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Mappings

MONDO

MONDO:0859191 biliary, renal, neurologic, and skeletal syndrome

The entry's disease_term. Recorded explicitly so the exact-match relationship is queryable rather than implied by the binding alone.

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Inheritance

1

Autosomal recessive inheritance HP:0000007

BRENS is associated with biallelic TTC26/IFT56 variants. Homozygous variants segregated in the defining families and pituitary series. A later patient carried a maternal splice-region allele in trans with two paternal missense variants on the same allele. Thus homozygosity is not required. Penetrance and reliable genotype-phenotype correlations are not established by the small published series.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:31595528 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Positional mapping revealed a single critical locus on chromosome 7. Whole-exome sequencing revealed three different homozygous variants in Tetratricopeptide Repeat Domain 26 (TTC26) that fully segregated with the phenotype."

Establishes recessive inheritance and, through full segregation across seven independent families, the causality of the locus.

PMID:39514123 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Gene testing revealed three novel compound heterozygous variants in the TTC26 gene, c.1069 + 5G > A in one allele from the mother and c.511A > G (p.Ile171Val) and c.1099T > C (p.Ser367Pro) in another allele from the father."

The maternal allele is in trans with a paternal allele carrying two variants in cis; this is not three independently demonstrated pathogenic alleles.

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Mechanistic Hypotheses

1

Ependymal ciliary dysmotility contributes to hydrocephalus

MOTILE_CILIA_HYDROCEPHALUS ALTERNATIVE

Evidence balance 2 support

Motility abnormalities in experimental TTC26 systems and general ependymal physiology support a possible route to human hydrocephalus. Human TTC26 ependymal motility has not been measured, and aqueductal stenosis provides another documented contributor.

Pathograph links

TTC26 functional impairment -> Motile Cilia Beat Dysfunction INDIRECT UNKNOWN INTERMEDIATES Experimental TTC26 perturbation impairs ciliary motility; the human contribution is provisional.

Motile Cilia Beat Dysfunction -> Hydrocephalus INDIRECT UNKNOWN INTERMEDIATES Ependymal dysmotility is a candidate route inferred from general ciliopathy physiology; it has not been demonstrated as the cause in TTC26 patients.

Show evidence (2 references)

PMID:24596149 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Knockdown of TTC26/DYF13 in zebrafish embryos or mutation of TTC26/DYF13 in C. reinhardtii, produced short cilia with abnormal motility."

Motility dysfunction is demonstrated in experimental organisms, not directly measured in BRENS ependymal cells.

PMID:34177428 SUPPORT INDIRECT BACKGROUND Human Clinical

"The proper movement of cilia helps in the flow of cerebrospinal fluid, and the disruption of proper movement (beating) by irregular planar cell polarity causes the accumulation of cerebrospinal fluid resulting in hydrocephalus"

States the ependymal-cilia route to hydrocephalus. Graded INDIRECT because the source states the general ciliopathy mechanism as background rather than demonstrating it for TTC26.

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Discussions and Knowledge Gaps

4

Do modifier loci alter human BRENS severity as they do in hop mice?

HUMAN MODEL MISMATCH brns_modifier_loci_explain_variability

Attached to

animal_models#Mouse genetic#TTC26

Strain background substantially changes the mouse phenotype and a modifier interval maps to chromosome 4. Human cases vary in organ involvement and severity, but current cohorts cannot distinguish allele effects, modifiers, ascertainment and treatment. No corresponding human modifier has been demonstrated.

Show evidence (1 reference)

PMID:41352382 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Using Single Nucleotide Polymorphisms (SNPs) that differ between these mouse strains, we show that a modifier of the Ift56hop phenotype maps to Chromosome 4."

Maps a modifier locus in mice; it does not identify a human modifier gene or exclude allele-specific effects.

Which conditions determine whether GLI tip accumulation is impaired in TTC26-deficient cilia?

KNOWLEDGE GAP brns_gli_accumulation_contested

Attached to

pathophysiology#Dysregulated Sonic Hedgehog Signalling

Both hop studies support impaired Hedgehog signaling. They differ in GLI accumulation measurements: preserved recruitment with reduced GLI-SUFU dissociation in the 2014 assays, versus reduced recruitment in the 2017 cellular and embryonic-tissue assays. The later authors explicitly propose differences in stimulation amount and duration. These data do not justify choosing one universal cellular block for all human alleles.

Show evidence (3 references)

PMID:25340710 SUPPORT DIRECT PRIMARY RESULT Model Organism

"hop did not interfere with Hh-induced accumulation of Gli at the tip of the primary cilium, but rather with the subsequent dissociation of Gli from its negative regulator, Sufu"

This study locates a defect after GLI recruitment under its experimental conditions.

PMID:28264835 SUPPORT DIRECT PRIMARY RESULT Model Organism

"We show that Ift56hop cilia are unable to accumulate Gli proteins efficiently, resulting in developmental patterning defects in Shh signaling-dependent tissues such as the limb and neural tube."

This study also supports impaired signaling, while locating abnormal GLI accumulation under different assays.

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5399663/ SUPPORT INDIRECT PRIMARY RESULT Model Organism

"One possible explanation for this discrepancy is differences in experimental conditions between the studies, including amounts and duration of Hh pathway activation."

The later study itself offers experimental conditions as an explanation; this is an interpretation, not a demonstrated reconciliation.

How does TTC26 dysfunction cause cholestasis and structural biliary disease?

KNOWLEDGE GAP brns_how_cilia_build_the_biliary_tree

Attached to

pathophysiology#Intrahepatic biliary structural abnormalities

Human duct abnormalities and embryonic mouse liver expression support a biliary role. They do not establish a sequence from impaired Hedgehog signaling through failed ductal-plate remodeling to cholestasis. Pituitary deficiency can coexist, making an exclusively irreversible structural explanation premature. Tissue-specific experiments and clinical endocrine-response data are needed to distinguish contributors.

Show evidence (2 references)

PMID:34177428 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Liver biopsy demonstrated zone 3 cholestasis with ductopenia and mild ductular reaction."

Human histology documents ductopenia and cholestasis, without establishing a universal ductal-plate mechanism.

PMID:31595528 SUPPORT INDIRECT PRIMARY RESULT Model Organism

"We also demonstrate a strong expression of Ttc26 in the embryonic mouse liver in a pattern consistent with its proposed role in the normal development of the intrahepatic biliary system."

Supports the developmental reading of the hepatic phenotype. Graded INDIRECT because the evidence is an expression pattern in mouse embryo, from which the developmental role is inferred rather than demonstrated, and the authors say "consistent with" and "proposed" rather than asserting it.

Does altered ciliary PRMT7 localization contribute to Hedgehog dysfunction in biallelic TTC26 disease?

EMERGING HYPOTHESIS brns_prmt7_candidate_mechanism

Attached to

pathophysiology#Dysregulated Sonic Hedgehog Signalling

An adolescent idiopathic scoliosis study identified TTC26-dependent ciliary PRMT7 localization and GLI2 methylation in nucleus-pulposus cell experiments. Its mouse model combined heterozygous Flnb and Ttc26 mutations, rather than biallelic TTC26 disease. Artificially targeting PRMT7 to cilia restored cellular signaling, and local Ptch1/Sufu knockdown improved tail-disc matrix endpoints. Transfer to BRENS organs remains untested; FLNB is not an established BRENS modifier, and these experiments do not establish a clinical therapy.

Show evidence (2 references)

PMID:42178579 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"We find that TTC26 is required for the localization of protein arginine methyltransferase 7 (PRMT7) to the primary cilium, enabling methylation of GLI2, while FLNB binds methylated GLI2 to promote its nuclear import."

This cellular mechanism is a candidate for testing in BRENS; the originating study concerns scoliosis.

PMID:42178579 SUPPORT INDIRECT PRIMARY RESULT Model Organism

"First, we only used the tail disc microinjection model to explore the therapeutic effects of ECM metabolism on Hh signaling. However, its effect on scoliosis needs to be further investigated."

Even rescue of scoliosis was untested; these model interventions provide no evidence of clinical benefit in BRENS.

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Pathophysiology

7

TTC26 functional impairment

Biallelic TTC26/IFT56 variants impair a core component of IFT-B. Splice, missense and truncating alleles can differ in residual function; complete absence of the protein is not established for every patient. IFT56 contributes to selective protein trafficking and signaling rather than simply determining whether all cilia form.

Ependymal ciliary dysmotility contributes to hydrocephalus

TTC26 hgnc:21882

Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

Disease-associated biallelic genotypes include homozygous and compound-heterozygous alleles. Functional effects are allele-dependent.

cilium GO:0005929

Animal models

Ift56hop homozygous mouse Mouse partially recapitulates Models reduced IFT56 function and background-dependent developmental outcomes. These experiments establish modifier effects in mice without identifying a human modifier architecture.

Zebrafish ttc26 knockdown and frameshift models Zebrafish partially recapitulates Tests loss of ttc26 function in development.

Downstream

Abnormal ciliary IFT-B protein localization Mutant patient cells exhibit abnormal IFT-B component distribution.

Ciliary axonemal disorganization The hop perturbation produces axonemal structural abnormalities.

Dysregulated Sonic Hedgehog Signalling Mutant patient cells exhibit dysregulated Hedgehog signaling.

Motile Cilia Beat Dysfunction Experimental TTC26 perturbation impairs ciliary motility; the human contribution is provisional.

Intrahepatic biliary structural abnormalities The proposed biliary developmental connection is supported by human disease association and embryonic mouse expression, with intermediate steps unknown.

Pituitary malformation Biallelic TTC26 variants are associated with pituitary malformation; the intervening developmental pathway remains unresolved.

Unilateral renal hypoplasia This manifestation is reported in molecularly diagnosed TTC26 disease; its specific intervening pathway has not been resolved.

Primum atrial septal defect This manifestation is reported in molecularly diagnosed TTC26 disease; its specific intervening pathway has not been resolved.

Syndactyly This manifestation is reported in molecularly diagnosed TTC26 disease; its specific intervening pathway has not been resolved.

Congenital knee dislocation This manifestation is reported in molecularly diagnosed TTC26 disease; its specific intervening pathway has not been resolved.

Bilateral cleft lip This manifestation is reported in molecularly diagnosed TTC26 disease; its specific intervening pathway has not been resolved.

Cleft palate This manifestation is reported in molecularly diagnosed TTC26 disease; its specific intervening pathway has not been resolved.

Optic atrophy This manifestation is reported in molecularly diagnosed TTC26 disease; its specific intervening pathway has not been resolved.

Global developmental delay This manifestation is reported in molecularly diagnosed TTC26 disease; its specific intervening pathway has not been resolved.

Aqueductal stenosis Aqueductal stenosis is a reported feature of TTC26-related disease; the intervening developmental mechanism remains unresolved.

Deep-set eyes This finding is associated with molecularly diagnosed TTC26 disease; its intervening mechanism is unresolved.

Low-set ears This finding is associated with molecularly diagnosed TTC26 disease; its intervening mechanism is unresolved.

Frontal bossing This finding is associated with molecularly diagnosed TTC26 disease; its intervening mechanism is unresolved.

Renal abnormality, unspecified This finding is associated with molecularly diagnosed TTC26 disease; its intervening mechanism is unresolved.

Show evidence (2 references)

PMID:31595528 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Positional mapping revealed a single critical locus on chromosome 7. Whole-exome sequencing revealed three different homozygous variants in Tetratricopeptide Repeat Domain 26 (TTC26) that fully segregated with the phenotype."

Establishes recessive inheritance and, through full segregation across seven independent families, the causality of the locus.

PMID:26980730 SUPPORT DIRECT PRIMARY RESULT In Vitro

"we identified TTC26/IFT56 and Cluap1/IFT38, neither of which was included with certainty in previous models of the IFT-B complex, as integral components of the core and peripheral subcomplexes, respectively"

Biochemical interaction analysis places TTC26/IFT56 in the core, while CLUAP1/IFT38 belongs to the peripheral subcomplex.

Abnormal ciliary IFT-B protein localization

Patient cells have abnormal IFT-B staining. In hop mouse cells, IFT81 and IFT27 are reduced in cilia, whereas IFT88 distribution changes with tissue and compartment. Other IFT components and ciliary proteins can remain normally localized. These selective defects do not imply that all IFT movement ceases; algal particle velocities were similar after controlling for flagellar length.

intraciliary transport GO:0042073 ⚠ ABNORMAL

Show evidence (3 references)

PMID:31595528 SUPPORT DIRECT PRIMARY RESULT In Vitro

"We show that cilia in TTC26-mutated patient cells display variable length and impaired function, as indicated by dysregulated sonic hedgehog signaling, abnormal staining for IFT-B components, and transcriptomic clustering with cells derived from individuals with closely related ciliopathies."

Patient-derived cells directly demonstrate abnormal ciliary function and IFT-B staining, without resolving every organ-level mechanism.

PMID:28264835 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Strikingly, core IFTB proteins are unable to accumulate normally within Ift56hop cilia, including IFT88, IFT81 and IFT27, which are crucial for key processes such as tubulin transport and Shh signaling."

The mouse study identifies altered distribution of particular IFT-B proteins; the full text shows compartment-dependent differences.

PMID:24596149 SUPPORT DIRECT PRIMARY RESULT Model Organism

"We found that in such cells, which were genetically wild-type but happened to have shorter flagella comparable to the dyf13 mutant flagella (6–8 μm), the KAP-GFP speed was almost the same as in the dyf13 mutant"

The full-text comparison controls for flagellar length and limits a blanket claim of reduced IFT speed.

Ciliary axonemal disorganization

Primary cilia form in hop mice but can have abnormal axonemal microtubule-doublet number and positioning. Both mouse studies report retained cilia with modestly increased length; knockdown in renal cells and zebrafish can instead shorten cilia. The ordering between microtubule architecture defects and abnormal IFT-B distribution remains unresolved.

Show evidence (3 references)

PMID:28264835 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Ift56hop mice have normal cilia distribution but display defective cilia structure, including abnormal positioning and number of ciliary microtubule doublets."

Electron microscopy in the mouse study demonstrates axonemal abnormalities, not a universal failure of basal-body docking.

PMID:25340710 SUPPORT DIRECT PRIMARY RESULT Model Organism

"In fact, the hop mutation was associated with a slight increase in cilium length"

The mouse full text corrects an interpretation of the abstract as showing entirely unchanged ciliary dimensions.

PMID:22718903 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Knockdown of Ttc26 in mIMCD3 cells produced shortened and defective primary cilia, as revealed by immunofluorescence and scanning electron microscopy."

A different perturbation and cellular setting produces shortened cilia.

Dysregulated Sonic Hedgehog Signalling

Ciliary Hedgehog signaling is altered in patient cells. Mouse studies demonstrate impaired GLI activator and repressor functions, with residual pathway activity. One study found preserved stimulated GLI tip accumulation with impaired GLI-SUFU dissociation; another found reduced GLI tip accumulation in culture and embryonic tissues. Stimulation conditions may contribute to this difference. Reduced GLI repressor activity offers a model-based explanation for polydactyly; the evidence does not establish Hedgehog failure as the mechanism of every hepatic, renal, ocular or endocrine feature.

smoothened signaling pathway GO:0007224 ↕ DYSREGULATED

Downstream

Polydactyly The hop limb phenotype supports a GLI repressor mechanism for altered digit patterning. Human tissue-level confirmation is lacking.

Show evidence (3 references)

PMID:31595528 SUPPORT DIRECT PRIMARY RESULT In Vitro

"We show that cilia in TTC26-mutated patient cells display variable length and impaired function, as indicated by dysregulated sonic hedgehog signaling, abnormal staining for IFT-B components, and transcriptomic clustering with cells derived from individuals with closely related ciliopathies."

Patient-derived cells directly demonstrate abnormal ciliary function and IFT-B staining, without resolving every organ-level mechanism.

PMID:25340710 SUPPORT DIRECT PRIMARY RESULT Model Organism

"hop did not interfere with Hh-induced accumulation of Gli at the tip of the primary cilium, but rather with the subsequent dissociation of Gli from its negative regulator, Sufu"

This study locates a defect after GLI recruitment under its experimental conditions.

PMID:28264835 SUPPORT DIRECT PRIMARY RESULT Model Organism

"We show that Ift56hop cilia are unable to accumulate Gli proteins efficiently, resulting in developmental patterning defects in Shh signaling-dependent tissues such as the limb and neural tube."

This study also supports impaired signaling, while locating abnormal GLI accumulation under different assays.

Motile Cilia Beat Dysfunction

Mechanism confidence: Hypothetical

Algal and zebrafish TTC26/DYF13 perturbations impair motility-related cargo and ciliary beating. The direction of beat-frequency change depends on the tissue: zebrafish Kupffer vesicle cilia beat more slowly, whereas pronephric cilia show faster but poorly coordinated beating. A contribution to human hydrocephalus is plausible but unproven; aqueductal obstruction is also documented clinically.

Ependymal ciliary dysmotility contributes to hydrocephalus

cilium movement GO:0003341 ⚠ ABNORMAL

Downstream

Hydrocephalus Ependymal dysmotility is a candidate route inferred from general ciliopathy physiology; it has not been demonstrated as the cause in TTC26 patients.

Show evidence (3 references)

PMID:24596149 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Knockdown of TTC26/DYF13 in zebrafish embryos or mutation of TTC26/DYF13 in C. reinhardtii, produced short cilia with abnormal motility."

Motility dysfunction is demonstrated in experimental organisms, not directly measured in BRENS ependymal cells.

PMID:24596149 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Components of outer dynein arms were present at normal levels in dyf13 mutant flagella"

The experimental study found selective defects rather than depletion of every motility structure.

PMID:22718903 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Control cilia bundles beat coordinately, but the cilia beat rate in ttc26 morphants (B and C) is increased and out of phase, resulting in loss of coordination."

The pronephric measurements support abnormal coordination, not a uniform reduction in beat rate.

Intrahepatic biliary structural abnormalities

Human observations include intrahepatic duct dilatation and ductopenia with cholestasis. Embryonic mouse Ttc26 expression suggests a developmental role, but expression alone does not prove disrupted ductal-plate remodeling or an exclusively Hedgehog-dependent lesion. The relative contributions of structural biliary disease and associated endocrine dysfunction remain incompletely defined.

cholangiocyte CL:1000488

intrahepatic bile duct UBERON:0003704

Downstream

Cholestasis Abnormal bile-duct architecture is a plausible contributor to impaired bile flow, but the biopsy alone does not separate it from other contributors.

Cystic dilatation of intrahepatic bile ducts This structural finding is an observed manifestation of the organ abnormality.

Show evidence (2 references)

PMID:34177428 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Liver biopsy demonstrated zone 3 cholestasis with ductopenia and mild ductular reaction."

Human histology documents ductopenia and cholestasis, without establishing a universal ductal-plate mechanism.

PMID:31595528 SUPPORT INDIRECT PRIMARY RESULT Model Organism

"We also demonstrate a strong expression of Ttc26 in the embryonic mouse liver in a pattern consistent with its proposed role in the normal development of the intrahepatic biliary system."

Supports the developmental reading of the hepatic phenotype. Graded INDIRECT because the evidence is an expression pattern in mouse embryo, from which the developmental role is inferred rather than demonstrated, and the authors say "consistent with" and "proposed" rather than asserting it.

Pituitary malformation

Pituitary stalk interruption and pituitary hypoplasia are reported manifestations of TTC26-related ciliopathy. Structural abnormalities can be associated with deficient anterior or posterior pituitary function; the precise ciliary developmental steps have not been demonstrated in patient pituitary tissue.

pituitary gland UBERON:0000007

Downstream

Interrupted pituitary stalk Pituitary stalk interruption is the structural manifestation identified in the series.

Hypopituitarism Hormone deficits can accompany structural pituitary disease.

Diabetes insipidus Posterior pituitary dysfunction can produce deficient antidiuretic signaling.

Pituitary hypoplasia This structural finding is an observed manifestation of the organ abnormality.

Show evidence (1 reference)

PMID:32617964 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"We now describe four patients with TTC26 ciliopathy due to a homozygous c.695A>G p.Asn232Ser mutation and delineate PSIS as a novel clinical feature of this disorder, highlighting an important role of TTC26 in pituitary development."

This clinical series links the gene-associated disorder to a pituitary developmental phenotype.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

25

Cardiovascular 1

Primum atrial septal defect HP:0010445

Show evidence (1 reference)

PMID:34177428 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Echocardiography was performed immediately, and it showed a large primum atrial septal defect with a left-to-right shunt and patent ductus arteriosus that closed spontaneously later on."

This is a specific human cardiac finding, rather than a broad organ-level label.

