tight junction defect
  description: >-
    TMEM67 variants confer the highest risk of liver fibrosis among JS
    genotypes. Mechanistically, B9D2 — a TMEM67 partner at the ciliary
    transition zone — also acts before ciliogenesis to mature and
    maintain epithelial tight junctions, ensuring biliary lumen
    formation. Loss of B9D2 function disrupts cholangiocyte tight
    junctions and biliary lumen formation, producing the ductal plate
    malformation that underlies congenital hepatic fibrosis and portal
    hypertension in JS.
  genes:
  - preferred_term: TMEM67
    term:
      id: hgnc:28396
      label: TMEM67
  - preferred_term: B9D2
    term:
      id: hgnc:28636
      label: B9D2
  cell_types:
  - preferred_term: cholangiocyte
    term:
      id: CL:1000488
      label: cholangiocyte
  biological_processes:
  - preferred_term: tight junction assembly
    term:
      id: GO:0120192
      label: tight junction assembly
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:39455645
    reference_title: "New functions of B9D2 in tight junctions and epithelial polarity."
    supports: SUPPORT
    snippet: "Our work demonstrates that before ciliogenesis occurs, B9D2 is crucial for the maturation and maintenance of tight junctions ensuring epithelial barrier tightness and appropriate biliary lumen formation."
    explanation: Establishes a non-ciliary B9D2 function in tight junctions and biliary lumen formation as the mechanism of biliary dysgenesis in JS.
    evidence_source: IN_VITRO
  - reference: PMID:35238134
    reference_title: "Genotype-phenotype correlates in Joubert syndrome: A review."
    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: Identifies TMEM67 as the JS genotype most strongly associated with liver fibrosis, downstream of the biliary ductal plate defect.
    evidence_source: HUMAN_CLINICAL
  downstream:
  - target: Hepatic fibrosis
    description: Ductal plate malformation drives congenital hepatic fibrosis.
  - target: Portal hypertension
    description: Progressive hepatic fibrosis raises portal venous pressure.
  - target: Esophageal varix
    description: Portal hypertension produces porto-systemic collaterals including esophageal varices.
- name: Brainstem control center dysfunction
  description: >-
    The same mid-hindbrain malformation that produces the molar tooth
    sign disrupts brainstem nuclei controlling respiratory rhythm and
    ocular motor pathways, manifesting in neonates as episodic tachypnea
    and apnea and as oculomotor apraxia and other abnormal eye
    movements.
  evidence:
  - reference: PMID:35860112
    reference_title: "Joubert syndrome a rare entity and role of radiology: A case report."
    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: Documents the early-onset brainstem-mediated respiratory dysrhythmias characteristic of JS.
    evidence_source: HUMAN_CLINICAL
  downstream:
  - target: Episodic tachypnea
    description: Brainstem respiratory control dysfunction drives episodic tachypnea.
  - target: Apnea
    description: Brainstem respiratory control dysfunction drives apneic episodes.
  - target: Sleep apnea
    description: Persistent brainstem control dysfunction contributes to sleep apnea later in life.
  - target: Oculomotor apraxia
    description: Brainstem ocular motor pathway disruption contributes to oculomotor apraxia.
  - target: Abnormality of eye movement
    description: Brainstem ocular motor pathway disruption produces abnormal eye movements.
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
    reference_title: "Genetics Review: Joubert Syndrome."
    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
    reference_title: "Genetics Review: Joubert Syndrome."
    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: VERY_FREQUENT
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:36803942
    reference_title: "Joubert syndrome: Molecular basis and treatment."
    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
  - reference: ORPHA:475
    supports: SUPPORT
    snippet: "HP:0001252 | Hypotonia | Very frequent (99-80%)"
    explanation: Orphanet classifies hypotonia as very frequent (99-80%) in isolated Joubert syndrome.
- name: Ataxia
  category: Neurologic
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:36803942
    reference_title: "Joubert syndrome: Molecular basis and treatment."
    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
  - reference: ORPHA:475
    supports: SUPPORT
    snippet: "HP:0001251 | Ataxia | Very frequent (99-80%)"
    explanation: Orphanet classifies ataxia as very frequent (99-80%) in isolated Joubert syndrome.
- name: Intellectual disability
  category: Neurodevelopmental
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:36803942
    reference_title: "Joubert syndrome: Molecular basis and treatment."
    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
  - reference: ORPHA:475
    supports: SUPPORT
    snippet: "HP:0001249 | Intellectual disability | Very frequent (99-80%)"
    explanation: Orphanet classifies intellectual disability as very frequent (99-80%) in isolated Joubert syndrome.
- name: Global developmental delay
  category: Neurodevelopmental
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:38502237
    reference_title: "Joubert syndrome-derived induced pluripotent stem cells show altered neuronal differentiation in vitro."
    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
  - reference: ORPHA:475
    supports: SUPPORT
    snippet: "HP:0001263 | Global developmental delay | Very frequent (99-80%)"
    explanation: Orphanet classifies global developmental delay as very frequent (99-80%) in isolated Joubert syndrome.
- 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
    reference_title: "Joubert syndrome a rare entity and role of radiology: A case report."
    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
    reference_title: "Joubert syndrome-derived induced pluripotent stem cells show altered neuronal differentiation in vitro."
    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: VERY_FREQUENT
  phenotype_term:
    preferred_term: Oculomotor apraxia
    term:
      id: HP:0000657
      label: Oculomotor apraxia
  evidence:
  - reference: PMID:36803942
    reference_title: "Joubert syndrome: Molecular basis and treatment."
    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
  - reference: ORPHA:475
    supports: SUPPORT
    snippet: "HP:0000657 | Oculomotor apraxia | Very frequent (99-80%)"
    explanation: Orphanet classifies oculomotor apraxia as very frequent (99-80%) in isolated Joubert syndrome.
- name: Strabismus
  category: Ophthalmologic
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: PMID:37547106
    reference_title: "Clinical and genetic characteristics of 36 children with Joubert syndrome."
    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
  - reference: ORPHA:475
    supports: SUPPORT
    snippet: "HP:0000486 | Strabismus | Occasional (29-5%)"
    explanation: Orphanet classifies strabismus as occasional (29-5%) in isolated Joubert syndrome.
- name: Retinal dystrophy
  category: Ophthalmologic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Retinal dystrophy
    term:
      id: HP:0000556
      label: Retinal dystrophy
  evidence:
  - reference: PMID:36803942
    reference_title: "Joubert syndrome: Molecular basis and treatment."
    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
    reference_title: "Joubert syndrome: Molecular basis and treatment."
    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_FREQUENT
  phenotype_term:
    preferred_term: Episodic tachypnea
    term:
      id: HP:0002876
      label: Episodic tachypnea
  evidence:
  - reference: PMID:35860112
    reference_title: "Joubert syndrome a rare entity and role of radiology: A case report."
    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
  - reference: ORPHA:475
    supports: SUPPORT
    snippet: "HP:0002876 | Episodic tachypnea | Very frequent (99-80%)"
    explanation: Orphanet classifies episodic tachypnea as very frequent (99-80%) in isolated Joubert syndrome, upgrading from single case report evidence.
- name: Apnea
  category: Respiratory
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Apnea
    term:
      id: HP:0002104
      label: Apnea
  evidence:
  - reference: PMID:35860112
    reference_title: "Joubert syndrome a rare entity and role of radiology: A case report."
    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
  - reference: ORPHA:475
    supports: SUPPORT
    snippet: "HP:0002104 | Apnea | Very frequent (99-80%)"
    explanation: Orphanet classifies apnea as very frequent (99-80%) in isolated Joubert syndrome.
- name: Renal cyst
  category: Renal
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Renal cyst
    term:
      id: HP:0000107
      label: Renal cyst
  evidence:
  - reference: PMID:36803942
    reference_title: "Joubert syndrome: Molecular basis and treatment."
    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
    reference_title: "Clinical and genetic spectrum from a prototype of ciliopathy: Joubert syndrome."
    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
    reference_title: "Joubert syndrome: Molecular basis and treatment."
    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: VERY_RARE
  phenotype_term:
    preferred_term: Portal hypertension
    term:
      id: HP:0001409
      label: Portal hypertension
  evidence:
  - reference: PMID:36580738
    reference_title: "Clinical and genetic spectrum from a prototype of ciliopathy: Joubert syndrome."
    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: VERY_RARE
  phenotype_term:
    preferred_term: Esophageal varix
    term:
      id: HP:0002040
      label: Esophageal varix
  evidence:
  - reference: PMID:36580738
    reference_title: "Clinical and genetic spectrum from a prototype of ciliopathy: Joubert syndrome."
    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
    reference_title: "Joubert syndrome: Molecular basis and treatment."
    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
    reference_title: "Adult Presentation of Joubert Syndrome Presenting With Dysphagia: A Case Report."
    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: Nystagmus
  category: Ophthalmologic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: ORPHA:475
    supports: SUPPORT
    snippet: "HP:0000639 | Nystagmus | Frequent (79-30%)"
    explanation: Orphanet classifies nystagmus as frequent (79-30%) in isolated Joubert syndrome.
- name: Long face
  category: Craniofacial
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Long face
    term:
      id: HP:0000276
      label: Long face
  evidence:
  - reference: ORPHA:475
    supports: SUPPORT
    snippet: "HP:0000276 | Long face | Frequent (79-30%)"
    explanation: Orphanet classifies long face as frequent (79-30%) in isolated Joubert syndrome.
- name: Gait disturbance
  category: Neurologic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Gait disturbance
    term:
      id: HP:0001288
      label: Gait disturbance
  evidence:
  - reference: ORPHA:475
    supports: SUPPORT
    snippet: "HP:0001288 | Gait disturbance | Frequent (79-30%)"
    explanation: Orphanet classifies gait disturbance as frequent (79-30%) in isolated Joubert syndrome.
- name: Feeding difficulties in infancy
  category: Gastrointestinal
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Feeding difficulties in infancy
    term:
      id: HP:0008872
      label: Feeding difficulties in infancy
  evidence:
  - reference: ORPHA:475
    supports: SUPPORT
    snippet: "HP:0008872 | Feeding difficulties in infancy | Frequent (79-30%)"
    explanation: Orphanet classifies feeding difficulties in infancy as frequent (79-30%) in isolated Joubert syndrome.
- name: Biparietal narrowing
  category: Craniofacial
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Biparietal narrowing
    term:
      id: HP:0004422
      label: Biparietal narrowing
  evidence:
  - reference: ORPHA:475
    supports: SUPPORT
    snippet: "HP:0004422 | Biparietal narrowing | Frequent (79-30%)"
    explanation: Orphanet classifies biparietal narrowing as frequent (79-30%) in isolated Joubert syndrome.
- name: Abnormal pattern of respiration
  category: Respiratory
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Abnormal pattern of respiration
    term:
      id: HP:0002793
      label: Abnormal pattern of respiration
  evidence:
  - reference: ORPHA:475
    supports: SUPPORT
    snippet: "HP:0002793 | Abnormal pattern of respiration | Very frequent (99-80%)"
    explanation: Orphanet classifies abnormal pattern of respiration as very frequent (99-80%) in isolated Joubert syndrome.
- name: Iris coloboma
  category: Ophthalmologic
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Iris coloboma
    term:
      id: HP:0000612
      label: Iris coloboma
  evidence:
  - reference: ORPHA:475
    supports: SUPPORT
    snippet: "HP:0000612 | Iris coloboma | Occasional (29-5%)"
    explanation: Orphanet classifies iris coloboma as occasional (29-5%) in isolated Joubert syndrome.
- name: Orofacial cleft
  category: Craniofacial
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Orofacial cleft
    term:
      id: HP:0000202
