IFT140-related Recessive Ciliopathy

Mendelian MONDO:0100509 Pathograph 11 Show in embeddings browser Ciliopathy

IFT140-related recessive ciliopathy is an autosomal recessive disorder caused by biallelic mutations in IFT140, a core component of the intraflagellar transport complex A (IFT-A) that mediates retrograde protein transport within primary cilia. The phenotype spans a continuum from isolated, early-onset congenital retinal dystrophy (non-syndromic retinitis pigmentosa) to a systemic skeletal "conorenal" ciliopathy that overlaps Mainzer-Saldino syndrome and Jeune asphyxiating thoracic dystrophy, with the cardinal triad of phalangeal cone-shaped epiphyses, progressive chronic kidney disease, and severe retinal dystrophy. Because IFT140 is expressed more highly in kidney and retina than in skeleton, renal failure and retinal degeneration are the most penetrant features, while thoracic constriction is often mild relative to other short-rib skeletal ciliopathies.

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1
Inheritance
4
Pathophys.
9
Phenotypes
1
Gaps
11
Pathograph
1
Genes
3
Medical Actions
2
Subtypes
1
Models
👪

Inheritance

1
Autosomal Recessive HP:0000007
Autosomal recessive inheritance from biallelic (homozygous or compound heterozygous) IFT140 mutations.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:26359340 SUPPORT Human Clinical
"Conorenal syndrome is a systemic skeletal ciliopathy characterised by skeletal and renal findings and caused by biallelic mutations in the gene intraflagellar transport 140 Chlamydomonas homologue (IFT140)."
Confirms biallelic (autosomal recessive) IFT140 inheritance.
◆

Subtypes

2
Non-syndromic (isolated) retinal dystrophy — retinitis pigmentosa 80 MONDO:0054708
IFT140 hgnc:29077 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in IFT140 (hgnc:29077). hgnc:29077 is a gene from the HUGO Gene Nomenclature Committee.
The milder pole of the IFT140 allelic continuum: an isolated, early-onset congenital retinal dystrophy (retinitis pigmentosa 80) without the systemic skeletal or renal features of the conorenal spectrum. A subset of biallelic IFT140 patients — including affected adults — have no evident extraocular disease and remain non-syndromic.
Show evidence (1 reference)
PMID:26359340 SUPPORT Human Clinical
"two older affected siblings in their twenties who remained non-syndromic and were excelling academically"
Documents biallelic IFT140 patients with isolated retinal disease and no extraocular involvement, defining the non-syndromic (RP80) pole.
Syndromic conorenal ciliopathy (Mainzer-Saldino / Jeune-overlap) MONDO:0009964
IFT140 hgnc:29077 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in IFT140 (hgnc:29077). hgnc:29077 is a gene from the HUGO Gene Nomenclature Committee.
The systemic pole of the spectrum: a skeletal "conorenal" ciliopathy overlapping Mainzer-Saldino syndrome and Jeune asphyxiating thoracic dystrophy, with the cardinal triad of phalangeal cone-shaped epiphyses, progressive chronic kidney disease, and severe retinal dystrophy. MONDO:0009964 (short-rib thoracic dysplasia 9 with or without polydactyly) is the leaf term for this pole and now anchors it; this entry previously recorded that no such term had been identified. The "with or without polydactyly" qualifier in that term records the same variability captured by the Polydactyly phenotype below.
Show evidence (1 reference)
PMID:22503633 SUPPORT Human Clinical
"Mainzer-Saldino syndrome (MSS) is a rare disorder characterized by phalangeal cone-shaped epiphyses, chronic renal failure, and early-onset, severe retinal dystrophy."
Defines the syndromic conorenal triad (skeletal cone-shaped epiphyses, renal failure, retinal dystrophy) that distinguishes this pole from isolated RP80.
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Discussions and Knowledge Gaps