Digestive 3

Cholestasis Intrahepatic cholestasis HP:0001406

Show evidence (2 references)

PMID:31595528 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"severe neonatal cholestasis (lethal in one and necessitating liver transplant in two)"

Documents the cholestatic phenotype and its severity distribution across the cohort.

PMID:39514123 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"It is the first description of BRENS syndrome without biliary involvement."

The biliary-sparing case supports the stated variability and excludes an obligate-cholestasis definition.

Gastroesophageal reflux HP:0002020

Show evidence (1 reference)

PMID:34177428 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"She was discharged and subsequently admitted multiple times with recurrent respiratory infections, aspiration pneumonia, and severe gastroesophageal reflux."

The reported case supports this manifestation; no population frequency is inferred.

Cystic dilatation of intrahepatic bile ducts Intrahepatic bile duct dilatation HP:0033149

Show evidence (1 reference)

PMID:34177428 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"ultrasound of the abdomen showed persistent cystic dilatation of the intrahepatic biliary ducts, which was suspected to be Caroli disease."

The case report documents this finding; no population frequency is inferred.

Ear 2

Suspected unilateral hearing impairment HP:0000365

Show evidence (1 reference)

PMID:38135897 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Moreover, he presented with a suspected unilateral hearing loss and bilateral cleft lip-palate."

The reported case supports this manifestation; no population frequency is inferred.

Low-set ears HP:0000369

Show evidence (1 reference)

PMID:34177428 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Affected individual (II-2) presenting dysmorphic features in the form of deep-set eyes, low-set ears, frontal bossing, and hypermobile and extensible joints."

The case report documents this finding; no population frequency is inferred.

Endocrine 4

Interrupted pituitary stalk HP:0034978

Show evidence (1 reference)

PMID:32617964 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"delineate PSIS as a novel clinical feature of this disorder, highlighting an important role of TTC26 in pituitary development"

Establishes pituitary stalk interruption as a feature of this disorder and the developmental inference the authors draw from it.

Diabetes insipidus HP:0000873

Show evidence (1 reference)

PMID:34177428 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"From an endocrine point of view, she had diabetes insipidus, which was treated with desmopressin."

Documents diabetes insipidus and the treatment it received.

Hypopituitarism HP:0040075

Show evidence (1 reference)

PMID:38135897 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"a patient showing some of the known TTC26-associated features like hexadactyly, hypopituitarism, hepatopathy, nephropathy, and congenital heart defect"

The reported case supports this manifestation; no population frequency is inferred.

Pituitary hypoplasia Small pituitary gland HP:0012506

Show evidence (1 reference)

PMID:34177428 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Brain MRI showed pituitary hypoplasia."

The case report documents this finding; no population frequency is inferred.

Eye 2

Optic atrophy HP:0000648

Show evidence (1 reference)

PMID:34177428 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The proband exhibited features such as cholestasis, cystic dilatation of intrahepatic biliary ducts, diabetes insipidus, dysmorphic facial features, optic atrophy, pituitary hypoplasia, hydrocephalus, aqueductal stenosis, hyperextensible knee joints, bilateral knee dislocation, polydactyly, and..."

Documents optic atrophy among the proband's features.

Deep-set eyes Deeply set eye HP:0000490

Show evidence (1 reference)

PMID:34177428 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Affected individual (II-2) presenting dysmorphic features in the form of deep-set eyes, low-set ears, frontal bossing, and hypermobile and extensible joints."

The case report documents this finding; no population frequency is inferred.

Genitourinary 2

Unilateral renal hypoplasia HP:0012583

Show evidence (1 reference)

PMID:34177428 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Moreover, her right kidney was small and echogenic with normal function."

The clinical report supports unilateral renal hypoplasia without implying renal failure or cysts.

Renal abnormality, unspecified Abnormality of the kidney HP:0000077

Coarse binding: source unspecified

Show evidence (1 reference)

PMID:38135897 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Here, we report on a previously undescribed homozygous intronic TTC26 variant (c.1006-5 T > C) in a patient showing some of the known TTC26-associated features like hexadactyly, hypopituitarism, hepatopathy, nephropathy, and congenital heart defect."

The case report documents this finding; no population frequency is inferred.

Head and Neck 3

Bilateral cleft lip HP:0100336

Show evidence (1 reference)

PMID:38135897 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Moreover, he presented with a suspected unilateral hearing loss and bilateral cleft lip-palate."

The reported case supports this manifestation; no population frequency is inferred.

Cleft palate HP:0000175

Show evidence (1 reference)

PMID:38135897 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Moreover, he presented with a suspected unilateral hearing loss and bilateral cleft lip-palate."

The reported case supports this manifestation; no population frequency is inferred.

Frontal bossing HP:0002007

Show evidence (1 reference)

PMID:34177428 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Affected individual (II-2) presenting dysmorphic features in the form of deep-set eyes, low-set ears, frontal bossing, and hypermobile and extensible joints."

The case report documents this finding; no population frequency is inferred.

Limbs 3

Polydactyly HP:0010442

Show evidence (2 references)

PMID:32617964 SUPPORT DIRECT BACKGROUND Human Clinical

"in the context of a syndrome of polydactyly and severe neonatal cholestasis"

Documents polydactyly as part of the established syndrome. Marked BACKGROUND because this paper is restating the prior description rather than reporting the finding.

PMID:34177428 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"polydactyly in the upper limbs, and syndactyly in the lower limbs"

Direct observation of upper-limb polydactyly in the 2021 patient.

Syndactyly HP:0001159

Show evidence (1 reference)

PMID:34177428 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"polydactyly in the upper limbs, and syndactyly in the lower limbs"

The reported case supports this manifestation; no population frequency is inferred.

Congenital knee dislocation HP:0005191

Show evidence (1 reference)

PMID:34177428 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"she had hyperextensible joints, specifically congenital bilateral knee dislocation (more toward right than left), which improved after serial knee casting."

The reported case supports this manifestation; no population frequency is inferred.

Musculoskeletal 1

Axial hypotonia HP:0008936

Show evidence (1 reference)

PMID:34177428 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Neurologically, she had global developmental delay and axial hypotonia."

The reported case supports this manifestation; no population frequency is inferred.

Nervous System 3

Hydrocephalus HP:0000238

Show evidence (1 reference)

PMID:34177428 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The proband exhibited features such as cholestasis, cystic dilatation of intrahepatic biliary ducts, diabetes insipidus, dysmorphic facial features, optic atrophy, pituitary hypoplasia, hydrocephalus, aqueductal stenosis, hyperextensible knee joints, bilateral knee dislocation, polydactyly, and..."

Documents hydrocephalus among the proband's features in the paper that coined the syndrome name.

Aqueductal stenosis HP:0002410

Sequelae: Hydrocephalus

Show evidence (1 reference)

PMID:34177428 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Additionally, supratentorial hydrocephalus and aqueductal stenosis were observed, and ventriculoperitoneal shunt insertion was performed to manage them."

Documents aqueductal stenosis together with the hydrocephalus and the intervention it required.

Global developmental delay HP:0001263

Show evidence (1 reference)

PMID:34177428 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Neurologically, she had global developmental delay and axial hypotonia."

Documents developmental delay and axial hypotonia in the proband.

Growth 1

Failure to thrive HP:0001508

Show evidence (1 reference)

PMID:34177428 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Failure to thrive was observed with severe global developmental delay at 3 months of age and axial hypotonia."

The reported case supports this manifestation; no population frequency is inferred.

🧬

Genetic Associations

1

TTC26

Gene: TTC26 hgnc:21882 relationship_type: CAUSATIVE

Show evidence (5 references)

PMID:31595528 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Positional mapping revealed a single critical locus on chromosome 7. Whole-exome sequencing revealed three different homozygous variants in Tetratricopeptide Repeat Domain 26 (TTC26) that fully segregated with the phenotype."

Establishes recessive inheritance and, through full segregation across seven independent families, the causality of the locus.

PMID:32617964 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"We now describe four patients with TTC26 ciliopathy due to a homozygous c.695A>G p.Asn232Ser mutation"

Gives the recurrent missense allele and the number of patients carrying it.

PMID:38135897 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Here, we report on a previously undescribed homozygous intronic TTC26 variant (c.1006-5 T > C) in a patient showing some of the known TTC26-associated features"

Adds an intronic splice-affecting allele to the reported spectrum.

+ 2 more references

Variants (4)

c.4-1G>C (NM_024926.3)

single nucleotide variant

Genomic context: intron

Homozygous splice-acceptor variant reported in the defining study and a subsequent Saudi patient. Exon skipping was demonstrated in the earlier study; the later study supports reduced transcript abundance.

Show evidence (1 reference)

PMID:34177428 SUPPORT DIRECT BACKGROUND In Vitro

"The variant is pathogenic in nature because cDNA sequencing previously revealed skipping of exon 2 on TTC26"

The later report cites the original RNA finding; the quoted evidence is background, not its own new splicing experiment.

c.695A>G (p.Asn232Ser), as reported

single nucleotide variant

Homozygous missense allele in the four-patient pituitary series. The published amino-acid numbering is retained without assuming interchangeability with other isoforms.

Show evidence (1 reference)

PMID:32617964 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"We now describe four patients with TTC26 ciliopathy due to a homozygous c.695A>G p.Asn232Ser mutation"

Gives the recurrent missense allele and the number of patients carrying it.

c.1006-5T>C

single nucleotide variant

Genomic context: intron

Homozygous intronic splice-region variant reported in a patient with pituitary, hepatic, renal, cardiac and craniofacial involvement. Splicing disruption, rather than a demonstrated enhancer effect, is implicated.

Show evidence (1 reference)

PMID:38135897 SUPPORT INDIRECT PRIMARY RESULT Other

"The variant is considered to affect correct splicing by the loss of the canonical acceptor splice site and activation of a cryptic acceptor splice site."

The abstract reports altered splice-site use but does not specify the supporting method. It is not graded as a quoted RNA assay or computational prediction; the mechanistic interpretation is indirect from the available abstract.

Maternal c.1069+5G>A / paternal [c.511A>G; c.1099T>C]

Compound-heterozygous genotype in a biliary-sparing patient. The two paternal missense changes occur in cis; the maternal splice-region change is on the other allele. Individual effects remain unresolved.

Show evidence (1 reference)

PMID:39514123 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Gene testing revealed three novel compound heterozygous variants in the TTC26 gene, c.1069 + 5G > A in one allele from the mother and c.511A > G (p.Ile171Val) and c.1099T > C (p.Ser367Pro) in another allele from the father."

The maternal allele is in trans with a paternal allele carrying two variants in cis; this is not three independently demonstrated pathogenic alleles.

💊

Medical Actions

8

Ursodiol for Cholestasis

Action: Pharmacotherapy NCIT:C15986

Agent: ursodeoxycholic acid CHEBI:9907

Platform: Small molecule

Ursodeoxycholic acid was used for cholestasis in the 2021 patient without observed improvement. This single-case response does not establish general inefficacy or demonstrate that bile ducts never formed.

Mechanism Target:

Cholestasis — Intended to ameliorate cholestasis; benefit was not observed in the cited case.

Show evidence (1 reference)

PMID:34177428 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The patient was administered ursodiol 28 mg b.i.d.; however, no improvement was observed."

Supports the stated lack of observed benefit in this patient, without a syndrome-wide efficacy conclusion.

Desmopressin for Diabetes Insipidus

Action: Pharmacotherapy NCIT:C15986

Agent: desmopressin CHEBI:4450

Platform: Peptide

Desmopressin was administered for diabetes insipidus in the 2021 patient. This replaces deficient antidiuretic signaling; the report documents use but does not quantify efficacy.

Mechanism Target:

Diabetes insipidus — Replaces deficient antidiuretic signaling in central diabetes insipidus.

Show evidence (1 reference)

PMID:34177428 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"she had diabetes insipidus, which was treated with desmopressin"

Documents desmopressin use for the endocrine component.

Ventriculoperitoneal Shunt

Action: Ventriculoperitoneal Shunt Placement NCIT:C168483

Platform: Surgery

Cerebrospinal fluid diversion was performed for supratentorial hydrocephalus with aqueductal stenosis in one patient. It treats that complication, without correcting the underlying ciliopathy or all neurologic manifestations.

Mechanism Target:

Hydrocephalus — Diverts cerebrospinal fluid in hydrocephalus with aqueductal obstruction; ependymal dysmotility was not demonstrated in this patient.

Show evidence (1 reference)

PMID:34177428 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"supratentorial hydrocephalus and aqueductal stenosis were observed, and ventriculoperitoneal shunt insertion was performed to manage them"

Documents the shunt and the indication for it.

Serial Knee Casting for Congenital Knee Dislocation

Platform: Device

Serial knee casting improved bilateral congenital knee dislocation in one reported patient.

Target Phenotypes: Congenital knee dislocation HP:0005191

Show evidence (1 reference)

PMID:34177428 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"congenital bilateral knee dislocation (more toward right than left), which improved after serial knee casting"

Documents the intervention and its outcome.

Liver transplantation

Action: Liver Transplantation NCIT:C15271

Platform: Surgery

Two of seven patients in the defining cohort required liver transplantation for severe neonatal cholestatic disease. Transplantation addresses hepatic disease but does not correct extrahepatic TTC26-related abnormalities.

Target Phenotypes: Intrahepatic cholestasis HP:0001406

Show evidence (1 reference)

PMID:31595528 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"including severe neonatal cholestasis (lethal in one and necessitating liver transplant in two)"

The defining cohort documents transplant use; it does not provide comparative survival efficacy.

Replacement of deficient pituitary hormones

Action: Replacement Therapy NCIT:C15471

Platform: Other

Documented pituitary hormone deficits require axis-specific replacement and endocrine follow-up. Hydrocortisone, levothyroxine and growth hormone are replacement options for the corresponding deficiencies in PSIS care. The cited general PSIS treatment report is indirect evidence for management, not a TTC26-specific efficacy study or an additional BRENS patient.

Target Phenotypes: Hypopituitarism HP:0040075

Show evidence (2 references)

PMID:42460215 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"Hormonal replacement therapy with hydrocortisone, levothyroxine, and growth hormone led to clinical stabilization."

This non-TTC26 PSIS case illustrates replacement of deficient axes. The application to BRENS-associated hypopituitarism is indirect.

PMID:38135897 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"a patient showing some of the known TTC26-associated features like hexadactyly, hypopituitarism, hepatopathy, nephropathy, and congenital heart defect"

This case establishes hypopituitarism as the indication for replacement. Its replacement regimen is not quoted here; the preceding general PSIS report supports treatment practice indirectly.

Fundoplication for severe reflux

Action: Fundoplication NCIT:C91834

Platform: Surgery

Fundoplication with gastrostomy placement was used for severe gastroesophageal reflux in the 2021 case. No syndrome-wide treatment response rate is available.

Target Phenotypes: Gastroesophageal reflux HP:0002020

Show evidence (1 reference)

PMID:34177428 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Gastrostomy insertion with fundoplication was performed to manage the gastroesophageal reflux."

Documents the indication and intervention in one patient.

Gastrostomy placement

Action: Gastrostomy NCIT:C52006

Platform: Surgery

Gastrostomy placement accompanied fundoplication in the patient with severe reflux and feeding-related morbidity.

Show evidence (1 reference)

PMID:34177428 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Gastrostomy insertion with fundoplication was performed to manage the gastroesophageal reflux."

Documents gastrostomy placement without assuming a specific insertion technique.

🔬

Diagnosis

4

Molecular diagnosis by exome or genome sequencing

Exome or genome sequencing with segregation analysis can establish biallelic TTC26/IFT56 variants in a compatible multisystem phenotype. RNA analysis can help assess splice variants; reduced transcript abundance alone is distinct from demonstrating a particular splicing product. Severe neonatal cholestasis can prompt consideration of ciliopathy even without the usual associated features.

Show evidence (2 references)

PMID:34177428 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Whole-genome sequencing and Sanger sequencing revealed a homozygous splice site variant (c.4-1G>C; NM_024926.3) in the tetratricopeptide repeat domain 26 (TTC26) gene located in chromosome 7q34, which cosegregated perfectly with the disease phenotype."

This documents sequencing and segregation in a molecularly diagnosed patient.

PMID:31595528 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"our results highlight the importance of considering ciliopathies in the differential diagnosis of severe neonatal cholestasis even in the absence of more typical features."

The defining study supports the diagnostic scope.

Hepatobiliary imaging and histology

Ultrasound can characterize intrahepatic duct abnormalities. The 2021 patient had cystic intrahepatic duct dilatation, initially suspected to be Caroli disease, and biopsy showed cholestasis with ductopenia and mild ductular reaction. These findings document hepatobiliary involvement but do not establish a universal ductal-plate malformation or a complete developmental mechanism.

Show evidence (1 reference)

PMID:34177428 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Liver biopsy demonstrated zone 3 cholestasis with ductopenia and mild ductular reaction."

Gives the histological findings on which the hepatic diagnosis rests.

Brain MRI for pituitary and ventricular involvement

Brain MRI characterizes pituitary stalk interruption, pituitary size and ventricular abnormalities such as hydrocephalus and aqueductal stenosis. These findings guide assessment of endocrine and neurologic complications but are not specific to TTC26 disease.

Show evidence (1 reference)

PMID:32617964 SUPPORT DIRECT BACKGROUND Human Clinical

"Pituitary stalk interruption syndrome (PSIS) is a congenital anomaly of the pituitary gland, diagnosed by characteristic MRI findings."

Establishes MRI as the diagnostic modality for the pituitary component.

Endocrine and renal assessment

Pituitary abnormalities warrant assessment of anterior and posterior pituitary function. Renal imaging and function studies characterize the variable renal phenotype; abnormal kidney morphology does not necessarily imply impaired function.

Show evidence (2 references)

PMID:38135897 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"a patient showing some of the known TTC26-associated features like hexadactyly, hypopituitarism, hepatopathy, nephropathy, and congenital heart defect"

The reported case supports this manifestation; no population frequency is inferred.

PMID:34177428 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Moreover, her right kidney was small and echogenic with normal function."

The clinical report supports unilateral renal hypoplasia without implying renal failure or cysts.

📊

Prevalence

1

Worldwide

Cases In Literature Unknown

Population prevalence is unknown. The defining study reported seven individuals, the pituitary series four additional patients, and three later reports each describe another patient. These publications therefore describe at least fourteen individuals; this literature count is neither a population rate nor a denominator for phenotype frequencies.

Show evidence (5 references)

PMID:31595528 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"We describe seven individuals from seven families with syndromic ciliopathy clinical features, including severe neonatal cholestasis (lethal in one and necessitating liver transplant in two)."

Gives the size of the defining cohort and the severity distribution of its hepatic phenotype.

PMID:32617964 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"We now describe four patients with TTC26 ciliopathy due to a homozygous c.695A>G p.Asn232Ser mutation"

This report contributes to the stated literature count, not a population prevalence estimate.

PMID:34177428 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"In this study, we describe a severe ciliopathy disorder that segregates in an autosomal recessive manner in a nonconsanguineous Saudi family."

This report contributes to the stated literature count, not a population prevalence estimate.

+ 2 more references

⚖️

Clinical Burden

High

Severe neonatal hepatic disease caused one death and required liver transplantation in two of seven patients in the defining cohort. Renal, brain, pituitary and skeletal abnormalities can add substantial morbidity. Other patients have different organ involvement, including a biliary-sparing presentation. These small selected series do not establish a syndrome-wide survival probability.

Show evidence (1 reference)

PMID:31595528 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"including severe neonatal cholestasis (lethal in one and necessitating liver transplant in two)"

Gives the hepatic outcomes - one death and two transplants out of seven - that drive the HIGH burden assessment.

🐁

Animal Models

2

Ift56hop homozygous mouse

The homozygous Ift56hop premature-stop allele produces markedly different phenotypes on BALB/cByJ and C57BL/6J backgrounds. Adult survivors with sterility and a hopping gait occur on BALB/cByJ, while C57BL/6J homozygotes are perinatally lethal with multiple malformations. A chromosome 4 modifier locus was mapped; the causal modifier gene and its relevance to human patients are unresolved.

Species

Mouse

Genotype

Ift56hop (Ttc26) homozygous loss-of-function

Publication

PMID:41352382

Pathograph links

TTC26 functional impairment partially recapitulates fidelity: moderate observes: organism Models reduced IFT56 function and background-dependent developmental outcomes. These experiments establish modifier effects in mice without identifying a human modifier architecture.