      label: Orofacial cleft
  evidence:
  - reference: ORPHA:475
    supports: SUPPORT
    snippet: "HP:0000202 | Orofacial cleft | Occasional (29-5%)"
    explanation: Orphanet classifies orofacial cleft as occasional (29-5%) in isolated Joubert syndrome.
- name: Hydrocephalus
  category: Neurologic
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Hydrocephalus
    term:
      id: HP:0000238
      label: Hydrocephalus
  evidence:
  - reference: ORPHA:475
    supports: SUPPORT
    snippet: "HP:0000238 | Hydrocephalus | Occasional (29-5%)"
    explanation: Orphanet classifies hydrocephalus as occasional (29-5%) in isolated Joubert syndrome.
- name: Encephalocele
  category: Neurologic
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Encephalocele
    term:
      id: HP:0002084
      label: Encephalocele
  evidence:
  - reference: ORPHA:475
    supports: SUPPORT
    snippet: "HP:0002084 | Encephalocele | Occasional (29-5%)"
    explanation: Orphanet classifies encephalocele as occasional (29-5%) in isolated Joubert syndrome.
- name: Scoliosis
  category: Skeletal
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: ORPHA:475
    supports: SUPPORT
    snippet: "HP:0002650 | Scoliosis | Occasional (29-5%)"
    explanation: Orphanet classifies scoliosis as occasional (29-5%) in isolated Joubert syndrome.
- name: Situs inversus totalis
  category: Other
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Situs inversus totalis
    term:
      id: HP:0001696
      label: Situs inversus totalis
  evidence:
  - reference: ORPHA:475
    supports: SUPPORT
    snippet: "HP:0001696 | Situs inversus totalis | Occasional (29-5%)"
    explanation: Orphanet classifies situs inversus totalis as occasional (29-5%) in isolated Joubert syndrome.
- name: Hand polydactyly
  category: Skeletal
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Hand polydactyly
    term:
      id: HP:0001161
      label: Hand polydactyly
  evidence:
  - reference: ORPHA:475
    supports: SUPPORT
    snippet: "HP:0001161 | Hand polydactyly | Occasional (29-5%)"
    explanation: Orphanet classifies hand polydactyly as occasional (29-5%) in isolated Joubert syndrome.
- name: Foot polydactyly
  category: Skeletal
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Foot polydactyly
    term:
      id: HP:0001829
      label: Foot polydactyly
  evidence:
  - reference: ORPHA:475
    supports: SUPPORT
    snippet: "HP:0001829 | Foot polydactyly | Occasional (29-5%)"
    explanation: Orphanet classifies foot polydactyly as occasional (29-5%) in isolated Joubert syndrome.
- name: Ptosis
  category: Ophthalmologic
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
  evidence:
  - reference: ORPHA:475
    supports: SUPPORT
    snippet: "HP:0000508 | Ptosis | Occasional (29-5%)"
    explanation: Orphanet classifies ptosis as occasional (29-5%) in isolated Joubert syndrome.
- name: Tremor
  category: Neurologic
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Tremor
    term:
      id: HP:0001337
      label: Tremor
  evidence:
  - reference: ORPHA:475
    supports: SUPPORT
    snippet: "HP:0001337 | Tremor | Occasional (29-5%)"
    explanation: Orphanet classifies tremor as occasional (29-5%) in isolated Joubert syndrome.
- name: Aplasia/Hypoplasia of the corpus callosum
  category: Neurologic
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Aplasia/Hypoplasia of the corpus callosum
    term:
      id: HP:0007370
      label: Aplasia/Hypoplasia of the corpus callosum
  evidence:
  - reference: ORPHA:475
    supports: SUPPORT
    snippet: "HP:0007370 | Aplasia/Hypoplasia of the corpus callosum | Occasional (29-5%)"
    explanation: Orphanet classifies corpus callosum anomalies as occasional (29-5%) in isolated Joubert syndrome.
- name: Aganglionic megacolon
  category: Gastrointestinal
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Aganglionic megacolon
    term:
      id: HP:0002251
      label: Aganglionic megacolon
  evidence:
  - reference: ORPHA:475
    supports: SUPPORT
    snippet: "HP:0002251 | Aganglionic megacolon | Occasional (29-5%)"
    explanation: Orphanet classifies aganglionic megacolon as occasional (29-5%) in isolated Joubert syndrome.
- name: Abnormal cardiovascular system morphology
  category: Cardiovascular
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Abnormal cardiovascular system morphology
    term:
      id: HP:0030680
      label: Abnormal cardiovascular system morphology
  evidence:
  - reference: ORPHA:475
    supports: SUPPORT
    snippet: "HP:0030680 | Abnormal cardiovascular system morphology | Occasional (29-5%)"
    explanation: Orphanet classifies abnormal cardiovascular system morphology as occasional (29-5%) in isolated Joubert syndrome.
- name: Seizure
  category: Neurologic
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:33717386
    reference_title: "A case report of Joubert syndrome with renal involvement and seizures in a neonate."
    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
  - reference: ORPHA:475
    supports: SUPPORT
    snippet: "HP:0001250 | Seizure | Occasional (29-5%)"
    explanation: Orphanet classifies seizures as occasional (29-5%) in isolated Joubert syndrome.
- 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
    reference_title: "Sleep, Respiration and Nocturnal Paroxysmal Events in Joubert Syndrome: A Case Report."
    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: Hearing impairment
  category: Otologic
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:37547106
    reference_title: "Clinical and genetic characteristics of 36 children with Joubert syndrome."
    supports: SUPPORT
    snippet: "Three-quarters of cases had one or more other organ or system involvement, with a greater predilection for vision and hearing impairment."
    explanation: A 36-child JS cohort reports vision and hearing impairment as common multi-organ features.
    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
    reference_title: "A case report of Joubert syndrome with renal involvement and seizures in a neonate."
    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
    reference_title: "A case report of Joubert syndrome with renal involvement and seizures in a neonate."
    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
    reference_title: "Joubert syndrome diagnosed renally late."
    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
    reference_title: "Joubert syndrome diagnosed renally late."
    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
    reference_title: "Joubert syndrome diagnosed renally late."
    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
    reference_title: "Clinical and genetic spectrum from a prototype of ciliopathy: Joubert syndrome."
    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
    reference_title: "Exome sequencing and RNA analysis identify two novel CPLANE1 variants causing Joubert syndrome."
    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
    reference_title: "Uncertain significance and molecular insights of CPLANE1 variants in prenatal diagnosis of Joubert syndrome: a case report."
    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
    reference_title: "Non-classic splicing mutation in the CPLANE1 (C5orf42) gene cause Joubert syndrome in a fetus with severe craniocerebral dysplasia."
    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
    reference_title: "Clinical and genetic spectrum from a prototype of ciliopathy: Joubert syndrome."
    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
    reference_title: "Genotype-phenotype correlates in Joubert syndrome: A review."
    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
    reference_title: "A case report of Joubert syndrome with renal involvement and seizures in a neonate."
    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
    reference_title: "Clinical and genetic spectrum from a prototype of ciliopathy: Joubert syndrome."
    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
    reference_title: "Genotype-phenotype correlates in Joubert syndrome: A review."
    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
    reference_title: "Novel ocular observations in a child with Joubert syndrome type 6 due to pathogenic variant in TMEM67 gene."
    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
    reference_title: "Compound heterozygous TMEM67 biallelic variants including a novel frameshift mutation in two Filipino adolescent siblings with Joubert syndrome."
    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
    reference_title: "Genotype-phenotype correlates in Joubert syndrome: A review."
    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
    reference_title: "Joubert syndrome diagnosed renally late."
    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
    reference_title: "Clinical and genetic spectrum from a prototype of ciliopathy: Joubert syndrome."
    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
    reference_title: "Clinical and genetic spectrum from a prototype of ciliopathy: Joubert syndrome."
    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
    reference_title: "Clinical and genetic spectrum from a prototype of ciliopathy: Joubert syndrome."
    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
    reference_title: "A CSPP1 variant associated with metabolic dysfunction in Joubert syndrome: a case report."
    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
    reference_title: "Clinical and genetic spectrum from a prototype of ciliopathy: Joubert syndrome."
    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
    reference_title: "Clinical and genetic spectrum from a prototype of ciliopathy: Joubert syndrome."
    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
    reference_title: "Clinical and genetic spectrum from a prototype of ciliopathy: Joubert syndrome."
    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
    reference_title: "Recurrent, founder and hypomorphic variants contribute to the genetic landscape of Joubert syndrome."
    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
    reference_title: "Molecular treatment options for patients carrying KIAA0586/TALPID3 variants."
    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: HUMAN_CLINICAL
  - reference: PMID:41020477
    reference_title: "Novel Pathogenic Biallelic Variants in KIAA0586 Expand the Variant Spectrum of Ciliopathies."
    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
    reference_title: "Clinical and genetic spectrum from a prototype of ciliopathy: Joubert syndrome."
    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
    reference_title: "Clinical and genetic spectrum from a prototype of ciliopathy: Joubert syndrome."
    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
    reference_title: "Novel mutation in RPGRIP1L gene causing Joubert syndrome: A case report."
    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
    reference_title: "Clinical and genetic characteristics of 36 children with Joubert syndrome."
    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
    reference_title: "A novel mutation of the RPGRIP1L gene in a Chinese boy with Joubert syndrome with oculorenal involvement."
    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
    reference_title: "Recurrent, founder and hypomorphic variants contribute to the genetic landscape of Joubert syndrome."
    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
    reference_title: "New insights into CC2D2A-related Joubert syndrome."
    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
    reference_title: "A novel non-sense variant in the OFD1 gene caused Joubert syndrome."
    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
    reference_title: "Clinical and molecular characteristics of tectonic (TCTN1) gene-related Joubert syndrome in a Saudi boy."
    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
    reference_title: "Clinical and genetic characteristics of 36 children with Joubert syndrome."
    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
    reference_title: "TOPORS as a novel causal gene for Joubert syndrome."
    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
- name: INPP5E
  association: Causative
  evidence:
  - reference: ORPHA:475
    supports: SUPPORT
    snippet: "INPP5E | inositol polyphosphate-5-phosphatase E | hgnc:21474 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists INPP5E as a disease-causing gene for isolated Joubert syndrome.
  gene_term:
    preferred_term: INPP5E
    term:
      id: hgnc:21474
      label: INPP5E
- name: ARL13B
  association: Causative
  evidence:
  - reference: ORPHA:475
    supports: SUPPORT
    snippet: "ARL13B | ARF like GTPase 13B | hgnc:25419 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists ARL13B as a disease-causing gene for isolated Joubert syndrome.
  - reference: CGGV:assertion_f6c474c9-4035-498c-a902-03be50d36205-2020-06-03T210114.719Z
    reference_title: "ARL13B / Joubert syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ARL13B | HGNC:25419 | Joubert syndrome | MONDO:0018772 | AR | Definitive"
    explanation: ClinGen classifies the ARL13B-Joubert syndrome gene-disease relationship as definitive with autosomal recessive inheritance.
