Alsahan-Harris Syndrome

Mendelian MONDO:0979871 Pathograph 13 Show in embeddings browser Ciliopathies

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 2020 confirmation report by Alsahan and Alkuraya and the phenotypic-spectrum expansion by Harris and colleagues (2023). The original TBC1D32-associated OFD-IX report predates the eponym.

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1
Mappings
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Inheritance
5
Pathophys.
15
Phenotypes
2
Gaps
13
Pathograph
1
Genes
4
Medical Actions
1
Differentials
1
Models
11
References
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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.
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Inheritance

1
Autosomal Recessive HP:0000007
Alsahan-Harris syndrome is inherited in an autosomal recessive manner, caused by biallelic (homozygous or compound heterozygous) pathogenic variants in TBC1D32.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:32060556 SUPPORT Human Clinical
"Biallelic TBC1D32 variants underlie syndromic hypopituitarism"
Establishes the biallelic basis of TBC1D32-related syndromic disease.
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"We describe seven unpublished probands with rare likely pathogenic variants or variants of uncertain significance that segregate with recessive disease in TBC1D32"
Recessive segregation across seven additional probands provides complementary multi-pedigree support for autosomal recessive inheritance.
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Discussions and Knowledge Gaps

2
Do the knockout-cell, Xenopus, and retinal-organoid mechanisms reproduce the tissue-specific consequences of patient TBC1D32 alleles across the complete human syndrome?
HUMAN MODEL MISMATCH OPEN tbc1d32_multisystem_mechanism_model_fidelity
Attached to
pathophysiology#TBC1D32/BROMI Ciliary Trafficking and IFT Turnaround Defect pathophysiology#Impaired Hedgehog Signal Transduction
IFT-turnaround evidence is dominated by engineered knockout cells and the Hedgehog inference partly relies on CCRK-knockout experiments. Patient-derived retinal models provide strong tissue-specific support, but no single model currently recapitulates the craniofacial, pituitary, retinal, auditory, and prenatal manifestations together.
Proposed experiments
Isogenic patient-allele IFT-turnaround and rescue study
exp_tbc1d32_isogenic_ift_rescue
Introduce representative patient loss-of-function and splice alleles into isogenic human ciliated-cell models and compare IFT turnaround, ciliary-tip cargo accumulation, and wild-type rescue.
Patient-allele Hedgehog-response study in developmental cell models
exp_tbc1d32_developmental_hedgehog_response
Test GLI processing and Hedgehog target-gene responses in patient-derived hypothalamic-pituitary and craniofacial developmental models.
Cross-organoid TBC1D32 allelic series
exp_tbc1d32_cross_organoid_allelic_series
Compare allele-specific phenotypes across retinal, pituitary, and craniofacial organoids.
Show evidence (2 references)
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"
The key IFT-turnaround evidence uses engineered knockout cells rather than the diverse patient alleles.
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"
Patient-derived retinal organoids support one organ-specific arm but do not establish fidelity for the whole multisystem disorder.
Are sensorineural hearing loss and oculomotor nerve palsy recurrent features of TBC1D32-related ciliopathy, and what are their penetrance and allelic basis?
KNOWLEDGE GAP OPEN tbc1d32_emerging_feature_penetrance
Hearing loss and oculomotor palsy were proposed from recent individual or very small case expansions. The available literature is too sparse to infer frequency, causality for every allele, or a shared tissue mechanism.
Proposed experiments
Registry-based audiology and ocular-motility phenotyping
exp_tbc1d32_registry_audiology_oculomotor
Perform standardized audiology and ocular-motility phenotyping in an international TBC1D32 registry.
Functional testing of emerging-feature alleles
exp_tbc1d32_emerging_feature_alleles
Test segregation and functional splice effects for alleles observed with the emerging features.
Show evidence (2 references)
PMID:40319332 SUPPORT Human Clinical
"These results suggest that SNHL may represent a new clinical feature associated with this gene."
The authors explicitly frame sensorineural hearing loss as a proposed new feature.
PMID:40702307 SUPPORT Human Clinical
"we propose oculomotor nerve palsy as an extended clinical feature of this disorder."
The 2025 case expansion explicitly presents oculomotor palsy as proposed rather than established.
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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 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves ciliated cell (CL:0000064). CL:0000064 is a cell type from the Cell Ontology.
TBC1D32 hgnc:21485 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TBC1D32 (hgnc:21485). hgnc:21485 is a gene from the HUGO Gene Nomenclature Committee.
intraflagellar transport GO:0042073 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal intraflagellar transport, annotated with intraciliary transport (GO:0042073). GO:0042073 is a biological process from the Gene Ontology. ⚠ ABNORMAL cilium assembly GO:0060271 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal cilium assembly (GO:0060271). GO:0060271 is a biological process from the Gene Ontology. ⚠ ABNORMAL protein localization to cilium GO:0061512 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal protein localization to cilium (GO:0061512). GO:0061512 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Photoreceptor Connecting Cilium Degeneration The TBC1D32 ciliary lesion disrupts retinal differentiation, connecting cilium integrity, and outer-segment trafficking in photoreceptors.
Hypothalamic-Pituitary Ciliary Dysfunction The TBC1D32 ciliary lesion perturbs cilium-dependent developmental signaling in the hypothalamic-pituitary axis.
Impaired Hedgehog Signal Transduction Deranged ciliary IFT turnaround disrupts the ciliary compartmentalization of Hedgehog pathway components, impairing cilium-dependent Hedgehog signal transduction.
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 Other
"Mutations in BROMI, CCRK, and ICK in humans cause ciliopathies"
The cell-biology paper summarizes the prior human disease association as background, 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 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated Hedgehog (smoothened) signaling pathway, annotated with smoothened signaling pathway (GO:0007224). GO:0007224 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Downstream
Oral-Facial-Digital Malformation Dysregulated cilium-dependent Hedgehog signaling disrupts limb and craniofacial-midline patterning, producing polydactyly and the oral-facial-digital features of the syndrome.
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 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal limb morphogenesis (GO:0035108). GO:0035108 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Midline Facial Cleft OFD-IX craniofacial patterning abnormalities include a midline facial cleft.
Colobomatous Microphthalmia or Anophthalmia OFD-IX ocular patterning abnormalities include colobomatous microphthalmia or anophthalmia.
Coloboma OFD-IX ocular patterning abnormalities include coloboma.
Polydactyly Disrupted limb patterning manifests as variable polydactyly.
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 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves photoreceptor cell (CL:0000210). CL:0000210 is a cell type from the Cell Ontology. retinal rod cell CL:0000604 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves retinal rod cell (CL:0000604). CL:0000604 is a cell type from the Cell Ontology.
photoreceptor cell maintenance GO:0045494 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased photoreceptor cell maintenance (GO:0045494). GO:0045494 is a biological process from the Gene Ontology. ↓ DECREASED
retina UBERON:0000966 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in retina (UBERON:0000966). UBERON:0000966 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Rod-Cone Dystrophy Photoreceptor connecting-cilium dysfunction and impaired outer-segment trafficking produce progressive rod-cone degeneration.
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 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal hypothalamus cell differentiation (GO:0021979). GO:0021979 is a biological process from the Gene Ontology. ⚠ ABNORMAL
hypothalamus UBERON:0001898 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in hypothalamus (UBERON:0001898). UBERON:0001898 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Hypopituitarism Abnormal cilium-dependent hypothalamic-pituitary development produces congenital hypopituitarism.
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.
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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.
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Phenotypes