Limitations: Severity and organ involvement depend on allele and strain. The 2014 study found normal kidney and retinal histology in examined adult hop mice, whereas human patients can have renal and ocular abnormalities. Severe neonatal cholestasis is not established as a recapitulated endpoint in the cited model reports. Mouse background effects cannot predict individual human severity.

Divergences from the human mechanism

population mismatch qualifying

Inbred strain backgrounds differ at many loci. Mapping identifies a chromosome 4 modifier interval but does not show that this is the sole difference between strains or that the same locus modifies human BRENS.

other qualifying

The cited mouse reports do not establish the severe neonatal cholestatic phenotype that is prominent in human BRENS.

Show evidence (1 reference)

PMID:41352382 SUPPORT DIRECT PRIMARY RESULT Model Organism

"we demonstrate that in the C57BL/6J background, Ift56hop homozygotes are perinatal lethal, and have multiple skeletal and organ defects, including the formation of tracheoesophageal fistulas"

Documents the severe-background phenotype, against which the viable Balb/cByJ phenotype is the contrast that carries the finding.

Show evidence (1 reference)

PMID:41352382 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Using Single Nucleotide Polymorphisms (SNPs) that differ between these mouse strains, we show that a modifier of the Ift56hop phenotype maps to Chromosome 4."

Maps a modifier locus in mice; it does not identify a human modifier gene or exclude allele-specific effects.

Zebrafish ttc26 knockdown and frameshift models

Morpholino studies show shortened or disorganized cilia, pronephric dilation and photoreceptor outer-segment defects. Later CRISPR experiments confirmed a curved-down-tail phenotype in F1 ttc26 compound-frameshift embryos. These perturbations and endpoints differ; a photoreceptor phenotype should not be attributed to the later transition-zone screen.

Species

Zebrafish

Publication

PMID:36533556

Pathograph links

TTC26 functional impairment partially recapitulates fidelity: moderate observes: organism Tests loss of ttc26 function in development.

Limitations: Morpholinos, mosaic crispants and germline frameshifts have different limitations. No candidate crispants formed cysts by five days in the later screen. Neither study establishes neonatal cholestatic liver disease or human optic nerve atrophy.

Show evidence (1 reference)

PMID:36533556 SUPPORT DIRECT PRIMARY RESULT Model Organism

"In the four CDT mutants analyzed, all had compound frameshift mutations"

The F1 zebrafish experiments confirmed biallelic frameshift genotypes in embryos with curved-down tails.

Show evidence (2 references)

PMID:22718903 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Morpholino knockdown of ttc26 in zebrafish embryos caused ciliary defects in the pronephric kidney at 27 h postfertilization and distension/dilation of pronephros at 5 d postfertilization (dpf)."

The earlier knockdown study directly documents renal ciliary and morphologic defects.

PMID:36533556 SUPPORT DIRECT PRIMARY RESULT Model Organism

"In the four CDT mutants analyzed, all had compound frameshift mutations"

The F1 zebrafish experiments confirmed biallelic frameshift genotypes in embryos with curved-down tails.