  gene_term:
    preferred_term: ARL13B
    term:
      id: hgnc:25419
      label: ARL13B
- name: TCTN2
  association: Causative
  evidence:
  - reference: ORPHA:475
    supports: SUPPORT
    snippet: "TCTN2 | tectonic family member 2 | hgnc:25774 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists TCTN2 as a disease-causing gene for isolated Joubert syndrome.
  gene_term:
    preferred_term: TCTN2
    term:
      id: hgnc:25774
      label: TCTN2
- name: TCTN3
  association: Causative
  evidence:
  - reference: ORPHA:475
    supports: SUPPORT
    snippet: "TCTN3 | tectonic family member 3 | hgnc:24519 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists TCTN3 as a disease-causing gene for isolated Joubert syndrome.
  gene_term:
    preferred_term: TCTN3
    term:
      id: hgnc:24519
      label: TCTN3
- name: B9D1
  association: Causative
  evidence:
  - reference: ORPHA:475
    supports: SUPPORT
    snippet: "B9D1 | B9 domain containing 1 | hgnc:24123 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists B9D1 as a disease-causing gene for isolated Joubert syndrome.
  gene_term:
    preferred_term: B9D1
    term:
      id: hgnc:24123
      label: B9D1
- name: B9D2
  association: Causative
  evidence:
  - reference: ORPHA:475
    supports: SUPPORT
    snippet: "B9D2 | B9 domain containing 2 | hgnc:28636 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists B9D2 as a disease-causing gene for isolated Joubert syndrome.
  gene_term:
    preferred_term: B9D2
    term:
      id: hgnc:28636
      label: B9D2
- name: TMEM237
  association: Causative
  evidence:
  - reference: ORPHA:475
    supports: SUPPORT
    snippet: "TMEM237 | transmembrane protein 237 | hgnc:14432 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists TMEM237 as a disease-causing gene for isolated Joubert syndrome.
  gene_term:
    preferred_term: TMEM237
    term:
      id: hgnc:14432
      label: TMEM237
- name: TOGARAM1
  association: Causative
  evidence:
  - reference: ORPHA:475
    supports: SUPPORT
    snippet: "TOGARAM1 | TOG array regulator of axonemal microtubules 1 | hgnc:19959 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists TOGARAM1 as a disease-causing gene for isolated Joubert syndrome.
  gene_term:
    preferred_term: TOGARAM1
    term:
      id: hgnc:19959
      label: TOGARAM1
- name: SUFU
  association: Causative
  evidence:
  - reference: ORPHA:475
    supports: SUPPORT
    snippet: "SUFU | SUFU negative regulator of hedgehog signaling | hgnc:16466 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists SUFU as a disease-causing gene for isolated Joubert syndrome.
  gene_term:
    preferred_term: SUFU
    term:
      id: hgnc:16466
      label: SUFU
- name: IFT74
  association: Causative
  evidence:
  - reference: ORPHA:475
    supports: SUPPORT
    snippet: "IFT74 | intraflagellar transport 74 | hgnc:21424 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists IFT74 as a disease-causing gene for isolated Joubert syndrome.
  gene_term:
    preferred_term: IFT74
    term:
      id: hgnc:21424
      label: IFT74
- name: PDE6D
  association: Causative
  evidence:
  - reference: ORPHA:475
    supports: SUPPORT
    snippet: "PDE6D | phosphodiesterase 6D | hgnc:8788 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists PDE6D as a disease-causing gene for isolated Joubert syndrome.
  gene_term:
    preferred_term: PDE6D
    term:
      id: hgnc:8788
      label: PDE6D
- name: PIBF1
  association: Causative
  evidence:
  - reference: ORPHA:475
    supports: SUPPORT
    snippet: "PIBF1 | progesterone immunomodulatory binding factor 1 | hgnc:23352 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists PIBF1 as a disease-causing gene for isolated Joubert syndrome.
  gene_term:
    preferred_term: PIBF1
    term:
      id: hgnc:23352
      label: PIBF1
- name: CBY1
  association: Causative
  evidence:
  - reference: ORPHA:475
    supports: SUPPORT
    snippet: "CBY1 | chibby 1, beta catenin antagonist | hgnc:1307 | Disease-causing germline mutation(s) (loss of function) in"
    explanation: Orphanet lists CBY1 loss-of-function as disease-causing for isolated Joubert syndrome.
  gene_term:
    preferred_term: CBY1
    term:
      id: hgnc:1307
      label: CBY1
- name: TMEM218
  association: Causative
  evidence:
  - reference: ORPHA:475
    supports: SUPPORT
    snippet: "TMEM218 | transmembrane protein 218 | hgnc:27344 | Disease-causing germline mutation(s) (loss of function) in"
    explanation: Orphanet lists TMEM218 loss-of-function as disease-causing for isolated Joubert syndrome.
  gene_term:
    preferred_term: TMEM218
    term:
      id: hgnc:27344
      label: TMEM218
- name: CEP104
  association: Causative
  evidence:
  - reference: ORPHA:475
    supports: SUPPORT
    snippet: "CEP104 | centrosomal protein 104 | hgnc:24866 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists CEP104 as a disease-causing gene for isolated Joubert syndrome.
  gene_term:
    preferred_term: CEP104
    term:
      id: hgnc:24866
      label: CEP104
- name: ARL3
  association: Causative
  evidence:
  - reference: ORPHA:475
    supports: SUPPORT
    snippet: "ARL3 | ARF like GTPase 3 | hgnc:694 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists ARL3 as a disease-causing gene for isolated Joubert syndrome.
  gene_term:
    preferred_term: ARL3
    term:
      id: hgnc:694
      label: ARL3
- name: KIAA0753
  association: Causative
  evidence:
  - reference: ORPHA:475
    supports: SUPPORT
    snippet: "KIAA0753 | KIAA0753 | hgnc:29110 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists KIAA0753 as a disease-causing gene for isolated Joubert syndrome.
  gene_term:
    preferred_term: KIAA0753
    term:
      id: hgnc:29110
      label: KIAA0753
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
    reference_title: "An infant with Joubert syndrome: A case report."
    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
    reference_title: "Rehabilitation Approach for Children With Joubert Syndrome and Related Disorders."
    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
    reference_title: "Rehabilitation Approach for Children With Joubert Syndrome and Related Disorders."
    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
    reference_title: "Rehabilitation Approach for Children With Joubert Syndrome and Related Disorders."
    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
    reference_title: "Rehabilitation Approach for Children With Joubert Syndrome and Related Disorders."
    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
    reference_title: "Joubert syndrome: a case report of neonatal presentation and early diagnosis."
    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
    reference_title: "The role of liver transplantation in COACH syndrome (Joubert syndrome with congenital hepatic fibrosis): A review of the literature."
    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
  target_mechanisms:
  - target: Biliary ductal plate malformation via ciliary tight junction defect
    treatment_effect: MODULATES
    description: >-
      Liver transplantation addresses end-stage portal hypertension caused by
      congenital hepatic fibrosis from ciliary tight-junction defects in bile
      duct morphogenesis; it does not correct the underlying ciliopathy.
- name: Nasobiliary drainage
  description: Procedural management for refractory cholestatic pruritus in JS with hepatic involvement.
  evidence:
  - reference: PMID:37799488
    reference_title: "Preoperative Nasobiliary Drainage as a Predictor of Response Before Surgical Fistula Creation in Joubert Syndrome With Refractory Cholestatic Pruritis."
    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
- name: Kidney transplantation
  description: Treatment for end-stage kidney disease in JS patients with progressive renal ciliopathy. Pre-emptive and post-dialysis kidney transplantation are both feasible.
  treatment_term:
    preferred_term: kidney transplantation
    term:
      id: NCIT:C15265
      label: Kidney Transplantation
  evidence:
  - reference: PMID:33432080
    reference_title: "Any modality of renal replacement therapy can be a treatment option for Joubert syndrome."
    supports: SUPPORT
    snippet: "Hemodialysis was performed using arteriovenous fistula in two cases, and kidney transplantation was performed 9 times in eight cases."
    explanation: This Japanese cohort of 11 JS patients with ESKD documents kidney transplantation as a feasible RRT modality.
    evidence_source: HUMAN_CLINICAL
  - reference: PMID:33432080
    reference_title: "Any modality of renal replacement therapy can be a treatment option for Joubert syndrome."
    supports: SUPPORT
    snippet: "Any type of RRT modality can be a treatment option for patients with JS and ESKD."
    explanation: The cohort's overall conclusion supports any RRT modality, including transplantation, as effective in JS-ESKD.
    evidence_source: HUMAN_CLINICAL
  target_mechanisms:
  - target: Renal tubular ciliary dysfunction
    treatment_effect: MODULATES
    description: >-
      Kidney transplantation replaces end-stage renal tissue lost to ciliopathy-
      driven tubular dysfunction; the transplanted organ has normal ciliary
      function, bypassing the JS renal defect.
- name: Renal dialysis
  description: Peritoneal dialysis or hemodialysis for JS patients with end-stage kidney disease, often as a bridge to transplantation.
  treatment_term:
    preferred_term: renal dialysis
    term:
      id: MAXO:0000601
      label: renal dialysis
  evidence:
  - reference: PMID:33432080
    reference_title: "Any modality of renal replacement therapy can be a treatment option for Joubert syndrome."
    supports: SUPPORT
    snippet: "Peritoneal dialysis (PD) was introduced in seven cases, with a median treatment duration of 5.4 (3.4-10.7) years."
    explanation: Documents peritoneal dialysis as a long-duration RRT modality used in JS patients with ESKD.
    evidence_source: HUMAN_CLINICAL
  target_mechanisms:
  - target: Renal tubular ciliary dysfunction
    treatment_effect: MODULATES
    description: >-
      Renal dialysis provides renal replacement for end-stage kidney disease
      caused by JS ciliopathy-driven tubular dysfunction, serving as bridge
      therapy or long-term substitute when transplantation is not feasible.
- name: Caffeine for neonatal apnea
  description: Caffeine citrate to ameliorate central apneic episodes in neonates with Joubert syndrome.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: caffeine
      term:
        id: CHEBI:27732
        label: caffeine
  evidence:
  - reference: PMID:15385018
    reference_title: "Anesthetic management in Joubert syndrome."
    supports: SUPPORT
    snippet: "suggest consideration of the use of caffeine to ameliorate the apneic episodes seen in early infancy in this syndrome."
    explanation: Case report recommends caffeine for neonatal apneic episodes in JS.
    evidence_source: HUMAN_CLINICAL
  target_mechanisms:
  - target: Brainstem control center dysfunction
    treatment_effect: MODULATES
    description: >-
      Caffeine is a non-selective adenosine receptor antagonist that stimulates
      central respiratory drive, compensating for the brainstem rhythmogenesis
      impairment arising from ciliopathy-driven midbrain-hindbrain patterning
      defects.
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
    reference_title: "An infant with Joubert syndrome: A case report."
    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
    reference_title: "Joubert syndrome: a case report of neonatal presentation and early diagnosis."
    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
    reference_title: "A case report of Joubert syndrome with renal involvement and seizures in a neonate."
    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
    reference_title: "Get Your Molar Tooth Right: Joubert Syndrome Misdiagnosis Unmasked by Whole-Exome Sequencing."
    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
    reference_title: "Pathogenic cryptic variants detectable through exome data reanalysis significantly increase the diagnostic yield in Joubert syndrome."
    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
    reference_title: "Meckel Gruber and Joubert Syndrome Diagnosed Prenatally: Allelism between the Two Ciliopathies, Complexities of Mutation Types and Digenic Inheritance."
    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
    reference_title: "Joubert syndrome: Molecular basis and treatment."
    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
    reference_title: "Joubert syndrome: Molecular basis and treatment."
    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
    reference_title: "Joubert syndrome: Molecular basis and treatment."
    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
    reference_title: "A case report of Joubert syndrome with renal involvement and seizures in a neonate."
    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
    reference_title: "A case report of Joubert syndrome with renal involvement and seizures in a neonate."
    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