15
Cardiovascular 1
Congenital Heart Disease Abnormal heart morphology HP:0001627 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal heart morphology (HP:0001627). HP:0001627 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24285566 SUPPORT Human Clinical
"there was variable presence of polydactyly, absent pituitary, and congenital heart disease."
Congenital heart disease was variable in a series containing one SCLT1 and one TBC1D32 proband whose phenotypes were not disaggregated by gene; the HPO binding captures the source's heart-specific level of detail.
Digestive 1
Intestinal Malrotation HP:0002566 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intestinal malrotation (HP:0002566). HP:0002566 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32060556 SUPPORT Human Clinical
"fetus with a cleft lip and partial intestinal malrotation from a terminated pregnancy within the same pedigree."
Partial intestinal malrotation was reported in an affected fetus.
Ear 1
Sensorineural Hearing Loss Sensorineural hearing impairment HP:0000407 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sensorineural hearing impairment (HP:0000407). HP:0000407 is a phenotype from the Human Phenotype Ontology.
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.
Endocrine 1
Anterior Pituitary Aplasia or Hypoplasia Anterior pituitary hypoplasia HP:0010627 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anterior pituitary hypoplasia (HP:0010627). HP:0010627 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32060556 SUPPORT Human Clinical
"A Finnish family of 2 siblings with panhypopituitarism, absent anterior pituitary, and mild craniofacial dysmorphism, and a Pakistani family with a proband with growth hormone deficiency, anterior pituitary hypoplasia, and developmental delay."
The report directly documents both absent and hypoplastic anterior pituitary anatomy; the bound HPO term represents the coded hypoplasia arm.
Eye 3
Colobomatous Microphthalmia or Anophthalmia HP:0000568 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microphthalmia (HP:0000568). HP:0000568 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24285566 SUPPORT Human Clinical
"oro-facio-digital syndrome type IX featuring midline cleft, microcephaly, and colobomatous microphathalmia/anophthalmia."
The preferred term preserves the reported colobomatous microphthalmia/anophthalmia spectrum while the bound term captures its microphthalmia component without inventing a precoordinated identifier. The two-gene series contained one SCLT1 and one TBC1D32 proband and did not disaggregate their phenotypes by gene.
Coloboma HP:0000589 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Coloboma (HP:0000589). HP:0000589 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24285566 SUPPORT Human Clinical
"oro-facio-digital syndrome type IX featuring midline cleft, microcephaly, and colobomatous microphathalmia/anophthalmia."
The quote explicitly identifies the ocular anomaly as colobomatous, but the series contained one SCLT1 and one TBC1D32 proband and did not disaggregate their phenotypes by gene.
Rod-Cone Dystrophy HP:0000510 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Rod-cone dystrophy (HP:0000510). HP:0000510 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 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.
PMID:40702307 SUPPORT Human Clinical
"A review of previously reported cases highlighted facial dysmorphism, retinal disease, and hypopituitarism as major clinical features of TBC1D32-related ciliopathy."
The 2025 literature review identifies retinal disease as one of the major recurring manifestations.
Head and Neck 3
Oral-Facial-Digital Syndrome Dysmorphic Features Abnormal facial shape HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Oral-facial-digital (OFD-IX) dysmorphic facial features, annotated with Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
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.
PMID:40702307 SUPPORT Human Clinical
"A review of previously reported cases highlighted facial dysmorphism, retinal disease, and hypopituitarism as major clinical features of TBC1D32-related ciliopathy."
The 2025 literature review identifies facial dysmorphism as one of the major recurring manifestations.
Microcephaly HP:0000252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcephaly (HP:0000252). HP:0000252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24285566 SUPPORT Human Clinical
"oro-facio-digital syndrome type IX featuring midline cleft, microcephaly, and colobomatous microphathalmia/anophthalmia."
The series contained one SCLT1 and one TBC1D32 proband and did not disaggregate their phenotypes by gene; it therefore supports the OFD-IX spectrum but not a definitive TBC1D32-specific assignment.
Cleft Lip HP:0410030 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cleft lip (HP:0410030). HP:0410030 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32060556 SUPPORT Human Clinical
"fetus with a cleft lip and partial intestinal malrotation"
A similarly affected fetus in the pedigree had cleft lip.
Limbs 1
Polydactyly HP:0010442 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Polydactyly (HP:0010442). HP:0010442 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24285566 SUPPORT Human Clinical
"there was variable presence of polydactyly, absent pituitary, and congenital heart disease."
Polydactyly was variable in a series containing one SCLT1 and one TBC1D32 proband whose phenotypes were not disaggregated by gene.
Nervous System 1
Neurodevelopmental Delay HP:0012758 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neurodevelopmental delay (HP:0012758). HP:0012758 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32060556 SUPPORT Human Clinical
"a proband with growth hormone deficiency, anterior pituitary hypoplasia, and developmental delay."
Developmental delay was reported in the syndromic hypopituitarism series.
Prenatal and Birth 1
Life-Limiting Prenatal Phenotype Abnormality of prenatal development or birth HP:0001197 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Severe prenatal phenotype with life-limiting congenital anomalies, annotated with Abnormality of prenatal development or birth (HP:0001197). HP:0001197 is a phenotype from the Human Phenotype Ontology.
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 2
Midline Facial Cleft HP:0100629 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Midline facial cleft (HP:0100629). HP:0100629 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24285566 SUPPORT Human Clinical
"oro-facio-digital syndrome type IX featuring midline cleft, microcephaly, and colobomatous microphathalmia/anophthalmia."
The series contained one SCLT1 and one TBC1D32 proband and did not disaggregate their phenotypes by gene; it therefore supports the OFD-IX spectrum but not a definitive TBC1D32-specific assignment.
Hypopituitarism HP:0040075 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypopituitarism (HP:0040075). HP:0040075 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:32060556 SUPPORT Human Clinical
"Biallelic TBC1D32 variants underlie syndromic hypopituitarism, and the underlying mechanism may be via disrupted Shh signaling."
A dedicated human series directly establishes syndromic hypopituitarism due to biallelic TBC1D32 variants.
PMID:40702307 SUPPORT Human Clinical
"A review of previously reported cases highlighted facial dysmorphism, retinal disease, and hypopituitarism as major clinical features of TBC1D32-related ciliopathy."
The 2025 literature review identifies hypopituitarism as one of the major recurring manifestations.
🧬