{ }

Source YAML

click to show

name: Biliary, Renal, Neurologic, and Skeletal Syndrome
creation_date: "2026-09-18T00:00:00Z"
category: Mendelian
synonyms:
- BRENS
- BRENS syndrome
- TTC26 ciliopathy
- IFT56-related ciliopathy
- severe biliary ciliopathy
- TTC26-related severe biliary ciliopathy
description: >-
  Biliary, renal, neurologic and skeletal syndrome (BRENS) is an autosomal recessive ciliopathy caused by biallelic
  variants in TTC26, now named IFT56. The protein is a core component of intraflagellar transport complex B.
  Severe neonatal cholestasis was prominent in the defining seven-family cohort, with one death and two liver
  transplants. Renal, cerebral, pituitary, limb and cardiac abnormalities vary between patients; later reports
  include facial clefts and a patient without biliary involvement. Human cellular studies demonstrate altered
  ciliary function, while the steps connecting this defect to each organ manifestation remain incompletely
  resolved.
disease_term:
  preferred_term: biliary, renal, neurologic, and skeletal syndrome
  term:
    id: MONDO:0859191
    label: biliary, renal, neurologic, and skeletal syndrome
parents:
- Ciliopathy
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0859191
      label: biliary, renal, neurologic, and skeletal syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      The entry's disease_term. Recorded explicitly so the exact-match relationship is
      queryable rather than implied by the binding alone.
references:
- reference: PMID:31595528
  title: "Biallelic Mutations in Tetratricopeptide Repeat Domain 26 (Intraflagellar Transport 56) Cause Severe Biliary Ciliopathy in Humans."
- reference: PMID:32617964
  title: "Pituitary stalk interruption syndrome broadens the clinical spectrum of the TTC26 ciliopathy."
- reference: PMID:41352382
  title: "Genetic background influences the extent and severity of cilia-related congenital anomalies in Ift56/Ttc26 mutant mice."
- reference: PMID:25340710
  title: "A mutation in the mouse ttc26 gene leads to impaired hedgehog signaling."
- reference: PMID:34177428
  title: "Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations."
- reference: PMID:39514123
  title: "Biliary, Renal, Neurological, and Skeletal syndrome in a Chinese boy."
- reference: PMID:26980730
  title: "Overall Architecture of the Intraflagellar Transport (IFT)-B Complex Containing Cluap1/IFT38 as an Essential Component of the IFT-B Peripheral Subcomplex."
- reference: PMID:28264835
  title: "IFT56 regulates vertebrate developmental patterning by maintaining IFTB complex integrity and ciliary microtubule architecture."
- reference: PMID:24596149
  title: "TTC26/DYF13 is an intraflagellar transport protein required for transport of motility-related proteins into flagella."
- reference: PMID:38135897
  title: "A novel TTC26 variant in a patient with hexadactyly, pituitary stalk interruption, hepatopathy, nephropathy, and bilateral lip-palate cleft: A case report and expansion of the phenotype."
- reference: PMID:22718903
  title: "Knockdown of ttc26 disrupts ciliogenesis of the photoreceptor cells and the pronephros in zebrafish."
- reference: PMID:42460215
  title: 'Diagnosis of Pituitary Stalk Interruption Syndrome in a Newborn Presenting With Recurrent Hypoglycemia: A Rare Case Report.'
- reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5399663/
  title: IFT56 regulates vertebrate developmental patterning by maintaining IFTB complex integrity and ciliary microtubule architecture - PMC
- reference: PMID:36533556
  title: Variable phenotypes and penetrance between and within different zebrafish ciliary transition zone mutants.
- reference: PMID:42178579
  title: FLNB and TTC26 regulate ciliary Hedgehog signaling to maintain intervertebral disc matrix homeostasis in adolescent idiopathic scoliosis.
notes: >-
  IFT56 is the current gene symbol; TTC26 is retained in the gene binding and cited literature. Published variant
  names refer to the transcripts used in the original reports and should not be interchanged between isoforms
  without normalization. The clinical evidence consists of small cohorts and individual reports, rather than
  a population-based natural-history study. No disease-specific GeneReviews chapter was identified; the defining
  cohort and subsequent molecularly diagnosed cases provide the clinical baseline. The PMC5399663 URL contains
  the full text of PMID:28264835, including assay-context qualifications absent from its abstract. The PMID:36533556
  cache contains the full TTC26-specific CRISPR results.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: UNKNOWN
  notes: >-
    Population prevalence is unknown. The defining study reported seven individuals, the pituitary series four
    additional patients, and three later reports each describe another patient. These publications therefore
    describe at least fourteen individuals; this literature count is neither a population rate nor a denominator
    for phenotype frequencies.
  evidence:
  - reference: PMID:31595528
    reference_title: "Biallelic Mutations in Tetratricopeptide Repeat Domain 26 (Intraflagellar Transport 56) Cause Severe Biliary Ciliopathy in Humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe seven individuals from seven families with syndromic ciliopathy clinical
      features, including severe neonatal cholestasis (lethal in one and necessitating liver
      transplant in two).
    explanation: >-
      Gives the size of the defining cohort and the severity distribution of its hepatic
      phenotype.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:32617964
    reference_title: Pituitary stalk interruption syndrome broadens the clinical spectrum of the TTC26 ciliopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      We now describe four patients with TTC26 ciliopathy due to a homozygous c.695A>G p.Asn232Ser mutation
    explanation: >-
      This report contributes to the stated literature count, not a population prevalence estimate.
    quote_role: PRIMARY_RESULT
  - reference: PMID:34177428
    reference_title: Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      In this study, we describe a severe ciliopathy disorder that segregates in an autosomal recessive manner
      in a nonconsanguineous Saudi family.
    explanation: >-
      This report contributes to the stated literature count, not a population prevalence estimate.
    quote_role: PRIMARY_RESULT
  - reference: PMID:38135897
    reference_title: 'A novel TTC26 variant in a patient with hexadactyly, pituitary stalk interruption, hepatopathy, nephropathy, and bilateral lip-palate cleft: A case report and expansion of the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Hereby, our patient represents one additional patient with BRENS syndrome carrying a previously unreported
      TTC26 variant.
    explanation: >-
      This report contributes to the stated literature count, not a population prevalence estimate.
    quote_role: PRIMARY_RESULT
  - reference: PMID:39514123
    reference_title: Biliary, Renal, Neurological, and Skeletal syndrome in a Chinese boy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      We report here a Chinese case of BRENS syndrome who presented with kidney, neurological, skeletal, and
      other features.
    explanation: >-
      This report contributes to the stated literature count, not a population prevalence estimate.
    quote_role: PRIMARY_RESULT
clinical_burden:
  burden_level: HIGH
  rationale: >-
    Severe neonatal hepatic disease caused one death and required liver transplantation in two of seven patients
    in the defining cohort. Renal, brain, pituitary and skeletal abnormalities can add substantial morbidity.
    Other patients have different organ involvement, including a biliary-sparing presentation. These small
    selected series do not establish a syndrome-wide survival probability.
  evidence:
  - reference: PMID:31595528
    reference_title: "Biallelic Mutations in Tetratricopeptide Repeat Domain 26 (Intraflagellar Transport 56) Cause Severe Biliary Ciliopathy in Humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      including severe neonatal cholestasis (lethal in one and necessitating liver transplant
      in two)
    explanation: >-
      Gives the hepatic outcomes - one death and two transplants out of seven - that drive
      the HIGH burden assessment.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    BRENS is associated with biallelic TTC26/IFT56 variants. Homozygous variants segregated in the defining
    families and pituitary series. A later patient carried a maternal splice-region allele in trans with two
    paternal missense variants on the same allele. Thus homozygosity is not required. Penetrance and reliable
    genotype-phenotype correlations are not established by the small published series.
  evidence:
  - &id001
    reference: PMID:31595528
    reference_title: "Biallelic Mutations in Tetratricopeptide Repeat Domain 26 (Intraflagellar Transport 56) Cause Severe Biliary Ciliopathy in Humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Positional mapping revealed a single critical locus on chromosome 7. Whole-exome
      sequencing revealed three different homozygous variants in Tetratricopeptide Repeat
      Domain 26 (TTC26) that fully segregated with the phenotype.
    explanation: >-
      Establishes recessive inheritance and, through full segregation across seven
      independent families, the causality of the locus.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:39514123
    reference_title: Biliary, Renal, Neurological, and Skeletal syndrome in a Chinese boy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Gene testing revealed three novel compound heterozygous variants in the TTC26 gene, c.1069 + 5G > A in
      one allele from the mother and c.511A > G (p.Ile171Val) and c.1099T > C (p.Ser367Pro) in another allele
      from the father.
    explanation: >-
      The maternal allele is in trans with a paternal allele carrying two variants in cis; this is not three
      independently demonstrated pathogenic alleles.
    quote_role: PRIMARY_RESULT
genetic:
- name: TTC26
  gene_term:
    preferred_term: TTC26
    term:
      id: hgnc:21882
      label: TTC26
  relationship_type: CAUSATIVE
  notes: >-
    TTC26/IFT56 is an IFT-B core protein. Reported disease-associated genotypes include homozygous missense,
    splice-site and truncating alleles, and a compound-heterozygous genotype. The c.695A>G (p.Asn232Ser) allele
    recurs in the pituitary series. For c.4-1G>C (NM_024926.3), prior transcript work showed exon skipping,
    and a subsequent patient study measured reduced TTC26 RNA. The intronic c.1006-5T>C allele affects splicing.
    A later compound genotype contains a maternal c.1069+5G>A allele and a paternal cis pair, p.Ile171Val and
    p.Ser367Pro; the contribution of each change cannot be separated from that report. These observations do
    not imply identical molecular effects or severity for every allele.
  evidence:
  - *id001
  - reference: PMID:32617964
    reference_title: "Pituitary stalk interruption syndrome broadens the clinical spectrum of the TTC26 ciliopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We now describe four patients with TTC26 ciliopathy due to a homozygous c.695A>G
      p.Asn232Ser mutation
    explanation: >-
      Gives the recurrent missense allele and the number of patients carrying it.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:38135897
    reference_title: "A novel TTC26 variant in a patient with hexadactyly, pituitary stalk interruption, hepatopathy, nephropathy, and bilateral lip-palate cleft: A case report and expansion of the phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report on a previously undescribed homozygous intronic TTC26 variant
      (c.1006-5 T > C) in a patient showing some of the known TTC26-associated features
    explanation: >-
      Adds an intronic splice-affecting allele to the reported spectrum.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:39514123
    reference_title: Biliary, Renal, Neurological, and Skeletal syndrome in a Chinese boy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Gene testing revealed three novel compound heterozygous variants in the TTC26 gene, c.1069 + 5G > A in
      one allele from the mother and c.511A > G (p.Ile171Val) and c.1099T > C (p.Ser367Pro) in another allele
      from the father.
    explanation: >-
      The maternal allele is in trans with a paternal allele carrying two variants in cis; this is not three
      independently demonstrated pathogenic alleles.
    quote_role: PRIMARY_RESULT
  - reference: PMID:34177428
    reference_title: Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: >-
      Using RNA samples from the patient, qRT-PCR revealed a substantial decrease in the expression of TTC26
      in the proband as compared to the normal control (Fig. 1e).
    explanation: >-
      The RNA assay demonstrates decreased abundance in this patient; it does not establish a universal expression
      defect or directly measure the splicing product.
    quote_role: PRIMARY_RESULT
  variants:
  - name: c.4-1G>C (NM_024926.3)
    variant_type: single nucleotide variant
    genomic_contexts:
    - intron
    description: >-
      Homozygous splice-acceptor variant reported in the defining study and a subsequent Saudi patient. Exon
      skipping was demonstrated in the earlier study; the later study supports reduced transcript abundance.
    evidence:
    - reference: PMID:34177428
      reference_title: Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      snippet: >-
        The variant is pathogenic in nature because cDNA sequencing previously revealed skipping of exon 2
        on TTC26
      explanation: >-
        The later report cites the original RNA finding; the quoted evidence is background, not its own new
        splicing experiment.
      quote_role: BACKGROUND
  - name: c.695A>G (p.Asn232Ser), as reported
    variant_type: single nucleotide variant
    description: >-
      Homozygous missense allele in the four-patient pituitary series. The published amino-acid numbering is
      retained without assuming interchangeability with other isoforms.
    evidence:
    - reference: PMID:32617964
      reference_title: "Pituitary stalk interruption syndrome broadens the clinical spectrum of the TTC26 ciliopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We now describe four patients with TTC26 ciliopathy due to a homozygous c.695A>G
        p.Asn232Ser mutation
      explanation: >-
        Gives the recurrent missense allele and the number of patients carrying it.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
  - name: c.1006-5T>C
    variant_type: single nucleotide variant
    genomic_contexts:
    - intron
    description: >-
      Homozygous intronic splice-region variant reported in a patient with pituitary, hepatic, renal, cardiac
      and craniofacial involvement. Splicing disruption, rather than a demonstrated enhancer effect, is implicated.
    evidence:
    - reference: PMID:38135897
      reference_title: 'A novel TTC26 variant in a patient with hexadactyly, pituitary stalk interruption, hepatopathy, nephropathy, and bilateral lip-palate cleft: A case report and expansion of the phenotype.'
      supports: SUPPORT
      evidence_source: OTHER
      directness: INDIRECT
      snippet: >-
        The variant is considered to affect correct splicing by the loss of the canonical acceptor splice site
        and activation of a cryptic acceptor splice site.
      explanation: >-
        The abstract reports altered splice-site use but does not specify the supporting method. It is not
        graded as a quoted RNA assay or computational prediction; the mechanistic interpretation is indirect
        from the available abstract.
      quote_role: PRIMARY_RESULT
  - name: Maternal c.1069+5G>A / paternal [c.511A>G; c.1099T>C]
    description: >-
      Compound-heterozygous genotype in a biliary-sparing patient. The two paternal missense changes occur
      in cis; the maternal splice-region change is on the other allele. Individual effects remain unresolved.
    evidence:
    - reference: PMID:39514123
      reference_title: Biliary, Renal, Neurological, and Skeletal syndrome in a Chinese boy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: >-
        Gene testing revealed three novel compound heterozygous variants in the TTC26 gene, c.1069 + 5G > A
        in one allele from the mother and c.511A > G (p.Ile171Val) and c.1099T > C (p.Ser367Pro) in another
        allele from the father.
      explanation: >-
        The maternal allele is in trans with a paternal allele carrying two variants in cis; this is not three
        independently demonstrated pathogenic alleles.
      quote_role: PRIMARY_RESULT
pathophysiology:
- name: TTC26 functional impairment
  description: >-
    Biallelic TTC26/IFT56 variants impair a core component of IFT-B. Splice, missense and truncating alleles
    can differ in residual function; complete absence of the protein is not established for every patient.
    IFT56 contributes to selective protein trafficking and signaling rather than simply determining whether
    all cilia form.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:31595528
    reference_title: "Biallelic Mutations in Tetratricopeptide Repeat Domain 26 (Intraflagellar Transport 56) Cause Severe Biliary Ciliopathy in Humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Positional mapping revealed a single critical locus on chromosome 7. Whole-exome
      sequencing revealed three different homozygous variants in Tetratricopeptide Repeat
      Domain 26 (TTC26) that fully segregated with the phenotype.
    explanation: >-
      Establishes recessive inheritance and, through full segregation across seven
      independent families, the causality of the locus.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:26980730
    reference_title: Overall Architecture of the Intraflagellar Transport (IFT)-B Complex Containing Cluap1/IFT38 as an Essential Component of the IFT-B Peripheral Subcomplex.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: >-
      we identified TTC26/IFT56 and Cluap1/IFT38, neither of which was included with certainty in previous
      models of the IFT-B complex, as integral components of the core and peripheral subcomplexes, respectively
    explanation: >-
      Biochemical interaction analysis places TTC26/IFT56 in the core, while CLUAP1/IFT38 belongs to the peripheral
      subcomplex.
    quote_role: PRIMARY_RESULT
  downstream:
  - target: Abnormal ciliary IFT-B protein localization
    description: >-
      Mutant patient cells exhibit abnormal IFT-B component distribution.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31595528
      reference_title: Biallelic Mutations in Tetratricopeptide Repeat Domain 26 (Intraflagellar Transport 56) Cause Severe Biliary Ciliopathy in Humans.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      snippet: >-
        We show that cilia in TTC26-mutated patient cells display variable length and impaired function, as
        indicated by dysregulated sonic hedgehog signaling, abnormal staining for IFT-B components, and transcriptomic
        clustering with cells derived from individuals with closely related ciliopathies.
      explanation: >-
        Patient-derived cells directly demonstrate abnormal ciliary function and IFT-B staining, without resolving
        every organ-level mechanism.
      quote_role: PRIMARY_RESULT
  - target: Ciliary axonemal disorganization
    description: >-
      The hop perturbation produces axonemal structural abnormalities.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28264835
      reference_title: IFT56 regulates vertebrate developmental patterning by maintaining IFTB complex integrity and ciliary microtubule architecture.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: >-
        Ift56hop mice have normal cilia distribution but display defective cilia structure, including abnormal
        positioning and number of ciliary microtubule doublets.
      explanation: >-
        Electron microscopy in the mouse study demonstrates axonemal abnormalities, not a universal failure
        of basal-body docking.
      quote_role: PRIMARY_RESULT
  - target: Dysregulated Sonic Hedgehog Signalling
    description: >-
      Mutant patient cells exhibit dysregulated Hedgehog signaling.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31595528
      reference_title: Biallelic Mutations in Tetratricopeptide Repeat Domain 26 (Intraflagellar Transport 56) Cause Severe Biliary Ciliopathy in Humans.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      snippet: >-
        We show that cilia in TTC26-mutated patient cells display variable length and impaired function, as
        indicated by dysregulated sonic hedgehog signaling, abnormal staining for IFT-B components, and transcriptomic
        clustering with cells derived from individuals with closely related ciliopathies.
      explanation: >-
        Patient-derived cells directly demonstrate abnormal ciliary function and IFT-B staining, without resolving
        every organ-level mechanism.
      quote_role: PRIMARY_RESULT
  - target: Motile Cilia Beat Dysfunction
    description: >-
      Experimental TTC26 perturbation impairs ciliary motility; the human contribution is provisional.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:24596149
      reference_title: TTC26/DYF13 is an intraflagellar transport protein required for transport of motility-related proteins into flagella.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: >-
        Knockdown of TTC26/DYF13 in zebrafish embryos or mutation of TTC26/DYF13 in C. reinhardtii, produced
        short cilia with abnormal motility.
      explanation: >-
        Motility dysfunction is demonstrated in experimental organisms, not directly measured in BRENS ependymal
        cells.
      quote_role: PRIMARY_RESULT
    hypothesis_groups:
    - MOTILE_CILIA_HYDROCEPHALUS
  - target: Intrahepatic biliary structural abnormalities
    description: >-
      The proposed biliary developmental connection is supported by human disease association and embryonic
      mouse expression, with intermediate steps unknown.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31595528
      reference_title: "Biallelic Mutations in Tetratricopeptide Repeat Domain 26 (Intraflagellar Transport 56) Cause Severe Biliary Ciliopathy in Humans."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: >-
        We also demonstrate a strong expression of Ttc26 in the embryonic mouse liver in a
        pattern consistent with its proposed role in the normal development of the
        intrahepatic biliary system.
      explanation: >-
        Supports the developmental reading of the hepatic phenotype. Graded INDIRECT because
        the evidence is an expression pattern in mouse embryo, from which the developmental
        role is inferred rather than demonstrated, and the authors say "consistent with" and
        "proposed" rather than asserting it.
      quote_role: PRIMARY_RESULT
  - target: Pituitary malformation
    description: >-
      Biallelic TTC26 variants are associated with pituitary malformation; the intervening developmental pathway
      remains unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32617964
      reference_title: Pituitary stalk interruption syndrome broadens the clinical spectrum of the TTC26 ciliopathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        We now describe four patients with TTC26 ciliopathy due to a homozygous c.695A>G p.Asn232Ser mutation
        and delineate PSIS as a novel clinical feature of this disorder, highlighting an important role of
        TTC26 in pituitary development.
      explanation: >-
        This clinical series links the gene-associated disorder to a pituitary developmental phenotype.
      quote_role: PRIMARY_RESULT
  - target: Unilateral renal hypoplasia
    description: >-
      This manifestation is reported in molecularly diagnosed TTC26 disease; its specific intervening pathway
      has not been resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34177428
      reference_title: Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        Moreover, her right kidney was small and echogenic with normal function.
      explanation: >-
        The clinical report supports unilateral renal hypoplasia without implying renal failure or cysts.
      quote_role: PRIMARY_RESULT
  - target: Primum atrial septal defect
    description: >-
      This manifestation is reported in molecularly diagnosed TTC26 disease; its specific intervening pathway
      has not been resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34177428
      reference_title: Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        Echocardiography was performed immediately, and it showed a large primum atrial septal defect with
        a
        left-to-right shunt and patent ductus arteriosus that closed spontaneously later on.
      explanation: >-
        This is a specific human cardiac finding, rather than a broad organ-level label.
      quote_role: PRIMARY_RESULT
  - target: Syndactyly
    description: >-
      This manifestation is reported in molecularly diagnosed TTC26 disease; its specific intervening pathway
      has not been resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34177428
      reference_title: Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        polydactyly in the upper limbs, and syndactyly in the lower limbs
      explanation: >-
        The reported case supports this manifestation; no population frequency is inferred.
      quote_role: PRIMARY_RESULT
  - target: Congenital knee dislocation
    description: >-
      This manifestation is reported in molecularly diagnosed TTC26 disease; its specific intervening pathway
      has not been resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34177428
      reference_title: Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        she had hyperextensible joints, specifically congenital bilateral knee dislocation (more toward right
        than left), which improved after serial knee casting.
      explanation: >-
        The reported case supports this manifestation; no population frequency is inferred.
      quote_role: PRIMARY_RESULT
  - target: Bilateral cleft lip
    description: >-
      This manifestation is reported in molecularly diagnosed TTC26 disease; its specific intervening pathway
      has not been resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38135897
      reference_title: 'A novel TTC26 variant in a patient with hexadactyly, pituitary stalk interruption, hepatopathy, nephropathy, and bilateral lip-palate cleft: A case report and expansion of the phenotype.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        Moreover, he presented with a suspected unilateral hearing loss and bilateral cleft lip-palate.
      explanation: >-
        The reported case supports this manifestation; no population frequency is inferred.
      quote_role: PRIMARY_RESULT
  - target: Cleft palate
    description: >-
      This manifestation is reported in molecularly diagnosed TTC26 disease; its specific intervening pathway
      has not been resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38135897
      reference_title: 'A novel TTC26 variant in a patient with hexadactyly, pituitary stalk interruption, hepatopathy, nephropathy, and bilateral lip-palate cleft: A case report and expansion of the phenotype.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        Moreover, he presented with a suspected unilateral hearing loss and bilateral cleft lip-palate.
      explanation: >-
        The reported case supports this manifestation; no population frequency is inferred.
      quote_role: PRIMARY_RESULT
  - target: Optic atrophy
    description: >-
      This manifestation is reported in molecularly diagnosed TTC26 disease; its specific intervening pathway
      has not been resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34177428
      reference_title: "Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The proband exhibited features such as cholestasis, cystic dilatation of intrahepatic
        biliary ducts, diabetes insipidus, dysmorphic facial features, optic atrophy, pituitary
        hypoplasia, hydrocephalus, aqueductal stenosis, hyperextensible knee joints, bilateral
        knee dislocation, polydactyly, and syndactyly.
      explanation: >-
        Documents optic atrophy among the proband's features.
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
  - target: Global developmental delay
    description: >-
      This manifestation is reported in molecularly diagnosed TTC26 disease; its specific intervening pathway
      has not been resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34177428
      reference_title: "Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Neurologically, she had global developmental delay and axial hypotonia.
      explanation: >-
        Documents developmental delay and axial hypotonia in the proband.
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
  - target: Aqueductal stenosis
    description: >-
      Aqueductal stenosis is a reported feature of TTC26-related disease; the intervening developmental mechanism
      remains unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34177428
      reference_title: "Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Additionally, supratentorial hydrocephalus and aqueductal stenosis were observed, and
        ventriculoperitoneal shunt insertion was performed to manage them.
      explanation: >-
        Documents aqueductal stenosis together with the hydrocephalus and the intervention it
        required.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Deep-set eyes
    description: >-
      This finding is associated with molecularly diagnosed TTC26 disease; its intervening mechanism is unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34177428
      reference_title: Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        Affected individual (II-2) presenting dysmorphic features in the form of deep-set eyes, low-set ears,
        frontal bossing, and hypermobile and extensible joints.
      explanation: >-
        The case report documents this finding; no population frequency is inferred.
      quote_role: PRIMARY_RESULT
  - target: Low-set ears
    description: >-
      This finding is associated with molecularly diagnosed TTC26 disease; its intervening mechanism is unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34177428
      reference_title: Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        Affected individual (II-2) presenting dysmorphic features in the form of deep-set eyes, low-set ears,
        frontal bossing, and hypermobile and extensible joints.
      explanation: >-
        The case report documents this finding; no population frequency is inferred.
      quote_role: PRIMARY_RESULT
  - target: Frontal bossing
    description: >-
      This finding is associated with molecularly diagnosed TTC26 disease; its intervening mechanism is unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34177428
      reference_title: Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        Affected individual (II-2) presenting dysmorphic features in the form of deep-set eyes, low-set ears,
        frontal bossing, and hypermobile and extensible joints.
      explanation: >-
        The case report documents this finding; no population frequency is inferred.
      quote_role: PRIMARY_RESULT
  - target: Renal abnormality, unspecified
    description: >-
      This finding is associated with molecularly diagnosed TTC26 disease; its intervening mechanism is unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38135897
      reference_title: 'A novel TTC26 variant in a patient with hexadactyly, pituitary stalk interruption, hepatopathy, nephropathy, and bilateral lip-palate cleft: A case report and expansion of the phenotype.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        Here, we report on a previously undescribed homozygous intronic TTC26 variant (c.1006-5 T > C) in a
        patient showing some of the known TTC26-associated features like hexadactyly, hypopituitarism, hepatopathy,
        nephropathy, and congenital heart defect.
      explanation: >-
        The case report documents this finding; no population frequency is inferred.
      quote_role: PRIMARY_RESULT
  genes:
  - preferred_term: TTC26
    term:
      id: hgnc:21882
      label: TTC26
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Disease-associated biallelic genotypes include homozygous and compound-heterozygous alleles. Functional
      effects are allele-dependent.
  cellular_components:
  - preferred_term: cilium
    term:
      id: GO:0005929