📚

References & Deep Research

Deep Research

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Disease Characteristics Research Template

Edison Scientific Literature 29 citations 2026-04-25T18:46:49.184030

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

Disease Name: Joubert syndrome
MONDO ID: (if available)
Category: Genetic

Research Objectives

Please provide a comprehensive research report on Joubert syndrome covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

What is the disease? Provide a concise overview.
What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
What are the common synonyms and alternative names?
Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
Risk Factors:

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Pathogenic Variants:
Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
Variant type/class (missense, frameshift, nonsense, splice-site, structural)
Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
Functional consequences (loss of function, gain of function, dominant negative)
Modifier Genes: Genes that modify disease severity or expression
Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

Search first: PubMed, Gene Ontology, Reactome
Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Molecular Profiling (if available):
Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
Advanced Technologies (if applicable):
Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

Organ Level:
Primary organs directly affected
Secondary organ involvement (complications, secondary effects)
Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

Onset:
Typical age of onset (congenital, pediatric, adult, geriatric)
Onset pattern (acute, subacute, chronic, insidious)

Search first: OMIM, Orphanet, HPO, PubMed
Progression:
Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
Progression rate (rapid, slow, variable)
Disease course pattern (episodic, relapsing-remitting, progressive, stable)
Disease duration (self-limited, chronic lifelong)

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

Epidemiology:
Prevalence (cases per 100,000 at given time)
Incidence (new cases per 100,000 per year)

Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
For Genetic Etiology:
Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
Population Demographics:
Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
Geographic distribution of specific variants
Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

Clinical Tests:
Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
Genetic Testing:

Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
Overview of recommended genetic testing approach
Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
FISH > Search first: ClinVar, cytogenetics databases, PubMed
Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
Omics-Based Diagnostics (if applicable):
RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
Clinical Criteria:
Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
Screening:
Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

Survival and Mortality:
Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
Morbidity and Function:
Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
Disease Course:
Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
Prediction:
Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

Pharmacotherapy:
Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
Advanced Therapeutics:
Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
Surgical and Interventional:
Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
Supportive and Rehabilitative:
Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
Experimental:
Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
Treatment Outcomes:
Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
Treatment Strategy:
Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

Prevention Levels:
Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
Immunization: Vaccine strategies (if applicable)

Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Screening and Early Detection:
Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
Behavioral Interventions: Lifestyle modifications to reduce risk

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

Search first: NSGC resources, ACMG guidelines, GeneReviews
Public Health:
Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
Prophylaxis: Preventive medications or procedures

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

Search first: NCBI Gene
Natural Disease:
Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
Comparative Biology:
Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
Transmission (if applicable):
Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

Model Types:
Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
Genetic Models:
Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
Model Characteristics:
Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
Applications:
Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
Resources:
Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic and clinical claims
Prioritize recent reviews and landmark papers
Include direct quotes from abstracts where possible to support key statements
Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Comprehensive Disease Characteristics Report: Joubert syndrome (genetic ciliopathy)

1. Disease information

Overview/definition. Joubert syndrome (JS; also “Joubert syndrome and related disorders,” JSRD) is a genetically heterogeneous, primary-cilium disorder (ciliopathy) defined clinically by hypotonia and neurodevelopmental impairment and radiologically by the molar tooth sign (MTS) reflecting a characteristic mid–hindbrain malformation. In a 2023 genetics report, JS is described as a “Mendelian disorder of the primary cilium defined by the clinical triad of hypotonia, developmental delay, and a distinct cerebellar malformation called the molar tooth sign” (abstract-level definition). (strong2023toporsasa pages 1-3)

Key identifiers (from available evidence). - OMIM phenotypic series: Joubert syndrome (JBTS) OMIM #213300 is explicitly referenced in a 2023 pediatric cohort paper. (dong2023clinicalandgenetic pages 1-2) - Subtypes: multiple numbered JBTS subtypes exist (e.g., JBTS9 with CC2D2A, JBTS10 with OFD1), as reflected in case reports and molecular literature. (li2023anovelnonsense pages 1-2) - Missing in current evidence capture: MONDO ID, Orphanet/ORPHA code, MeSH ID, ICD-10/ICD-11 codes were not directly retrievable in the tool-collected sources and should be added from OMIM/Orphanet/NCBI MeSH/WHO ICD resources.

