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1
Mappings
1
Inheritance
5
Pathophys.
5
Phenotypes
8
Pathograph
1
Genes
3
Medical Actions
8
References
🔗

Mappings

MONDO
MONDO:0979871 Alsahan-Harris syndrome
skos:exactMatch MONDO
MONDO:0979871 (Alsahan-Harris syndrome) is the disease term for this entry and carries an OMIM:621307 xref and a TBC1D32 (HGNC:21485) gene association, matching the curated identity.
👪

Inheritance

1
Autosomal Recessive
Alsahan-Harris syndrome is inherited in an autosomal recessive manner, caused by biallelic (homozygous or compound heterozygous) pathogenic variants in TBC1D32.
Show evidence (1 reference)
PMID:36826837 SUPPORT Human Clinical
"We describe seven unpublished probands with rare likely pathogenic variants or variants of uncertain significance that segregate with recessive disease in TBC1D32"
Establishes recessive segregation of TBC1D32 variants across multiple pedigrees, supporting autosomal recessive inheritance.

Pathophysiology

5
TBC1D32/BROMI Ciliary Trafficking and IFT Turnaround Defect
TBC1D32 (BROMI) is a ciliary protein required for the intraflagellar transport (IFT) turnaround at the ciliary tip. It interacts with CCRK/CDK20, which phosphorylates and activates the ICK/CILK1 kinase that controls the change in direction of the IFT machinery. Loss of TBC1D32 function (modelled by BROMI-knockout cells and mouse mutants) produces abnormally long cilia with accumulation of IFT proteins and ICK at the bulged ciliary tip, deranging the bidirectional cargo trafficking on which cilium-dependent signaling depends.
ciliated cell CL:0000064
TBC1D32 hgnc:21485
intraflagellar transport GO:0042073 ⚠ ABNORMAL cilium assembly GO:0060271 ⚠ ABNORMAL protein localization to cilium GO:0061512 ⚠ ABNORMAL
Show evidence (3 references)
PMID:35609210 SUPPORT In Vitro
"BROMI/TBC1D32 interacts with CCRK/CDK20, which phosphorylates and activates the intestinal cell kinase (ICK)/CILK1 kinase, to regulate the change in direction of the IFT machinery at the ciliary tip."
Defines the molecular role of TBC1D32/BROMI in regulating IFT turnaround at the ciliary tip, the upstream lesion of this ciliopathy.
PMID:35609210 SUPPORT In Vitro
"Ciliary defects observed in CCRK-knockout (KO), BROMI-KO, and FAM149B1-KO cells, including abnormally long cilia and accumulation of the IFT machinery and ICK at the ciliary tip, resembled one another"
Demonstrates that loss of TBC1D32/BROMI produces abnormal cilia with IFT accumulation at the ciliary tip, the cellular trafficking defect.
PMID:35609210 SUPPORT Human Clinical
"Mutations in BROMI, CCRK, and ICK in humans cause ciliopathies"
Confirms that TBC1D32/BROMI mutations cause ciliopathy in humans, anchoring this gene-specific lesion to the ciliopathy module.
Impaired Hedgehog Signal Transduction
The CCRK-BROMI(TBC1D32) module governs ciliary Hedgehog signaling. Loss of CCRK or its TBC1D32/BROMI partner causes overaccumulation of IFT proteins at the ciliary tip and abnormal enrichment of Hedgehog pathway components (GPR161 and Smoothened) on the ciliary membrane, deregulating cilium-dependent Hedgehog signal transduction. Because Hedgehog signaling patterns the limb and craniofacial midline, its disruption underlies the polydactyly and oral-facial-digital malformations of the syndrome.
Hedgehog (smoothened) signaling pathway GO:0007224 ↕ DYSREGULATED
Show evidence (2 references)
PMID:34624068 SUPPORT In Vitro
"CCRK/CDK20 was reported to interact with BROMI/TBC1D32 and regulate ciliary Hedgehog signaling."
Establishes that the CCRK-BROMI(TBC1D32) interaction regulates ciliary Hedgehog signaling, the central effector pathway of this ciliopathy.
PMID:34624068 SUPPORT In Vitro
