Ciliopathies (Disorders of Cilium Structure and Function)

name: Ciliopathies
display_name: Ciliopathies (Disorders of Cilium Structure and Function)
creation_date: "2026-06-13T00:00:00Z"
description: >-
  The ciliopathies are a group of Mendelian disorders caused by defects in the
  structure or function of the cilium. Diverse lesions in genes encoding basal
  body, transition zone, and intraflagellar transport (IFT) components disrupt
  the assembly, gating, and cargo trafficking of the primary (non-motile)
  cilium — the cell's signaling antenna — converging on impaired
  cilium-dependent Hedgehog and non-canonical Wnt/planar cell polarity
  signaling. Because cilia are nearly ubiquitous, the shared signaling failure
  is read out differently in each ciliated tissue, producing the pleiotropic,
  multisystem phenotype (retinal degeneration, cystic-fibrotic kidney disease,
  skeletal dysplasia with polydactyly, cerebellar/CNS malformation, obesity and
  metabolic dysfunction) that unites the classic syndromic ciliopathies. A
  parallel motile-cilia arm captures the distinct mechanism of primary ciliary
  dyskinesia, in which axonemal motility defects impair mucociliary clearance
  and left-right body patterning.
grouping_basis:
- SHARED_MECHANISM
- SHARED_PATHWAY
grouping_rationale: >-
  Grouped on the shared cilium mechanism: each member conforms to the
  ciliopathy_dysfunction module, in which a basal body / transition zone / IFT
  or axonemal lesion disrupts cilium-dependent signaling or motility. Members
  are kept as separate Disease entries because they differ in the affected
  ciliary subcompartment (BBSome trafficking in Bardet-Biedl; transition zone
  in Joubert and Meckel; dynein-2/retrograde IFT in Jeune and short-rib
  polydactyly; the inversin compartment in nephronophthisis; centriolar OFD1 in
  orofaciodigital syndrome; axonemal dynein arms in primary ciliary dyskinesia)
  and in which organ systems dominate the clinical picture. The module itself
  distinguishes two mechanistic arms — a primary (non-motile) cilium signaling
  arm that underlies the syndromic ciliopathies, and a motile cilium arm that
  underlies primary ciliary dyskinesia. Criteria are stated as NECESSARY:
  cilium-module conformance is entailed by membership and is used to audit the
  listed members, but isolated ciliary features alone (e.g., a single cystic
  kidney) do not by themselves establish a syndromic ciliopathy.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0005308
      label: ciliopathy
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      The grouping concept corresponds to the MONDO ciliopathy class, and the
      membership criterion mirrors the MONDO OWL logical definition (disease and
      RO:0004020 some GO:0005929 — "has basis in dysfunction of cilium").
      exactMatch records the intended conceptual alignment; MONDO descendants
      without DisMech entries are curation gaps rather than a reason to weaken
      the mapping predicate.
    consistency:
    - reference: MONDO
      consistent: CONSISTENT
      notes: >-
        7/9 listed members are is-a descendants of MONDO:0005308. The two
        exceptions (Nephronophthisis -> MONDO:0019005; Short-Rib Polydactyly
        Syndrome -> MONDO:0015461) are bona fide ciliopathies whose dismech
        entries map to broader sibling MONDO grouping terms rather than to a
        node beneath MONDO:0005308. Treat these outside-subtree members as
        MONDO/member-alignment signals, while treating uncurated MONDO
        ciliopathy descendants as DisMech curation gaps.
membership_criteria:
- description: >-
    A member conforms to the ciliopathy module, either through its primary
    (non-motile) cilium signaling arm (a basal body / transition zone / IFT
    lesion impairing cilium-dependent signal transduction) or through its
    motile cilium arm (an axonemal beat defect impairing mucociliary clearance
    and laterality).
  criteria_semantics: NECESSARY
  logic:
    operator: OR
    description: >-
      Conforms to either the primary-cilium signaling arm or the motile-cilium
      arm of the ciliopathy module.
    operands:
    - criterion_predicate: CONFORMS_TO_MODULE
      module: ciliopathy_dysfunction#Basal Body and Transition Zone Dysfunction
      description: >-
        Primary-cilium arm: conforms to the basal body and transition zone
        dysfunction node that triggers impaired Hedgehog/Wnt-PCP signaling.