1
How should this biallelic IFT140 ciliopathy be kept separate from the monoallelic IFT140 cystic kidney phenotype?
INTERPRETATION ift140_biallelic_vs_monoallelic_adpkd
Attached to
disease# genetic#IFT140 Biallelic Mutations
Monoallelic IFT140 loss of function causes a mild autosomal dominant polycystic kidney phenotype that is common enough to rank behind only PKD1 and PKD2 among cystic kidney disease probands. It shares a gene with this entry but is a different disease with different inheritance, severity and organ involvement, and the two are easy to conflate in a gene-first search. This entry is the biallelic recessive ciliopathy only. IFT140 also sits about 0.5 Mb from PKD1 at 16p13.3, which is a recognised source of diagnostic confusion, and PKD1 variants may modify the IFT140 phenotype.
Show evidence (3 references)
PMID:34890546 SUPPORT Human Clinical
"bi-allelic IFT140 variants cause the syndromic ciliopathy, short-rib thoracic dysplasia (SRTD9)"
States the biallelic requirement for the syndromic ciliopathy and distinguishes it from the monoallelic phenotype described in the same paper.
PMID:34890546 SUPPORT Human Clinical
"The distinctive monoallelic phenotype is mild PKD with large cysts, limited kidney insufficiency, and few liver cysts."
Characterises the separate monoallelic phenotype that must not be merged into this entry.
PMID:34890546 SUPPORT Human Clinical
"The proximity of IFT140 to PKD1 (∼0.5 Mb) in 16p13.3 can cause diagnostic confusion, and PKD1 variants could modify the IFT140 phenotype."
Documents the locus proximity that creates diagnostic confusion and a possible modifier effect.
⚙