Genetic Associations

1
TBC1D32 (BROMI) Variants (Causative)
Gene: TBC1D32 hgnc:21485 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TBC1D32 (hgnc:21485). hgnc:21485 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (4 references)
PMID:32060556 SUPPORT Human Clinical
"Biallelic TBC1D32 variants underlie syndromic hypopituitarism"
The dedicated loss-of-function series directly establishes the biallelic TBC1D32 gene-disease relationship.
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"
The largest clinical expansion adds seven probands with TBC1D32 variants segregating with recessive disease across the phenotypic spectrum.
PMID:35609210 SUPPORT Other
"Mutations in BROMI, CCRK, and ICK in humans cause ciliopathies"
The cell-biology paper summarizes the prior human disease association as background; dedicated clinical series provide the primary relationship.
+ 1 more reference
💊

Medical Actions

4
Pituitary Hormone Replacement
Action: hormone replacement therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is hormone replacement therapy (NCIT:C15599). NCIT:C15599 is a clinical intervention from the NCI Thesaurus. Ontology label: Hormone Replacement Therapy NCIT:C15599
Replace deficient target-gland hormones according to the affected pituitary axes under pediatric endocrine supervision; adrenal insufficiency requires urgent recognition and treatment when present.
Mechanism Target:
MODULATES Hypothalamic-Pituitary Ciliary Dysfunction — Replacement bypasses deficient pituitary-axis output but does not correct the underlying developmental ciliary defect.
Supportive and Multidisciplinary Care
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Coordinate endocrine, ophthalmologic, audiologic, developmental, and other specialist care according to each individual's manifestations.
Surgical Correction of Malformations
Action: surgical procedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is surgical procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Consider surgical correction of oral-facial or digital malformations when clinically indicated after multidisciplinary assessment.
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Counsel families regarding autosomal recessive inheritance, including a 25% recurrence risk for each pregnancy when both parents are carriers, and available carrier, prenatal, and preimplantation testing after molecular diagnosis.
🔬

Diagnosis

1
Molecular Genetic Diagnosis
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.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:32060556 SUPPORT Human Clinical
"The patients were investigated by whole genome sequencing."
The disease-specific cohort documents genome sequencing as the molecular route used to identify biallelic TBC1D32 variants.
PMID:24285566 SUPPORT Human Clinical
"single novel truncating variant as revealed by exome sequencing"
The original OFD-IX discovery series documents exome sequencing as an additional molecular diagnostic route.
🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Alsahan-Harris Syndrome:

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Animal Models

1
Morpholino-mediated reduction of tbc1d32 Xenopus laevis
An in-vivo Xenopus knockdown model was combined with human patient-derived iPSC retinal models to test TBC1D32-dependent retinal differentiation and ciliogenesis. It supports the retinal mechanism but does not reproduce or validate the full human multisystem phenotype.
Abnormal retinal differentiation Abnormal retinal ciliogenesis Otic vesicle tbc1d32 expression
Species
Xenopus laevis
Genotype
Morpholino-mediated reduction of tbc1d32
Genes
TBC1D32 hgnc:21485 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns TBC1D32 (hgnc:21485). hgnc:21485 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (2 references)
PMID:37768732 SUPPORT Model Organism
"by combining an in vivo Xenopus model and human iPSC-derived retinal models, we describe a critical role for TBC1D32 in retinal differentiation and ciliogenesis"
The study explicitly identifies the Xenopus component and the retinal differentiation/ciliogenesis outcomes it helped establish.
PMID:37768732 SUPPORT Model Organism
"we also detected tbc1d32 in the Xenopus otic vesicle"
Otic-vesicle expression supplies model-organism support for an auditory developmental role, while the authors appropriately frame the link to deafness as suggestive.
{ }