"the overaccumulation of IFT proteins at the bulged ciliary tips, which appear to be eliminated as extracellular vesicles, and the enrichment of GPR161 and Smoothened on the ciliary membrane"
Shows that loss of the CCRK-BROMI module abnormally enriches Hedgehog pathway components (GPR161, Smoothened) on the ciliary membrane, mechanistically linking the trafficking defect to Hedgehog dysregulation.
Oral-Facial-Digital Malformation
TBC1D32 variants produce an oral-facial-digital syndrome phenotype (designated OFD-IX) characterized by polydactyly and craniofacial dysmorphism, reflecting deranged cilium-dependent Hedgehog patterning of the limb and craniofacial midline. Sensorineural hearing loss has been proposed as an additional feature of the gene's phenotypic spectrum.
limb morphogenesis GO:0035108 ⚠ ABNORMAL
Show evidence (2 references)
PMID:40319332 SUPPORT Human Clinical
"Mutations in TBC1D32 were associated to retinal dystrophy and OFD, defining this form as OFD-IX."
Establishes the oral-facial-digital (OFD-IX) phenotype as a TBC1D32 manifestation, the malformation read-out of the Hedgehog-patterning defect.
PMID:40319332 SUPPORT Human Clinical
"A clinical exome analysis performed on a patient presenting with OFD-IX and sensorineural hearing loss (SNHL) identified two variants in TBC1D32"
Documents an OFD-IX patient with TBC1D32 variants and sensorineural hearing loss, supporting the malformation and hearing components.
Photoreceptor Connecting Cilium Degeneration
TBC1D32 is expressed during retinal development and is required for ciliogenesis of the retinal pigment epithelium and for photoreceptor connecting-cilium function. TBC1D32 variants disrupt outer-segment trafficking in cones and rods, causing inherited retinal degeneration presenting as retinitis pigmentosa / rod-cone degeneration. This retinal arm has been reported both within the syndromic TBC1D32 spectrum and as a non-syndromic rod-cone degeneration.
photoreceptor cell CL:0000210 retinal rod cell CL:0000604
photoreceptor cell maintenance GO:0045494 ↓ DECREASED
Show evidence (2 references)
PMID:37768732 SUPPORT In Vitro
"Overall, our data highlight a critical role for TBC1D32 in the retina and demonstrate that TBC1D32 mutations lead to RP."
Demonstrates, using iPSC-derived retinal models, that TBC1D32 mutations cause retinitis pigmentosa, supporting the retinal-degeneration arm.
PMID:37768732 SUPPORT In Vitro
"our results suggested photoreceptor differentiation defects, including connecting cilium anomalies, that resulted in impaired trafficking to the outer segment in cones and rods"
Identifies connecting-cilium anomalies and impaired outer-segment trafficking in TBC1D32-mutant photoreceptors, the cellular basis of the degeneration.
Hypothalamic-Pituitary Ciliary Dysfunction
TBC1D32 is expressed in the developing hypothalamus and pituitary gland, where cilium-dependent (including Hedgehog) signaling governs ventral forebrain and pituitary development. TBC1D32 variants have been implicated in congenital hypopituitarism, linking the ciliary defect to hypothalamic-pituitary developmental endocrinopathy rather than to the leptin-driven obesity of the classic metabolic-ciliopathy node.
hypothalamus cell differentiation GO:0021979 ⚠ ABNORMAL
hypothalamus UBERON:0001898
Show evidence (2 references)
PMID:36826837 SUPPORT Human Clinical
"TBC1D32 is involved in the development and function of cilia and is expressed in the developing hypothalamus and pituitary gland."
Establishes hypothalamic-pituitary expression of TBC1D32, the developmental basis of the endocrine arm of the syndrome.
PMID:38717911 SUPPORT Human Clinical
"we add new evidence of pathogenicity in the genes PIBF1 and TBC1D32"
Provides additional human evidence of TBC1D32 pathogenicity in a congenital hypopituitarism cohort, supporting the hypothalamic-pituitary arm.