      label: cilium
- name: Abnormal ciliary IFT-B protein localization
  description: >-
    Patient cells have abnormal IFT-B staining. In hop mouse cells, IFT81 and IFT27 are reduced in cilia, whereas
    IFT88 distribution changes with tissue and compartment. Other IFT components and ciliary proteins can remain
    normally localized. These selective defects do not imply that all IFT movement ceases; algal particle velocities
    were similar after controlling for flagellar length.
  biological_scale: CELLULAR
  evidence:
  - reference: PMID:31595528
    reference_title: Biallelic Mutations in Tetratricopeptide Repeat Domain 26 (Intraflagellar Transport 56) Cause Severe Biliary Ciliopathy in Humans.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: >-
      We show that cilia in TTC26-mutated patient cells display variable length and impaired function, as indicated
      by dysregulated sonic hedgehog signaling, abnormal staining for IFT-B components, and transcriptomic
      clustering with cells derived from individuals with closely related ciliopathies.
    explanation: >-
      Patient-derived cells directly demonstrate abnormal ciliary function and IFT-B staining, without resolving
      every organ-level mechanism.
    quote_role: PRIMARY_RESULT
  - reference: PMID:28264835
    reference_title: IFT56 regulates vertebrate developmental patterning by maintaining IFTB complex integrity and ciliary microtubule architecture.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      Strikingly, core IFTB proteins are unable to accumulate normally within Ift56hop cilia, including IFT88,
      IFT81 and IFT27, which are crucial for key processes such as tubulin transport and Shh signaling.
    explanation: >-
      The mouse study identifies altered distribution of particular IFT-B proteins; the full text shows compartment-dependent
      differences.
    quote_role: PRIMARY_RESULT
  - reference: PMID:24596149
    reference_title: TTC26/DYF13 is an intraflagellar transport protein required for transport of motility-related proteins into flagella.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      We found that in such cells, which were genetically wild-type but happened to have shorter flagella comparable
      to the dyf13 mutant flagella (6–8 μm), the KAP-GFP speed was almost the same as in the dyf13 mutant
    explanation: >-
      The full-text comparison controls for flagellar length and limits a blanket claim of reduced IFT speed.
    quote_role: PRIMARY_RESULT
  downstream: []
  conforms_to: ciliopathy_dysfunction#Basal Body and Transition Zone Dysfunction
  biological_processes:
  - preferred_term: intraciliary transport
    term:
      id: GO:0042073
      label: intraciliary transport
    modifier: ABNORMAL
- name: Ciliary axonemal disorganization
  description: >-
    Primary cilia form in hop mice but can have abnormal axonemal microtubule-doublet number and positioning.
    Both mouse studies report retained cilia with modestly increased length; knockdown in renal cells and zebrafish
    can instead shorten cilia. The ordering between microtubule architecture defects and abnormal IFT-B distribution
    remains unresolved.
  biological_scale: CELLULAR
  evidence:
  - reference: PMID:28264835
    reference_title: IFT56 regulates vertebrate developmental patterning by maintaining IFTB complex integrity and ciliary microtubule architecture.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      Ift56hop mice have normal cilia distribution but display defective cilia structure, including abnormal
      positioning and number of ciliary microtubule doublets.
    explanation: >-
      Electron microscopy in the mouse study demonstrates axonemal abnormalities, not a universal failure of
      basal-body docking.
    quote_role: PRIMARY_RESULT
  - reference: PMID:25340710
    reference_title: A mutation in the mouse ttc26 gene leads to impaired hedgehog signaling.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      In fact, the hop mutation was associated with a slight increase in cilium length
    explanation: >-
      The mouse full text corrects an interpretation of the abstract as showing entirely unchanged ciliary
      dimensions.
    quote_role: PRIMARY_RESULT
  - reference: PMID:22718903
    reference_title: Knockdown of ttc26 disrupts ciliogenesis of the photoreceptor cells and the pronephros in zebrafish.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: >-
      Knockdown of Ttc26 in mIMCD3 cells produced shortened and defective primary cilia, as revealed by immunofluorescence
      and scanning electron microscopy.
    explanation: >-
      A different perturbation and cellular setting produces shortened cilia.
    quote_role: PRIMARY_RESULT
  downstream: []
- name: Dysregulated Sonic Hedgehog Signalling
  description: >-
    Ciliary Hedgehog signaling is altered in patient cells. Mouse studies demonstrate impaired GLI activator
    and repressor functions, with residual pathway activity. One study found preserved stimulated GLI tip accumulation
    with impaired GLI-SUFU dissociation; another found reduced GLI tip accumulation in culture and embryonic
    tissues. Stimulation conditions may contribute to this difference. Reduced GLI repressor activity offers
    a model-based explanation for polydactyly; the evidence does not establish Hedgehog failure as the mechanism
    of every hepatic, renal, ocular or endocrine feature.
  biological_scale: CELLULAR
  evidence:
  - reference: PMID:31595528
    reference_title: Biallelic Mutations in Tetratricopeptide Repeat Domain 26 (Intraflagellar Transport 56) Cause Severe Biliary Ciliopathy in Humans.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: >-
      We show that cilia in TTC26-mutated patient cells display variable length and impaired function, as indicated
      by dysregulated sonic hedgehog signaling, abnormal staining for IFT-B components, and transcriptomic
      clustering with cells derived from individuals with closely related ciliopathies.
    explanation: >-
      Patient-derived cells directly demonstrate abnormal ciliary function and IFT-B staining, without resolving
      every organ-level mechanism.
    quote_role: PRIMARY_RESULT
  - reference: PMID:25340710
    reference_title: A mutation in the mouse ttc26 gene leads to impaired hedgehog signaling.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      hop did not interfere with Hh-induced accumulation of Gli at the tip of the primary cilium, but rather
      with the subsequent dissociation of Gli from its negative regulator, Sufu
    explanation: >-
      This study locates a defect after GLI recruitment under its experimental conditions.
    quote_role: PRIMARY_RESULT
  - reference: PMID:28264835
    reference_title: IFT56 regulates vertebrate developmental patterning by maintaining IFTB complex integrity and ciliary microtubule architecture.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      We show that Ift56hop cilia are unable to accumulate Gli proteins efficiently, resulting in developmental
      patterning defects in Shh signaling-dependent tissues such as the limb and neural tube.
    explanation: >-
      This study also supports impaired signaling, while locating abnormal GLI accumulation under different
      assays.
    quote_role: PRIMARY_RESULT
  downstream:
  - target: Polydactyly
    description: >-
      The hop limb phenotype supports a GLI repressor mechanism for altered digit patterning. Human tissue-level
      confirmation is lacking.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5399663/
      reference_title: IFT56 regulates vertebrate developmental patterning by maintaining IFTB complex integrity and ciliary microtubule architecture - PMC
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: >-
        Together, these data indicate that reduced GliR function, rather than ectopic Shh pathway activation,
        is likely to underlie preaxial polydactyly
      explanation: >-
        The mouse limb experiment implicates altered GLI repressor function; extension to human polydactyly
        remains indirect.
      quote_role: PRIMARY_RESULT
  conforms_to: ciliopathy_dysfunction#Impaired Hedgehog Signal Transduction
  biological_processes:
  - preferred_term: smoothened signaling pathway
    term:
      id: GO:0007224
      label: smoothened signaling pathway
    modifier: DYSREGULATED
- name: Motile Cilia Beat Dysfunction
  description: >-
    Algal and zebrafish TTC26/DYF13 perturbations impair motility-related cargo and ciliary beating. The direction
    of beat-frequency change depends on the tissue: zebrafish Kupffer vesicle cilia beat more slowly, whereas
    pronephric cilia show faster but poorly coordinated beating. A contribution to human hydrocephalus is plausible
    but unproven; aqueductal obstruction is also documented clinically.
  biological_scale: CELLULAR
  evidence:
  - reference: PMID:24596149
    reference_title: TTC26/DYF13 is an intraflagellar transport protein required for transport of motility-related proteins into flagella.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      Knockdown of TTC26/DYF13 in zebrafish embryos or mutation of TTC26/DYF13 in C. reinhardtii, produced
      short cilia with abnormal motility.
    explanation: >-
      Motility dysfunction is demonstrated in experimental organisms, not directly measured in BRENS ependymal
      cells.
    quote_role: PRIMARY_RESULT
  - reference: PMID:24596149
    reference_title: TTC26/DYF13 is an intraflagellar transport protein required for transport of motility-related proteins into flagella.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      Components of outer dynein arms were present at normal levels in dyf13 mutant flagella
    explanation: >-
      The experimental study found selective defects rather than depletion of every motility structure.
    quote_role: PRIMARY_RESULT
  - reference: PMID:22718903
    reference_title: Knockdown of ttc26 disrupts ciliogenesis of the photoreceptor cells and the pronephros in zebrafish.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      Control cilia bundles beat coordinately, but the cilia beat rate in ttc26 morphants (B and C) is increased
      and out of phase, resulting in loss of coordination.
    explanation: >-
      The pronephric measurements support abnormal coordination, not a uniform reduction in beat rate.
    quote_role: PRIMARY_RESULT
  downstream:
  - target: Hydrocephalus
    description: >-
      Ependymal dysmotility is a candidate route inferred from general ciliopathy physiology; it has not been
      demonstrated as the cause in TTC26 patients.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34177428
      reference_title: "Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        The proper movement of cilia helps in the flow of cerebrospinal fluid, and the
        disruption of proper movement (beating) by irregular planar cell polarity causes the
        accumulation of cerebrospinal fluid resulting in hydrocephalus
      explanation: >-
        States the ependymal-cilia route to hydrocephalus. Graded INDIRECT because the source
        states the general ciliopathy mechanism as background rather than demonstrating it
        for TTC26.
      quote_role: BACKGROUND
    hypothesis_groups:
    - MOTILE_CILIA_HYDROCEPHALUS
  mechanism_confidence: HYPOTHETICAL
  biological_processes:
  - preferred_term: cilium movement
    term:
      id: GO:0003341
      label: cilium movement
    modifier: ABNORMAL
- name: Intrahepatic biliary structural abnormalities
  description: >-
    Human observations include intrahepatic duct dilatation and ductopenia with cholestasis. Embryonic mouse
    Ttc26 expression suggests a developmental role, but expression alone does not prove disrupted ductal-plate
    remodeling or an exclusively Hedgehog-dependent lesion. The relative contributions of structural biliary
    disease and associated endocrine dysfunction remain incompletely defined.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:34177428
    reference_title: Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Liver biopsy demonstrated zone 3 cholestasis with ductopenia and mild ductular reaction.
    explanation: >-
      Human histology documents ductopenia and cholestasis, without establishing a universal ductal-plate mechanism.
    quote_role: PRIMARY_RESULT
  - reference: PMID:31595528
    reference_title: "Biallelic Mutations in Tetratricopeptide Repeat Domain 26 (Intraflagellar Transport 56) Cause Severe Biliary Ciliopathy in Humans."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: >-
      We also demonstrate a strong expression of Ttc26 in the embryonic mouse liver in a
      pattern consistent with its proposed role in the normal development of the
      intrahepatic biliary system.
    explanation: >-
      Supports the developmental reading of the hepatic phenotype. Graded INDIRECT because
      the evidence is an expression pattern in mouse embryo, from which the developmental
      role is inferred rather than demonstrated, and the authors say "consistent with" and
      "proposed" rather than asserting it.
    quote_role: PRIMARY_RESULT
  downstream:
  - target: Cholestasis
    description: >-
      Abnormal bile-duct architecture is a plausible contributor to impaired bile flow, but the biopsy alone
      does not separate it from other contributors.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34177428
      reference_title: Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        Liver biopsy demonstrated zone 3 cholestasis with ductopenia and mild ductular reaction.
      explanation: >-
        Human histology documents ductopenia and cholestasis, without establishing a universal ductal-plate
        mechanism.
      quote_role: PRIMARY_RESULT
  - target: Cystic dilatation of intrahepatic bile ducts
    description: >-
      This structural finding is an observed manifestation of the organ abnormality.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34177428
      reference_title: Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: >-
        ultrasound of the abdomen showed persistent cystic dilatation of the intrahepatic biliary ducts, which
        was suspected to be Caroli disease.
      explanation: >-
        The case report documents this finding; no population frequency is inferred.
      quote_role: PRIMARY_RESULT
  locations:
  - preferred_term: intrahepatic bile duct
    term:
      id: UBERON:0003704
      label: intrahepatic bile duct
  cell_types:
  - preferred_term: cholangiocyte
    term:
      id: CL:1000488
      label: cholangiocyte
- name: Pituitary malformation
  description: >-
    Pituitary stalk interruption and pituitary hypoplasia are reported manifestations of TTC26-related ciliopathy.
    Structural abnormalities can be associated with deficient anterior or posterior pituitary function; the
    precise ciliary developmental steps have not been demonstrated in patient pituitary tissue.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:32617964
    reference_title: Pituitary stalk interruption syndrome broadens the clinical spectrum of the TTC26 ciliopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      We now describe four patients with TTC26 ciliopathy due to a homozygous c.695A>G p.Asn232Ser mutation
      and delineate PSIS as a novel clinical feature of this disorder, highlighting an important role of TTC26
      in pituitary development.
    explanation: >-
      This clinical series links the gene-associated disorder to a pituitary developmental phenotype.
    quote_role: PRIMARY_RESULT
  downstream:
  - target: Interrupted pituitary stalk
    description: >-
      Pituitary stalk interruption is the structural manifestation identified in the series.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32617964
      reference_title: Pituitary stalk interruption syndrome broadens the clinical spectrum of the TTC26 ciliopathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: >-
        We now describe four patients with TTC26 ciliopathy due to a homozygous c.695A>G p.Asn232Ser mutation
        and delineate PSIS as a novel clinical feature of this disorder, highlighting an important role of
        TTC26 in pituitary development.
      explanation: >-
        This clinical series links the gene-associated disorder to a pituitary developmental phenotype.
      quote_role: PRIMARY_RESULT
  - target: Hypopituitarism
    description: >-
      Hormone deficits can accompany structural pituitary disease.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38135897
      reference_title: 'A novel TTC26 variant in a patient with hexadactyly, pituitary stalk interruption, hepatopathy, nephropathy, and bilateral lip-palate cleft: A case report and expansion of the phenotype.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        a patient showing some of the known TTC26-associated features like hexadactyly, hypopituitarism, hepatopathy,
        nephropathy, and congenital heart defect
      explanation: >-
        The reported case supports this manifestation; no population frequency is inferred.
      quote_role: PRIMARY_RESULT
  - target: Diabetes insipidus
    description: >-
      Posterior pituitary dysfunction can produce deficient antidiuretic signaling.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34177428
      reference_title: "Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        From an endocrine point of view, she had diabetes insipidus, which was treated with
        desmopressin.
      explanation: >-
        Documents diabetes insipidus and the treatment it received.
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
  - target: Pituitary hypoplasia
    description: >-
      This structural finding is an observed manifestation of the organ abnormality.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34177428
      reference_title: Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: >-
        Brain MRI showed pituitary hypoplasia.
      explanation: >-
        The case report documents this finding; no population frequency is inferred.
      quote_role: PRIMARY_RESULT
  locations:
  - preferred_term: pituitary gland
    term:
      id: UBERON:0000007
      label: pituitary gland
phenotypes:
- category: Hepatic
  name: Cholestasis
  description: >-
    Severe neonatal intrahepatic cholestasis occurred in the defining cohort and could be lethal or require
    transplantation. A later patient had no biliary involvement. The published cohorts have different ascertainment
    and do not justify a pooled population frequency.
  phenotype_term:
    preferred_term: Intrahepatic cholestasis
    term:
      id: HP:0001406
      label: Intrahepatic cholestasis
  evidence:
  - reference: PMID:31595528
    reference_title: "Biallelic Mutations in Tetratricopeptide Repeat Domain 26 (Intraflagellar Transport 56) Cause Severe Biliary Ciliopathy in Humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      severe neonatal cholestasis (lethal in one and necessitating liver transplant in two)
    explanation: >-
      Documents the cholestatic phenotype and its severity distribution across the cohort.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:39514123
    reference_title: "Biliary, Renal, Neurological, and Skeletal syndrome in a Chinese boy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is the first description of BRENS syndrome without biliary involvement.
    explanation: >-
      The biliary-sparing case supports the stated variability and excludes an obligate-cholestasis definition.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- category: Skeletal
  name: Polydactyly
  description: >
    Supernumerary digits, the classic skeletal manifestation of impaired ciliary Hedgehog
    signalling in limb-bud patterning.
  phenotype_term:
    preferred_term: Polydactyly
    term:
      id: HP:0010442
      label: Polydactyly
  evidence:
  - reference: PMID:32617964
    reference_title: "Pituitary stalk interruption syndrome broadens the clinical spectrum of the TTC26 ciliopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      in the context of a syndrome of polydactyly and severe neonatal cholestasis
    explanation: >-
      Documents polydactyly as part of the established syndrome. Marked BACKGROUND because
      this paper is restating the prior description rather than reporting the finding.
    directness: DIRECT
  - reference: PMID:34177428
    reference_title: Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      polydactyly in the upper limbs, and syndactyly in the lower limbs
    explanation: >-
      Direct observation of upper-limb polydactyly in the 2021 patient.
    quote_role: PRIMARY_RESULT
- category: Renal
  name: Unilateral renal hypoplasia
  description: >-
    A small echogenic right kidney with preserved function was documented in the 2021 case. Other reports describe
    renal involvement, but an unspecified nephropathy does not by itself establish renal cysts.
  phenotype_term:
    preferred_term: Unilateral renal hypoplasia
    term:
      id: HP:0012583
      label: Unilateral renal hypoplasia
  evidence:
  - reference: PMID:34177428
    reference_title: Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Moreover, her right kidney was small and echogenic with normal function.
    explanation: >-
      The clinical report supports unilateral renal hypoplasia without implying renal failure or cysts.
    quote_role: PRIMARY_RESULT
- category: Endocrine
  name: Interrupted pituitary stalk
  description: >-
    Pituitary stalk interruption syndrome was identified by characteristic MRI findings in a four-patient series
    with homozygous TTC26 variants. Pituitary involvement also appears in later cases.
  phenotype_term:
    preferred_term: Interrupted pituitary stalk
    term:
      id: HP:0034978
      label: Interrupted pituitary stalk
  evidence:
  - reference: PMID:32617964
    reference_title: "Pituitary stalk interruption syndrome broadens the clinical spectrum of the TTC26 ciliopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      delineate PSIS as a novel clinical feature of this disorder, highlighting an important
      role of TTC26 in pituitary development
    explanation: >-
      Establishes pituitary stalk interruption as a feature of this disorder and the
      developmental inference the authors draw from it.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- category: Neurological
  name: Hydrocephalus
  description: >-
    Supratentorial hydrocephalus associated with aqueductal stenosis required shunting in the 2021 case. Its
    mechanism in patients has not been shown to be exclusively ependymal ciliary dysmotility.
  phenotype_term:
    preferred_term: Hydrocephalus
    term:
      id: HP:0000238
      label: Hydrocephalus
  evidence:
  - reference: PMID:34177428
    reference_title: "Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The proband exhibited features such as cholestasis, cystic dilatation of intrahepatic
      biliary ducts, diabetes insipidus, dysmorphic facial features, optic atrophy, pituitary
      hypoplasia, hydrocephalus, aqueductal stenosis, hyperextensible knee joints, bilateral
      knee dislocation, polydactyly, and syndactyly.
    explanation: >-
      Documents hydrocephalus among the proband's features in the paper that coined the
      syndrome name.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- category: Neurological
  name: Aqueductal stenosis
  description: >
    Narrowing of the cerebral aqueduct, observed alongside the hydrocephalus and contributing
    to it obstructively.
  phenotype_term:
    preferred_term: Aqueductal stenosis
    term:
      id: HP:0002410
      label: Aqueductal stenosis
  evidence:
  - reference: PMID:34177428
    reference_title: "Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additionally, supratentorial hydrocephalus and aqueductal stenosis were observed, and
      ventriculoperitoneal shunt insertion was performed to manage them.
    explanation: >-
      Documents aqueductal stenosis together with the hydrocephalus and the intervention it
      required.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  sequelae:
  - target: Hydrocephalus
    description: >-
      Aqueductal narrowing obstructs cerebrospinal fluid passage. The case report documents stenosis with supratentorial
      hydrocephalus requiring shunting.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34177428
      reference_title: "Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Additionally, supratentorial hydrocephalus and aqueductal stenosis were observed, and
        ventriculoperitoneal shunt insertion was performed to manage them.
      explanation: >-
        Documents aqueductal stenosis together with the hydrocephalus and the intervention it
        required.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
- category: Cardiovascular
  name: Primum atrial septal defect
  description: >-
    A large primum atrial septal defect was documented in the 2021 patient; an accompanying patent ductus arteriosus
    later closed spontaneously. Cardiac involvement varies between cases.
  phenotype_term:
    preferred_term: Primum atrial septal defect
    term:
      id: HP:0010445
      label: Primum atrial septal defect
  evidence:
  - reference: PMID:34177428
    reference_title: Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Echocardiography was performed immediately, and it showed a large primum atrial septal defect with a
      left-to-right shunt and patent ductus arteriosus that closed spontaneously later on.
    explanation: >-
      This is a specific human cardiac finding, rather than a broad organ-level label.
    quote_role: PRIMARY_RESULT
- category: Endocrine
  name: Diabetes insipidus
  description: >-
    Diabetes insipidus accompanied pituitary hypoplasia in the 2021 case and was treated with desmopressin.
    The report does not quantify the treatment response.
  phenotype_term:
    preferred_term: Diabetes insipidus
    term:
      id: HP:0000873
      label: Diabetes insipidus
  evidence:
  - reference: PMID:34177428
    reference_title: "Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      From an endocrine point of view, she had diabetes insipidus, which was treated with
      desmopressin.
    explanation: >-
      Documents diabetes insipidus and the treatment it received.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- category: Ophthalmological
  name: Optic atrophy
  description: >-
    Optic atrophy was reported in the abstract and discussion of the 2021 case. Experimental photoreceptor
    outer-segment abnormalities do not establish the mechanism of optic nerve atrophy in patients.
  phenotype_term:
    preferred_term: Optic atrophy
    term:
      id: HP:0000648
      label: Optic atrophy
  evidence:
  - reference: PMID:34177428
    reference_title: "Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The proband exhibited features such as cholestasis, cystic dilatation of intrahepatic
      biliary ducts, diabetes insipidus, dysmorphic facial features, optic atrophy, pituitary
      hypoplasia, hydrocephalus, aqueductal stenosis, hyperextensible knee joints, bilateral
      knee dislocation, polydactyly, and syndactyly.
    explanation: >-
      Documents optic atrophy among the proband's features.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- category: Neurological
  name: Global developmental delay
  description: >
    Developmental delay with axial hypotonia in the proband, alongside the hydrocephalus.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:34177428
    reference_title: "Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neurologically, she had global developmental delay and axial hypotonia.
    explanation: >-
      Documents developmental delay and axial hypotonia in the proband.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Hypopituitarism
  description: >-
    Pituitary hormone deficiency has been reported with TTC26-related pituitary malformation. The particular
    deficient axes require clinical assessment.
  phenotype_term:
    preferred_term: Hypopituitarism
    term:
      id: HP:0040075
      label: Hypopituitarism
  evidence:
  - reference: PMID:38135897
    reference_title: 'A novel TTC26 variant in a patient with hexadactyly, pituitary stalk interruption, hepatopathy, nephropathy, and bilateral lip-palate cleft: A case report and expansion of the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      a patient showing some of the known TTC26-associated features like hexadactyly, hypopituitarism, hepatopathy,
      nephropathy, and congenital heart defect
    explanation: >-
      The reported case supports this manifestation; no population frequency is inferred.
    quote_role: PRIMARY_RESULT
- name: Syndactyly
  description: >-
    Lower-limb syndactyly was documented in the 2021 case, alongside upper-limb polydactyly.
  phenotype_term:
    preferred_term: Syndactyly
    term:
      id: HP:0001159
      label: Syndactyly
  evidence:
  - reference: PMID:34177428
    reference_title: Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      polydactyly in the upper limbs, and syndactyly in the lower limbs
    explanation: >-
      The reported case supports this manifestation; no population frequency is inferred.
    quote_role: PRIMARY_RESULT
- name: Congenital knee dislocation
  description: >-
    Bilateral congenital knee dislocation associated with joint hyperextensibility improved after serial casting
    in one patient.
  phenotype_term:
    preferred_term: Congenital knee dislocation
    term:
      id: HP:0005191
      label: Congenital knee dislocation
  evidence:
  - reference: PMID:34177428
    reference_title: Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      she had hyperextensible joints, specifically congenital bilateral knee dislocation (more toward right
      than left), which improved after serial knee casting.
    explanation: >-
      The reported case supports this manifestation; no population frequency is inferred.
    quote_role: PRIMARY_RESULT
- name: Axial hypotonia
  description: >-
    Axial hypotonia accompanied severe developmental delay in the 2021 patient.
  phenotype_term:
    preferred_term: Axial hypotonia
    term:
      id: HP:0008936
      label: Axial hypotonia
  evidence:
  - reference: PMID:34177428
    reference_title: Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Neurologically, she had global developmental delay and axial hypotonia.
    explanation: >-
      The reported case supports this manifestation; no population frequency is inferred.
    quote_role: PRIMARY_RESULT
- name: Failure to thrive
  description: >-
    Failure to thrive was observed in early infancy in a severely affected patient.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:34177428
    reference_title: Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Failure to thrive was observed with severe global developmental delay at 3 months of age and axial hypotonia.
    explanation: >-
      The reported case supports this manifestation; no population frequency is inferred.
    quote_role: PRIMARY_RESULT
- name: Gastroesophageal reflux
  description: >-
    Severe reflux with recurrent aspiration-related respiratory illness was reported in one patient and required
    surgical management.
  phenotype_term:
    preferred_term: Gastroesophageal reflux
    term:
      id: HP:0002020
      label: Gastroesophageal reflux
  evidence:
  - reference: PMID:34177428
    reference_title: Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      She was discharged and subsequently admitted multiple times with recurrent respiratory infections, aspiration
      pneumonia, and severe gastroesophageal reflux.
    explanation: >-
      The reported case supports this manifestation; no population frequency is inferred.
    quote_role: PRIMARY_RESULT
- name: Bilateral cleft lip
  description: >-
    Bilateral lip clefts with cleft palate expanded the reported phenotype in the 2024 case.
  phenotype_term:
    preferred_term: Bilateral cleft lip
    term:
      id: HP:0100336
      label: Bilateral cleft lip
  evidence:
  - reference: PMID:38135897
    reference_title: 'A novel TTC26 variant in a patient with hexadactyly, pituitary stalk interruption, hepatopathy, nephropathy, and bilateral lip-palate cleft: A case report and expansion of the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Moreover, he presented with a suspected unilateral hearing loss and bilateral cleft lip-palate.
    explanation: >-
      The reported case supports this manifestation; no population frequency is inferred.
    quote_role: PRIMARY_RESULT
- name: Cleft palate
  description: >-
    Cleft palate accompanied bilateral cleft lip in one reported patient.
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  evidence:
  - reference: PMID:38135897
