Update Joubert Syndrome throughout

Author: caufieldjh

kb/disorders/Joubert_syndrome.yaml

@@ -19,12 +19,6 @@ has_subtypes:
     term:
       id: MONDO:0008944
       label: Joubert syndrome 1
-- name: Joubert syndrome 10
-  subtype_term:
-    preferred_term: Joubert syndrome 10
-    term:
-      id: MONDO:0010431
-      label: Joubert syndrome 10
 - name: Joubert syndrome 2
   subtype_term:
     preferred_term: Joubert syndrome 2
@@ -301,7 +295,10 @@ epidemiology:
     evidence_source: HUMAN_CLINICAL
 inheritance:
 - name: Autosomal Recessive
-  description: Joubert syndrome is typically inherited in an autosomal recessive pattern.
+  description: >-
+    Joubert syndrome is typically inherited in an autosomal recessive pattern,
+    though an X-linked recessive form (Joubert syndrome 10, OFD1 on Xp22.2)
+    exists.
   evidence:
   - reference: PMID:36803942
     supports: SUPPORT
@@ -310,17 +307,27 @@ inheritance:
       \ of the cerebellum and the so-called \"molar tooth sign.\""
     explanation: This statement explicitly describes autosomal recessive inheritance.
     evidence_source: HUMAN_CLINICAL
+- name: X-linked recessive
+  description: >-
+    Joubert syndrome 10 is an X-linked recessive form caused by OFD1 mutations
+    on Xp22.2.
+  evidence:
+  - reference: PMID:31373179
+    supports: SUPPORT
+    snippet: "pathogenic variants in OFD1 were found to be associated with X-linked intellectual disability, Joubert syndrome type 10 (JBTS10),"
+    explanation: This review links OFD1 pathogenic variants to Joubert syndrome 10 in an X-linked context.
+    evidence_source: HUMAN_CLINICAL
+  - reference: PMID:31373179
+    supports: SUPPORT
+    snippet: "OFD1, residing on chromosome Xp22.2,"
+    explanation: This provides the OFD1 locus on Xp22.2 supporting X-linked inheritance.
+    evidence_source: HUMAN_CLINICAL
 pathophysiology:
-- name: Mutations affect primary cilium proteins
+- name: Ciliary gene mutations disrupt primary cilium assembly
   description: >-
     Causative JS genes encode proteins required for primary cilium structure
-    and function.
+    and assembly, disrupting cilium biogenesis in vivo.
   biological_processes:
-  - preferred_term: cilium organization
-    term:
-      id: GO:0044782
-      label: cilium organization
-    modifier: DYSREGULATED
   - preferred_term: cilium assembly
     term:
       id: GO:0060271
@@ -329,16 +336,18 @@ pathophysiology:
   evidence:
   - reference: PMID:38502237
     supports: SUPPORT
-    snippet: "Over 40 causative genes have been reported, all encoding for proteins\
-      \ implicated in the structure or functioning of the primary cilium, a subcellular\
-      \ organelle widely present in embryonic and adult tissues."
-    explanation: JS genes encode primary cilium components, motivating a primary cilium
-      organization/assembly defect.
+    snippet: "Over 40 causative genes have been reported, all encoding for proteins implicated in the structure or functioning of the primary cilium, a subcellular organelle widely present in embryonic and adult tissues."
+    explanation: JS genes encode primary cilium components, supporting disrupted cilium assembly.
+    evidence_source: IN_VITRO
+  - reference: PMID:41165761
+    supports: SUPPORT
+    snippet: "B9 proteins localized to centrioles prior to ciliogenesis, where they facilitated the initiation of ciliogenesis."
+    explanation: This supports impaired ciliogenesis initiation as a core ciliary assembly defect.
     evidence_source: IN_VITRO
-- name: Ciliary structural defects in patient-derived neural cells
+- name: Abnormal cilium structure and length
   description: >-
-    Differentiating JS patient-derived iPSCs show abnormal primary cilium
-    number and morphology.