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Alsahan-Harris Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.

Phenotypes

5
Ear 1
Sensorineural Hearing Loss Sensorineural hearing impairment HP:0000407
Show evidence (1 reference)
PMID:40319332 SUPPORT Human Clinical
"These results suggest that SNHL may represent a new clinical feature associated with this gene."
Proposes sensorineural hearing loss as a clinical feature of TBC1D32-related disease.
Eye 1
Rod-Cone Dystrophy Rod-cone dystrophy HP:0000510
Show evidence (2 references)
PMID:37768732 SUPPORT Human Clinical
"We report 4 patients presenting with RP from 3 unrelated families with variants in TBC1D32, which to date has never been associated with an IRD."
Documents four patients with retinitis pigmentosa carrying TBC1D32 variants, establishing the retinal-degeneration phenotype.
PMID:39930170 SUPPORT Human Clinical
"Recently, TBC1D32 has been proposed as a novel recessive RCD gene, as rare bi-allelic pathogenic variants were found in three unrelated European families."
Provides independent secondary evidence of TBC1D32 as a recessive rod-cone degeneration gene.
Head and Neck 1
Oral-Facial-Digital Syndrome Dysmorphic Features Abnormal facial shape HP:0001999
Show evidence (1 reference)
PMID:40319332 SUPPORT Human Clinical
"oro-facial-digital syndrome (OFD) is caused by mutations in ciliary genes, leading to dysmorphic features. Mutations in TBC1D32 were associated to retinal dystrophy and OFD, defining this form as OFD-IX."
Establishes OFD-IX with dysmorphic facial features as a defining TBC1D32 manifestation.
Prenatal and Birth 1
Life-Limiting Prenatal Phenotype Abnormality of prenatal development or birth HP:0001197
Show evidence (1 reference)
PMID:36826837 SUPPORT Human Clinical
"a severe prenatal phenotype associated with life-limiting congenital anomalies"
Documents a severe, life-limiting prenatal phenotype at the severe end of the TBC1D32 spectrum; the generic prenatal-abnormality term matches the level of detail the abstract provides.
Other 1
Hypopituitarism Hypopituitarism HP:0040075
Show evidence (1 reference)
PMID:38717911 SUPPORT Human Clinical
"we add new evidence of pathogenicity in the genes PIBF1 and TBC1D32"
Implicates TBC1D32 pathogenic variants in a congenital hypopituitarism cohort, supporting the endocrine phenotype.
🧬

Genetic Associations

1
TBC1D32 (BROMI) Variants (Causative)
Gene: TBC1D32 hgnc:21485
Show evidence (2 references)
PMID:36826837 SUPPORT Human Clinical
"We describe seven unpublished probands with rare likely pathogenic variants or variants of uncertain significance that segregate with recessive disease in TBC1D32"
Reports multiple probands with recessive-segregating TBC1D32 variants, establishing TBC1D32 as the causative gene.
PMID:35609210 SUPPORT Human Clinical
"Mutations in BROMI, CCRK, and ICK in humans cause ciliopathies"
Confirms that BROMI (TBC1D32) mutations cause ciliopathy in humans, establishing the disease-gene relationship.
💊

Medical Actions

3
Supportive and Multidisciplinary Care
Action: supportive care MAXO:0000950
There is no disease-modifying therapy. Management is supportive and multidisciplinary, addressing the endocrine (hypopituitarism), visual (retinal degeneration), audiologic (sensorineural hearing loss), and developmental manifestations through specialist follow-up and symptomatic care.
Surgical Correction of Malformations
Action: surgical procedure MAXO:0000004
Surgical correction of structural malformations such as polydactyly and oral-facial anomalies is performed as clinically indicated.
Genetic Counseling
Action: Genetic Counseling NCIT:C15240
Autosomal recessive inheritance entails a 25% recurrence risk for siblings. Once biallelic TBC1D32 variants are identified, carrier testing, prenatal testing, and preimplantation genetic testing become available to families.
{ }