Pathophysiology

4
IFT-A Retrograde Intraflagellar Transport Failure
Biallelic IFT140 mutations disrupt the intraflagellar transport complex A (IFT-A), which drives retrograde (tip-to-base) protein transport along the ciliary axoneme. Loss of IFT140 function alters the ciliary abundance and localization of the transport machinery, impairing primary cilium assembly, maintenance, and signaling competence in ciliated cells. This molecular lesion is the shared upstream event from which the organ-specific renal, retinal, and skeletal phenotypes diverge.
IFT140 hgnc:29077 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves IFT140 (hgnc:29077). hgnc:29077 is a gene from the HUGO Gene Nomenclature Committee.
Retrograde Intraflagellar Transport GO:0035721 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Retrograde Intraflagellar Transport, annotated with intraciliary retrograde transport (GO:0035721). GO:0035721 is a biological process from the Gene Ontology. Intraflagellar Transport GO:0042073 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Intraflagellar Transport, annotated with intraciliary transport (GO:0042073). GO:0042073 is a biological process from the Gene Ontology. Cilium Assembly GO:0060271 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Cilium Assembly (GO:0060271). GO:0060271 is a biological process from the Gene Ontology.
Primary Cilium GO:0005929 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves Primary Cilium, annotated with cilium (GO:0005929). GO:0005929 is a cellular component from the Gene Ontology.
Animal models
Cauli mouse (Ift140 ENU allele) Mouse recapitulates Mutant embryos show craniofacial dysmorphism, digit anomalies, cardiac anomalies and somite patterning defects, a number of which the authors attribute to altered Hedgehog signalling.
Downstream
Photoreceptor Connecting Cilium Degeneration
Renal Tubular Cystic and Fibrotic Disease
Skeletal Dysplasia with Thoracic Constriction
Show evidence (2 references)
PMID:22503633 SUPPORT Human Clinical
"IFT140 is one of the six currently known components of the intraflagellar transport complex A (IFT-A) that regulates retrograde protein transport in ciliated cells."
Establishes IFT140 as an IFT-A subunit governing retrograde ciliary transport, the molecular basis of this ciliopathy.
PMID:22503633 SUPPORT In Vitro
"Ciliary abundance and localization of anterograde IFTs were altered in fibroblasts of affected individuals, a result that supports the pivotal role of IFT140 in proper development and function of ciliated cells."
Patient fibroblasts show disrupted ciliary transport machinery, demonstrating the functional consequence of IFT140 loss on the primary cilium.
Photoreceptor Connecting Cilium Degeneration
The photoreceptor connecting cilium is a specialized primary cilium that transports phototransduction proteins to the outer segment. IFT-A retrograde transport failure compromises this conduit, producing an early-onset, severe congenital retinal dystrophy that can occur in isolation (non-syndromic retinitis pigmentosa, RP80) or as part of the systemic conorenal phenotype.
Photoreceptor Cell CL:0000210 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Photoreceptor Cell (CL:0000210). CL:0000210 is a cell type from the Cell Ontology.
Photoreceptor Connecting Cilium GO:0005929 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves Photoreceptor Connecting Cilium, annotated with cilium (GO:0005929). GO:0005929 is a cellular component from the Gene Ontology.
Downstream
Retinal Dystrophy
Nystagmus
Show evidence (2 references)
PMID:26359340 SUPPORT Human Clinical
"Recessive IFT140 mutations cause a severe congenital retinal dystrophy with high hyperopia and often early photophilia."
Documents the retinal-degeneration arm of the IFT140 ciliopathy spectrum arising from photoreceptor ciliary dysfunction.
PMID:22503633 SUPPORT Human Clinical
"Mainzer-Saldino syndrome (MSS) is a rare disorder characterized by phalangeal cone-shaped epiphyses, chronic renal failure, and early-onset, severe retinal dystrophy."
Severe early-onset retinal dystrophy is a cardinal feature of the syndromic IFT140 phenotype.
Renal Tubular Cystic and Fibrotic Disease
Primary cilia on renal tubular epithelial cells sense luminal flow and maintain tubular architecture. IFT140 deficiency disrupts this ciliary signaling, driving a nephronophthisis-like tubulointerstitial process with cystic and fibrotic change that progresses to end-stage renal disease, typically within the first decade of life. The severity mirrors the cystic kidney phenotype of Ift140 conditional knockout mice and the high renal expression of IFT140.
Renal Tubular Epithelial Cell CL:1000507 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Renal Tubular Epithelial Cell, annotated with kidney tubule cell (CL:1000507). CL:1000507 is a cell type from the Cell Ontology.
Primary Cilium GO:0005929 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves Primary Cilium, annotated with cilium (GO:0005929). GO:0005929 is a cellular component from the Gene Ontology.
Downstream
Stage 5 Chronic Kidney Disease
Show evidence (2 references)
PMID:23418020 SUPPORT Human Clinical
"IFT140 patients presented with mild chest narrowing, but all had end-stage renal failure under 13 years of age and retinal dystrophy when examined for ocular dysfunction."
Establishes early progressive renal failure as a near-universal, highly penetrant feature of IFT140-related ciliopathy.
PMID:23418020 SUPPORT Model Organism
"This is consistent with the severe cystic phenotype of Ift140 conditional knockout mice"
A conditional Ift140 mouse knockout recapitulates the cystic renal phenotype, supporting the causal ciliary mechanism in the kidney.
Skeletal Dysplasia with Thoracic Constriction
Primary cilia transduce Hedgehog signaling required for endochondral ossification and growth-plate chondrocyte proliferation. IFT-A dysfunction perturbs ciliary Hedgehog signaling in chondrocytes, producing the skeletal features of the conorenal/Mainzer-Saldino spectrum, including phalangeal cone-shaped epiphyses and a constricted thorax. Thoracic narrowing is usually milder in IFT140 disease than in other short-rib skeletal ciliopathies.
Chondrocyte CL:0000138 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Chondrocyte (CL:0000138). CL:0000138 is a cell type from the Cell Ontology.
Hedgehog Signaling GO:0007224 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Hedgehog Signaling, annotated with smoothened signaling pathway (GO:0007224). GO:0007224 is a biological process from the Gene Ontology.
Downstream
Cone-shaped Epiphysis
Thoracic Hypoplasia
Show evidence (2 references)
PMID:22503633 SUPPORT Human Clinical
"Mainzer-Saldino syndrome (MSS) is a rare disorder characterized by phalangeal cone-shaped epiphyses, chronic renal failure, and early-onset, severe retinal dystrophy."
Phalangeal cone-shaped epiphyses are the cardinal skeletal manifestation of the syndromic IFT140 phenotype.
PMID:23418020 SUPPORT Human Clinical
"IFT140 patients presented with mild chest narrowing, but all had end-stage renal failure under 13 years of age and retinal dystrophy when examined for ocular dysfunction."
Documents the comparatively mild thoracic constriction characteristic of IFT140-related skeletal ciliopathy.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for IFT140-related Recessive Ciliopathy Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