    - criterion_predicate: CONFORMS_TO_MODULE
      module: ciliopathy_dysfunction#Motile Cilia Beat Dysfunction
      description: >-
        Motile-cilium arm: conforms to the motile cilia beat dysfunction node
        (primary ciliary dyskinesia).
members:
- member: Bardet-Biedl syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Defects in the BBSome (e.g., BBS1) impair ciliary membrane-protein
      trafficking. Distinguished by the combination of rod-cone dystrophy,
      postaxial polydactyly, truncal obesity, hypogonadism, renal anomalies,
      and learning difficulties — the prototypical pleiotropic syndromic
      ciliopathy.
    gene:
      preferred_term: BBS1
      term:
        id: hgnc:966
        label: BBS1
- member: Alstrom Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      ALMS1 encodes a centrosomal/basal body protein. Overlaps with
      Bardet-Biedl (cone-rod dystrophy, obesity, insulin resistance,
      sensorineural hearing loss, dilated cardiomyopathy) but is distinguished
      by the absence of polydactyly and of cognitive impairment.
    gene:
      preferred_term: ALMS1
      term:
        id: hgnc:428
        label: ALMS1
- member: Joubert syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Transition-zone gene defects (e.g., CPLANE1, CEP290, TMEM67, AHI1)
      produce the pathognomonic molar tooth sign (cerebellar vermis hypoplasia)
      with abnormal eye movements, episodic hyperpnea/apnea, and developmental
      delay; the CNS malformation arm dominates.
    gene:
      preferred_term: CPLANE1
      term:
        id: hgnc:25801
        label: CPLANE1
- member: Acrocallosal Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic KIF7 (Costal2 ortholog) loss-of-function deregulates GLI
      targets and impairs GLI3 processing at the cilium tip, driving the
      Hedgehog-signaling arm. Distinguished by the combination of corpus
      callosum agenesis/hypoplasia, macrocephaly with prominent forehead and
      hypertelorism, and postaxial/preaxial polydactyly with hallux
      duplication; shares the molar tooth sign with Joubert syndrome and is
      allelic with the more severe hydrolethalus syndrome.
    gene:
      preferred_term: KIF7
      term:
        id: hgnc:30497
        label: KIF7
    module: ciliopathy_dysfunction#Impaired Hedgehog Signal Transduction
- member: Multiple Epiphyseal Dysplasia, Al-Gazali Type
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      A homozygous hypomorphic KIF7 (Costal2 ortholog) missense mutation
      (p.N1060S) deregulates GLI targets and impairs GLI3 processing at the
      cilium tip, driving the Hedgehog-signaling arm. Distinguished from the
      other KIF7 ciliopathies by a skeletal-predominant presentation of multiple
      epiphyseal dysplasia with macrocephaly and a distinctive facial
      appearance, rather than the corpus callosum agenesis and polydactyly of
      acrocallosal syndrome or the lethal anomalies of hydrolethalus syndrome.
    gene:
      preferred_term: KIF7
      term:
        id: hgnc:30497
        label: KIF7
    module: ciliopathy_dysfunction#Impaired Hedgehog Signal Transduction
- member: Alsahan-Harris Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic TBC1D32 (BROMI/C6orf170) loss-of-function disrupts the
      CCRK/CDK20-BROMI-ICK/CILK1-controlled intraflagellar transport turnaround
      at the ciliary tip, deregulating cilium-dependent Hedgehog signaling.
      Distinguished by a highly variable multisystem spectrum (designated
      OFD-IX) combining oral-facial-digital anomalies and polydactyly,
      hypothalamic-pituitary involvement (congenital hypopituitarism),
      inherited retinal degeneration (retinitis pigmentosa / rod-cone
      degeneration), and sensorineural hearing loss, with a severe
      life-limiting prenatal phenotype at the extreme end.
    gene:
      preferred_term: TBC1D32
      term:
        id: hgnc:21485
        label: TBC1D32
    module: ciliopathy_dysfunction#Impaired Hedgehog Signal Transduction
- member: Hydrolethalus Syndrome 2
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic KIF7 loss-of-function at the severe, perinatally lethal extreme
      of the Hedgehog-signaling arm — allelic with acrocallosal syndrome but
      uniformly lethal. Distinguished by a severe midline brain malformation
      (hydrocephaly with absent midline structures and corpus callosum
      agenesis), pre-/postaxial polydactyly, and cleft palate; affected fetuses
      are stillborn or die shortly after birth.