Source YAML

click to show
name: Alsahan-Harris Syndrome
creation_date: "2026-06-21T00:00:00Z"
category: Mendelian
description: >-
  Alsahan-Harris syndrome is a rare autosomal recessive ciliopathy caused by
  biallelic variants in TBC1D32 (also known historically as BROMI or C6orf170).
  TBC1D32/BROMI is a ciliary protein that, together with CCRK/CDK20 and
  ICK/CILK1, regulates the intraflagellar transport (IFT) turnaround at the
  ciliary tip and is required for proper cilium-dependent Hedgehog signaling.
  Loss of TBC1D32 function disrupts ciliary protein trafficking and Hedgehog
  signal transduction, producing a complex, phenotypically variable
  multisystem ciliopathy. Reported features span an oral-facial-digital
  syndrome spectrum (designated OFD-IX) with polydactyly and craniofacial
  anomalies, hypothalamic-pituitary involvement (congenital hypopituitarism),
  inherited retinal degeneration (retinitis pigmentosa / rod-cone
  degeneration), sensorineural hearing loss, and, at the severe end, a prenatal
  phenotype with life-limiting congenital anomalies. The eponym honors the
  first human confirmation of the TBC1D32-related ciliopathy by Alsahan and
  Alkuraya (2020) and the phenotypic-spectrum expansion by Harris and
  colleagues (2023).
disease_term:
  preferred_term: Alsahan-Harris syndrome
  term:
    id: MONDO:0979871
    label: Alsahan-Harris syndrome
parents:
- Ciliopathies
inheritance:
- name: Autosomal Recessive
  description: >-
    Alsahan-Harris syndrome is inherited in an autosomal recessive manner,
    caused by biallelic (homozygous or compound heterozygous) pathogenic
    variants in TBC1D32.
  evidence:
  - reference: PMID:36826837
    reference_title: "Diagnosis of TBC1D32-associated conditions: Expanding the phenotypic spectrum of a complex ciliopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe seven unpublished probands with rare likely pathogenic
      variants or variants of uncertain significance that segregate with
      recessive disease in TBC1D32
    explanation: >-
      Establishes recessive segregation of TBC1D32 variants across multiple
      pedigrees, supporting autosomal recessive inheritance.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0979871
      label: Alsahan-Harris syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO:0979871 (Alsahan-Harris syndrome) is the disease term for this
      entry and carries an OMIM:621307 xref and a TBC1D32 (HGNC:21485)
      gene association, matching the curated identity.
pathophysiology:
- name: TBC1D32/BROMI Ciliary Trafficking and IFT Turnaround Defect
  conforms_to: "ciliopathy_dysfunction#Basal Body and Transition Zone Dysfunction"
  description: >-
    TBC1D32 (BROMI) is a ciliary protein required for the intraflagellar
    transport (IFT) turnaround at the ciliary tip. It interacts with CCRK/CDK20,
    which phosphorylates and activates the ICK/CILK1 kinase that controls the
    change in direction of the IFT machinery. Loss of TBC1D32 function
    (modelled by BROMI-knockout cells and mouse mutants) produces abnormally
    long cilia with accumulation of IFT proteins and ICK at the bulged ciliary
    tip, deranging the bidirectional cargo trafficking on which cilium-dependent
    signaling depends.
  genes:
  - preferred_term: TBC1D32
    term:
      id: hgnc:21485
      label: TBC1D32
  cell_types:
  - preferred_term: ciliated cell
    term:
      id: CL:0000064
      label: ciliated cell
  biological_processes:
  - preferred_term: intraflagellar transport
    term:
      id: GO:0042073
      label: intraciliary transport
    modifier: ABNORMAL
  - preferred_term: cilium assembly
    term:
      id: GO:0060271
      label: cilium assembly
    modifier: ABNORMAL
  - preferred_term: protein localization to cilium
    term:
      id: GO:0061512
      label: protein localization to cilium
    modifier: ABNORMAL
  evidence:
  - reference: PMID:35609210
    reference_title: "BROMI/TBC1D32 together with CCRK/CDK20 and FAM149B1/JBTS36 contributes to intraflagellar transport turnaround involving ICK/CILK1."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      BROMI/TBC1D32 interacts with CCRK/CDK20, which phosphorylates and
      activates the intestinal cell kinase (ICK)/CILK1 kinase, to regulate the
      change in direction of the IFT machinery at the ciliary tip.
    explanation: >-
      Defines the molecular role of TBC1D32/BROMI in regulating IFT turnaround
      at the ciliary tip, the upstream lesion of this ciliopathy.
  - reference: PMID:35609210
    reference_title: "BROMI/TBC1D32 together with CCRK/CDK20 and FAM149B1/JBTS36 contributes to intraflagellar transport turnaround involving ICK/CILK1."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Ciliary defects observed in CCRK-knockout (KO), BROMI-KO, and FAM149B1-KO
      cells, including abnormally long cilia and accumulation of the IFT
      machinery and ICK at the ciliary tip, resembled one another
    explanation: >-
      Demonstrates that loss of TBC1D32/BROMI produces abnormal cilia with IFT
      accumulation at the ciliary tip, the cellular trafficking defect.
  - reference: PMID:35609210