9
Eye 3
Retinal Dystrophy HP:0000556 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Retinal dystrophy (HP:0000556). HP:0000556 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26359340 SUPPORT Human Clinical
"Recessive IFT140 mutations cause a severe congenital retinal dystrophy with high hyperopia and often early photophilia."
Severe congenital retinal dystrophy is a core feature of the IFT140 phenotype.
Nystagmus HP:0000639 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nystagmus (HP:0000639). HP:0000639 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26359340 SUPPORT Human Clinical
"All had poor vision and nystagmus since birth, with visual acuity after 5 years old of hand motions or light perception."
Documents congenital nystagmus with profound visual loss in IFT140 patients.
High Hyperopia High hypermetropia HP:0008499 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is High hyperopia, annotated with High hypermetropia (HP:0008499). HP:0008499 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26359340 SUPPORT Human Clinical
"high hyperopia was typical, and electroretinography was non-recordable."
High hyperopia is a typical refractive finding in IFT140-related retinal dystrophy.
Genitourinary 1
Stage 5 Chronic Kidney Disease HP:0003774 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Stage 5 chronic kidney disease (HP:0003774). HP:0003774 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23418020 SUPPORT Human Clinical
"IFT140 patients presented with mild chest narrowing, but all had end-stage renal failure under 13 years of age and retinal dystrophy when examined for ocular dysfunction."
Establishes early end-stage renal failure as a near-universal feature.
Limbs 1
Polydactyly HP:0010442 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Polydactyly (HP:0010442). HP:0010442 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23418020 SUPPORT Human Clinical
"Other features that occur more variably are short long bones and polydactyly"
Records polydactyly as a variable rather than constant feature of this phenotype group.
Musculoskeletal 2
Cone-shaped Epiphysis HP:0010579 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cone-shaped epiphysis (HP:0010579). HP:0010579 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22503633 SUPPORT Human Clinical
"Mainzer-Saldino syndrome (MSS) is a rare disorder characterized by phalangeal cone-shaped epiphyses, chronic renal failure, and early-onset, severe retinal dystrophy."
Phalangeal cone-shaped epiphyses are a cardinal feature of syndromic IFT140 disease.
Thoracic Hypoplasia HP:0005257 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thoracic hypoplasia (HP:0005257). HP:0005257 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23418020 SUPPORT Human Clinical
"IFT140 patients presented with mild chest narrowing, but all had end-stage renal failure under 13 years of age and retinal dystrophy when examined for ocular dysfunction."
Documents the comparatively mild thoracic constriction in IFT140 disease.
Nervous System 1
Developmental Delay Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Developmental delay, annotated with Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26359340 SUPPORT Human Clinical
"Eight children had developmental delay"
Developmental delay was documented in 8 of the children in the IFT140 ophthalmic cohort.
Growth 1
Short Stature HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23418020 SUPPORT Human Clinical
"All IFT140 patients but patient JATD2 were of short stature"
Short stature was present in all but one IFT140 patient, likely secondary to renal insufficiency.
🧬

Genetic Associations

1
IFT140 Biallelic Mutations (Causative)
Gene: IFT140 hgnc:29077 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is IFT140 (hgnc:29077). hgnc:29077 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Autosomal Recessive
Show evidence (2 references)
PMID:22503633 SUPPORT Human Clinical
"Through a combination of ciliome resequencing and Sanger sequencing, we identified IFT140 mutations in six MSS families and in a family with the clinically overlapping Jeune syndrome."
Identifies IFT140 as the causative gene across the MSS/Jeune-overlap spectrum.
PMID:23418020 SUPPORT Human Clinical
"IFT140 is therefore a major cause of cono-renal syndromes (JATD and MSS)."
Establishes IFT140 as a major cause of the conorenal ciliopathy spectrum.
💊

Medical Actions

3
Renal Replacement Therapy
Action: organ transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is organ transplantation (NCIT:C15289). NCIT:C15289 is a clinical intervention from the NCI Thesaurus. Ontology label: Organ Transplantation NCIT:C15289
Platform: Surgery
Progressive kidney disease in IFT140-related ciliopathy reaches end-stage renal failure in childhood, necessitating dialysis and kidney transplantation as definitive renal-replacement management.
Show evidence (1 reference)
PMID:23418020 SUPPORT Human Clinical
"IFT140 patients presented with mild chest narrowing, but all had end-stage renal failure under 13 years of age and retinal dystrophy when examined for ocular dysfunction."
Universal early end-stage renal failure establishes the indication for renal-replacement therapy (dialysis and transplantation).
Low Vision Supportive Care
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Severe congenital retinal dystrophy with profound visual impairment is managed with low-vision rehabilitation, optical correction of the typical high hyperopia, and educational/developmental support.
Show evidence (1 reference)
PMID:26359340 SUPPORT Human Clinical
"All had poor vision and nystagmus since birth, with visual acuity after 5 years old of hand motions or light perception."
Profound early visual loss establishes the need for low-vision supportive management.
Genetic Counseling
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Autosomal recessive inheritance with a 25% recurrence risk warrants genetic counseling, carrier/cascade testing, and discussion of reproductive options including prenatal and preimplantation genetic diagnosis.
Show evidence (1 reference)
PMID:26359340 SUPPORT Human Clinical
"Conorenal syndrome is a systemic skeletal ciliopathy characterised by skeletal and renal findings and caused by biallelic mutations in the gene intraflagellar transport 140 Chlamydomonas homologue (IFT140)."
Biallelic (autosomal recessive) inheritance underpins recurrence-risk counseling and cascade testing.
🔬