    gene:
      preferred_term: KIF7
      term:
        id: hgnc:30497
        label: KIF7
    module: ciliopathy_dysfunction#Impaired Hedgehog Signal Transduction
- member: Meckel Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Transition-zone defects (e.g., MKS1, TMEM67, CC2D2A) at the severe,
      perinatally lethal end of the spectrum: occipital encephalocele, cystic
      renal dysplasia, and postaxial polydactyly — allelic with Joubert
      syndrome but uniformly lethal.
    gene:
      preferred_term: MKS1
      term:
        id: hgnc:7121
        label: MKS1
- member: Nephronophthisis
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      NPHP1 (inversin compartment) defects produce a corticomedullary cystic
      kidney disease that progresses to end-stage renal disease, with little or
      no extrarenal involvement in the isolated form — the renal arm of the
      ciliopathy spectrum.
    gene:
      preferred_term: NPHP1
      term:
        id: hgnc:7905
        label: NPHP1
- member: Jeune Asphyxiating Thoracic Dystrophy
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Retrograde IFT / dynein-2 defects (e.g., IFT172 and dynein-2 components)
      impair growth-plate Hedgehog signaling, producing a narrow, bell-shaped
      thorax with short ribs and respiratory insufficiency — the skeletal arm,
      on a spectrum with short-rib polydactyly syndrome.
    gene:
      preferred_term: IFT172
      term:
        id: hgnc:30391
        label: IFT172
- member: Short-Rib Polydactyly Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      DYNC2H1 (dynein-2 heavy chain) and IFT gene defects give the most severe,
      lethal skeletal ciliopathy: markedly short ribs with thoracic
      hypoplasia plus polydactyly — distinguished from Jeune by perinatal
      lethality and the constancy of polydactyly.
    gene:
      preferred_term: DYNC2H1
      term:
        id: hgnc:2962
        label: DYNC2H1
- member: Orofaciodigital Syndrome Type I
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      OFD1 encodes a centriolar distal-appendage/basal body protein; X-linked
      dominant with male lethality. Distinguished by oral (lingual hamartomas,
      clefting), facial, and digital (polydactyly, syndactyly) anomalies with
      polycystic kidney disease.
    gene:
      preferred_term: OFD1
      term:
        id: hgnc:2567
        label: OFD1
- member: Orofaciodigital Syndrome 17
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      INTU encodes a subunit of the CPLANE (ciliogenesis and planar-cell-polarity
      effector) module that positions the ciliary basal body and is required for
      IFT-A assembly and intraflagellar transport; autosomal recessive.
      Distinguished from the X-linked OFD1 form by its recessive INTU/CPLANE-IFT
      basis and an allelic spectrum that also spans short-rib thoracic dysplasia
      20 with polydactyly and nephronophthisis, with the molar tooth sign,
      preaxial/postaxial polydactyly, oral hamartomas, congenital heart defect,
      and renal malformation.
    gene:
      preferred_term: INTU
      term:
        id: hgnc:29239
        label: INTU
    module: ciliopathy_dysfunction#Basal Body and Transition Zone Dysfunction
- member: Heart Defect-Tongue Hamartoma-Polysyndactyly Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      WDPCP (the human homolog of Fritz / BBS15 gene) encodes a planar cell
      polarity effector that localizes to the ciliary transition zone, recruits
      septins for ciliogenesis, and directly modulates the actin cytoskeleton to
      control convergent-extension morphogenesis; autosomal recessive.