+    Primary cilia show abnormal number, morphology, and length in JS models,
+    indicating disrupted cilium organization.
   biological_processes:
   - preferred_term: cilium organization
     term:
@@ -348,65 +357,24 @@ pathophysiology:
   evidence:
   - reference: PMID:38502237
     supports: SUPPORT
-    snippet: "In addition, analysis of primary cilium count and morphology showed\
-      \ notable ciliary defects in all differentiating JS patient-derived iPSCs compared\
-      \ to controls."
+    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
-- name: Zebrafish models show ciliary defects
-  description: >-
-    Zebrafish models of ciliopathy-associated genes show ciliary defects,
-    supporting abnormal cilium organization in vivo.
-  biological_processes:
-  - preferred_term: cilium organization
-    term:
-      id: GO:0044782
-      label: cilium organization
-    modifier: ABNORMAL
-  evidence:
   - reference: PMID:36802443
     supports: SUPPORT
-    snippet: "Deficiency of the minor spliceosome component U4atac snRNA secondarily results\
-      \ in ciliary defects in human and zebrafish."
-    explanation: Zebrafish models demonstrate ciliary defects consistent with
-      abnormal cilium organization.
+    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
-- name: Altered primary cilia in zebrafish brains
-  description: >-
-    Zebrafish models of JS genes show altered primary cilia across the brain,
-    consistent with disrupted cilium organization.
-  biological_processes:
-  - preferred_term: cilium organization
-    term:
-      id: GO:0044782
-      label: cilium organization
-    modifier: ABNORMAL
-  evidence:
   - reference: PMID:39400299
     supports: SUPPORT
     snippet: "We found that JBTS mutants have altered primary cilia throughout the brain."
-    explanation: Zebrafish JBTS mutants show altered primary cilia in brain
-      tissue.
+    explanation: Zebrafish JBTS mutants show altered primary cilia in brain tissue.
     evidence_source: MODEL_ORGANISM
-- name: Transition zone mutations yield variable ciliopathy phenotypes
-  description: >-
-    Zebrafish transition zone gene mutations show variable ciliopathy phenotypes,
-    indicating dysregulated cilium organization.
-  biological_processes:
-  - preferred_term: cilium organization
-    term:
-      id: GO:0044782
-      label: cilium organization
-    modifier: DYSREGULATED
-  evidence:
-  - reference: PMID:36533556
+  - reference: PMID:40951761
     supports: SUPPORT
-    snippet: "We performed a comprehensive analysis of ten zebrafish TZ mutants, including\
-      \ mks1, tmem216, tmem67, rpgrip1l, cc2d2a, b9d2, cep290, tctn1, nphp1 and\
-      \ nphp4."
-    explanation: Zebrafish transition zone mutants show variable ciliopathy
-      phenotypes consistent with dysregulated cilium organization.
-    evidence_source: MODEL_ORGANISM
+    snippet: "The patient-derived fibroblasts exhibited reduced primary cilia length and altered distribution of PCM1."
+    explanation: KIAA0586/TALPID3 variants are associated with reduced cilia length.
+    evidence_source: IN_VITRO
 - name: Impaired intraciliary transport
   description: >-
     Disruption of ciliary gene products (e.g., CEP290) impairs intraciliary transport
@@ -420,86 +388,23 @@ pathophysiology:
   evidence:
   - reference: PMID:33717386
     supports: SUPPORT
-    snippet: "Recently, it has been proposed that CEP290 gene product may also play\
-      \ a role in the microtubule-based ciliary transport, in the vesicle transport,\
-      \ the development and maintenance of the cilium"
-    explanation: CEP290 dysfunction is linked to impaired intraciliary transport and
-      cilium maintenance.