Diagnosis

3
Clinical and Radiographic Conorenal Diagnosis
The syndromic conorenal/Mainzer-Saldino pole is recognized clinically and radiographically by phalangeal cone-shaped epiphyses with chronic renal failure and early severe retinal dystrophy; Jeune-overlap cases may show mild chest narrowing with prominent renal and retinal disease.
diagnostic procedure NCIT:C18020 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:22503633 SUPPORT Human Clinical
"Mainzer-Saldino syndrome (MSS) is a rare disorder characterized by phalangeal cone-shaped epiphyses, chronic renal failure, and early-onset, severe retinal dystrophy."
Defines the core clinical/radiographic triad used to recognize the conorenal IFT140 phenotype.
PMID:23418020 SUPPORT Human Clinical
"IFT140 patients presented with mild chest narrowing, but all had end-stage renal failure under 13 years of age and retinal dystrophy when examined for ocular dysfunction."
Supports the Jeune-overlap diagnostic pattern of mild thoracic narrowing with early severe renal and retinal involvement.
Molecular Genetic Confirmation and IFT140 Screening
Molecular diagnosis is established by identifying biallelic IFT140 mutations. IFT140 should be prioritized in skeletal ciliopathy-spectrum patients, especially JATD/MSS presentations with kidney disease with or without retinal involvement. A single pathogenic variant on panel or exome sequencing does not exclude the diagnosis: a recurrent exons 27-30 tandem duplication is missed by both, and was found only on genome sequencing in one patient and then by targeted screening for that duplication in a second. In a clinically convincing patient with one variant, look for the second by a method that can see a structural change.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Show evidence (4 references)
PMID:22503633 SUPPORT Human Clinical
"Through a combination of ciliome resequencing and Sanger sequencing, we identified IFT140 mutations in six MSS families and in a family with the clinically overlapping Jeune syndrome."
Supports IFT140 molecular testing as confirmatory across the Mainzer-Saldino/Jeune-overlap spectrum.
PMID:23418020 SUPPORT Human Clinical
"The present study strengthens the rationale for IFT140 screening in skeletal ciliopathy spectrum patients that have kidney disease and/or retinal dystrophy."
Directly supports prioritizing IFT140 screening in skeletal ciliopathy patients with renal and/or retinal involvement.
DOI:10.3390/genes14081553 SUPPORT DIRECT Human Clinical
"In both cases, at first only one pathogenic variant was detected following panel or exome NGS sequencing."
The reason a single variant on panel or exome testing does not exclude IFT140 disease - in both of these patients the second allele was invisible to the first-line assay.
+ 1 more reference
Ophthalmic Diagnostic Evaluation
Ophthalmic evaluation can identify the IFT140 retinal phenotype, including severe congenital retinal dystrophy with poor vision and nystagmus from birth, typical high hyperopia, and non-recordable electroretinography.
ophthalmic diagnostic procedure NCIT:C38060 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:26359340 SUPPORT Human Clinical
"All had poor vision and nystagmus since birth"
Defines the early severe visual presentation that can prompt ophthalmic evaluation for IFT140-related retinal dystrophy.
PMID:26359340 SUPPORT Human Clinical
"high hyperopia was typical, and electroretinography was non-recordable."
Supports high hyperopia and non-recordable electroretinography as ophthalmic diagnostic findings in IFT140-related disease.
📊