    reference_title: "BROMI/TBC1D32 together with CCRK/CDK20 and FAM149B1/JBTS36 contributes to intraflagellar transport turnaround involving ICK/CILK1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in BROMI, CCRK, and ICK in humans cause ciliopathies
    explanation: >-
      Confirms that TBC1D32/BROMI mutations cause ciliopathy in humans,
      anchoring this gene-specific lesion to the ciliopathy module.
  downstream:
  - target: Impaired Hedgehog Signal Transduction
    description: >-
      Deranged ciliary IFT turnaround disrupts the ciliary compartmentalization
      of Hedgehog pathway components, impairing cilium-dependent Hedgehog
      signal transduction.
- name: Impaired Hedgehog Signal Transduction
  conforms_to: "ciliopathy_dysfunction#Impaired Hedgehog Signal Transduction"
  description: >-
    The CCRK-BROMI(TBC1D32) module governs ciliary Hedgehog signaling. Loss of
    CCRK or its TBC1D32/BROMI partner causes overaccumulation of IFT proteins
    at the ciliary tip and abnormal enrichment of Hedgehog pathway components
    (GPR161 and Smoothened) on the ciliary membrane, deregulating
    cilium-dependent Hedgehog signal transduction. Because Hedgehog signaling
    patterns the limb and craniofacial midline, its disruption underlies the
    polydactyly and oral-facial-digital malformations of the syndrome.
  biological_processes:
  - preferred_term: Hedgehog (smoothened) signaling pathway
    term:
      id: GO:0007224
      label: smoothened signaling pathway
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:34624068
    reference_title: "CCRK/CDK20 regulates ciliary retrograde protein trafficking via interacting with BROMI/TBC1D32."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      CCRK/CDK20 was reported to interact with BROMI/TBC1D32 and regulate
      ciliary Hedgehog signaling.
    explanation: >-
      Establishes that the CCRK-BROMI(TBC1D32) interaction regulates ciliary
      Hedgehog signaling, the central effector pathway of this ciliopathy.
  - reference: PMID:34624068
    reference_title: "CCRK/CDK20 regulates ciliary retrograde protein trafficking via interacting with BROMI/TBC1D32."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      the overaccumulation of IFT proteins at the bulged ciliary tips, which
      appear to be eliminated as extracellular vesicles, and the enrichment of
      GPR161 and Smoothened on the ciliary membrane
    explanation: >-
      Shows that loss of the CCRK-BROMI module abnormally enriches Hedgehog
      pathway components (GPR161, Smoothened) on the ciliary membrane,
      mechanistically linking the trafficking defect to Hedgehog dysregulation.
  downstream:
  - target: Oral-Facial-Digital Malformation
    causal_link_type: DIRECT
    description: >-
      Dysregulated cilium-dependent Hedgehog signaling disrupts limb and
      craniofacial-midline patterning, producing polydactyly and the
      oral-facial-digital features of the syndrome.
- name: Oral-Facial-Digital Malformation
  conforms_to: "ciliopathy_dysfunction#Skeletal Dysplasia with Polydactyly and Thoracic Constriction"
  description: >-
    TBC1D32 variants produce an oral-facial-digital syndrome phenotype
    (designated OFD-IX) characterized by polydactyly and craniofacial
    dysmorphism, reflecting deranged cilium-dependent Hedgehog patterning of the
    limb and craniofacial midline. Sensorineural hearing loss has been proposed
    as an additional feature of the gene's phenotypic spectrum.
  biological_processes:
  - preferred_term: limb morphogenesis
    term:
      id: GO:0035108
      label: limb morphogenesis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:40319332
    reference_title: "Two novel mutations in TBC1D32 add complexity to the oro-facial-digital syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in TBC1D32 were associated to retinal dystrophy and OFD,
      defining this form as OFD-IX.
    explanation: >-
      Establishes the oral-facial-digital (OFD-IX) phenotype as a TBC1D32
      manifestation, the malformation read-out of the Hedgehog-patterning
      defect.
  - reference: PMID:40319332
    reference_title: "Two novel mutations in TBC1D32 add complexity to the oro-facial-digital syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A clinical exome analysis performed on a patient presenting with OFD-IX
      and sensorineural hearing loss (SNHL) identified two variants in TBC1D32
    explanation: >-
      Documents an OFD-IX patient with TBC1D32 variants and sensorineural
      hearing loss, supporting the malformation and hearing components.
- name: Photoreceptor Connecting Cilium Degeneration
  conforms_to: "ciliopathy_dysfunction#Photoreceptor Connecting Cilium Degeneration"
  description: >-
    TBC1D32 is expressed during retinal development and is required for
    ciliogenesis of the retinal pigment epithelium and for photoreceptor
    connecting-cilium function. TBC1D32 variants disrupt outer-segment
    trafficking in cones and rods, causing inherited retinal degeneration
    presenting as retinitis pigmentosa / rod-cone degeneration. This retinal
    arm has been reported both within the syndromic TBC1D32 spectrum and as a
    non-syndromic rod-cone degeneration.
  cell_types:
  - preferred_term: photoreceptor cell
    term:
      id: CL:0000210
      label: photoreceptor cell
  - preferred_term: retinal rod cell
    term:
      id: CL:0000604
      label: retinal rod cell
  locations:
  - preferred_term: retina
    term:
      id: UBERON:0000966
      label: retina
  biological_processes:
  - preferred_term: photoreceptor cell maintenance
    term:
      id: GO:0045494
      label: photoreceptor cell maintenance
    modifier: DECREASED
  evidence:
  - reference: PMID:37768732
    reference_title: "TBC1D32 variants disrupt retinal ciliogenesis and cause retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Overall, our data highlight a critical role for TBC1D32 in the retina and
      demonstrate that TBC1D32 mutations lead to RP.
    explanation: >-
      Demonstrates, using iPSC-derived retinal models, that TBC1D32 mutations
      cause retinitis pigmentosa, supporting the retinal-degeneration arm.
  - reference: PMID:37768732
    reference_title: "TBC1D32 variants disrupt retinal ciliogenesis and cause retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      our results suggested photoreceptor differentiation defects, including
      connecting cilium anomalies, that resulted in impaired trafficking to the
      outer segment in cones and rods
    explanation: >-
      Identifies connecting-cilium anomalies and impaired outer-segment
      trafficking in TBC1D32-mutant photoreceptors, the cellular basis of the
      degeneration.
  downstream:
  - target: Rod-Cone Dystrophy
    causal_link_type: DIRECT
    description: >-
      Photoreceptor connecting-cilium dysfunction and impaired outer-segment
      trafficking produce progressive rod-cone degeneration.
- name: Hypothalamic-Pituitary Ciliary Dysfunction
  conforms_to: "ciliopathy_dysfunction#Hypothalamic Ciliary Signaling and Metabolic Dysfunction"
  description: >-
    TBC1D32 is expressed in the developing hypothalamus and pituitary gland,
    where cilium-dependent (including Hedgehog) signaling governs ventral
    forebrain and pituitary development. TBC1D32 variants have been implicated
    in congenital hypopituitarism, linking the ciliary defect to
    hypothalamic-pituitary developmental endocrinopathy rather than to the
    leptin-driven obesity of the classic metabolic-ciliopathy node.
  locations:
  - preferred_term: hypothalamus
    term:
      id: UBERON:0001898
      label: hypothalamus
  biological_processes:
  - preferred_term: hypothalamus cell differentiation
    term:
      id: GO:0021979
      label: hypothalamus cell differentiation
    modifier: ABNORMAL
  evidence:
  - reference: PMID:36826837
    reference_title: "Diagnosis of TBC1D32-associated conditions: Expanding the phenotypic spectrum of a complex ciliopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      TBC1D32 is involved in the development and function of cilia and is
      expressed in the developing hypothalamus and pituitary gland.
    explanation: >-
      Establishes hypothalamic-pituitary expression of TBC1D32, the
      developmental basis of the endocrine arm of the syndrome.
  - reference: PMID:38717911
    reference_title: "Exome Sequencing Has a High Diagnostic Rate in Sporadic Congenital Hypopituitarism and Reveals Novel Candidate Genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we add new evidence of pathogenicity in the genes PIBF1 and TBC1D32
    explanation: >-
      Provides additional human evidence of TBC1D32 pathogenicity in a
      congenital hypopituitarism cohort, supporting the hypothalamic-pituitary
      arm.
  downstream:
  - target: Hypopituitarism
    causal_link_type: DIRECT
    description: >-
      Abnormal cilium-dependent hypothalamic-pituitary development produces
      congenital hypopituitarism.
phenotypes:
- name: Oral-Facial-Digital Syndrome Dysmorphic Features
  category: Craniofacial
  description: >-
    TBC1D32 variants produce an oral-facial-digital syndrome (OFD-IX), a ciliary
    OFD-spectrum disorder presenting with dysmorphic facial features. The HP term
    Abnormal facial shape captures the reported dysmorphism; the cited abstract
    establishes the OFD-IX designation and dysmorphic features but does not
    enumerate the individual oral-facial-digital anomalies.
  phenotype_term:
    preferred_term: Oral-facial-digital (OFD-IX) dysmorphic facial features
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:40319332
    reference_title: "Two novel mutations in TBC1D32 add complexity to the oro-facial-digital syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      oro-facial-digital syndrome (OFD) is caused by mutations in ciliary
      genes, leading to dysmorphic features. Mutations in TBC1D32 were
      associated to retinal dystrophy and OFD, defining this form as OFD-IX.
    explanation: >-
      Establishes OFD-IX with dysmorphic facial features as a defining TBC1D32
      manifestation.
- name: Rod-Cone Dystrophy
  category: Eye
  description: >-
    Inherited retinal degeneration presenting as retinitis pigmentosa /
    rod-cone degeneration, with progressive loss of rod and then cone
    photoreceptors, is part of the TBC1D32 phenotypic spectrum.
  phenotype_term:
    preferred_term: Rod-cone dystrophy
    term:
      id: HP:0000510
      label: Rod-cone dystrophy