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
  2020 confirmation report by Alsahan and Alkuraya and the phenotypic-spectrum
  expansion by Harris and colleagues (2023). The original TBC1D32-associated
  OFD-IX report predates the eponym.
disease_term:
  preferred_term: Alsahan-Harris syndrome
  term:
    id: MONDO:0979871
    label: Alsahan-Harris syndrome
parents:
- Ciliopathies
inheritance:
- name: Autosomal Recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  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:32060556
    reference_title: Loss-of-Function Variants in TBC1D32 Underlie Syndromic Hypopituitarism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biallelic TBC1D32 variants underlie syndromic hypopituitarism
    explanation: >-
      Establishes the biallelic basis of TBC1D32-related syndromic disease.
  - 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: >-
      Recessive segregation across seven additional probands provides
      complementary multi-pedigree support for 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"
  biological_scale: CELLULAR
  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: OTHER
    snippet: >-
      Mutations in BROMI, CCRK, and ICK in humans cause ciliopathies
    explanation: >-
      The cell-biology paper summarizes the prior human disease association as
      background, anchoring this gene-specific lesion to the ciliopathy module.
  downstream:
  - target: Photoreceptor Connecting Cilium Degeneration
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      The TBC1D32 ciliary lesion disrupts retinal differentiation, connecting
      cilium integrity, and outer-segment trafficking in photoreceptors.
    evidence:
    - 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: >-
        Patient-derived retinal models connect TBC1D32 dysfunction to the
        photoreceptor ciliary and trafficking lesion.
  - target: Hypothalamic-Pituitary Ciliary Dysfunction
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      The TBC1D32 ciliary lesion perturbs cilium-dependent developmental
      signaling in the hypothalamic-pituitary axis.
    evidence:
    - reference: PMID:32060556
      reference_title: Loss-of-Function Variants in TBC1D32 Underlie Syndromic Hypopituitarism.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Biallelic TBC1D32 variants underlie syndromic hypopituitarism, and the
        underlying mechanism may be via disrupted Shh signaling.
      explanation: >-
        Human data connect TBC1D32 loss to the pituitary phenotype while
        appropriately qualifying the proposed Hedgehog-mediated mechanism.
  - target: Impaired Hedgehog Signal Transduction
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Deranged ciliary IFT turnaround disrupts the ciliary compartmentalization
      of Hedgehog pathway components, impairing cilium-dependent Hedgehog
      signal transduction.
    evidence:
    - reference: PMID:32060556
      reference_title: Loss-of-Function Variants in TBC1D32 Underlie Syndromic Hypopituitarism.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Biallelic TBC1D32 variants underlie syndromic hypopituitarism, and the
        underlying mechanism may be via disrupted Shh signaling.
      explanation: >-
        Human genotype-phenotype data support the proposed Hedgehog link, but
        the wording correctly preserves that the causal route remains inferred.
- name: Impaired Hedgehog Signal Transduction
  conforms_to: "ciliopathy_dysfunction#Impaired Hedgehog Signal Transduction"
  biological_scale: CELLULAR
  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: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Dysregulated cilium-dependent Hedgehog signaling disrupts limb and
      craniofacial-midline patterning, producing polydactyly and the
      oral-facial-digital features of the syndrome.
    evidence:
    - reference: PMID:24285566
      reference_title: Ciliary genes TBC1D32/C6orf170 and SCLT1 are mutated in patients with OFD type IX.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Our findings suggest a previously unrecognized role of SCLT1 and
        TBC1D32 in the pathogenesis of ciliopathy in humans.
      explanation: >-
        The human discovery series links truncating TBC1D32 variation to OFD-IX;
        the intervening Hedgehog-patterning route is mechanistically plausible
        but was not directly tested in those patients.
- name: Oral-Facial-Digital Malformation
  conforms_to: "ciliopathy_dysfunction#Skeletal Dysplasia with Polydactyly and Thoracic Constriction"
  biological_scale: TISSUE
  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.
  downstream:
  - target: Midline Facial Cleft
    causal_link_type: DIRECT
    description: OFD-IX craniofacial patterning abnormalities include a midline facial cleft.
    evidence:
    - reference: PMID:24285566
      reference_title: Ciliary genes TBC1D32/C6orf170 and SCLT1 are mutated in patients with OFD type IX.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        oro-facio-digital syndrome type IX featuring midline cleft, microcephaly,
        and colobomatous microphathalmia/anophthalmia.
      explanation: >-
        The two-gene series reports one SCLT1 and one TBC1D32 proband without
        disaggregating the phenotypes by gene, so the TBC1D32 attribution is
        partial.
  - target: Colobomatous Microphthalmia or Anophthalmia
    causal_link_type: DIRECT
    description: OFD-IX ocular patterning abnormalities include colobomatous microphthalmia or anophthalmia.
    evidence:
    - reference: PMID:24285566
      reference_title: Ciliary genes TBC1D32/C6orf170 and SCLT1 are mutated in patients with OFD type IX.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        oro-facio-digital syndrome type IX featuring midline cleft, microcephaly,
        and colobomatous microphathalmia/anophthalmia.
      explanation: >-
        The two-gene series reports one SCLT1 and one TBC1D32 proband without
        disaggregating the phenotypes by gene, so the TBC1D32 attribution is
        partial.
  - target: Coloboma
    causal_link_type: DIRECT
    description: OFD-IX ocular patterning abnormalities include coloboma.
    evidence:
    - reference: PMID:24285566
      reference_title: Ciliary genes TBC1D32/C6orf170 and SCLT1 are mutated in patients with OFD type IX.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        oro-facio-digital syndrome type IX featuring midline cleft, microcephaly,
        and colobomatous microphathalmia/anophthalmia.
      explanation: >-
        The source identifies a colobomatous ocular anomaly, but the two-gene
        series does not disaggregate phenotypes by causal gene.
  - target: Polydactyly
    causal_link_type: DIRECT
    description: Disrupted limb patterning manifests as variable polydactyly.
    evidence:
    - reference: PMID:24285566
      reference_title: Ciliary genes TBC1D32/C6orf170 and SCLT1 are mutated in patients with OFD type IX.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        there was variable presence of polydactyly, absent pituitary, and
        congenital heart disease.
      explanation: >-
        Polydactyly was variable in a series containing one SCLT1 and one
        TBC1D32 proband whose phenotypes were not disaggregated by gene.
- name: Photoreceptor Connecting Cilium Degeneration
  conforms_to: "ciliopathy_dysfunction#Photoreceptor Connecting Cilium Degeneration"
  biological_scale: CELLULAR
  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.
    evidence:
    - 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: >-