+    snippet: "Recently, it has been proposed that CEP290 gene product may also play a role in the microtubule-based ciliary transport, in the vesicle transport, the development and maintenance of the cilium"
+    explanation: CEP290 dysfunction is linked to impaired intraciliary transport and cilium maintenance.
     evidence_source: HUMAN_CLINICAL
-- name: Reduced primary cilia length in KIAA0586/TALPID3 variants
+- name: Neurodevelopmental defects
   description: >-
-    Patient-derived fibroblasts with KIAA0586/TALPID3 variants show reduced primary
-    cilia length and altered PCM1 distribution.
-  biological_processes:
-  - preferred_term: cilium organization
-    term:
-      id: GO:0044782
-      label: cilium organization
-    modifier: ABNORMAL
-  evidence:
-  - reference: PMID:40951761
-    supports: SUPPORT
-    snippet: "The patient-derived fibroblasts exhibited reduced primary cilia length\
-      \ and altered distribution of PCM1."
-    explanation: KIAA0586/TALPID3 variants are associated with abnormal primary cilia
-      structure.
-    evidence_source: IN_VITRO
-- name: Impaired neuronal differentiation in mid-hindbrain lineages
-  description: >-
-    Patient-derived iPSCs show impaired differentiation toward mid-hindbrain
-    precursors.
-  biological_processes:
-  - preferred_term: neuron differentiation
-    term:
-      id: GO:0030182
-      label: neuron differentiation
-    modifier: DYSREGULATED
+    Disrupted ciliary biology impairs neurodevelopmental programs, contributing
+    to mid-hindbrain and cerebellar developmental abnormalities.
   evidence:
   - reference: PMID:38502237
     supports: SUPPORT
-    snippet: "All JS patient-derived iPSCs, regardless of the mutant gene, showed\
-      \ a similar impairment to differentiate into mid-hindbrain and cerebellar granule\
-      \ cells when compared to healthy controls."
-    explanation: This indicates impaired neuronal differentiation in mid-hindbrain
-      lineages.
+    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
-- name: Impaired cerebellar granule cell differentiation
-  description: >-
-    Differentiation into cerebellar granule cells is reduced in JS
-    patient-derived iPSC models.
-  biological_processes:
-  - preferred_term: cerebellum development
-    term:
-      id: GO:0021549
-      label: cerebellum development
-    modifier: DYSREGULATED
-  evidence:
-  - reference: PMID:38502237
-    supports: SUPPORT
-    snippet: "All JS patient-derived iPSCs, regardless of the mutant gene, showed\
-      \ a similar impairment to differentiate into mid-hindbrain and cerebellar granule\
-      \ cells when compared to healthy controls."
-    explanation: Impaired differentiation into cerebellar granule cells supports dysregulated
-      cerebellum development.
-    evidence_source: IN_VITRO
-- name: Hindbrain malformation with molar tooth sign
-  description: >-
-    Disrupted cerebellar development results in characteristic hindbrain
-    malformations including the molar tooth sign.
-  biological_processes:
-  - preferred_term: cerebellum development
-    term:
-      id: GO:0021549
-      label: cerebellum development
-    modifier: DYSREGULATED
-  evidence:
   - reference: PMID:40537162
     supports: SUPPORT
-    snippet: "Classic defects include hypoplasia of the cerebellar vermis, thickened\
-      \ cerebellar peduncles, and deepened interpeduncular fossa, which is regarded\
-      \ as a \"molar tooth\" sign."
-    explanation: This review describes the hindbrain malformations characteristic
-      of JS.
+    snippet: "Classic defects include hypoplasia of the cerebellar vermis, thickened cerebellar peduncles, and deepened interpeduncular fossa, which is regarded as a \"molar tooth\" sign."