Synonyms/alternative names (in use in recent literature). Joubert syndrome (JS), JBTS, Joubert syndrome and related disorders (JSRD), “Joubert anomaly,” and “cerebello-oculo-renal syndromes (JS/CORS)” appear in recent sources. (alhashimi2024neuroimagingcharacteristicsas pages 10-11, NCT00873678 chunk 1)

Evidence origin. Statements in this report are primarily derived from aggregated disease-level resources and cohorts (reviews, cohort studies, ClinicalTrials.gov records) plus case reports for variant expansion; not EHR-derived.

2. Etiology

2.1 Disease causal factors

Primary cause: Germline pathogenic variants in genes encoding proteins that function “in and around the primary cilium” (transition zone, basal body/centrosome, intraflagellar transport, ciliary membrane). (weghe2022thejoubert–meckel–nephronophthisisspectrum pages 1-3)

Genetic heterogeneity: - “Over 40” causal genes are widely cited. (strong2023toporsasa pages 1-3, gana2022genotype–phenotypecorrelatesin pages 1-2) - A 2022 review states “Over 40 causative genes have been identified… explaining up to 94% of cases.” (gana2022genotype–phenotypecorrelatesin pages 1-2) - Despite this, one 2023 gene-discovery paper notes molecular diagnosis is not made in ~30–40% of individuals meeting clinical criteria (highlighting missing variant classes, non-coding variants, structural variants, and/or novel genes). (strong2023toporsasa pages 1-3)

Inheritance patterns: Most commonly autosomal recessive, but rare X-linked recessive and autosomal dominant JS cases are reported. (strong2023toporsasa pages 1-3, gonzalezgordillo2023joubertsyndromea pages 1-2, li2023anovelnonsense pages 1-2)

2.2 Risk factors

Genetic risk: having biallelic pathogenic variants in JS genes (AR), or hemizygous pathogenic variants in X-linked genes such as OFD1 (JBTS10). (li2023anovelnonsense pages 1-2)
Population founder effects / elevated carrier frequency:
TOPORS p.(Pro10Gln) is proposed as a novel JS cause with evidence for elevated carrier frequency in people of Dominican ancestry from a large biobank query. (strong2023toporsasa pages 1-3)
A North Macedonia early-pregnancy-loss cohort identified a relatively frequent CPLANE1 “complex allele” (c.1819delT;c.7817T>A) with markedly higher JS incidence among Albanian families. (bozhinovski2024highincidenceof pages 3-5)

Environmental risk factors: No credible non-genetic environmental causal factors are established in the provided evidence.

2.3 Protective factors

No validated genetic or environmental protective factors were identified in the tool-retrieved evidence.

2.4 Gene–environment interactions

No specific gene–environment interaction evidence was identified in the retrieved sources.

3. Phenotypes (clinical spectrum)

3.1 Core neurologic phenotype (typical early onset)

Core features repeatedly emphasized include developmental delay, hypotonia, ataxia, oculomotor apraxia/abnormal eye movements, and episodic neonatal breathing dysregulation. (dong2023clinicalandgenetic pages 1-2, alhashimi2024neuroimagingcharacteristicsas pages 10-11, li2023anovelmutation pages 1-2)

Cohort statistics (human clinical). In a retrospective cohort of 36 children: - Developmental delay: 94.44% (34/36). (dong2023clinicalandgenetic pages 1-2) - MTS on imaging: 86.11% (31/36) had a “typical molar tooth sign”; 5 had a “bat wing sign.” (dong2023clinicalandgenetic pages 1-2) - Abnormal respiratory rhythm: 7 cases (six neonatal respiratory distress; one neonatal intermittent apnea). (dong2023clinicalandgenetic pages 3-5) - Abnormal VEEG: 7.69% (subset tested). (dong2023clinicalandgenetic pages 1-2)

Suggested HPO terms (non-exhaustive). - Hypotonia: HP:0001252 - Global developmental delay: HP:0001263 - Ataxia: HP:0001251 - Oculomotor apraxia: HP:0000657 - Abnormal respiratory pattern / apnea: HP:0002104 (apnea), HP:0002793 (irregular breathing) - Molar tooth sign: HP:0002419 (commonly used HPO term)

3.2 Multisystem involvement

A large review emphasizes that ~two-thirds of patients show extra-CNS involvement, commonly affecting eye/retina, kidney, liver, and skeleton. (gana2022genotype–phenotypecorrelatesin pages 1-2, li2023anovelmutation pages 1-2)

Vision/ocular: In the 36-child cohort, ocular abnormalities included nystagmus/strabismus/retinal abnormalities/optic-nerve anomalies; multiple types could co-occur in a child. (dong2023clinicalandgenetic pages 3-5)

Kidney/urinary: - In the 36-child cohort: urinary system involvement in 7 cases (including mildly abnormal renal function, nephrolithiasis, collecting system abnormality). (dong2023clinicalandgenetic pages 3-5) - In a 17-child China cohort focused on renal disease: renal involvement was the second most frequent domain, including ESKD 35%, hematuria 29%, proteinuria 29%, diffuse lesions 24%, cystic lesions 12%. (ying2022attentiontorenal pages 1-2)

Liver: The 36-child cohort reported liver damage in 4 cases (elevated transaminases; hepatosplenomegaly). (dong2023clinicalandgenetic pages 3-5)

Hearing: hearing abnormalities occurred in 8 cases in the 36-child cohort (including cochlear malformation). (dong2023clinicalandgenetic pages 3-5)

Suggested HPO terms (multisystem examples). - Retinal dystrophy: HP:0000556 - Chronic kidney disease: HP:0012622; nephronophthisis: HP:0000090 - Hepatic fibrosis: HP:0001395 - Polydactyly: HP:0010442 - Sensorineural hearing impairment: HP:0000407

3.3 Quality-of-life impact

Direct QoL instrument results (EQ-5D/SF-36/PROMIS) were not captured in the retrieved evidence. Functional impact is indirectly supported by the need for rehabilitation and, in severe cases, tracheostomy/G-tube dependence due to apnea and feeding problems. (strong2023toporsasa pages 3-4, wei2024novelcompoundheterozygous pages 6-7)

4. Genetic / molecular information

4.1 Causal genes (representative; not exhaustive)

Genes repeatedly referenced in 2021–2024 clinical genetics sources include CPLANE1, CEP290, TMEM67, AHI1, RPGRIP1L, CC2D2A, CEP120, CSPP1, OFD1, among many others. (dong2023clinicalandgenetic pages 3-5, juan2024optimalprenatalgenetic pages 4-6, li2023anovelnonsense pages 1-2, wei2024novelcompoundheterozygous pages 6-7)

New/expanded gene discovery (2023). TOPORS was nominated as a novel JS gene based on a Dominican ancestry proband homozygous for c.29C>A; p.(Pro10Gln) and supportive biobank carrier-frequency evidence in Dominicans. (strong2023toporsasa pages 1-3)

4.2 Pathogenic variant classes and functional consequences

Observed classes include: - Loss-of-function (nonsense/frameshift/splice) variants (e.g., OFD1 nonsense variant with transcript reduction consistent with nonsense-mediated decay). (li2023anovelnonsense pages 1-2) - Copy-number deletions (e.g., CC2D2A 7.16 kb deletion in a compound genotype). (strong2023toporsasa pages 1-3) - Intronic/non-coding splicing variants are recognized as an important mechanism (reviewed conceptually in non-coding/splicing-focused work), though detailed diagnostic gains were not captured from 2023–2024 primary JS cohorts in the current evidence set. (dabrusco2023exploringthenoncoding pages 106-110)

ACMG/AMP classification usage: Case reports and cohorts explicitly classify variants as pathogenic/likely pathogenic/VUS per ACMG criteria. (dong2023clinicalandgenetic pages 3-5, li2023anovelmutation pages 1-2)

4.3 Gene–phenotype correlations (actionable surveillance)

A 2022 genotype–phenotype review highlights clinically actionable correlations: - TMEM67: significantly higher risk of liver fibrosis. - NPHP1, RPGRIP1L, TMEM237: frequent renal involvement. - CEP290 and AHI1: higher risk of retinal dystrophy; CEP290 also linked to chronic kidney disease risk. These correlations are presented as guiding “personalized management” and organ surveillance. (gana2022genotype–phenotypecorrelatesin pages 1-2)

4.4 Modifier genes / oligogenicity

A kidney genetics review of modifier concepts (not JS-specific) and the JS/MKS/NPH spectrum review discuss the use of zebrafish/C. elegans and other systems to explore genetic interactions/modifiers in ciliopathies; specific validated JS modifier alleles were not captured in the current evidence set. (weghe2022thejoubert–meckel–nephronophthisisspectrum pages 13-15, weghe2022thejoubert–meckel–nephronophthisisspectrum pages 15-16)

4.5 Epigenetics / chromosomal abnormalities

No JS-specific epigenetic mechanisms were identified in the retrieved evidence.

5. Environmental information

JS is a monogenic ciliopathy in the retrieved evidence; no specific toxins/lifestyle/infectious triggers were supported by the tool-collected sources.