        Patient-derived retinal organoids directly connect the ciliary defect
        to impaired cone and rod outer-segment trafficking.
- name: Hypothalamic-Pituitary Ciliary Dysfunction
  biological_scale: TISSUE
  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: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Abnormal cilium-dependent hypothalamic-pituitary development produces
      congenital hypopituitarism.
    evidence:
    - reference: PMID:32060556
      reference_title: Loss-of-Function Variants in TBC1D32 Underlie Syndromic Hypopituitarism.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Biallelic TBC1D32 variants underlie syndromic hypopituitarism, and the
        underlying mechanism may be via disrupted Shh signaling.
      explanation: >-
        The dedicated human series establishes syndromic hypopituitarism while
        appropriately qualifying the proposed Hedgehog-mediated mechanism.
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.
  - reference: PMID:40702307
    reference_title: "Expanding the clinical and molecular spectrum of TBC1D32-related ciliopathy: case reports and literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A review of previously reported cases highlighted facial dysmorphism,
      retinal disease, and hypopituitarism as major clinical features of
      TBC1D32-related ciliopathy.
    explanation: >-
      The 2025 literature review identifies facial dysmorphism as one of the
      major recurring manifestations.
- name: Midline Facial Cleft
  category: Craniofacial
  description: >-
    A midline facial cleft was part of the severe OFD-IX presentation in the
    original TBC1D32/SCLT1 discovery series.
  phenotype_term:
    preferred_term: Midline facial cleft
    term:
      id: HP:0100629
      label: Midline facial cleft
  evidence:
  - reference: PMID:24285566
    reference_title: Ciliary genes TBC1D32/C6orf170 and SCLT1 are mutated in patients with OFD type IX.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      oro-facio-digital syndrome type IX featuring midline cleft, microcephaly,
      and colobomatous microphathalmia/anophthalmia.
    explanation: >-
      The series contained one SCLT1 and one TBC1D32 proband and did not
      disaggregate their phenotypes by gene; it therefore supports the OFD-IX
      spectrum but not a definitive TBC1D32-specific assignment.
- name: Microcephaly
  category: Nervous System
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:24285566
    reference_title: Ciliary genes TBC1D32/C6orf170 and SCLT1 are mutated in patients with OFD type IX.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      oro-facio-digital syndrome type IX featuring midline cleft, microcephaly,
      and colobomatous microphathalmia/anophthalmia.
    explanation: >-
      The series contained one SCLT1 and one TBC1D32 proband and did not
      disaggregate their phenotypes by gene; it therefore supports the OFD-IX
      spectrum but not a definitive TBC1D32-specific assignment.
- name: Colobomatous Microphthalmia or Anophthalmia
  category: Eye
  description: >-
    Severe ocular developmental anomalies range from colobomatous
    microphthalmia to anophthalmia in the original OFD-IX spectrum.
  phenotype_term:
    preferred_term: Microphthalmia
    term:
      id: HP:0000568
      label: Microphthalmia
  evidence:
  - reference: PMID:24285566
    reference_title: Ciliary genes TBC1D32/C6orf170 and SCLT1 are mutated in patients with OFD type IX.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      oro-facio-digital syndrome type IX featuring midline cleft, microcephaly,
      and colobomatous microphathalmia/anophthalmia.
    explanation: >-
      The preferred term preserves the reported colobomatous
      microphthalmia/anophthalmia spectrum while the bound term captures its
      microphthalmia component without inventing a precoordinated identifier.
      The two-gene series contained one SCLT1 and one TBC1D32 proband and did
      not disaggregate their phenotypes by gene.
- name: Coloboma
  category: Eye
  description: >-
    Coloboma is separately represented so the colobomatous component of the
    severe ocular malformation spectrum is ontology-queryable.
  phenotype_term:
    preferred_term: Coloboma
    term:
      id: HP:0000589
      label: Coloboma
  evidence:
  - reference: PMID:24285566
    reference_title: Ciliary genes TBC1D32/C6orf170 and SCLT1 are mutated in patients with OFD type IX.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      oro-facio-digital syndrome type IX featuring midline cleft, microcephaly,
      and colobomatous microphathalmia/anophthalmia.
    explanation: >-
      The quote explicitly identifies the ocular anomaly as colobomatous, but
      the series contained one SCLT1 and one TBC1D32 proband and did not
      disaggregate their phenotypes by gene.
- name: Polydactyly
  category: Musculoskeletal
  phenotype_term:
    preferred_term: Polydactyly
    term:
      id: HP:0010442
      label: Polydactyly
  evidence:
  - reference: PMID:24285566
    reference_title: Ciliary genes TBC1D32/C6orf170 and SCLT1 are mutated in patients with OFD type IX.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      there was variable presence of polydactyly, absent pituitary, and
      congenital heart disease.
    explanation: >-
      Polydactyly was variable in a series containing one SCLT1 and one
      TBC1D32 proband whose phenotypes were not disaggregated by gene.
- name: Congenital Heart Disease
  category: Cardiovascular
  phenotype_term:
    preferred_term: Abnormal heart morphology
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:24285566
    reference_title: Ciliary genes TBC1D32/C6orf170 and SCLT1 are mutated in patients with OFD type IX.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      there was variable presence of polydactyly, absent pituitary, and
      congenital heart disease.
    explanation: >-
      Congenital heart disease was variable in a series containing one SCLT1
      and one TBC1D32 proband whose phenotypes were not disaggregated by gene;
      the HPO binding captures the source's heart-specific level of detail.
- 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.
  - reference: PMID:40702307
    reference_title: "Expanding the clinical and molecular spectrum of TBC1D32-related ciliopathy: case reports and literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A review of previously reported cases highlighted facial dysmorphism,
      retinal disease, and hypopituitarism as major clinical features of
      TBC1D32-related ciliopathy.
    explanation: >-
      The 2025 literature review identifies retinal disease as one of the major
      recurring manifestations.
- 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:32060556
    reference_title: Loss-of-Function Variants in TBC1D32 Underlie Syndromic Hypopituitarism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biallelic TBC1D32 variants underlie syndromic hypopituitarism, and the
      underlying mechanism may be via disrupted Shh signaling.
    explanation: >-
      A dedicated human series directly establishes syndromic hypopituitarism
      due to biallelic TBC1D32 variants.
  - reference: PMID:40702307
    reference_title: "Expanding the clinical and molecular spectrum of TBC1D32-related ciliopathy: case reports and literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A review of previously reported cases highlighted facial dysmorphism,
      retinal disease, and hypopituitarism as major clinical features of