  evidence:
  - reference: PMID:37768732
    reference_title: "TBC1D32 variants disrupt retinal ciliogenesis and cause retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report 4 patients presenting with RP from 3 unrelated families with
      variants in TBC1D32, which to date has never been associated with an IRD.
    explanation: >-
      Documents four patients with retinitis pigmentosa carrying TBC1D32
      variants, establishing the retinal-degeneration phenotype.
  - reference: PMID:39930170
    reference_title: "Novel Potentially Pathogenic Variants in TBC1D32 Cause Non-syndromic Rod-Cone Degeneration."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recently, TBC1D32 has been proposed as a novel recessive RCD gene, as
      rare bi-allelic pathogenic variants were found in three unrelated
      European families.
    explanation: >-
      Provides independent secondary evidence of TBC1D32 as a recessive
      rod-cone degeneration gene.
- name: Sensorineural Hearing Loss
  category: Ear
  description: >-
    Sensorineural hearing loss has been proposed as a clinical feature of the
    TBC1D32-related phenotype, consistent with the role of ciliary Hedgehog
    signaling in cochlear development.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:40319332
    reference_title: "Two novel mutations in TBC1D32 add complexity to the oro-facial-digital syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These results suggest that SNHL may represent a new clinical feature
      associated with this gene.
    explanation: >-
      Proposes sensorineural hearing loss as a clinical feature of
      TBC1D32-related disease.
- name: Hypopituitarism
  category: Endocrine
  description: >-
    Congenital hypopituitarism reflects TBC1D32 involvement in the development
    of the hypothalamus and pituitary gland.
  phenotype_term:
    preferred_term: Hypopituitarism
    term:
      id: HP:0040075
      label: Hypopituitarism
  evidence:
  - reference: PMID:38717911
    reference_title: "Exome Sequencing Has a High Diagnostic Rate in Sporadic Congenital Hypopituitarism and Reveals Novel Candidate Genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we add new evidence of pathogenicity in the genes PIBF1 and TBC1D32
    explanation: >-
      Implicates TBC1D32 pathogenic variants in a congenital hypopituitarism
      cohort, supporting the endocrine phenotype.
- name: Life-Limiting Prenatal Phenotype
  category: Prenatal
  description: >-
    At the severe end of the spectrum, TBC1D32 biallelic variants are
    associated with a severe prenatal phenotype with life-limiting congenital
    anomalies, identified through prenatal exome sequencing in fetal probands.
    A generic prenatal-abnormality HP term is used because the abstract
    asserts the severe life-limiting prenatal phenotype without enumerating the
    specific congenital anomalies.
  phenotype_term:
    preferred_term: Severe prenatal phenotype with life-limiting congenital anomalies
    term:
      id: HP:0001197
      label: Abnormality of prenatal development or birth
  evidence:
  - reference: PMID:36826837
    reference_title: "Diagnosis of TBC1D32-associated conditions: Expanding the phenotypic spectrum of a complex ciliopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a severe prenatal phenotype associated with life-limiting congenital
      anomalies
    explanation: >-
      Documents a severe, life-limiting prenatal phenotype at the severe end of
      the TBC1D32 spectrum; the generic prenatal-abnormality term matches the
      level of detail the abstract provides.
genetic:
- name: TBC1D32 (BROMI) Variants
  association: Causative
  gene_term:
    preferred_term: TBC1D32
    term:
      id: hgnc:21485
      label: TBC1D32
  notes: >-
    Biallelic (homozygous or compound heterozygous) variants in TBC1D32 (6q22),
    historically named BROMI or C6orf170, cause Alsahan-Harris syndrome
    (OMIM:621307). TBC1D32/BROMI functions with CCRK/CDK20 and ICK/CILK1 to
    regulate IFT turnaround at the ciliary tip and cilium-dependent Hedgehog
    signaling. The human TBC1D32-related ciliopathy was first confirmed by
    Alsahan and Alkuraya (PMID:32573025); the phenotypic spectrum was expanded
    by Harris et al. (PMID:36826837).
  evidence:
  - reference: PMID:36826837
    reference_title: "Diagnosis of TBC1D32-associated conditions: Expanding the phenotypic spectrum of a complex ciliopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe seven unpublished probands with rare likely pathogenic
      variants or variants of uncertain significance that segregate with
      recessive disease in TBC1D32
    explanation: >-
      Reports multiple probands with recessive-segregating TBC1D32 variants,
      establishing TBC1D32 as the causative gene.
  - reference: PMID:35609210
    reference_title: "BROMI/TBC1D32 together with CCRK/CDK20 and FAM149B1/JBTS36 contributes to intraflagellar transport turnaround involving ICK/CILK1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in BROMI, CCRK, and ICK in humans cause ciliopathies
    explanation: >-
      Confirms that BROMI (TBC1D32) mutations cause ciliopathy in humans,
      establishing the disease-gene relationship.