6. Mechanism / pathophysiology

6.1 Core concept: primary cilium dysfunction

Primary cilia are near-ubiquitous microtubule-based organelles acting as “cellular antennae” that mediate Hedgehog (Hh) and other signaling pathways; JS arises when variants disrupt proteins acting “in and around the primary cilium.” (weghe2022thejoubert–meckel–nephronophthisisspectrum pages 1-3)

6.2 Signaling pathways and ciliary subdomains implicated

Mechanistic work in the JS–MKS–NPH spectrum emphasizes: - Transition zone function and ciliary membrane phosphoinositides (e.g., INPP5E localization and PI distribution), which influence localization of Hh regulators (e.g., SMO, GPR161, TULP3). (weghe2022thejoubert–meckel–nephronophthisisspectrum pages 13-15) - Hh-dependent neurodevelopmental processes contributing to brain malformations (vermian hypoplasia, axon guidance/decussation defects). (weghe2022thejoubert–meckel–nephronophthisisspectrum pages 15-16) - Zebrafish mechanistic summaries highlight additional signaling: Wnt and prostaglandin/PGE2→cAMP→IFT and Hippo/Yap roles in ciliogenesis/kidney ciliopathy phenotypes. (wang2024zebrafishasa pages 1-2)

6.3 Causal chain (example: neurodevelopment)

Variant in ciliary gene → disrupted cilium structure/transition zone/ciliary trafficking → altered cilium-dependent morphogen signaling (notably Hh; also other pathways) → impaired neural proliferation/fate specification/migration/axon guidance → mid–hindbrain malformation → MTS and hypotonia/ataxia/oculomotor/breathing dysregulation. (weghe2022thejoubert–meckel–nephronophthisisspectrum pages 15-16, weghe2022thejoubert–meckel–nephronophthisisspectrum pages 13-15)

6.4 Suggested GO / CL terms

GO Biological Process (examples): - Hedgehog signaling pathway: GO:0007224 - Cilium assembly: GO:0060271 - Intraflagellar transport: GO:0030990 - Neuron migration: GO:0001764 - Axon guidance: GO:0007411

GO Cellular Component: - Primary cilium: GO:0072372 - Ciliary transition zone: GO:0097546 - Centrosome: GO:0005813

Cell Ontology (examples): - Neuron: CL:0000540 - Retinal photoreceptor cell: CL:0000210 - Kidney epithelial cell: CL:0000066

6.5 Molecular profiling / advanced technologies

A 2021–2024 interventional biomarker study for ciliopathies (including JS) explicitly plans transcriptome, proteome, metabolome profiling using urine-derived renal epithelial cells and iPSC-derived renal organoids to develop prognostic renal biomarkers. (NCT04874909 chunk 1)

7. Anatomical structures affected (multi-level)

7.1 Organ/system level (UBERON suggestions)

Brain (CNS): cerebellum and brainstem (mid–hindbrain) malformation producing MTS. (alhashimi2024neuroimagingcharacteristicsas pages 10-11, dong2023clinicalandgenetic media e70ab935)
UBERON: brain UBERON:0000955, cerebellum UBERON:0002037, brainstem UBERON:0002298, cerebellar vermis UBERON:0004670
Eye/retina: retinal dystrophy and other ocular motor abnormalities are frequent. (dong2023clinicalandgenetic pages 3-5, gana2022genotype–phenotypecorrelatesin pages 1-2)
UBERON: retina UBERON:0000966
Kidney: nephronophthisis/cystic disease/ESKD in a substantial subset. (ying2022attentiontorenal pages 1-2, takagi2021anymodalityof pages 1-2)
UBERON: kidney UBERON:0002113
Liver: hepatic fibrosis/liver injury in subsets and elevated risk with TMEM67. (gana2022genotype–phenotypecorrelatesin pages 1-2, dong2023clinicalandgenetic pages 3-5)
UBERON: liver UBERON:0002107

7.2 Subcellular localization

Primary cilium, ciliary transition zone, basal body/centrosome are central sites. (weghe2022thejoubert–meckel–nephronophthisisspectrum pages 1-3, weghe2022thejoubert–meckel–nephronophthisisspectrum pages 13-15)

8. Temporal development

Onset: often congenital/infancy with neonatal respiratory dysregulation and early hypotonia/developmental delay. (gonzalezgordillo2023joubertsyndromea pages 1-2, dong2023clinicalandgenetic pages 3-5)

Progression: variable; extra-CNS involvement may present later and requires longitudinal surveillance. (gana2022genotype–phenotypecorrelatesin pages 1-2)

9. Inheritance and population

9.1 Epidemiology

Commonly cited frequency: 1:80,000–1:100,000 live births. (gonzalezgordillo2023joubertsyndromea pages 1-2, takagi2021anymodalityof pages 1-2)
Population-based prevalence estimate: 1.7 per 100,000 among ages 0–19 years. (gana2022genotype–phenotypecorrelatesin pages 1-2, li2023anovelmutation pages 1-2)

9.2 Population genetics / founder effects

Dominican ancestry: TOPORS p.(Pro10Gln) variant suggested to have elevated carrier frequency (biobank evidence), raising consideration for ancestry-informed testing. (strong2023toporsasa pages 1-3)
Albanian families (North Macedonia): early pregnancy loss study reports JS incidence 2.03% (5/246) in euploid products of conception and 6.25% (5/80) in Albanian families; supports targeted screening for a specific CPLANE1 complex allele. (bozhinovski2024highincidenceof pages 3-5)

Sex ratio: a 36-child cohort had 18 male/18 female (1:1) but this is not a population-level estimate. (dong2023clinicalandgenetic pages 1-2)

10. Diagnostics

10.1 Clinical criteria and imaging

MRI hallmark: MTS is repeatedly emphasized as the diagnostic hallmark; detailed anatomic description includes thickened/elongated superior cerebellar peduncles, deep interpeduncular fossa, and vermian hypoplasia/aplasia. (strong2023toporsasa pages 1-3, alhashimi2024neuroimagingcharacteristicsas pages 10-11)

Visual evidence (MRI). Figure panels from a 2023 pediatric cohort show classic MTS and related signs on brain MRI (molar tooth sign and bat-wing sign). (dong2023clinicalandgenetic media e70ab935)

10.2 Genetic testing strategy

WES/WGS/panels: Exome sequencing is widely used due to high locus heterogeneity; a 2023 cohort used WES in a subset and identified novel variants in several genes. (dong2023clinicalandgenetic pages 3-5)

Prenatal diagnosis and diagnostic yield (2024). In fetuses with posterior fossa malformation, one 2024 cohort reports WES detection rates stratified by phenotype; importantly, the detection rate for fetuses classified as JS was 83.33% (5/6), leading the authors to recommend WES as a first-line prenatal test for suspected JS. (juan2024optimalprenatalgenetic pages 4-6)

Differential diagnosis (high-level). Related ciliopathy-spectrum disorders include Meckel syndrome and nephronophthisis, with overlapping gene sets and organ involvement. (weghe2022thejoubert–meckel–nephronophthisisspectrum pages 1-3)

11. Outcome / prognosis

Prognosis drivers: presence and severity of extra-CNS involvement (kidney, liver, retina) drive long-term outcomes. (gana2022genotype–phenotypecorrelatesin pages 1-2)

Cohort evidence (2023): A 36-child cohort found prognosis after rehabilitation was better in “pure JBTS” than JBTS with multi-organ involvement (statistically significant, P<0.05). (dong2023clinicalandgenetic pages 1-2)

Renal failure outcomes and survival (RRT series). In 11 JS patients with ESKD receiving renal replacement therapy: peritoneal dialysis was used in 7 (median duration 5.4 years), hemodialysis in 2, and kidney transplantation performed 9 times in 8 patients; only one graft failed during follow-up and all were alive except one who died of hepatic failure while on PD. (takagi2021anymodalityof pages 1-2)

12. Treatment

12.1 Disease-modifying therapy

No specific curative therapy is supported in the retrieved evidence; management is supportive and preventive (organ surveillance). (wei2024novelcompoundheterozygous pages 6-7)

12.2 Supportive/rehabilitative care (real-world implementation)

Multidisciplinary care is consistently emphasized (neurology, nephrology, ophthalmology, etc.). (alhashimi2024neuroimagingcharacteristicsas pages 10-11, gonzalezgordillo2023joubertsyndromea pages 1-2)
Rehabilitation therapies (physical/occupational/speech) are suggested to improve movement and speech impairment; cohort data support better outcomes in “pure JBTS” after formal rehabilitation. (dong2023clinicalandgenetic pages 1-2, wei2024novelcompoundheterozygous pages 6-7)
Respiratory management can include caffeine for central apneas in neonatal presentations (case-level evidence). (gonzalezgordillo2023joubertsyndromea pages 1-2)
Renal replacement therapy options include PD, HD, and transplantation with generally feasible outcomes (small cohort evidence). (takagi2021anymodalityof pages 1-2)

Suggested MAXO terms (examples): - Physical therapy: MAXO:0000011 (physical therapy) - Occupational therapy: MAXO:0000012 - Speech therapy: MAXO:0000013 - Genetic counseling: MAXO:0000117 - Kidney transplantation: MAXO:0001175 - Peritoneal dialysis: MAXO:0000555 - Hemodialysis: MAXO:0000556

12.3 Experimental / clinical-trial landscape

NCT00873678 (completed; observational; AP-HP): aimed to assess prevalence and mutational spectrum for AHI1, NPHP1, CEP290 and evaluate genotype–phenotype correlations in JS. (NCT00873678 chunk 1)
NCT04874909 (CILLICORIRCM; interventional diagnostic/biomarker): aims to identify prognostic biomarkers (multi-omics; patient-derived kidney models such as urine-derived renal epithelial cells and iPSC-derived organoids) to predict renal impairment progression in ciliopathies including JS. (NCT04874909 chunk 1)

13. Prevention

Primary prevention: not applicable (genetic).