      TBC1D32-related ciliopathy.
    explanation: >-
      The 2025 literature review identifies hypopituitarism as one of the major
      recurring manifestations.
- name: Anterior Pituitary Aplasia or Hypoplasia
  category: Endocrine
  description: >-
    Pituitary imaging in affected families showed absent or hypoplastic anterior
    pituitary tissue, providing an anatomical substrate for hormone deficiency.
  phenotype_term:
    preferred_term: Anterior pituitary hypoplasia
    term:
      id: HP:0010627
      label: Anterior pituitary hypoplasia
  evidence:
  - reference: PMID:32060556
    reference_title: Loss-of-Function Variants in TBC1D32 Underlie Syndromic Hypopituitarism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A Finnish family of 2 siblings with panhypopituitarism, absent anterior
      pituitary, and mild craniofacial dysmorphism, and a Pakistani family with
      a proband with growth hormone deficiency, anterior pituitary hypoplasia,
      and developmental delay.
    explanation: >-
      The report directly documents both absent and hypoplastic anterior
      pituitary anatomy; the bound HPO term represents the coded hypoplasia arm.
- name: Neurodevelopmental Delay
  category: Nervous System
  phenotype_term:
    preferred_term: Neurodevelopmental delay
    term:
      id: HP:0012758
      label: Neurodevelopmental delay
  evidence:
  - reference: PMID:32060556
    reference_title: Loss-of-Function Variants in TBC1D32 Underlie Syndromic Hypopituitarism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a proband with growth hormone deficiency, anterior pituitary hypoplasia,
      and developmental delay.
    explanation: Developmental delay was reported in the syndromic hypopituitarism series.
- name: Cleft Lip
  category: Craniofacial
  phenotype_term:
    preferred_term: Cleft lip
    term:
      id: HP:0410030
      label: Cleft lip
  evidence:
  - reference: PMID:32060556
    reference_title: Loss-of-Function Variants in TBC1D32 Underlie Syndromic Hypopituitarism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      fetus with a cleft lip and partial intestinal malrotation
    explanation: A similarly affected fetus in the pedigree had cleft lip.
- name: Intestinal Malrotation
  category: Gastrointestinal
  phenotype_term:
    preferred_term: Intestinal malrotation
    term:
      id: HP:0002566
      label: Intestinal malrotation
  evidence:
  - reference: PMID:32060556
    reference_title: Loss-of-Function Variants in TBC1D32 Underlie Syndromic Hypopituitarism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      fetus with a cleft lip and partial intestinal malrotation from a
      terminated pregnancy within the same pedigree.
    explanation: Partial intestinal malrotation was reported in an affected fetus.
- 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. Reported loss-of-function alleles include frameshift and
    splice-site variants; RNA analysis of recent splice variants demonstrated
    exon skipping with premature truncation. The human TBC1D32-related
    ciliopathy was first reported in the 2014 OFD-IX series (PMID:24285566),
    confirmed by Alsahan and Alkuraya (PMID:32573025), and expanded by Harris
    et al. (PMID:36826837).
  evidence:
  - reference: PMID:32060556
    reference_title: Loss-of-Function Variants in TBC1D32 Underlie Syndromic Hypopituitarism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biallelic TBC1D32 variants underlie syndromic hypopituitarism
    explanation: >-
      The dedicated loss-of-function series directly establishes the biallelic
      TBC1D32 gene-disease relationship.
  - 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: >-
      The largest clinical expansion adds seven probands with TBC1D32 variants
      segregating with recessive disease across the phenotypic spectrum.
  - 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: OTHER
    snippet: >-
      Mutations in BROMI, CCRK, and ICK in humans cause ciliopathies
    explanation: >-
      The cell-biology paper summarizes the prior human disease association as
      background; dedicated clinical series provide the primary relationship.
  - reference: PMID:40702307
    reference_title: "Expanding the clinical and molecular spectrum of TBC1D32-related ciliopathy: case reports and literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      RNA analysis revealed exon skipping, leading to frameshift and premature
      protein truncation.
    explanation: >-
      Functional RNA analysis establishes a loss-of-function consequence for
      the newly reported splice-site variants.
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: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:32060556
    reference_title: Loss-of-Function Variants in TBC1D32 Underlie Syndromic Hypopituitarism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patients were investigated by whole genome sequencing.
    explanation: >-
      The disease-specific cohort documents genome sequencing as the molecular
      route used to identify biallelic TBC1D32 variants.
  - reference: PMID:24285566
    reference_title: Ciliary genes TBC1D32/C6orf170 and SCLT1 are mutated in patients with OFD type IX.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      single novel truncating variant as revealed by exome sequencing
    explanation: >-
      The original OFD-IX discovery series documents exome sequencing as an
      additional molecular diagnostic route.
differential_diagnoses:
- name: SCLT1-related Orofaciodigital Syndrome Type IX
  description: >-
    SCLT1-related disease can present with the same severe OFD-IX combination of
    midline cleft, microcephaly, ocular malformation, polydactyly, pituitary
    abnormality, and congenital heart disease.
  distinguishing_features:
  - Molecular testing identifies biallelic pathogenic variants in SCLT1 rather than TBC1D32.
  - The overlapping clinical presentation alone does not establish the causal gene.
  evidence:
  - reference: PMID:24285566
    reference_title: Ciliary genes TBC1D32/C6orf170 and SCLT1 are mutated in patients with OFD type IX.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we have identified two simplex cases with a severe ciliopathy phenotype
      consistent with oro-facio-digital syndrome type IX featuring midline
      cleft, microcephaly, and colobomatous microphathalmia/anophthalmia. In
      addition, there was variable presence of polydactyly, absent pituitary,
      and congenital heart disease. The autozygome of each index harbored a
      single novel truncating variant as revealed by exome sequencing, and the
      affected genes (SCLT1 and TBC1D32/C6orf170) have established roles in
      centrosomal biology and ciliogenesis.
    explanation: >-
      The discovery paper identifies both genes in phenotypically overlapping
      simplex OFD-IX cases, making SCLT1-related disease the closest molecular
      differential.
animal_models:
- species: Xenopus laevis
  genotype: Morpholino-mediated reduction of tbc1d32
  genes:
  - preferred_term: TBC1D32
    term:
      id: hgnc:21485
      label: TBC1D32
  description: >-
    An in-vivo Xenopus knockdown model was combined with human patient-derived
    iPSC retinal models to test TBC1D32-dependent retinal differentiation and
    ciliogenesis. It supports the retinal mechanism but does not reproduce or
    validate the full human multisystem phenotype.
  associated_phenotypes:
  - Abnormal retinal differentiation
  - Abnormal retinal ciliogenesis
  - Otic vesicle tbc1d32 expression
  evidence:
  - reference: PMID:37768732
    reference_title: TBC1D32 variants disrupt retinal ciliogenesis and cause retinitis pigmentosa.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      by combining an in vivo Xenopus model and human iPSC-derived retinal
      models, we describe a critical role for TBC1D32 in retinal differentiation
      and ciliogenesis
    explanation: >-
      The study explicitly identifies the Xenopus component and the retinal
      differentiation/ciliogenesis outcomes it helped establish.
  - reference: PMID:37768732
    reference_title: TBC1D32 variants disrupt retinal ciliogenesis and cause retinitis pigmentosa.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      we also detected tbc1d32 in the Xenopus otic vesicle
    explanation: >-
      Otic-vesicle expression supplies model-organism support for an auditory
      developmental role, while the authors appropriately frame the link to
      deafness as suggestive.
treatments:
- name: Pituitary Hormone Replacement
  description: >-
    Replace deficient target-gland hormones according to the affected pituitary
    axes under pediatric endocrine supervision; adrenal insufficiency requires
    urgent recognition and treatment when present.
  treatment_term:
    preferred_term: hormone replacement therapy
    term:
      id: NCIT:C15599
      label: Hormone Replacement Therapy
  target_mechanisms:
  - target: Hypothalamic-Pituitary Ciliary Dysfunction
    treatment_effect: MODULATES
    description: >-
      Replacement bypasses deficient pituitary-axis output but does not correct
      the underlying developmental ciliary defect.
- name: Supportive and Multidisciplinary Care
  description: >-
    Coordinate endocrine, ophthalmologic, audiologic, developmental, and other
    specialist care according to each individual's manifestations.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
- name: Surgical Correction of Malformations
  description: >-
    Consider surgical correction of oral-facial or digital malformations when
    clinically indicated after multidisciplinary assessment.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
- name: Genetic Counseling
  description: >-
    Counsel families regarding autosomal recessive inheritance, including a
    25% recurrence risk for each pregnancy when both parents are carriers, and
    available carrier, prenatal, and preimplantation testing after molecular
    diagnosis.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
clinical_trials: []
datasets: []
computational_models: []
discussions:
- discussion_id: tbc1d32_multisystem_mechanism_model_fidelity
  prompt: >-
    Do the knockout-cell, Xenopus, and retinal-organoid mechanisms reproduce the
    tissue-specific consequences of patient TBC1D32 alleles across the complete
    human syndrome?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#TBC1D32/BROMI Ciliary Trafficking and IFT Turnaround Defect
  - pathophysiology#Impaired Hedgehog Signal Transduction
  rationale: >-
    IFT-turnaround evidence is dominated by engineered knockout cells and the
    Hedgehog inference partly relies on CCRK-knockout experiments. Patient-derived
    retinal models provide strong tissue-specific support, but no single model
    currently recapitulates the craniofacial, pituitary, retinal, auditory, and
    prenatal manifestations together.
  proposed_experiments:
  - experiment_id: exp_tbc1d32_isogenic_ift_rescue
    name: Isogenic patient-allele IFT-turnaround and rescue study
    description: >-
      Introduce representative patient loss-of-function and splice alleles into
      isogenic human ciliated-cell models and compare IFT turnaround, ciliary-tip
      cargo accumulation, and wild-type rescue.
  - experiment_id: exp_tbc1d32_developmental_hedgehog_response
    name: Patient-allele Hedgehog-response study in developmental cell models
    description: >-
      Test GLI processing and Hedgehog target-gene responses in patient-derived
      hypothalamic-pituitary and craniofacial developmental models.
  - experiment_id: exp_tbc1d32_cross_organoid_allelic_series
    name: Cross-organoid TBC1D32 allelic series
    description: >-
      Compare allele-specific phenotypes across retinal, pituitary, and
      craniofacial organoids.
  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: >-
      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: >-
      The key IFT-turnaround evidence uses engineered knockout cells rather than
      the diverse patient alleles.
  - 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: >-
      Patient-derived retinal organoids support one organ-specific arm but do
      not establish fidelity for the whole multisystem disorder.
- discussion_id: tbc1d32_emerging_feature_penetrance
  prompt: >-
    Are sensorineural hearing loss and oculomotor nerve palsy recurrent features
    of TBC1D32-related ciliopathy, and what are their penetrance and allelic basis?
  kind: KNOWLEDGE_GAP
  status: OPEN
  rationale: >-
    Hearing loss and oculomotor palsy were proposed from recent individual or
    very small case expansions. The available literature is too sparse to infer
    frequency, causality for every allele, or a shared tissue mechanism.
  proposed_experiments:
  - experiment_id: exp_tbc1d32_registry_audiology_oculomotor
    name: Registry-based audiology and ocular-motility phenotyping
    description: >-
      Perform standardized audiology and ocular-motility phenotyping in an
      international TBC1D32 registry.
  - experiment_id: exp_tbc1d32_emerging_feature_alleles
    name: Functional testing of emerging-feature alleles
    description: >-
      Test segregation and functional splice effects for alleles observed with
      the emerging features.
  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: The authors explicitly frame sensorineural hearing loss as a proposed new feature.
  - reference: PMID:40702307
    reference_title: "Expanding the clinical and molecular spectrum of TBC1D32-related ciliopathy: case reports and literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we propose oculomotor nerve palsy as an extended clinical feature of this
      disorder.
    explanation: The 2025 case expansion explicitly presents oculomotor palsy as proposed rather than established.
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 the 2020 Alsahan
  and Alkuraya confirmation report (PMID:32573025) and Harris et al.'s 2023
  phenotypic-spectrum expansion (PMID:36826837). The original human association
  was reported earlier in the 2014 TBC1D32/SCLT1 OFD-IX discovery series
  (PMID:24285566). The Alsahan brief report has no PubMed abstract text and is
  therefore cited here only as nomenclature provenance, not as an evidence
  snippet. The literature remains a small set of families and case reports;
  phenotype frequencies, genotype-phenotype correlations, natural history, and
  disease-specific management evidence are not established. This is a
  TBC1D32-specific ciliopathy and must not be conflated with other
  oral-facial-digital syndromes, including OFD I caused by OFD1 and OFD17
  caused by INTU, or with SCLT1-related OFD-IX.
references:
- reference: PMID:24285566
  title: Ciliary genes TBC1D32/C6orf170 and SCLT1 are mutated in patients with OFD type IX.
- reference: PMID:32060556
  title: Loss-of-Function Variants in TBC1D32 Underlie Syndromic Hypopituitarism.
- 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."
- reference: PMID:40702307
  title: "Expanding the clinical and molecular spectrum of TBC1D32-related ciliopathy: case reports and literature Review."
📚