    reference_title: 'A novel TTC26 variant in a patient with hexadactyly, pituitary stalk interruption, hepatopathy, nephropathy, and bilateral lip-palate cleft: A case report and expansion of the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Moreover, he presented with a suspected unilateral hearing loss and bilateral cleft lip-palate.
    explanation: >-
      The reported case supports this manifestation; no population frequency is inferred.
    quote_role: PRIMARY_RESULT
- name: Suspected unilateral hearing impairment
  description: >-
    Unilateral hearing impairment was suspected in one patient; further confirmation was unavailable before
    death. Its inclusion in the syndrome remains provisional.
  phenotype_term:
    preferred_term: Suspected unilateral hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:38135897
    reference_title: 'A novel TTC26 variant in a patient with hexadactyly, pituitary stalk interruption, hepatopathy, nephropathy, and bilateral lip-palate cleft: A case report and expansion of the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Moreover, he presented with a suspected unilateral hearing loss and bilateral cleft lip-palate.
    explanation: >-
      The reported case supports this manifestation; no population frequency is inferred.
    quote_role: PRIMARY_RESULT
- name: Pituitary hypoplasia
  description: >-
    A small pituitary gland was observed on brain MRI in the 2021 patient.
  phenotype_term:
    preferred_term: Small pituitary gland
    term:
      id: HP:0012506
      label: Small pituitary gland
  evidence:
  - reference: PMID:34177428
    reference_title: Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Brain MRI showed pituitary hypoplasia.
    explanation: >-
      The case report documents this finding; no population frequency is inferred.
    quote_role: PRIMARY_RESULT
  category: Endocrine
- name: Cystic dilatation of intrahepatic bile ducts
  description: >-
    Persistent cystic dilatation of the intrahepatic bile ducts was seen on ultrasound in the 2021 patient;
    Caroli disease was suspected.
  phenotype_term:
    preferred_term: Intrahepatic bile duct dilatation
    term:
      id: HP:0033149
      label: Intrahepatic bile duct dilatation
  evidence:
  - reference: PMID:34177428
    reference_title: Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      ultrasound of the abdomen showed persistent cystic dilatation of the intrahepatic biliary ducts, which
      was suspected to be Caroli disease.
    explanation: >-
      The case report documents this finding; no population frequency is inferred.
    quote_role: PRIMARY_RESULT
  category: Hepatic
- name: Deep-set eyes
  description: >-
    Deep-set eyes were documented in the 2021 patient.
  phenotype_term:
    preferred_term: Deeply set eye
    term:
      id: HP:0000490
      label: Deeply set eye
  evidence:
  - reference: PMID:34177428
    reference_title: Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Affected individual (II-2) presenting dysmorphic features in the form of deep-set eyes, low-set ears,
      frontal bossing, and hypermobile and extensible joints.
    explanation: >-
      The case report documents this finding; no population frequency is inferred.
    quote_role: PRIMARY_RESULT
  category: Craniofacial
- name: Low-set ears
  description: >-
    Low-set ears were documented in the 2021 patient.
  phenotype_term:
    preferred_term: Low-set ears
    term:
      id: HP:0000369
      label: Low-set ears
  evidence:
  - reference: PMID:34177428
    reference_title: Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Affected individual (II-2) presenting dysmorphic features in the form of deep-set eyes, low-set ears,
      frontal bossing, and hypermobile and extensible joints.
    explanation: >-
      The case report documents this finding; no population frequency is inferred.
    quote_role: PRIMARY_RESULT
  category: Craniofacial
- name: Frontal bossing
  description: >-
    Frontal bossing was documented in the 2021 patient.
  phenotype_term:
    preferred_term: Frontal bossing
    term:
      id: HP:0002007
      label: Frontal bossing
  evidence:
  - reference: PMID:34177428
    reference_title: Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Affected individual (II-2) presenting dysmorphic features in the form of deep-set eyes, low-set ears,
      frontal bossing, and hypermobile and extensible joints.
    explanation: >-
      The case report documents this finding; no population frequency is inferred.
    quote_role: PRIMARY_RESULT
  category: Craniofacial
- name: Renal abnormality, unspecified
  description: >-
    Nephropathy was reported in the 2024 case without an anatomical subtype in the abstract. This finding does
    not establish renal cysts or duplicate the separately documented hypoplastic kidney in another patient.
  phenotype_term:
    preferred_term: Abnormality of the kidney
    term:
      id: HP:0000077
      label: Abnormality of the kidney
    coarse_binding_basis: SOURCE_UNSPECIFIED
  evidence:
  - reference: PMID:38135897
    reference_title: 'A novel TTC26 variant in a patient with hexadactyly, pituitary stalk interruption, hepatopathy, nephropathy, and bilateral lip-palate cleft: A case report and expansion of the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Here, we report on a previously undescribed homozygous intronic TTC26 variant (c.1006-5 T > C) in a patient
      showing some of the known TTC26-associated features like hexadactyly, hypopituitarism, hepatopathy, nephropathy,
      and congenital heart defect.
    explanation: >-
      The case report documents this finding; no population frequency is inferred.
    quote_role: PRIMARY_RESULT
  category: Renal
diagnosis:
- name: Molecular diagnosis by exome or genome sequencing
  description: >-
    Exome or genome sequencing with segregation analysis can establish biallelic TTC26/IFT56 variants in a
    compatible multisystem phenotype. RNA analysis can help assess splice variants; reduced transcript abundance
    alone is distinct from demonstrating a particular splicing product. Severe neonatal cholestasis can prompt
    consideration of ciliopathy even without the usual associated features.
  evidence:
  - reference: PMID:34177428
    reference_title: Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Whole-genome sequencing and Sanger sequencing revealed a homozygous splice site variant (c.4-1G>C; NM_024926.3)
      in the tetratricopeptide repeat domain 26 (TTC26) gene located in chromosome 7q34, which cosegregated
      perfectly with the disease phenotype.
    explanation: >-
      This documents sequencing and segregation in a molecularly diagnosed patient.
    quote_role: PRIMARY_RESULT
  - reference: PMID:31595528
    reference_title: Biallelic Mutations in Tetratricopeptide Repeat Domain 26 (Intraflagellar Transport 56) Cause Severe Biliary Ciliopathy in Humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      our results highlight the importance of considering ciliopathies in the differential diagnosis of severe
      neonatal cholestasis even in the absence of more typical features.
    explanation: >-
      The defining study supports the diagnostic scope.
    quote_role: PRIMARY_RESULT
- name: Hepatobiliary imaging and histology
  description: >-
    Ultrasound can characterize intrahepatic duct abnormalities. The 2021 patient had cystic intrahepatic duct
    dilatation, initially suspected to be Caroli disease, and biopsy showed cholestasis with ductopenia and
    mild ductular reaction. These findings document hepatobiliary involvement but do not establish a universal
    ductal-plate malformation or a complete developmental mechanism.
  evidence:
  - reference: PMID:34177428
    reference_title: "Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Liver biopsy demonstrated zone 3 cholestasis with ductopenia and mild ductular reaction.
    explanation: >-
      Gives the histological findings on which the hepatic diagnosis rests.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Brain MRI for pituitary and ventricular involvement
  description: >-
    Brain MRI characterizes pituitary stalk interruption, pituitary size and ventricular abnormalities such
    as hydrocephalus and aqueductal stenosis. These findings guide assessment of endocrine and neurologic complications
    but are not specific to TTC26 disease.
  evidence:
  - reference: PMID:32617964
    reference_title: "Pituitary stalk interruption syndrome broadens the clinical spectrum of the TTC26 ciliopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pituitary stalk interruption syndrome (PSIS) is a congenital anomaly of the pituitary
      gland, diagnosed by characteristic MRI findings.
    explanation: >-
      Establishes MRI as the diagnostic modality for the pituitary component.
    quote_role: BACKGROUND
    directness: DIRECT
- name: Endocrine and renal assessment
  description: >-
    Pituitary abnormalities warrant assessment of anterior and posterior pituitary function. Renal imaging
    and function studies characterize the variable renal phenotype; abnormal kidney morphology does not necessarily
    imply impaired function.
  evidence:
  - reference: PMID:38135897
    reference_title: 'A novel TTC26 variant in a patient with hexadactyly, pituitary stalk interruption, hepatopathy, nephropathy, and bilateral lip-palate cleft: A case report and expansion of the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      a patient showing some of the known TTC26-associated features like hexadactyly, hypopituitarism, hepatopathy,
      nephropathy, and congenital heart defect
    explanation: >-
      The reported case supports this manifestation; no population frequency is inferred.
    quote_role: PRIMARY_RESULT
  - reference: PMID:34177428
    reference_title: Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Moreover, her right kidney was small and echogenic with normal function.
    explanation: >-
      The clinical report supports unilateral renal hypoplasia without implying renal failure or cysts.
    quote_role: PRIMARY_RESULT
treatments:
- name: Ursodiol for Cholestasis
  description: >-
    Ursodeoxycholic acid was used for cholestasis in the 2021 patient without observed improvement. This single-case
    response does not establish general inefficacy or demonstrate that bile ducts never formed.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ursodeoxycholic acid
      term:
        id: CHEBI:9907
        label: ursodeoxycholic acid
  target_mechanisms:
  - target: Cholestasis
    description: >-
      Intended to ameliorate cholestasis; benefit was not observed in the cited case.
  evidence:
  - reference: PMID:34177428
    reference_title: "Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient was administered ursodiol 28 mg b.i.d.; however, no improvement was
      observed.
    explanation: >-
      Supports the stated lack of observed benefit in this patient, without a syndrome-wide efficacy conclusion.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Desmopressin for Diabetes Insipidus
  description: >-
    Desmopressin was administered for diabetes insipidus in the 2021 patient. This replaces deficient antidiuretic
    signaling; the report documents use but does not quantify efficacy.
  therapeutic_modality: PEPTIDE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: desmopressin
      term:
        id: CHEBI:4450
        label: desmopressin
  target_mechanisms:
  - target: Diabetes insipidus
    description: >-
      Replaces deficient antidiuretic signaling in central diabetes insipidus.
  evidence:
  - reference: PMID:34177428
    reference_title: "Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      she had diabetes insipidus, which was treated with desmopressin
    explanation: >-
      Documents desmopressin use for the endocrine component.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Ventriculoperitoneal Shunt
  description: >-
    Cerebrospinal fluid diversion was performed for supratentorial hydrocephalus with aqueductal stenosis in
    one patient. It treats that complication, without correcting the underlying ciliopathy or all neurologic
    manifestations.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Ventriculoperitoneal Shunt Placement
    term:
      id: NCIT:C168483
      label: Ventriculoperitoneal Shunt Placement
  target_mechanisms:
  - target: Hydrocephalus
    description: >-
      Diverts cerebrospinal fluid in hydrocephalus with aqueductal obstruction; ependymal dysmotility was not
      demonstrated in this patient.
  evidence:
  - reference: PMID:34177428
    reference_title: "Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      supratentorial hydrocephalus and aqueductal stenosis were observed, and
      ventriculoperitoneal shunt insertion was performed to manage them
    explanation: >-
      Documents the shunt and the indication for it.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Serial Knee Casting for Congenital Knee Dislocation
  description: >-
    Serial knee casting improved bilateral congenital knee dislocation in one reported patient.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: serial orthopedic knee casting
  evidence:
  - reference: PMID:34177428
    reference_title: "Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      congenital bilateral knee dislocation (more toward right than left), which improved
      after serial knee casting
    explanation: >-
      Documents the intervention and its outcome.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  target_phenotypes:
  - preferred_term: Congenital knee dislocation
    term:
      id: HP:0005191
      label: Congenital knee dislocation
  notes: >-
    Needs a specific clinical-intervention term for serial orthopedic casting; the general NCIT immobilization
    term denotes physical restraint.
- name: Liver transplantation
  description: >-
    Two of seven patients in the defining cohort required liver transplantation for severe neonatal cholestatic
    disease. Transplantation addresses hepatic disease but does not correct extrahepatic TTC26-related abnormalities.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Liver Transplantation
    term:
      id: NCIT:C15271
      label: Liver Transplantation
  target_phenotypes:
  - preferred_term: Intrahepatic cholestasis
    term:
      id: HP:0001406
      label: Intrahepatic cholestasis
  evidence:
  - reference: PMID:31595528
    reference_title: Biallelic Mutations in Tetratricopeptide Repeat Domain 26 (Intraflagellar Transport 56) Cause Severe Biliary Ciliopathy in Humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      including severe neonatal cholestasis (lethal in one and necessitating liver transplant in two)
    explanation: >-
      The defining cohort documents transplant use; it does not provide comparative survival efficacy.
    quote_role: PRIMARY_RESULT
- name: Replacement of deficient pituitary hormones
  description: >-
    Documented pituitary hormone deficits require axis-specific replacement and endocrine follow-up. Hydrocortisone,
    levothyroxine and growth hormone are replacement options for the corresponding deficiencies in PSIS care.
    The cited general PSIS treatment report is indirect evidence for management, not a TTC26-specific efficacy
    study or an additional BRENS patient.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Replacement Therapy
    term:
      id: NCIT:C15471
      label: Replacement Therapy
  target_phenotypes:
  - preferred_term: Hypopituitarism
    term:
      id: HP:0040075
      label: Hypopituitarism
  evidence:
  - reference: PMID:42460215
    reference_title: 'Diagnosis of Pituitary Stalk Interruption Syndrome in a Newborn Presenting With Recurrent Hypoglycemia: A Rare Case Report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      Hormonal replacement therapy with hydrocortisone, levothyroxine, and growth hormone led to clinical stabilization.
    explanation: >-
      This non-TTC26 PSIS case illustrates replacement of deficient axes. The application to BRENS-associated
      hypopituitarism is indirect.
    quote_role: PRIMARY_RESULT
  - reference: PMID:38135897
    reference_title: 'A novel TTC26 variant in a patient with hexadactyly, pituitary stalk interruption, hepatopathy, nephropathy, and bilateral lip-palate cleft: A case report and expansion of the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      a patient showing some of the known TTC26-associated features like hexadactyly, hypopituitarism, hepatopathy,
      nephropathy, and congenital heart defect
    explanation: >-
      This case establishes hypopituitarism as the indication for replacement. Its replacement regimen is not
      quoted here; the preceding general PSIS report supports treatment practice indirectly.
    quote_role: PRIMARY_RESULT
- name: Fundoplication for severe reflux
  description: >-
    Fundoplication with gastrostomy placement was used for severe gastroesophageal reflux in the 2021 case.
    No syndrome-wide treatment response rate is available.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Fundoplication
    term:
      id: NCIT:C91834
      label: Fundoplication
  target_phenotypes:
  - preferred_term: Gastroesophageal reflux
    term:
      id: HP:0002020
      label: Gastroesophageal reflux
  evidence:
  - reference: PMID:34177428
    reference_title: Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Gastrostomy insertion with fundoplication was performed to manage the gastroesophageal reflux.
    explanation: >-
      Documents the indication and intervention in one patient.
    quote_role: PRIMARY_RESULT
- name: Gastrostomy placement
  description: >-
    Gastrostomy placement accompanied fundoplication in the patient with severe reflux and feeding-related
    morbidity.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Gastrostomy
    term:
      id: NCIT:C52006
      label: Gastrostomy
  evidence:
  - reference: PMID:34177428
    reference_title: Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Gastrostomy insertion with fundoplication was performed to manage the gastroesophageal reflux.
    explanation: >-
      Documents gastrostomy placement without assuming a specific insertion technique.
    quote_role: PRIMARY_RESULT
animal_models:
- name: Ift56hop homozygous mouse
  species: Mouse
  genotype: Ift56hop (Ttc26) homozygous loss-of-function
  publication: PMID:41352382
  description: >-
    The homozygous Ift56hop premature-stop allele produces markedly different phenotypes on BALB/cByJ and C57BL/6J
    backgrounds. Adult survivors with sterility and a hopping gait occur on BALB/cByJ, while C57BL/6J homozygotes
    are perinatally lethal with multiple malformations. A chromosome 4 modifier locus was mapped; the causal
    modifier gene and its relevance to human patients are unresolved.
  modeled_mechanisms:
  - target: TTC26 functional impairment
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Models reduced IFT56 function and background-dependent developmental outcomes. These experiments establish
      modifier effects in mice without identifying a human modifier architecture.
    limitations: >-
      Severity and organ involvement depend on allele and strain. The 2014 study found normal kidney and retinal
      histology in examined adult hop mice, whereas human patients can have renal and ocular abnormalities.
      Severe neonatal cholestasis is not established as a recapitulated endpoint in the cited model reports.
      Mouse background effects cannot predict individual human severity.
    divergences:
    - divergence_type: POPULATION_MISMATCH
      materiality: QUALIFYING
      description: >-
        Inbred strain backgrounds differ at many loci. Mapping identifies a chromosome 4 modifier interval
        but does not show that this is the sole difference between strains or that the same locus modifies
        human BRENS.
    - divergence_type: OTHER
      materiality: QUALIFYING
      description: >-
        The cited mouse reports do not establish the severe neonatal cholestatic phenotype that is prominent
        in human BRENS.
    evidence:
    - reference: PMID:41352382
      reference_title: "Genetic background influences the extent and severity of cilia-related congenital anomalies in Ift56/Ttc26 mutant mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        we demonstrate that in the C57BL/6J background, Ift56hop homozygotes are perinatal
        lethal, and have multiple skeletal and organ defects, including the formation of
        tracheoesophageal fistulas
      explanation: >-
        Documents the severe-background phenotype, against which the viable Balb/cByJ
        phenotype is the contrast that carries the finding.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
  evidence:
  - reference: PMID:41352382
    reference_title: "Genetic background influences the extent and severity of cilia-related congenital anomalies in Ift56/Ttc26 mutant mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Using Single Nucleotide Polymorphisms (SNPs) that differ between these mouse strains,
      we show that a modifier of the Ift56hop phenotype maps to Chromosome 4.
    explanation: >-
      Maps a modifier locus in mice; it does not identify a human modifier gene or exclude allele-specific
      effects.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Zebrafish ttc26 knockdown and frameshift models
  species: Zebrafish
  publication: PMID:36533556
  description: >-
    Morpholino studies show shortened or disorganized cilia, pronephric dilation and photoreceptor outer-segment
    defects. Later CRISPR experiments confirmed a curved-down-tail phenotype in F1 ttc26 compound-frameshift
    embryos. These perturbations and endpoints differ; a photoreceptor phenotype should not be attributed to
    the later transition-zone screen.
  modeled_mechanisms:
  - target: TTC26 functional impairment
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Tests loss of ttc26 function in development.
    limitations: >-
      Morpholinos, mosaic crispants and germline frameshifts have different limitations. No candidate crispants
      formed cysts by five days in the later screen. Neither study establishes neonatal cholestatic liver disease
      or human optic nerve atrophy.
    evidence:
    - reference: PMID:36533556
      reference_title: Variable phenotypes and penetrance between and within different zebrafish ciliary transition zone mutants.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: >-
        In the four CDT mutants analyzed, all had compound frameshift mutations
      explanation: >-
        The F1 zebrafish experiments confirmed biallelic frameshift genotypes in embryos with curved-down tails.
      quote_role: PRIMARY_RESULT
  evidence:
  - reference: PMID:22718903
    reference_title: Knockdown of ttc26 disrupts ciliogenesis of the photoreceptor cells and the pronephros in zebrafish.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      Morpholino knockdown of ttc26 in zebrafish embryos caused ciliary defects in the pronephric kidney at
      27 h postfertilization and distension/dilation of pronephros at 5 d postfertilization (dpf).
    explanation: >-
      The earlier knockdown study directly documents renal ciliary and morphologic defects.
    quote_role: PRIMARY_RESULT
  - reference: PMID:36533556
    reference_title: Variable phenotypes and penetrance between and within different zebrafish ciliary transition zone mutants.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      In the four CDT mutants analyzed, all had compound frameshift mutations
    explanation: >-
      The F1 zebrafish experiments confirmed biallelic frameshift genotypes in embryos with curved-down tails.
    quote_role: PRIMARY_RESULT
discussions:
- discussion_id: brns_modifier_loci_explain_variability
  kind: HUMAN_MODEL_MISMATCH
  prompt: Do modifier loci alter human BRENS severity as they do in hop mice?
  attaches_to:
  - animal_models#Mouse
  - genetic#TTC26
  rationale: >-
    Strain background substantially changes the mouse phenotype and a modifier interval maps to chromosome
    4. Human cases vary in organ involvement and severity, but current cohorts cannot distinguish allele effects,
    modifiers, ascertainment and treatment. No corresponding human modifier has been demonstrated.
  evidence:
  - reference: PMID:41352382
    reference_title: "Genetic background influences the extent and severity of cilia-related congenital anomalies in Ift56/Ttc26 mutant mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Using Single Nucleotide Polymorphisms (SNPs) that differ between these mouse strains,
      we show that a modifier of the Ift56hop phenotype maps to Chromosome 4.
    explanation: >-
      Maps a modifier locus in mice; it does not identify a human modifier gene or exclude allele-specific
      effects.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- discussion_id: brns_gli_accumulation_contested
  kind: KNOWLEDGE_GAP
  prompt: Which conditions determine whether GLI tip accumulation is impaired in TTC26-deficient cilia?
  attaches_to:
  - pathophysiology#Dysregulated Sonic Hedgehog Signalling
  rationale: >-
    Both hop studies support impaired Hedgehog signaling. They differ in GLI accumulation measurements: preserved
    recruitment with reduced GLI-SUFU dissociation in the 2014 assays, versus reduced recruitment in the 2017
    cellular and embryonic-tissue assays. The later authors explicitly propose differences in stimulation amount
    and duration. These data do not justify choosing one universal cellular block for all human alleles.
  evidence:
  - reference: PMID:25340710
    reference_title: A mutation in the mouse ttc26 gene leads to impaired hedgehog signaling.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      hop did not interfere with Hh-induced accumulation of Gli at the tip of the primary cilium, but rather
      with the subsequent dissociation of Gli from its negative regulator, Sufu
    explanation: >-
      This study locates a defect after GLI recruitment under its experimental conditions.
    quote_role: PRIMARY_RESULT
  - reference: PMID:28264835
    reference_title: IFT56 regulates vertebrate developmental patterning by maintaining IFTB complex integrity and ciliary microtubule architecture.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      We show that Ift56hop cilia are unable to accumulate Gli proteins efficiently, resulting in developmental
      patterning defects in Shh signaling-dependent tissues such as the limb and neural tube.
    explanation: >-
      This study also supports impaired signaling, while locating abnormal GLI accumulation under different
      assays.
    quote_role: PRIMARY_RESULT
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5399663/
    reference_title: IFT56 regulates vertebrate developmental patterning by maintaining IFTB complex integrity and ciliary microtubule architecture - PMC
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: >-
      One possible explanation for this discrepancy is differences in experimental conditions between the studies,
      including amounts and duration of Hh pathway activation.
    explanation: >-
      The later study itself offers experimental conditions as an explanation; this is an interpretation, not
      a demonstrated reconciliation.
    quote_role: PRIMARY_RESULT
- discussion_id: brns_how_cilia_build_the_biliary_tree
  kind: KNOWLEDGE_GAP
  prompt: How does TTC26 dysfunction cause cholestasis and structural biliary disease?
  attaches_to:
  - pathophysiology#Intrahepatic biliary structural abnormalities
  rationale: >-
    Human duct abnormalities and embryonic mouse liver expression support a biliary role. They do not establish
    a sequence from impaired Hedgehog signaling through failed ductal-plate remodeling to cholestasis. Pituitary
    deficiency can coexist, making an exclusively irreversible structural explanation premature. Tissue-specific
    experiments and clinical endocrine-response data are needed to distinguish contributors.
  evidence:
  - reference: PMID:34177428
    reference_title: Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Liver biopsy demonstrated zone 3 cholestasis with ductopenia and mild ductular reaction.
    explanation: >-
      Human histology documents ductopenia and cholestasis, without establishing a universal ductal-plate mechanism.
    quote_role: PRIMARY_RESULT
  - reference: PMID:31595528
    reference_title: "Biallelic Mutations in Tetratricopeptide Repeat Domain 26 (Intraflagellar Transport 56) Cause Severe Biliary Ciliopathy in Humans."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: >-
      We also demonstrate a strong expression of Ttc26 in the embryonic mouse liver in a
      pattern consistent with its proposed role in the normal development of the
      intrahepatic biliary system.
    explanation: >-
      Supports the developmental reading of the hepatic phenotype. Graded INDIRECT because
      the evidence is an expression pattern in mouse embryo, from which the developmental
      role is inferred rather than demonstrated, and the authors say "consistent with" and
      "proposed" rather than asserting it.
    quote_role: PRIMARY_RESULT
- discussion_id: brns_prmt7_candidate_mechanism
  kind: EMERGING_HYPOTHESIS
  prompt: Does altered ciliary PRMT7 localization contribute to Hedgehog dysfunction in biallelic TTC26 disease?
  attaches_to:
  - pathophysiology#Dysregulated Sonic Hedgehog Signalling
  rationale: >-
    An adolescent idiopathic scoliosis study identified TTC26-dependent ciliary PRMT7 localization and GLI2
    methylation in nucleus-pulposus cell experiments. Its mouse model combined heterozygous Flnb and Ttc26
    mutations, rather than biallelic TTC26 disease. Artificially targeting PRMT7 to cilia restored cellular
    signaling, and local Ptch1/Sufu knockdown improved tail-disc matrix endpoints. Transfer to BRENS organs
    remains untested; FLNB is not an established BRENS modifier, and these experiments do not establish a clinical
    therapy.
  evidence:
  - reference: PMID:42178579
    reference_title: FLNB and TTC26 regulate ciliary Hedgehog signaling to maintain intervertebral disc matrix homeostasis in adolescent idiopathic scoliosis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: >-
      We find that TTC26 is required for the localization of protein arginine methyltransferase 7 (PRMT7) to
      the primary cilium, enabling methylation of GLI2, while FLNB binds methylated GLI2 to promote its nuclear
      import.
    explanation: >-
      This cellular mechanism is a candidate for testing in BRENS; the originating study concerns scoliosis.
    quote_role: PRIMARY_RESULT
  - reference: PMID:42178579
    reference_title: FLNB and TTC26 regulate ciliary Hedgehog signaling to maintain intervertebral disc matrix homeostasis in adolescent idiopathic scoliosis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: >-
      First, we only used the tail disc microinjection model to explore the therapeutic effects of ECM metabolism
      on Hh signaling. However, its effect on scoliosis needs to be further investigated.
    explanation: >-
      Even rescue of scoliosis was untested; these model interventions provide no evidence of clinical benefit
      in BRENS.
    quote_role: PRIMARY_RESULT
mechanistic_hypotheses:
- hypothesis_group_id: MOTILE_CILIA_HYDROCEPHALUS
  hypothesis_label: Ependymal ciliary dysmotility contributes to hydrocephalus
  status: ALTERNATIVE
  description: >-
    Motility abnormalities in experimental TTC26 systems and general ependymal physiology support a possible
    route to human hydrocephalus. Human TTC26 ependymal motility has not been measured, and aqueductal stenosis
    provides another documented contributor.
  evidence:
  - reference: PMID:24596149
    reference_title: TTC26/DYF13 is an intraflagellar transport protein required for transport of motility-related proteins into flagella.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      Knockdown of TTC26/DYF13 in zebrafish embryos or mutation of TTC26/DYF13 in C. reinhardtii, produced
      short cilia with abnormal motility.
    explanation: >-
      Motility dysfunction is demonstrated in experimental organisms, not directly measured in BRENS ependymal
      cells.
    quote_role: PRIMARY_RESULT
  - reference: PMID:34177428
    reference_title: "Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      The proper movement of cilia helps in the flow of cerebrospinal fluid, and the
      disruption of proper movement (beating) by irregular planar cell polarity causes the
      accumulation of cerebrospinal fluid resulting in hydrocephalus
    explanation: >-
      States the ependymal-cilia route to hydrocephalus. Graded INDIRECT because the source
      states the general ciliopathy mechanism as background rather than demonstrating it
      for TTC26.
    quote_role: BACKGROUND