Secondary/tertiary prevention: - Prevention of complications relies on early diagnosis and structured multisystem surveillance guided by genotype–phenotype correlations (e.g., closer liver monitoring for TMEM67; renal for RPGRIP1L/NPHP1/TMEM237; retinal for CEP290/AHI1). (gana2022genotype–phenotypecorrelatesin pages 1-2)

Reproductive options / prenatal diagnosis: - Prenatal imaging plus genetic testing (trio-WES) is increasingly used; a 2024 cohort supports first-line WES for prenatal suspected JS based on high detection rate (5/6). (juan2024optimalprenatalgenetic pages 4-6) - Targeted carrier screening may be warranted in specific populations with enriched alleles (e.g., CPLANE1 complex allele in Albanian couples with recurrent early pregnancy loss; TOPORS p.Pro10Gln in Dominican ancestry). (bozhinovski2024highincidenceof pages 3-5, strong2023toporsasa pages 1-3)

14. Other species / natural disease

No naturally occurring non-human JS disease cases were captured in the retrieved evidence. However, comparative biology across species is central to the field because ciliary structure/function is evolutionarily conserved, enabling mechanistic inference from models. (weghe2022thejoubert–meckel–nephronophthisisspectrum pages 13-15)

15. Model organisms

Key model systems used in ciliopathy/JS research and phenotypes recapitulated: - Zebrafish: frequently recapitulate ciliopathy phenotypes relevant to JS–MKS–NPH, including decreased cilia in brain ventricles/kidney structures, retinal degeneration, and pronephric cysts in many models; also laterality and craniofacial phenotypes. (weghe2022thejoubert–meckel–nephronophthisisspectrum pages 13-15) - Mouse: primary mammalian model; phenotypes include retinal degeneration, polydactyly, disrupted Hedgehog signaling, laterality defects, fibrocystic kidney disease, craniofacial malformations, and neural developmental defects. (weghe2022thejoubert–meckel–nephronophthisisspectrum pages 15-16) - C. elegans and Chlamydomonas: used for genetic screens and foundational intraflagellar transport/ciliary biology discoveries relevant to ciliopathies. (weghe2022thejoubert–meckel–nephronophthisisspectrum pages 13-15)

High-yield evidence map

Domain	Key data points	Best supporting citations
Definition	Rare primary ciliopathy/neurodevelopmental disorder defined by hypotonia, developmental delay, and the molar tooth sign (MTS); variable multiorgan involvement	(strong2023toporsasa pages 1-3, dong2023clinicalandgenetic pages 1-2)
Epidemiology	Prevalence/incidence commonly cited as 1:80,000–1:100,000 live births; population-based prevalence 1.7/100,000 among ages 0–19 years	(gonzalezgordillo2023joubertsyndromea pages 1-2, gana2022genotype–phenotypecorrelatesin pages 1-2, li2023anovelmutation pages 1-2)
Inheritance	Mostly autosomal recessive; rare X-linked recessive and autosomal dominant cases reported	(strong2023toporsasa pages 1-3, gonzalezgordillo2023joubertsyndromea pages 1-2, li2023anovelnonsense pages 1-2)
Diagnostic hallmark	MTS = thick/elongated superior cerebellar peduncles + deep interpeduncular fossa + cerebellar vermis hypoplasia/aplasia; MRI hallmark for diagnosis	(strong2023toporsasa pages 1-3, alhashimi2024neuroimagingcharacteristicsas pages 10-11, dong2023clinicalandgenetic media e70ab935)
Clinical cohort (36 children)	Developmental delay 94.44% (34/36); typical MTS 86.11% (31/36); ~75% had extra-organ/system involvement; abnormal respiratory rhythm in 7 cases	(dong2023clinicalandgenetic pages 1-2, dong2023clinicalandgenetic pages 3-5)
Organ involvement	About two-thirds of patients have extra-CNS involvement; retinal, kidney, liver, and skeletal disease are major non-neurologic domains	(gana2022genotype–phenotypecorrelatesin pages 1-2, li2023anovelmutation pages 1-2, li2023anovelnonsense pages 1-2)
Renal involvement cohort (17 cases)	Renal involvement second most common: ESKD 35%, hematuria 29%, proteinuria 29%, diffuse renal lesions 24%, cystic lesions 12%, echogenic parenchyma 12%	(ying2022attentiontorenal pages 1-2)
Genetics	>40 causal genes identified; can explain up to 94% of cases, yet 30–40% of clinically diagnosed individuals still lack molecular diagnosis in some series	(gana2022genotype–phenotypecorrelatesin pages 1-2, strong2023toporsasa pages 1-3, dong2023clinicalandgenetic pages 1-2)
Recent discovery	TOPORS proposed as novel JBTS gene; homozygous p.Pro10Gln found in Dominican ancestry, with biobank evidence of elevated carrier frequency/founder effect concern	(strong2023toporsasa pages 1-3, strong2023toporsasa pages 3-4)
Diagnostic yields	Prenatal posterior fossa malformation cohort: WES diagnostic rate 83.33% (5/6) in fetuses with Joubert syndrome; authors recommend WES first-line for prenatal JS	(juan2024optimalprenatalgenetic pages 4-6)
Population/founder signals	Early pregnancy loss products of conception: CPLANE1-related JS incidence 2.03% overall (5/246), 6.25% in Albanian families; targeted screening suggested in this population	(bozhinovski2024highincidenceof pages 3-5)
Management & outcomes	No disease-specific cure; multidisciplinary surveillance/rehab recommended. In 11 JS patients on renal replacement therapy: PD in 7, HD in 2, kidney transplant in 8 patients/9 grafts; 1 graft failure; all alive except 1 death from hepatic failure	(wei2024novelcompoundheterozygous pages 6-7, takagi2021anymodalityof pages 1-2, gonzalezgordillo2023joubertsyndromea pages 1-2)
Gene–phenotype correlations	TMEM67 → higher liver fibrosis risk; NPHP1/RPGRIP1L/TMEM237 → renal involvement; CEP290 and AHI1 → retinal dystrophy risk, CEP290 also CKD risk	(gana2022genotype–phenotypecorrelatesin pages 1-2)

Table: This table summarizes high-yield facts about Joubert syndrome across epidemiology, inheritance, diagnosis, organ involvement, genetics, recent discoveries, and outcomes. It is designed as a compact evidence map with direct links to the strongest supporting context IDs.

Notes on evidence gaps (important for knowledge-base curation)

Ontology identifiers (MONDO/Orphanet/MeSH/ICD) were not directly retrieved by the current tool calls; they should be filled from authoritative resources (OMIM, Orphanet, MeSH, ICD-11 browser) in a subsequent curation pass.
PMIDs were not available in the retrieved text extracts; therefore, this report cites DOI/URL-bearing sources and ClinicalTrials.gov identifiers as available.
Quality-of-life instruments and large prospective natural history survival statistics were not captured in the retrieved evidence; current outcome statements rely on cohorts (36-child clinical cohort; 11-patient renal-replacement cohort; 17-child renal cohort). (dong2023clinicalandgenetic pages 1-2, takagi2021anymodalityof pages 1-2, ying2022attentiontorenal pages 1-2)