References & Deep Research

References

11
PMID:24285566
Ciliary genes TBC1D32/C6orf170 and SCLT1 are mutated in patients with OFD type IX.
No top-level findings curated for this source.
PMID:32060556
Loss-of-Function Variants in TBC1D32 Underlie Syndromic Hypopituitarism.
No top-level findings curated for this source.
PMID:36826837
Diagnosis of TBC1D32-associated conditions: Expanding the phenotypic spectrum of a complex ciliopathy.
No top-level findings curated for this source.
PMID:40319332
Two novel mutations in TBC1D32 add complexity to the oro-facial-digital syndrome.
No top-level findings curated for this source.
PMID:37768732
TBC1D32 variants disrupt retinal ciliogenesis and cause retinitis pigmentosa.
No top-level findings curated for this source.
PMID:39930170
Novel Potentially Pathogenic Variants in TBC1D32 Cause Non-syndromic Rod-Cone Degeneration.
No top-level findings curated for this source.
PMID:38717911
Exome Sequencing Has a High Diagnostic Rate in Sporadic Congenital Hypopituitarism and Reveals Novel Candidate Genes.
No top-level findings curated for this source.
PMID:35609210
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.
PMID:34624068
CCRK/CDK20 regulates ciliary retrograde protein trafficking via interacting with BROMI/TBC1D32.
No top-level findings curated for this source.
PMID:32573025
Confirming TBC1D32-related ciliopathy in humans.
No top-level findings curated for this source.
PMID:40702307
Expanding the clinical and molecular spectrum of TBC1D32-related ciliopathy: case reports and literature Review.
No top-level findings curated for this source.