      Distinguished from the OFD1 and INTU forms by its WDPCP/PCP-and-actin basis
      and a defining triad of tongue hamartomas, polysyndactyly, and congenital
      heart defects (notably coarctation of the aorta).
    gene:
      preferred_term: WDPCP
      term:
        id: hgnc:28027
        label: WDPCP
    module: ciliopathy_dysfunction#Planar Cell Polarity and Non-Canonical Wnt Disruption
- member: Primary_Ciliary_Dyskinesia
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Axonemal dynein-arm defects (e.g., DNAH5, DNAI1) impair motile-cilium
      beat rather than primary-cilium signaling — the distinct motile-cilium
      arm. Causes impaired mucociliary clearance (chronic sinopulmonary
      disease, bronchiectasis), laterality defects (situs inversus /
      Kartagener), and infertility.
    gene:
      preferred_term: DNAH5
      term:
        id: hgnc:2950
        label: DNAH5
- member: Senior-Loken Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Transition-zone / connecting-cilium nephrocystin defects (e.g.,
      IQCB1/NPHP5, CEP290/NPHP6) couple the renal arm (nephronophthisis) to a
      retinitis pigmentosa-like retinal dystrophy — the oculo-renal ciliopathy.
      Distinguished from isolated Nephronophthisis by the obligate, highly
      penetrant retinal degeneration arising from photoreceptor connecting-cilium
      dysfunction.
    gene:
      preferred_term: IQCB1
      term:
        id: hgnc:28949
        label: IQCB1
- member: Oculocerebrodental Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic loss of PIK3C2A, a class II phosphoinositide 3-kinase producing
      PI(3)P and PI(3,4)P2, depletes the ciliary-base phosphoinositides required
      for primary cilium formation and function — a phosphoinositide-metabolism
      ciliopathy rather than a structural basal-body/transition-zone or axonemal
      defect. Distinguished by congenital (pulverulent) cataracts with secondary
      glaucoma, short stature with multiple skeletal abnormalities, coarse facial
      and dental features, and neurological manifestations with hearing loss;
      shares phosphoinositide-disorder overlap with Lowe syndrome (OCRL).
    gene:
      preferred_term: PIK3C2A
      term:
        id: hgnc:8971
        label: PIK3C2A
    module: ciliopathy_dysfunction#Basal Body and Transition Zone Dysfunction
- member: Leber Congenital Amaurosis with Early-Onset Deafness
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Heterozygous dominant-negative variants in the cilia-enriched β-tubulin
      isotype TUBB4B (recurrently at Arg391) dampen microtubule dynamics and
      perturb centriole and cilium biogenesis — a tubulinopathy that sits at the
      tubulinopathy/ciliopathy interface rather than a structural basal-body or
      IFT defect. Distinguished as a purely sensory ciliopathy: severe congenital
      photoreceptor degeneration (Leber congenital amaurosis) combined with
      early-onset sensorineural hearing loss, reflecting the non-redundant role
      of the TUBB4B isotype in photoreceptor connecting cilia and cochlear
      sensory cells, without the multisystem visceral involvement of the
      transition-zone/BBSome ciliopathies.
    gene:
      preferred_term: TUBB4B
      term:
        id: hgnc:20771
        label: TUBB4B
    module: ciliopathy_dysfunction#Photoreceptor Connecting Cilium Degeneration
- member: Leber Congenital Amaurosis 10
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic variants in CEP290, a core ciliary transition-zone protein,
      disrupt the connecting-cilium gate and intraflagellar transport in
      photoreceptors. The common hypomorphic deep-intronic c.2991+1655A>G
      (IVS26) allele permits residual CEP290 function in most organs but is
      inadequate for the highly specialized photoreceptor cilium, producing an
      isolated, non-syndromic retinal ciliopathy (severe early-onset blindness)
      rather than the multisystem visceral involvement seen with severe CEP290
      alleles (Joubert, Meckel, Senior-Loken). Distinguished from the TUBB4B
      sensory ciliopathy by its retina-restricted phenotype and its amenability
      to allele-specific splice-correcting (sepofarsen) and CRISPR (EDIT-101)
      therapy.
    gene:
      preferred_term: CEP290
      term:
        id: hgnc:29021
        label: CEP290
    module: ciliopathy_dysfunction#Photoreceptor Connecting Cilium Degeneration
- member: Cranioectodermal Dysplasia
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic defects in the retrograde intraflagellar-transport IFT-A complex
      (IFT122, WDR35, IFT43, WDR19) impair basal-body/transition-zone ciliary
      assembly. Distinguished by the combination of sagittal craniosynostosis
      with dolichocephaly, an ectodermal arm (sparse slow-growing hair,
      hypodontia, nail and skin abnormalities), a narrow thorax with short ribs
      and short limbs/brachydactyly, and progressive nephronophthisis-like renal
      disease with hepatic fibrosis — a skeletal-ectodermal IFT-A ciliopathy
      (Sensenbrenner syndrome).