References

(strong2023toporsasa pages 1-3): Alanna Strong, Hui‐Qi Qu, Sinéad Cullina, Morgan L. McManus, Elaine H. Zackai, Joseph Glessner, Eimear E. Kenny, and Hakon Hakonarson. Topors as a novel causal gene for joubert syndrome. American Journal of Medical Genetics Part A, 191:2156-2163, May 2023. URL: https://doi.org/10.1002/ajmg.a.63303, doi:10.1002/ajmg.a.63303. This article has 5 citations.
(dong2023clinicalandgenetic pages 1-2): Yan Dong, Ke Zhang, He Yao, Tianming Jia, Jun Wang, Dengna Zhu, Falin Xu, Meiying Cheng, Shichao Zhao, and Xiaoyi Shi. Clinical and genetic characteristics of 36 children with joubert syndrome. Frontiers in Pediatrics, Jul 2023. URL: https://doi.org/10.3389/fped.2023.1102639, doi:10.3389/fped.2023.1102639. This article has 16 citations.
(li2023anovelnonsense pages 1-2): Chen Li, Xingwang Wang, Fake Li, Hongke Ding, Ling Liu, Ying Xiong, Chaoxiang Yang, Yan Zhang, Jing Wu, and Aihua Yin. A novel non-sense variant in the ofd1 gene caused joubert syndrome. Frontiers in Genetics, Jan 2023. URL: https://doi.org/10.3389/fgene.2022.1064762, doi:10.3389/fgene.2022.1064762. This article has 6 citations and is from a peer-reviewed journal.
(alhashimi2024neuroimagingcharacteristicsas pages 10-11): Israa Alhashimi, Sohaib Zoghoul, Sondos K Khalil, Zahra B Yousif, Ammar Jumah, and Yaman Alkailani. Neuroimaging characteristics as diagnostic tools in joubert syndrome and related disorders: a case report and literature review. Cureus, Sep 2024. URL: https://doi.org/10.7759/cureus.69872, doi:10.7759/cureus.69872. This article has 4 citations.
(NCT00873678 chunk 1): Assessment of the Prevalence of Genes AHI1, NPHP1 and CEP290 in Joubert Syndrome. Assistance Publique - Hôpitaux de Paris. 2007. ClinicalTrials.gov Identifier: NCT00873678
(weghe2022thejoubert–meckel–nephronophthisisspectrum pages 1-3): Julie C. Van De Weghe, Arianna Gomez, and Dan Doherty. The joubert–meckel–nephronophthisis spectrum of ciliopathies. Annual Review of Genomics and Human Genetics, 23:301-329, Aug 2022. URL: https://doi.org/10.1146/annurev-genom-121321-093528, doi:10.1146/annurev-genom-121321-093528. This article has 73 citations and is from a domain leading peer-reviewed journal.
(gana2022genotype–phenotypecorrelatesin pages 1-2): Simone Gana, Valentina Serpieri, and Enza Maria Valente. Genotype–phenotype correlates in joubert syndrome: a review. American Journal of Medical Genetics. Part C, Seminars in Medical Genetics, 190:72-88, Mar 2022. URL: https://doi.org/10.1002/ajmg.c.31963, doi:10.1002/ajmg.c.31963. This article has 125 citations.
(gonzalezgordillo2023joubertsyndromea pages 1-2): Carla I. González-Gordillo, Leslie E. Orozco-Soto, Juan R. Osegueda-Mayen, Alejandra Nava-Tapia, and Dario Martinez-Monreal. Joubert syndrome: a case report of neonatal presentation and early diagnosis. Boletín Médico del Hospital Infantil de México, Jul 2023. URL: https://doi.org/10.24875/bmhim.22000075, doi:10.24875/bmhim.22000075. This article has 3 citations.
(bozhinovski2024highincidenceof pages 3-5): Gjorgji Bozhinovski, Marija Terzikj, Katerina Kubelka-Sabit, and Dijana Plaseska-Karanfilska. High incidence of cplane1-related joubert syndrome in the products of conceptions from early pregnancy losses. Balkan Medical Journal, pages 97-104, Mar 2024. URL: https://doi.org/10.4274/balkanmedj.galenos.2024.2023-10-72, doi:10.4274/balkanmedj.galenos.2024.2023-10-72. This article has 6 citations.
(li2023anovelmutation pages 1-2): Qian Li, Qianying Liu, Suwen Liu, Lichun Yu, Zhenle Yang, Cong Wang, Jing Wang, and Shuzhen Sun. A novel mutation of the rpgrip1l gene in a chinese boy with joubert syndrome with oculorenal involvement. BMC Pediatrics, Nov 2023. URL: https://doi.org/10.1186/s12887-023-04415-1, doi:10.1186/s12887-023-04415-1. This article has 1 citations and is from a peer-reviewed journal.
(dong2023clinicalandgenetic pages 3-5): Yan Dong, Ke Zhang, He Yao, Tianming Jia, Jun Wang, Dengna Zhu, Falin Xu, Meiying Cheng, Shichao Zhao, and Xiaoyi Shi. Clinical and genetic characteristics of 36 children with joubert syndrome. Frontiers in Pediatrics, Jul 2023. URL: https://doi.org/10.3389/fped.2023.1102639, doi:10.3389/fped.2023.1102639. This article has 16 citations.
(ying2022attentiontorenal pages 1-2): Liang Ying, Wang Hui, FuQian, Zhou Nan, Jiang Yeping, and Mi Lan. Attention to renal involvement: report of 17 joubert syndrome cases in children of a single center in china. BMC Pediatrics, Jul 2022. URL: https://doi.org/10.1186/s12887-022-03496-8, doi:10.1186/s12887-022-03496-8. This article has 7 citations and is from a peer-reviewed journal.
(strong2023toporsasa pages 3-4): Alanna Strong, Hui‐Qi Qu, Sinéad Cullina, Morgan L. McManus, Elaine H. Zackai, Joseph Glessner, Eimear E. Kenny, and Hakon Hakonarson. Topors as a novel causal gene for joubert syndrome. American Journal of Medical Genetics Part A, 191:2156-2163, May 2023. URL: https://doi.org/10.1002/ajmg.a.63303, doi:10.1002/ajmg.a.63303. This article has 5 citations.
(wei2024novelcompoundheterozygous pages 6-7): Caichuan Wei, Haiju Zhang, Miaoying Fu, Jingping Ye, and Baozhen Yao. Novel compound heterozygous variants in the cspp1 gene causes joubert syndrome: case report and literature review of the cspp1 gene’s pathogenic mechanism. Frontiers in Pediatrics, Mar 2024. URL: https://doi.org/10.3389/fped.2024.1305754, doi:10.3389/fped.2024.1305754. This article has 4 citations.
(juan2024optimalprenatalgenetic pages 4-6): Zhang Juan, Cui-Xia Guo, Yuanjie Cui, Liu Yan, Yao Ling, Tiejuan Zhang, Wang Li, Jijing Han, Guohui Zhang, Yousheng Yan, Qingqing Wu, and Lijuan Sun. Optimal prenatal genetic diagnostic approach for posterior fossa malformation: karyotyping, copy number variant testing, or whole-exome sequencing? European Journal of Medical Research, Jul 2024. URL: https://doi.org/10.1186/s40001-024-01993-3, doi:10.1186/s40001-024-01993-3. This article has 3 citations and is from a peer-reviewed journal.
(dabrusco2023exploringthenoncoding pages 106-110): F D'Abrusco. Exploring the non-coding regions of the genome: the contribution of cryptic splicing variants to the onset of joubert syndrome. Unknown journal, 2023.
(weghe2022thejoubert–meckel–nephronophthisisspectrum pages 13-15): Julie C. Van De Weghe, Arianna Gomez, and Dan Doherty. The joubert–meckel–nephronophthisis spectrum of ciliopathies. Annual Review of Genomics and Human Genetics, 23:301-329, Aug 2022. URL: https://doi.org/10.1146/annurev-genom-121321-093528, doi:10.1146/annurev-genom-121321-093528. This article has 73 citations and is from a domain leading peer-reviewed journal.
(weghe2022thejoubert–meckel–nephronophthisisspectrum pages 15-16): Julie C. Van De Weghe, Arianna Gomez, and Dan Doherty. The joubert–meckel–nephronophthisis spectrum of ciliopathies. Annual Review of Genomics and Human Genetics, 23:301-329, Aug 2022. URL: https://doi.org/10.1146/annurev-genom-121321-093528, doi:10.1146/annurev-genom-121321-093528. This article has 73 citations and is from a domain leading peer-reviewed journal.
(wang2024zebrafishasa pages 1-2): Fan Wang and Fei Zhao. Zebrafish as a model for studying ciliary development and disease. International Journal of Marine Science, Jan 2024. URL: https://doi.org/10.5376/ijms.2024.14.0037, doi:10.5376/ijms.2024.14.0037. This article has 2 citations.
(NCT04874909 chunk 1): Classification, Functional Stratification and Biomarkers in Ciliopathy (CILLICORIRCM). Assistance Publique - Hôpitaux de Paris. 2021. ClinicalTrials.gov Identifier: NCT04874909
(dong2023clinicalandgenetic media e70ab935): Yan Dong, Ke Zhang, He Yao, Tianming Jia, Jun Wang, Dengna Zhu, Falin Xu, Meiying Cheng, Shichao Zhao, and Xiaoyi Shi. Clinical and genetic characteristics of 36 children with joubert syndrome. Frontiers in Pediatrics, Jul 2023. URL: https://doi.org/10.3389/fped.2023.1102639, doi:10.3389/fped.2023.1102639. This article has 16 citations.
(takagi2021anymodalityof pages 1-2): Yoko Takagi, Kenichiro Miura, Tomoo Yabuuchi, Naoto Kaneko, Kiyonobu Ishizuka, Mariko Takei, Chikage Yajima, Yuka Ikeuchi, Yasuko Kobayashi, Takumi Takizawa, Masataka Hisano, Yoshinori Tsurusaki, Naomichi Matsumoto, and Motoshi Hattori. Any modality of renal replacement therapy can be a treatment option for joubert syndrome. Scientific Reports, Jan 2021. URL: https://doi.org/10.1038/s41598-020-80712-4, doi:10.1038/s41598-020-80712-4. This article has 6 citations and is from a peer-reviewed journal.

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Subtypes

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Biochemical Markers

Differential Diagnoses

Related Datasets

Clinical Trials

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References & Deep Research

Deep Research

Disease Characteristics Research Template

Target Disease

Research Objectives

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Citation Requirements

Output Format

Comprehensive Disease Characteristics Report: Joubert syndrome (genetic ciliopathy)

1. Disease information

2. Etiology

2.1 Disease causal factors

2.2 Risk factors

2.3 Protective factors

2.4 Gene–environment interactions

3. Phenotypes (clinical spectrum)

3.1 Core neurologic phenotype (typical early onset)

3.2 Multisystem involvement

3.3 Quality-of-life impact

4. Genetic / molecular information

4.1 Causal genes (representative; not exhaustive)

4.2 Pathogenic variant classes and functional consequences

4.3 Gene–phenotype correlations (actionable surveillance)

4.4 Modifier genes / oligogenicity

4.5 Epigenetics / chromosomal abnormalities

5. Environmental information

6. Mechanism / pathophysiology

6.1 Core concept: primary cilium dysfunction

6.2 Signaling pathways and ciliary subdomains implicated

6.3 Causal chain (example: neurodevelopment)

6.4 Suggested GO / CL terms

6.5 Molecular profiling / advanced technologies

7. Anatomical structures affected (multi-level)

7.1 Organ/system level (UBERON suggestions)

7.2 Subcellular localization

8. Temporal development

9. Inheritance and population

9.1 Epidemiology

9.2 Population genetics / founder effects

10. Diagnostics

10.1 Clinical criteria and imaging

10.2 Genetic testing strategy

11. Outcome / prognosis

12. Treatment

12.1 Disease-modifying therapy

12.2 Supportive/rehabilitative care (real-world implementation)

12.3 Experimental / clinical-trial landscape

13. Prevention

14. Other species / natural disease

15. Model organisms

High-yield evidence map

Notes on evidence gaps (important for knowledge-base curation)