diagnosis:
- name: Molecular Genetic Diagnosis
  description: >-
    Diagnosis rests on identification of biallelic pathogenic TBC1D32 variants
    by exome or genome sequencing in a patient with compatible ciliopathy
    features (oral-facial-digital anomalies, retinal degeneration,
    hypothalamic-pituitary involvement). Because expressivity is highly
    variable, TBC1D32 should be considered across this phenotypic spectrum.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: MAXO:0000533
      label: molecular genetic testing
  evidence:
  - reference: PMID:36826837
    reference_title: "Diagnosis of TBC1D32-associated conditions: Expanding the phenotypic spectrum of a complex ciliopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Exome sequencing is a powerful tool in prenatal and postnatal genetics
      and can help identify novel candidate genes critical to human development.
    explanation: >-
      Supports exome sequencing as the diagnostic modality through which
      TBC1D32-related conditions are identified.
treatments:
- name: Supportive and Multidisciplinary Care
  description: >-
    There is no disease-modifying therapy. Management is supportive and
    multidisciplinary, addressing the endocrine (hypopituitarism), visual
    (retinal degeneration), audiologic (sensorineural hearing loss), and
    developmental manifestations through specialist follow-up and symptomatic
    care.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
- name: Surgical Correction of Malformations
  description: >-
    Surgical correction of structural malformations such as polydactyly and
    oral-facial anomalies is performed as clinically indicated.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: MAXO:0000004
      label: surgical procedure
- name: Genetic Counseling
  description: >-
    Autosomal recessive inheritance entails a 25% recurrence risk for siblings.
    Once biallelic TBC1D32 variants are identified, carrier testing, prenatal
    testing, and preimplantation genetic testing become available to families.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
notes: >-
  Gene synonymy: TBC1D32 is also known historically as BROMI and C6orf170;
  these names are used interchangeably across the cited mechanistic literature.
  Disease/nomenclature: the TBC1D32-related oral-facial-digital syndrome has
  been designated OFD-IX (oral-facial-digital syndrome type IX). Eponym
  provenance: the name Alsahan-Harris syndrome derives from Alsahan and Alkuraya
  (PMID:32573025), who confirmed the TBC1D32-related ciliopathy in humans, and
  from Harris et al. (PMID:36826837), who expanded the phenotypic spectrum. The
  Alsahan brief report (PMID:32573025) has no PubMed abstract text and is
  therefore cited here only as nomenclature provenance, not as an evidence
  snippet. This is a TBC1D32-specific ciliopathy and must not be conflated with
  other oral-facial-digital syndromes (e.g., OFD I, caused by OFD1, or OFD17,
  caused by INTU).
references:
- reference: PMID:36826837
  title: "Diagnosis of TBC1D32-associated conditions: Expanding the phenotypic spectrum of a complex ciliopathy."
- reference: PMID:40319332
  title: "Two novel mutations in TBC1D32 add complexity to the oro-facial-digital syndrome."
- reference: PMID:37768732
  title: "TBC1D32 variants disrupt retinal ciliogenesis and cause retinitis pigmentosa."
- reference: PMID:39930170
  title: "Novel Potentially Pathogenic Variants in TBC1D32 Cause Non-syndromic Rod-Cone Degeneration."
- reference: PMID:38717911
  title: "Exome Sequencing Has a High Diagnostic Rate in Sporadic Congenital Hypopituitarism and Reveals Novel Candidate Genes."
- reference: PMID:35609210
  title: "BROMI/TBC1D32 together with CCRK/CDK20 and FAM149B1/JBTS36 contributes to intraflagellar transport turnaround involving ICK/CILK1."
- reference: PMID:34624068
  title: "CCRK/CDK20 regulates ciliary retrograde protein trafficking via interacting with BROMI/TBC1D32."
- reference: PMID:32573025
  title: "Confirming TBC1D32-related ciliopathy in humans."
📚

References & Deep Research

References

8
Diagnosis of TBC1D32-associated conditions: Expanding the phenotypic spectrum of a complex ciliopathy.
No top-level findings curated for this source.
Two novel mutations in TBC1D32 add complexity to the oro-facial-digital syndrome.
No top-level findings curated for this source.
TBC1D32 variants disrupt retinal ciliogenesis and cause retinitis pigmentosa.
No top-level findings curated for this source.
Novel Potentially Pathogenic Variants in TBC1D32 Cause Non-syndromic Rod-Cone Degeneration.
No top-level findings curated for this source.
Exome Sequencing Has a High Diagnostic Rate in Sporadic Congenital Hypopituitarism and Reveals Novel Candidate Genes.
No top-level findings curated for this source.
BROMI/TBC1D32 together with CCRK/CDK20 and FAM149B1/JBTS36 contributes to intraflagellar transport turnaround involving ICK/CILK1.
No top-level findings curated for this source.
CCRK/CDK20 regulates ciliary retrograde protein trafficking via interacting with BROMI/TBC1D32.
No top-level findings curated for this source.
Confirming TBC1D32-related ciliopathy in humans.
No top-level findings curated for this source.