+    explanation: This review describes neurodevelopmental malformations characteristic of JS.
     evidence_source: HUMAN_CLINICAL
 phenotypes:
 - name: Molar tooth sign on MRI
@@ -1025,6 +930,11 @@ genetic:
       \ confirmed by whole exome sequencing."
     explanation: This JS type 6 case confirms a pathogenic TMEM67 variant.
     evidence_source: HUMAN_CLINICAL
+  - reference: PMID:39849212
+    supports: SUPPORT
+    snippet: "Whole Exome Sequencing (WES), performed via buccal swab, showed biallelic pathogenic variants at NM_153704.6:c.2086 C > T (NP_714915.3:p.Leu696Phe) and NM_153704.6:c.431del (NP_714915.3:p.Leu144CysfsTer19) in TMEM67, which are associated with Joubert Syndrome 6 (OMIM:610688) in a compound heterozygous state."
+    explanation: This case report identifies biallelic TMEM67 variants associated with Joubert syndrome 6.
+    evidence_source: HUMAN_CLINICAL
   gene_term:
     preferred_term: TMEM67
     term:
@@ -1092,6 +1002,11 @@ genetic:
       \ KIF7, RPGRIP1L, including some previously unreported variants in these genes."
     explanation: This cohort reports CSPP1 among causative JS genes.
     evidence_source: HUMAN_CLINICAL
+  - reference: PMID:40898267
+    supports: SUPPORT
+    snippet: "Pathogenic CSPP1 variants account for approximately 3% of Joubert syndrome cases."
+    explanation: This case report notes CSPP1 pathogenic variants contribute to JS, supporting CSPP1 as a causative gene.
+    evidence_source: HUMAN_CLINICAL
   gene_term:
     preferred_term: CSPP1
     term:
@@ -1150,6 +1065,11 @@ genetic:
       \ syndrome (JS), which is a genetically heterogeneous disorder."
     explanation: This study links KIAA0586/TALPID3 variants to JS.
     evidence_source: IN_VITRO
+  - reference: PMID:41020477
+    supports: SUPPORT
+    snippet: "JBTS23, a subtype of Joubert syndrome, is caused by variations in the KIAA0586 gene."
+    explanation: This report identifies pathogenic KIAA0586 variants in a JS subtype, supporting causative association.
+    evidence_source: HUMAN_CLINICAL
   gene_term:
     preferred_term: KIAA0586
     term:
@@ -1472,6 +1392,28 @@ datasets:
       \ 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

references_cache/GEO_GSE217001.md

@@ -0,0 +1,11 @@
+---
+reference_id: "GEO:GSE217001"
+title: Variable phenotypes and penetrance between and within different zebrafish transition zone mutants
+content_type: summary
+---
+
+# Variable phenotypes and penetrance between and within different zebrafish transition zone mutants
+
+## Content
+
+Meckel Syndrome, Nephronophthisis, Joubert Syndrome, and Bardet-Biedl Syndrome have mutations in proteins that localize to the ciliary transition zone (TZ). The phenotypically distinct syndromes suggest these TZ proteins have differing functions. However, mutations in a single TZ gene can result in multiple syndromes suggesting the phenotype is influenced by modifier genes. We performed a comprehensive analysis of ten zebrafish TZ mutants including mks1, tmem216, tmem67, rpgrip1l, cc2d2a, b9d2, cep290, tctn1, nphp1, and nphp4, as well as mutants in ift88 and ift172. Our data indicate variations in phenotypes exists between different TZ mutants, supporting different tissue specific functions of these TZ genes. Further we observed phenotypic variations within progeny of a single TZ mutant, reminiscent of multiple disease syndromes being associated with mutations in one gene. In some mutants the dynamics of the phenotype became complex with transitory phenotypes that are corrected over time. We have also demonstrated that multiple-guide derived CRISPR/Cas9 F0 “Crispant” embryos recapitulate zygotic null phenotypes, and rapidly identified ciliary phenotypes in 11 cilia-associated gene candidates (ankfn1, ccdc65, cfap57, fhad1, nme7, pacrg, saxo2, c1orf194, ttc26, zmynd12, and cfap52).