    gene:
      preferred_term: IFT122
      term:
        id: hgnc:13556
        label: IFT122
    module: ciliopathy_dysfunction#Basal Body and Transition Zone Dysfunction
- member: McKusick-Kaufman syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic MKKS (a group-II chaperonin-like protein required for BBSome
      assembly) variants perturb ciliary trafficking and Hedgehog signal
      transduction. Distinguished by the triad of hydrometrocolpos, postaxial
      polydactyly, and congenital heart disease, characteristically WITHOUT the
      retinal dystrophy, obesity, and cognitive impairment of its allelic
      disorder Bardet-Biedl syndrome type 6 (also MKKS) — the central
      MKKS-vs-BBS6 differential, since some patients reclassify as BBS over time.
    gene:
      preferred_term: MKKS
      term:
        id: hgnc:7108
        label: MKKS
    module: ciliopathy_dysfunction#Impaired Hedgehog Signal Transduction
- member: IFT140-related Recessive Ciliopathy
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic IFT140 (a core IFT-A subunit) variants impair retrograde
      intraflagellar transport, the return arm of the IFT cycle. Distinguished
      from the other IFT-A skeletal ciliopathies (Cranioectodermal Dysplasia,
      Jeune) by its retina- and kidney-weighted allelic continuum: because
      IFT140 is expressed more highly in retina and kidney than in skeleton,
      the phenotype runs from isolated non-syndromic retinal dystrophy
      (retinitis pigmentosa 80) at one pole to a conorenal skeletal ciliopathy
      overlapping Mainzer-Saldino and Jeune at the other, with thoracic
      constriction typically milder than in the short-rib group.
    gene:
      preferred_term: IFT140
      term:
        id: hgnc:29077
        label: IFT140
    module: ciliopathy_dysfunction#Basal Body and Transition Zone Dysfunction
- member: CFAP418-related retinal ciliopathy
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic CFAP418 (C8orf37) variants disrupt a cilium-associated protein
      that localizes to the base of the photoreceptor connecting cilium — a
      cilia-base/transition-zone locus rather than a component of the BBSome
      trafficking machine itself. Distinguished by a photoreceptor-dominant
      allelic continuum in which retinal degeneration is the shared, most
      dosage-sensitive feature: isolated cone-rod dystrophy (CORD16) or
      retinitis pigmentosa with early macular involvement (RP64) at the
      non-syndromic pole, grading into full Bardet-Biedl syndrome (BBS21) with
      obesity, postaxial polydactyly, and renal anomalies at the syndromic pole.
    gene:
      preferred_term: CFAP418
      term:
        id: hgnc:27232
        label: CFAP418
    module: ciliopathy_dysfunction#Photoreceptor Connecting Cilium Degeneration
- member: EYS-Related Retinitis Pigmentosa
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic EYS (eyes shut homolog) variants remove a large extracellular
      structural protein of the photoreceptor periciliary space and connecting
      cilium, where it acts as a spacer maintaining outer-segment architecture.
      Distinguished from the syndromic members as a non-syndromic,
      retina-restricted ciliopathy: because EYS is eye-specific, there is no
      renal, skeletal, CNS, or metabolic pleiotropy, and the presentation is
      classic rod-first retinitis pigmentosa (RP25) — one of the most common
      causes of autosomal recessive RP in European and East Asian cohorts.
    gene:
      preferred_term: EYS
      term:
        id: hgnc:21555
        label: EYS
    module: ciliopathy_dysfunction#Basal Body and Transition Zone Dysfunction
notes: >-
  Worked example of a grouping whose membership criterion is an OR over two
  distinct mechanistic arms of a single module (primary-cilium signaling vs
  motile-cilium beat). Because the members declare conforms_to edges to the
  ciliopathy_dysfunction module, `just check-groupings` reports them as
  SATISFIED. The criteria are NECESSARY, so the evaluator audits only the
  listed members for violations; it does not scan non-members for candidate
  additions (that requires SUFFICIENT or NECESSARY_AND_SUFFICIENT criteria,
  which are deliberately not used here — isolated ciliary features do not by
  themselves establish a syndromic ciliopathy).