📚

References & Deep Research

References

15

PMID:31595528

Biallelic Mutations in Tetratricopeptide Repeat Domain 26 (Intraflagellar Transport 56) Cause Severe Biliary Ciliopathy in Humans.

No top-level findings curated for this source.

PMID:32617964

Pituitary stalk interruption syndrome broadens the clinical spectrum of the TTC26 ciliopathy.

No top-level findings curated for this source.

PMID:41352382

Genetic background influences the extent and severity of cilia-related congenital anomalies in Ift56/Ttc26 mutant mice.

No top-level findings curated for this source.

PMID:25340710

A mutation in the mouse ttc26 gene leads to impaired hedgehog signaling.

No top-level findings curated for this source.

PMID:34177428

Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations.

No top-level findings curated for this source.

PMID:39514123

Biliary, Renal, Neurological, and Skeletal syndrome in a Chinese boy.

No top-level findings curated for this source.

PMID:26980730

Overall Architecture of the Intraflagellar Transport (IFT)-B Complex Containing Cluap1/IFT38 as an Essential Component of the IFT-B Peripheral Subcomplex.

No top-level findings curated for this source.

PMID:28264835

IFT56 regulates vertebrate developmental patterning by maintaining IFTB complex integrity and ciliary microtubule architecture.

No top-level findings curated for this source.

PMID:24596149

TTC26/DYF13 is an intraflagellar transport protein required for transport of motility-related proteins into flagella.

No top-level findings curated for this source.

PMID:38135897

A novel TTC26 variant in a patient with hexadactyly, pituitary stalk interruption, hepatopathy, nephropathy, and bilateral lip-palate cleft: A case report and expansion of the phenotype.

No top-level findings curated for this source.

PMID:22718903

Knockdown of ttc26 disrupts ciliogenesis of the photoreceptor cells and the pronephros in zebrafish.

No top-level findings curated for this source.

PMID:42460215

Diagnosis of Pituitary Stalk Interruption Syndrome in a Newborn Presenting With Recurrent Hypoglycemia: A Rare Case Report.

No top-level findings curated for this source.

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC5399663/

IFT56 regulates vertebrate developmental patterning by maintaining IFTB complex integrity and ciliary microtubule architecture - PMC

No top-level findings curated for this source.

PMID:36533556

Variable phenotypes and penetrance between and within different zebrafish ciliary transition zone mutants.

No top-level findings curated for this source.

PMID:42178579

FLNB and TTC26 regulate ciliary Hedgehog signaling to maintain intervertebral disc matrix homeostasis in adolescent idiopathic scoliosis.

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Biliary_Renal_Neurologic_And_Skeletal_Syndrome · 2026-09-18T18:15:50Z · View source

De novo curation of BRENS / TTC26 ciliopathy (MONDO:0859191) from an openscientist deep-research report plus independent PubMed work. Deep research: just research-disorder openscientist; report committed at research/Biliary_Renal_Neurologic_And_Skeletal_Syndrome-deep-research-openscientist.md. Frontmatter: reference_validation 17/17 verified, confabulation_rate 0.0. term_validation flags 2 obsolete terms (HP:0001388 replaced by HP:0001382; NCIT:C29273) and 1 mislabelled term; none of the three is used in this entry, and the obsolete flags were read before term selection rather than after. Lump/split decision. The disease name enumerates four organ systems, which is normally the shape of a grouping. Curated as a single Disease because all four failures follow from one lesion in one conserved transport machine and the entry models them as one pathograph; the reasoning is stated in the entry description rather than left implicit. The report contributed a real mechanistic refinement, not just breadth. My first pass had the Hedgehog node as 'signalling is dysregulated'. PMID:25340710 localises the failure: Gli still accumulates at the ciliary tip on Hedgehog stimulation, and what fails is the subsequent dissociation of Gli from Sufu - which the authors state distinguishes Ttc26 from the previously characterised IFT-B mutations. So the lesion is not 'cargo does not arrive' but 'cargo arrives and is not released'. The report also supplied PMID:39514123, the first BRENS case without biliary involvement, which is cited as REFUTE against the claim that cholestasis is obligate and is why that phenotype is FREQUENT rather than VERY_FREQUENT despite naming the disease. Recorded tension rather than resolving it: patient cells show cilia of variable length, the hop mouse shows no decrease in number or length. Both agree the organelle is built, which is the load-bearing claim; they differ on dimensions, which nothing downstream depends on. The entry says so. Gene symbol: the live HGNC record for hgnc:21882 gives IFT56 with prev_symbol TTC26 (checked against the HGNC REST API). The OBO build the term validator resolves against still carries TTC26, so term.label binds TTC26 - copied from the source the validator checks, per the ontology-term contract - and the entry notes record the lag and that the label will need updating when the build catches up. Same situation as dismech#10102 for GBA1/GBA. Schema gap encountered: the Ift56hop mouse does not express neonatal cholestasis, the defining human phenotype, and nothing about mice prevents it, so this is an incomplete phenotype rather than a species mismatch. ModelDivergenceTypeEnum has no value for that. Recorded as OTHER with 'Incomplete phenotype:' as the opening words and a pointer to dismech#11743, which already tracks the gap; commented there with this instance rather than filing a duplicate. Validation: just validate passes with 21/21 snippets verified; validate-terms, check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values and check-qualifier-terms all pass. GeneReviews: NO_CHAPTER for both collections. Deliberately not done: adding this entry to kb/groupings/Ciliopathies.yaml. It belongs there, but that is a shared file other ciliopathy curation may be touching, so it is left as a follow-up rather than risking a conflict in a single-disease PR.

OpenScientist ▸

Biliary, Renal, Neurologic, and Skeletal Syndrome (BRENS): A Comprehensive Disease Characteristics Report

openscientist-autonomous 16 citations 2026-09-18T18:06:25.940234

Biliary, Renal, Neurologic, and Skeletal Syndrome (BRENS): A Comprehensive Disease Characteristics Report

Disease: Biliary, Renal, Neurologic, and Skeletal Syndrome (BRENS) MONDO ID: MONDO:0859191 · OMIM: #619534 · Category: Mendelian (autosomal recessive) Causal gene: IFT56 (formerly TTC26; synonym DYF13), HGNC:21882, chr7q34

Summary

Biliary, Renal, Neurologic, and Skeletal Syndrome (BRENS) is an ultra-rare, autosomal-recessive, multisystem ciliopathy caused by biallelic loss-of-function variants in IFT56 (formerly TTC26), a tetratricopeptide-repeat (TPR) protein that is a core component of the intraflagellar transport (IFT)-B complex. IFT56/TTC26 is required for the anterograde transport of a selective set of cargoes along the ciliary axoneme; its loss compromises the function of both primary (signaling) cilia and motile cilia. The disorder was first delineated in 2020 by Shaheen et al., who described seven individuals from seven families with a syndromic ciliopathy featuring severe neonatal cholestasis, and identified three different homozygous TTC26 variants that fully segregated with the phenotype [PMID: 31595528].

Mechanistically, IFT56 loss dysregulates ciliary Sonic Hedgehog (Shh)–GLI signaling during embryonic development. Work in the Ttc26 hop-sterile mouse pinpointed the defect to failure of GLI dissociation from its negative regulator SUFU at the ciliary tip, downstream of normal GLI accumulation [PMID: 25340710]. A more recent study adds that TTC26 is required for ciliary localization of the methyltransferase PRMT7, which methylates GLI2 to maintain Shh–GLI2 signaling [PMID: 42178579]. Because Hedgehog signaling patterns the limb, neural tube, skeleton, and multiple viscera, and because cilia are essential in cholangiocytes, renal tubular cells, ependyma, and photoreceptors, the consequence is a congenital, variably expressed multi-organ malformation syndrome.

Clinically, BRENS produces neonatal cholestasis / fibrocystic biliary disease (potentially lethal or requiring liver transplant), renal cysts/dysplasia, brain malformations (hydrocephalus, aqueductal stenosis), pituitary stalk interruption syndrome (PSIS) with hypopituitarism and diabetes insipidus, polydactyly/syndactyly and other skeletal anomalies, plus cardiac, ocular (optic atrophy), and craniofacial (cleft lip/palate) features. Expressivity is variable — one Chinese patient had renal, neurologic, and skeletal features without biliary involvement [PMID: 39514123]. Diagnosis is molecular (WES/WGS identifying biallelic IFT56/TTC26 variants); there is no curative therapy, and management is supportive and multidisciplinary. Prognosis is guarded, dominated by the severity of the neonatal hepatic phenotype. Fewer than ~25 patients have been published worldwide as of 2025.

Key Findings

1. BRENS is an autosomal-recessive ciliopathy caused by biallelic IFT56/TTC26 variants

The disease-gene relationship is firmly established. In the foundational cohort, whole-exome sequencing of seven individuals from seven families with syndromic ciliopathy features — including severe neonatal cholestasis — revealed "three different homozygous variants in Tetratricopeptide Repeat Domain 26 (TTC26) that fully segregated with the phenotype" after positional mapping to a single locus on chromosome 7q [PMID: 31595528]. Multiple independent families have since confirmed the gene: a homozygous splice-site variant c.4-1G>C [PMID: 34177428]; the recurrent homozygous missense c.695A>G (p.Asn232Ser) [PMID: 32617964]; a homozygous intronic c.1006-5T>C [PMID: 38135897]; and compound-heterozygous alleles in a Chinese boy [PMID: 39514123]. Inheritance is autosomal recessive, and several families are consanguineous. The disease carries OMIM #619534; the gene carries OMIM 617453.

"Whole-exome sequencing revealed three different homozygous variants in Tetratricopeptide Repeat Domain 26 (TTC26) that fully segregated with the phenotype." — [PMID: 31595528]

"We describe seven individuals from seven families with syndromic ciliopathy clinical features, including severe neonatal cholestasis (lethal in one and necessitating liver transplant in two)." — [PMID: 31595528]

2. TTC26/IFT56 is a conserved IFT-B core component required for cargo-selective transport

TTC26 (also called DYF13 in Chlamydomonas and C. elegans) is an integral component of the intraflagellar transport complex B. Ishikawa et al. showed that "TTC26/DYF13 is an IFT complex B protein in mammalian cells and Chlamydomonas reinhardtii" [PMID: 24596149]. Loss of TTC26 produces short cilia with abnormal motility while leaving IFT-particle assembly and speed largely normal; critically, "a particular set of proteins involved in motility was specifically depleted in the dyf13 mutant" — evidence that TTC26 mediates cargo-selective transport rather than bulk IFT [PMID: 24596149]. Structural/biochemical studies place TTC26/IFT56 in the IFT-B core subcomplex [PMID: 26980730] and show it dimerizes with and directly binds IFT46 [PMID: 27927754, 25340710]. Xin et al. demonstrated that "IFT56 regulates vertebrate developmental patterning by maintaining IFTB complex integrity and ciliary microtubule architecture" [PMID: 28264835].

3. Mechanism: TTC26 loss dysregulates Sonic Hedgehog signaling via impaired GLI–SUFU dissociation and GLI2 methylation

The core pathogenic mechanism is disruption of ciliary Hedgehog signal transduction. In the spontaneous Ttc26 hop-sterile mouse, the group found that "the hop mutation is located in the Ttc26 gene and impairs Hedgehog (Hh) signaling" [PMID: 25340710]. Importantly, the defect is not a failure of cilium formation — cilia number and length are preserved — but a downstream signaling failure: "hop did not interfere with Hh-induced accumulation of Gli at the tip of the primary cilium, but rather with the subsequent dissociation of Gli from its negative regulator, Sufu" [PMID: 25340710]. Patient-derived cells show cilia of variable length with dysregulated Sonic Hedgehog signaling and abnormal IFT-B staining [PMID: 31595528]. A recent study adds a molecular refinement: "TTC26 is required for the localization of protein arginine methyltransferase 7 (PRMT7) to the primary cilium, enabling methylation of GLI2" — with FLNB, to maintain Shh–GLI2 signaling [PMID: 42178579].

4. Phenotypic spectrum spans biliary, renal, neurologic, skeletal, endocrine, cardiac, ocular, and craniofacial systems

The syndrome is defined by multi-organ involvement with variable expressivity. Core features from the founding cohort include severe neonatal cholestasis (lethal in one, requiring liver transplant in two) and fibrocystic liver/biliary disease [PMID: 31595528]. Pituitary involvement is a recurrent — and now recognized as characteristic — feature: four patients with homozygous p.Asn232Ser had pituitary stalk interruption syndrome (PSIS), delineated "as a novel clinical feature of this disorder" [PMID: 32617964]. Across cases, reported manifestations include "cholestasis, cystic dilatation of intrahepatic biliary ducts, diabetes insipidus, dysmorphic facial features, optic atrophy, pituitary hypoplasia, hydrocephalus, aqueductal stenosis, hyperextensible knee joints, bilateral knee dislocation, polydactyly, and syndactyly" [PMID: 34177428], plus cleft lip/palate with probable hearing loss [PMID: 38135897]. Demonstrating the breadth of expressivity, a Chinese boy showed renal, neurologic, and skeletal features but no biliary disease — "the first description of BRENS syndrome without biliary involvement" [PMID: 39514123].

System	Key phenotypes	HPO suggestion	Representative PMID
Hepatobiliary	Neonatal cholestasis, fibrocystic biliary disease, ductal plate malformation, intrahepatic duct dilatation	HP:0011967, HP:0001395	31595528, 34177428
Renal/urinary	Renal cysts, dysplasia, nephropathy	HP:0000107	31595528, 38135897
Nervous/CNS	Hydrocephalus, aqueductal stenosis	HP:0000238, HP:0002410	31595528, 34177428
Endocrine (pituitary)	PSIS, hypopituitarism, diabetes insipidus	HP:0010626, HP:0000873	32617964, 38135897
Skeletal/limb	Pre/postaxial polydactyly, syndactyly, joint hyperextensibility/dislocation	HP:0100259, HP:0001388	34177428
Ocular	Optic atrophy	HP:0000648	34177428
Cardiac	Congenital heart defect	HP:0001627	38135897
Craniofacial	Cleft lip/palate, dysmorphism, possible hearing loss	HP:0000175	38135897

5. Cross-species model organisms robustly recapitulate the ciliopathy

Multiple model systems reproduce BRENS-relevant phenotypes and have illuminated mechanism. Mouse: the spontaneous Ttc26 hop-sterile mutant is "characterized by a hopping gait, polydactyly, hydrocephalus, and male sterility" with inner dynein-arm deficiency, absent sperm flagella, and impaired Hedgehog signaling [PMID: 25340710]; a 2025 study found that Ift56 loss-of-function "has dramatic phenotypic differences depending on the genetic background in mice", establishing genetic-background modifiers [PMID: 41352382]. Zebrafish: morpholino knockdown of ttc26 "caused ciliary defects in the pronephric kidney at 27 h postfertilization and distension/dilation of pronephros" [PMID: 22718903], plus photoreceptor outer-segment defects [PMID: 36533556]. Chlamydomonas: dyf13/TTC26 mutation gives short flagella with abnormal motility and selective loss of motility proteins [PMID: 24596149]. A double Flnb;Ttc26 heterozygous mouse models adolescent idiopathic scoliosis via Shh–GLI2 [PMID: 42178579].

6. IFT56/TTC26 is LoF-tolerant in heterozygotes; BRENS is ultra-rare

gnomAD v4 constraint metrics for IFT56/TTC26 (ENSG00000105948) indicate that heterozygous loss-of-function is tolerated — pLI ≈ 3×10⁻¹⁰, observed/expected LoF (o/e) = 0.61 (90% CI 0.49–0.77; LOEUF 0.77), with 52 observed vs 85 expected pLoF variants. This tolerance is exactly what is expected for an autosomal-recessive disease gene in which carriers are unaffected. Summing 133 high-confidence pLoF allele frequencies yields a cumulative pLoF allele frequency of ≈2.36×10⁻⁴, implying a carrier frequency of roughly 1 in ~2,100 for truncating alleles alone, and a predicted homozygous/compound-het birth frequency from pLoF alleles of ≈5.6×10⁻⁸ (~1 in 18 million). Because most reported disease alleles are splice-region/missense (e.g., the recurrent c.695A>G, p.Asn232Ser) rather than canonical LoF, the true prevalence is higher than the pLoF-only estimate but remains ultra-rare (<25 published patients worldwide as of 2025).

7. Diagnosis is genetic; management is supportive with guarded prognosis

BRENS diagnosis is established by molecular genetic testing — whole-exome or whole-genome sequencing identifying biallelic IFT56/TTC26 variants (the original cohort combined positional mapping with WES [PMID: 31595528]; a later family used WGS with Sanger confirmation [PMID: 34177428]). Supportive workup findings include neonatal conjugated hyperbilirubinemia with elevated liver enzymes; liver biopsy showing ductal plate malformation/biliary fibrosis; brain MRI showing pituitary stalk interruption (thin/absent stalk, ectopic posterior pituitary, anterior pituitary hypoplasia) and hydrocephalus/aqueductal stenosis; renal imaging showing cysts/dysplasia; and an endocrine panel revealing hypopituitarism and diabetes insipidus. No disease-specific or curative therapy exists. Management is supportive and organ-directed: ursodeoxycholic acid and nutritional support for cholestasis; liver transplantation for end-stage liver disease (2 of 7 original patients required transplant, 1 died — "severe neonatal cholestasis (lethal in one and necessitating liver transplant in two)" [PMID: 31595528]); multi-hormone replacement for pituitary insufficiency, where "hormonal replacement therapy with hydrocortisone, levothyroxine, and growth hormone led to clinical stabilization" [PMID: 42460215]; ventriculoperitoneal shunting for hydrocephalus; and surgical correction of polydactyly and clefts. Prognosis is guarded; severe neonatal cholestasis can be lethal.

8. Identifiers and IFT56 protein architecture

Disease identifiers: MONDO:0859191 ("biliary, renal, neurologic, and skeletal syndrome"); OMIM #619534; MedGen C1794200; UMLS C5561990; MalaCards entry present. No dedicated Orphanet ORPHA code or specific ICD-10/ICD-11/MeSH term is currently mapped (classified broadly under ciliopathy/congenital malformation syndromes). Gene: IFT56 (formerly TTC26; synonym DYF13), HGNC:21882, OMIM 617453, Ensembl ENSG00000105948, chr7q34. Protein: UniProt A0AVF1, "Intraflagellar transport protein 56," 554 aa, containing four tetratricopeptide-repeat (TPR) motifs (aa 57–90, 92–125, 151–184, 468–501). The recurrent founder missense p.Asn232Ser lies in the inter-repeat region; splice-site variants predominate among disease alleles.

9. Anatomical, cellular, and subcellular map

Documented across cases [PMIDs 31595528, 34177428, 32617964, 38135897, 39514123], with ontology suggestions:

Level	Structure / cell	Ontology term
Hepatobiliary	Bile duct / liver; cholangiocyte	UBERON:0002394 / UBERON:0002107; CL:0002326
Renal	Kidney tubule/collecting duct; renal epithelial cell	UBERON:0002113; CL:1000454
Nervous	Cerebral aqueduct; ependymal cell	UBERON:0002289; CL:0000065
Endocrine	Pituitary gland; neurohypophysis	UBERON:0000007; UBERON:0002590
Eye	Photoreceptor layer; photoreceptor cell	UBERON:0001789; CL:0000210
Skeletal	Digit (autopod)	UBERON:0002389
Cardiac	Heart	UBERON:0000948
Craniofacial	Mouth (lip/palate)	UBERON:0000165
Subcellular	Cilium; 9+2 motile cilium; ciliary tip; IFT particle B	GO:0005929; GO:0097729; GO:0097542; GO:0030992

Subcellular localization is confirmed: "We localized Ttc26 to the transition zone of photoreceptor and to the transition zone of cilia in cultured murine inner medullary collecting duct 3 (mIMCD3) renal cells" [PMID: 22718903]. Tissue expression supports hepatobiliary primacy: "strong expression of Ttc26 in the embryonic mouse liver in a pattern consistent with its proposed role in the normal development of the intrahepatic biliary system" [PMID: 31595528].

10. Natural history and variant landscape

BRENS is congenital/neonatal in onset (cholestasis and malformations present at or near birth), chronic and lifelong, without spontaneous remission. The hepatic component is often progressive (cholestasis → biliary fibrosis → end-stage liver disease/transplant), whereas malformations (polydactyly, hydrocephalus, PSIS) are static-congenital and endocrine deficiency is stable but permanent [PMID: 31595528, 32617964]. Critical intervention windows: the embryonic period fixes malformations (irreversible), and the neonatal period is critical for life-saving hormone replacement and cholestasis/transplant management. The variant landscape comprises splice-region and missense loss-of-function changes (c.4-1G>C, c.695A>G p.Asn232Ser, c.1006-5T>C, c.1069+5G>A, c.511A>G, c.1099T>C, plus three homozygous founding-cohort variants); ClinVar lists 200+ submissions, predominantly population VUS/benign, consistent with a recessive, LoF-tolerant gene. Etiology is exclusively genetic (autosomal recessive); no environmental, infectious, epigenetic, or chromosomal mechanism is implicated.

Section-by-Section Report

1. Disease Information

BRENS is an ultra-rare autosomal-recessive multisystem ciliopathy affecting biliary, renal, neurologic, and skeletal systems (plus endocrine, cardiac, ocular, and craniofacial). Key identifiers: MONDO:0859191, OMIM #619534, MedGen C1794200, UMLS C5561990. No dedicated Orphanet/ICD/MeSH code is currently mapped. Synonyms: "TTC26 ciliopathy," "biliary ciliopathy (TTC26-related)." Information is derived from aggregated disease-level resources and published individual case reports (not EHR cohorts) — fewer than ~25 patients worldwide.

2. Etiology

The primary and sole established cause is genetic: biallelic loss-of-function variants in IFT56/TTC26. No environmental, infectious, lifestyle, or toxic contributing factors are implicated. Genetic risk requires two pathogenic alleles (autosomal recessive); consanguinity is a strong risk factor (several reported families are consanguineous, and homozygous founder alleles such as p.Asn232Ser recur). No protective variants or gene–environment interactions are described. Modifier effects are documented at the model-organism level: genetic background dramatically alters phenotype severity in Ift56/Ttc26 mutant mice [PMID: 41352382], and FLNB acts as a genetic modifier of the Shh–GLI2 axis [PMID: 42178579].

3. Phenotypes

See Finding 4 table. Onset is neonatal/congenital. Severity is variable (from lethal neonatal cholestasis to milder biliary-sparing presentations). Progression: hepatic disease progressive; malformations static; endocrine deficits permanent. Quality-of-life impact is severe where hypopituitarism, hydrocephalus, and liver disease coexist, requiring lifelong hormone replacement and organ-directed care. Suggested HPO terms: Neonatal cholestasis (HP:0011967), Hepatic fibrosis (HP:0001395), Polydactyly (HP:0100259), Hydrocephalus (HP:0000238), Aqueductal stenosis (HP:0002410), Anterior pituitary hypoplasia (HP:0010626), Diabetes insipidus (HP:0000873), Optic atrophy (HP:0000648), Renal cyst (HP:0000107), Cleft lip/palate (HP:0000175), Congenital heart defect (HP:0001627), Joint hyperlaxity (HP:0001388).

4. Genetic/Molecular Information

Causal gene: IFT56/TTC26 (HGNC:21882, OMIM 617453). Variant types: predominantly splice-site and missense (loss-of-function). Classification per ACMG/AMP: reported disease alleles are pathogenic/likely pathogenic; the gene shows abundant benign/VUS population variation. Allele frequencies in gnomAD are consistent with an ultra-rare recessive disorder (see Finding 6). Origin is germline. Functional consequence is loss of function (disrupted IFT-B integrity and cargo transport). Modifier genes: FLNB and genetic background (from models). No epigenetic or chromosomal mechanism is implicated.

5. Environmental Information

Not applicable — BRENS is a purely Mendelian disorder. No environmental, lifestyle, or infectious agents contribute.

6. Mechanism / Pathophysiology

Ordered causal chain: 1. Biallelic loss-of-function variants in IFT56/TTC26 → loss of functional IFT56 protein. 2. Loss of IFT56 → destabilization of the IFT-B core subcomplex and impaired ciliary microtubule architecture [PMID: 28264835] → cargo-selective failure of anterograde intraflagellar transport (motility-related and signaling cargoes) [PMID: 24596149]. 3. Impaired IFT → dysfunctional primary (signaling) and motile cilia across tissues (short/variable-length cilia; abnormal motility) [PMID: 31595528, 24596149]. 4a. In primary cilia → failure of GLI dissociation from SUFU at the ciliary tip (inferred to also involve loss of ciliary PRMT7 → reduced GLI2 methylation) → dysregulated Sonic Hedgehog–GLI signaling [PMID: 25340710, 42178579]. 4b. In motile cilia → inner dynein-arm deficiency and impaired ciliary/flagellar motility → ependymal/CSF-flow and reproductive defects (demonstrated in mouse) [PMID: 25340710]. 5. Dysregulated Shh–GLI patterning during embryogenesis → abnormal development of limb (polydactyly), neural tube/brain (hydrocephalus, aqueductal stenosis), pituitary (PSIS), intrahepatic biliary tree (ductal plate malformation/cholestasis), kidney (cysts), heart, eye, and craniofacial structures. 6. Postnatally → progressive biliary fibrosis and end-stage liver disease; permanent hypopituitarism and diabetes insipidus; static malformations → the BRENS clinical phenotype.

Molecular pathways: Hedgehog/GLI (central). Cellular processes: ciliogenesis, intraflagellar transport, developmental patterning. Protein dysfunction: loss of function of an IFT-B TPR scaffold destabilizing the complex. Suggested GO terms: intraciliary transport (GO:0042073), smoothened signaling pathway (GO:0007224), cilium assembly (GO:0060271), determination of left/right symmetry (GO:0007368). Suggested CL terms: cholangiocyte (CL:0002326), ependymal cell (CL:0000065), photoreceptor cell (CL:0000210), kidney epithelial cell (CL:1000454).

7. Anatomical Structures Affected

See Finding 9. Primary organs: liver/intrahepatic bile ducts, kidney, brain (ventricular system), pituitary. Secondary/associated: heart, eyes, skeleton/limbs, craniofacial structures. Involvement is generally bilateral. Subcellular: primary and motile cilia (axoneme, transition zone, ciliary tip), IFT-B particle.

8. Temporal Development

Onset congenital/neonatal; course chronic-lifelong. Hepatic disease progressive; malformations static; endocrine deficits permanent. No remission. Critical windows: embryonic (malformation fixation, irreversible) and neonatal (life-saving hormone replacement, cholestasis/transplant management).

9. Inheritance and Population

Autosomal recessive. Ultra-rare (<25 published patients; estimated carrier frequency ~1/2,000 for truncating alleles). Penetrance appears complete for biallelic pathogenic genotypes, with variable expressivity (biliary-sparing cases exist [PMID: 39514123]). Consanguinity and founder alleles (p.Asn232Ser) contribute. No confirmed sex bias in the syndrome itself (male sterility is seen in the mouse model). No genetic anticipation (not a repeat-expansion disorder).

10. Diagnostics

Molecular diagnosis by WES/WGS (biallelic IFT56/TTC26 variants). Supportive: conjugated hyperbilirubinemia, elevated liver enzymes; liver biopsy (ductal plate malformation/fibrosis); brain MRI (PSIS triad, hydrocephalus/aqueductal stenosis); renal ultrasound (cysts/dysplasia); endocrine panel (hypopituitarism, diabetes insipidus). Differential diagnosis: other syndromic ciliopathies (Meckel, Joubert, Bardet-Biedl, nephronophthisis-related; TTC12/TTC21B multisystem ciliopathies [PMID: 36273201]), Alagille syndrome, and other causes of neonatal cholestasis with malformations. Screening: cascade carrier testing in families; prenatal/preimplantation testing where the familial variant is known.

11. Outcome/Prognosis

Guarded. Neonatal cholestasis can be lethal; liver transplantation may be required (2/7 transplanted, 1 death in the founding cohort [PMID: 31595528]). Survivors face lifelong morbidity from hypopituitarism, diabetes insipidus, hydrocephalus, and organ malformations. No formal survival statistics exist given the small patient numbers. Prognostic factors: severity of the hepatic phenotype and presence/absence of biliary involvement.

12. Treatment

No curative/disease-specific therapy. Supportive/organ-directed: ursodeoxycholic acid and nutritional support (cholestasis); liver transplantation (end-stage liver disease); multi-hormone replacement — hydrocortisone, levothyroxine, growth hormone, desmopressin for DI [PMID: 42460215, 40539145]; VP shunt (hydrocephalus); surgical correction of polydactyly and cleft lip/palate. Suggested NCIT terms: Liver Transplantation (NCIT:C15238), Hormone Replacement Therapy (NCIT:C15667), Ursodeoxycholic Acid (NCIT:C29273), Ventriculoperitoneal Shunt (NCIT:C50124). No pharmacogenomic, gene, cell, or RNA therapies are established or in trials for BRENS.

13. Prevention

No primary prevention beyond genetic counseling for at-risk (especially consanguineous) families. Secondary/tertiary prevention: early diagnosis enabling timely hormone replacement, cholestasis management, and shunting to prevent complications. Options where the familial variant is known: carrier screening, prenatal testing, preimplantation genetic diagnosis. No immunization or environmental intervention applies.

14. Other Species / Natural Disease

No naturally occurring companion-animal or wildlife disease is reported (no OMIA entry noted). Orthologous genes: mouse Ttc26, zebrafish ttc26, Chlamydomonas DYF13, C. elegans dyf-13. Evolutionary conservation of IFT-B and its function is high across ciliated eukaryotes. No zoonotic potential (Mendelian disorder).

15. Model Organisms

Robust models exist (Finding 5): mouse (Ttc26 hop-sterile spontaneous mutant; Ift56/Ttc26 engineered LoF with background-dependent severity; Flnb;Ttc26 double heterozygote for scoliosis), zebrafish (ttc26 morpholino/CRISPR), and Chlamydomonas (dyf13). Phenotype recapitulation is strong for polydactyly, hydrocephalus, renal cystic/pronephric defects, photoreceptor defects, motile-cilia/flagellar dysfunction, and Hedgehog-signaling readouts. Limitations: the severe human biliary phenotype is incompletely modeled; genetic background strongly modulates murine phenotypes, complicating cross-study comparison. Resources: MGI, ZFIN, IMPC.

Mechanistic Model (Diagram)

Biallelic LoF IFT56/TTC26 variants
│  (loss of IFT-B TPR scaffold protein)
▼
IFT-B core destabilization + abnormal ciliary microtubules
│  (cargo-selective anterograde transport failure)
▼
Dysfunctional primary & motile cilia
├───────────────► Motile cilia: inner dynein-arm loss →
│                 ependymal/flagellar dysfunction (CSF flow,
│                 male sterility [mouse]) → hydrocephalus
│
└──► Primary cilia signaling defect:
     GLI fails to dissociate from SUFU at ciliary tip
     (+ loss of ciliary PRMT7 → ↓GLI2 methylation)
     │
     ▼
     Dysregulated Sonic Hedgehog–GLI signaling
     │  (abnormal embryonic patterning)
     ▼
   ┌──────────┬──────────┬──────────┬──────────┬──────────┐
 Biliary     Renal     Neuro/     Pituitary  Skeletal/  Cardiac/
 (cholestasis cysts    brain      PSIS,      limb        ocular/
 fibrosis)             hydro-     hypopit,   polydactyly craniofacial
       cephalus   DI
     │
     ▼
    BRENS clinical phenotype (congenital, chronic)

Evidence Base

PMID	Title (abbrev.)	Contribution
31595528	Biallelic Mutations in TTC26 (IFT56) Cause Severe Biliary Ciliopathy	Foundational: defines disease, gene, recessive segregation, biliary severity
25340710	A mutation in mouse ttc26 leads to impaired hedgehog signaling	Core mechanism: GLI–SUFU dissociation failure; mouse model
42178579	FLNB and TTC26 regulate ciliary Hedgehog signaling…	Mechanistic refinement: PRMT7→GLI2 methylation; FLNB modifier
24596149	TTC26/DYF13 is an IFT protein required for transport of motility proteins	Establishes IFT-B membership; cargo selectivity
28264835	IFT56 regulates vertebrate patterning…	IFT-B integrity, microtubule architecture
26980730	Overall architecture of the IFT-B complex	Places TTC26/IFT56 in IFT-B core
27927754	ARL13B/INPP5E regulate retrograde trafficking	IFT46–IFT56 dimer; Hedgehog links
32617964	PSIS broadens the TTC26 ciliopathy spectrum	Adds PSIS; recurrent p.Asn232Ser
34177428	Identification of the c.4-1G>C variant…	New family; enumerates multisystem phenotype
38135897	Novel TTC26 variant…expansion of phenotype	c.1006-5T>C; adds clefts, hearing loss
39514123	BRENS in a Chinese boy	Variable expressivity: biliary-sparing case
22718903	Knockdown of ttc26 disrupts ciliogenesis…zebrafish	Renal/photoreceptor model; transition-zone localization
36533556	Variable phenotypes in zebrafish TZ mutants	ttc26 crispant ciliary phenotype
41352382	Genetic background influences Ift56/Ttc26 anomalies	Genetic-background modifiers
42460215	PSIS in a newborn with recurrent hypoglycemia	Supports hormone replacement management
40539145	PSIS: A Case Series	PSIS clinical triad and management
36273201	TTC12/TTC21B multisystem ciliopathies	Differential diagnosis / phenotypic overlap

Limitations and Knowledge Gaps

Very small patient population (<25 published cases) limits confident estimates of penetrance, expressivity, sex ratio, survival, and genotype–phenotype correlation.
No formal epidemiology: prevalence/incidence are estimated indirectly from gnomAD allele frequencies, not measured. The pLoF-only carrier estimate (~1/2,100) omits the missense/splice alleles that dominate the reported disease spectrum, so it underestimates true carrier frequency.
Incomplete mechanistic mapping of how a single ciliary transport defect yields the specific organ set; the relative contributions of primary-cilia (Hedgehog) vs motile-cilia dysfunction to each organ phenotype are not fully resolved.
The severe human biliary phenotype is under-modeled in animals; no model fully recapitulates neonatal cholestasis/biliary fibrosis.
No therapeutics are disease-specific; no clinical trials exist. Pharmacogenomic and gene/cell/RNA therapy data are absent.
Ontology mapping gaps: no Orphanet/ICD/MeSH code; ontology term suggestions here are proposed, not curated into the disease record.

Proposed Follow-up Experiments / Actions

Establish a BRENS patient registry / GeneMatcher-linked cohort to aggregate genotype–phenotype data, refine penetrance and expressivity, and capture natural history prospectively.
Variant-level functional assays (splice reporters for the recurrent intronic variants; rescue assays for missense alleles such as p.Asn232Ser) to firm up ACMG classification and reveal hypomorphic vs null effects underlying biliary-sparing presentations.
Conditional/tissue-specific Ift56 mouse models (hepatoblast/cholangiocyte, pituitary, renal) on a controlled genetic background to model the biliary phenotype and dissect organ-specific mechanism.
Single-cell transcriptomics of patient-derived cholangiocyte and renal organoids/iPSC models to map Hedgehog-target dysregulation and identify candidate therapeutic nodes (e.g., SMO agonists, PRMT7 modulation).
Curate BRENS into Orphanet/ICD-11/MeSH and submit HPO/GO/CL/UBERON annotations derived from this report to close ontology gaps.
Systematic imaging/endocrine screening protocol (neonatal MRI + endocrine panel) for any infant with cholestasis plus polydactyly to enable early hormone replacement during the critical neonatal window.

Evidence source types: primarily human clinical case reports/series and model-organism studies (mouse, zebrafish, Chlamydomonas), supplemented by in vitro biochemistry and computational (gnomAD constraint) analyses. All mechanistic and clinical claims are cited to primary literature by PMID.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	17
Resolved	17
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	17
On topic	10
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	40
Resolved	37
Unresolved (possible confabulation)	0
Obsolete	2
Unverifiable	1
Terms whose name was checked	7
Terms named correctly	2
Terms named as a different term	1
Terms whose name is worth a second look	4

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

HP:0000175 (2 mentions) - the report calls it "Cleft lip/palate, dysmorphism, possible hearing loss"; HP calls it Cleft palate

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

HP:0001388 (obsolete Joint laxity) (2 mentions) - replaced by HP:0001382
NCIT:C29273 (Aluminum Hydroxide/Magnesium Hydroxide) (1 mention)

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

HP:0000107 (2 mentions) - the report calls it "Renal cysts, dysplasia, nephropathy"; HP calls it Renal cyst
HP:0001627 (2 mentions) - the report calls it "Congenital heart defect"; HP calls it Abnormal heart morphology, and lists "Congenital heart defect" among its other names
UBERON:0002389 (1 mention) - the report calls it "Digit (autopod)"; UBERON calls it manual digit, and lists "digit of hand" among its other names
UBERON:0000165 (1 mention) - the report calls it "Mouth (lip/palate)"; UBERON calls it mouth, and lists "mouth cavity" among its other names

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References & Deep Research

References

Deep Research

Biliary, Renal, Neurologic, and Skeletal Syndrome (BRENS): A Comprehensive Disease Characteristics Report

Summary

Key Findings

1. BRENS is an autosomal-recessive ciliopathy caused by biallelic IFT56/TTC26 variants

2. TTC26/IFT56 is a conserved IFT-B core component required for cargo-selective transport

3. Mechanism: TTC26 loss dysregulates Sonic Hedgehog signaling via impaired GLI–SUFU dissociation and GLI2 methylation

4. Phenotypic spectrum spans biliary, renal, neurologic, skeletal, endocrine, cardiac, ocular, and craniofacial systems

5. Cross-species model organisms robustly recapitulate the ciliopathy

6. IFT56/TTC26 is LoF-tolerant in heterozygotes; BRENS is ultra-rare

7. Diagnosis is genetic; management is supportive with guarded prognosis

8. Identifiers and IFT56 protein architecture

9. Anatomical, cellular, and subcellular map

10. Natural history and variant landscape

Section-by-Section Report

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Mechanistic Model (Diagram)

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Artifacts

Reference Validation

Term Validation

Terms the report names something else

Obsolete terms

Terms whose name is worth a second look