Prevalence

1
Published literature worldwide
Rare; precise population prevalence not established
IFT140-related ciliopathy is reported in small consanguineous family and fetal/clinical series rather than population registries; a recurrent founder allele (c.1990G>A) is described on the Arabian Peninsula.
Show evidence (1 reference)
PMID:26359340 SUPPORT Human Clinical
"The c.1990G>A mutation represents a founder effect or mutational hotspot on the Arabian Peninsula."
Supports rarity and a regional founder effect rather than a common, registry-defined disorder.
🐁

Animal Models

1
Cauli mouse (Ift140 ENU allele)
An ENU-induced Ift140 allele causing mid-gestation embryonic lethality in homozygotes, presented by its authors as a model of Jeune syndrome. The same report identified a homozygous recessive IFT140 variant in a Jeune syndrome patient.
Species
Mouse
Genotype
Ift140 ENU-induced mutation, homozygous
Publication
PMID:24009529
Pathograph links
IFT-A Retrograde Intraflagellar Transport Failure recapitulates fidelity: moderate Mutant embryos show craniofacial dysmorphism, digit anomalies, cardiac anomalies and somite patterning defects, a number of which the authors attribute to altered Hedgehog signalling.
Limitations: Homozygotes die in mid-gestation with neural tube defects and cardiac anomalies that are not features of the human disease, so the model cannot report on the postnatal renal and retinal course that dominates human management. The authors also state that signalling systems other than Hedgehog are likely involved.
Show evidence (1 reference)
PMID:24009529 SUPPORT Model Organism
"A number of these phenotypes can be attributed to alterations in Hedgehog signalling, although additional signalling systems are also likely to be involved."
Supports treating this model as informative for the transport-failure node while recording that Hedgehog is not the whole mechanism.
Show evidence (1 reference)
PMID:24009529 SUPPORT Model Organism
"We have identified a novel ENU mutant allele of Ift140, which causes a mid-gestation embryonic lethal phenotype in homozygous mutant mice."
Establishes the model's genotype and its lethality, which bounds what it can be used for.
{ }

Source YAML

click to show 
name: IFT140-related Recessive Ciliopathy
creation_date: '2026-06-28T12:00:00Z'
category: Mendelian
description: >
  IFT140-related recessive ciliopathy is an autosomal recessive disorder caused by
  biallelic mutations in IFT140, a core component of the intraflagellar transport
  complex A (IFT-A) that mediates retrograde protein transport within primary cilia.
  The phenotype spans a continuum from isolated, early-onset congenital retinal
  dystrophy (non-syndromic retinitis pigmentosa) to a systemic skeletal "conorenal"
  ciliopathy that overlaps Mainzer-Saldino syndrome and Jeune asphyxiating thoracic
  dystrophy, with the cardinal triad of phalangeal cone-shaped epiphyses, progressive
  chronic kidney disease, and severe retinal dystrophy. Because IFT140 is expressed
  more highly in kidney and retina than in skeleton, renal failure and retinal
  degeneration are the most penetrant features, while thoracic constriction is often
  mild relative to other short-rib skeletal ciliopathies.
disease_term:
  preferred_term: IFT140-related recessive ciliopathy
  term:
    id: MONDO:0100509
    label: IFT140-related recessive ciliopathy
parents:
- Ciliopathy
has_subtypes:
- name: Non-syndromic RP80
  display_name: Non-syndromic (isolated) retinal dystrophy — retinitis pigmentosa 80
  subtype_term:
    preferred_term: retinitis pigmentosa 80
    term:
      id: MONDO:0054708
      label: retinitis pigmentosa 80
  description: >-
    The milder pole of the IFT140 allelic continuum: an isolated, early-onset
    congenital retinal dystrophy (retinitis pigmentosa 80) without the systemic
    skeletal or renal features of the conorenal spectrum. A subset of biallelic
    IFT140 patients — including affected adults — have no evident extraocular
    disease and remain non-syndromic.
  genes:
  - preferred_term: IFT140
    term:
      id: hgnc:29077
      label: IFT140
  evidence:
  - reference: PMID:26359340
    reference_title: "The ophthalmic phenotype of IFT140-related ciliopathy ranges from isolated to syndromic congenital retinal dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      two older affected siblings in their twenties who remained non-syndromic and
      were excelling academically
    explanation: >-
      Documents biallelic IFT140 patients with isolated retinal disease and no
      extraocular involvement, defining the non-syndromic (RP80) pole.
- name: Syndromic Conorenal
  display_name: Syndromic conorenal ciliopathy (Mainzer-Saldino / Jeune-overlap)
  subtype_term:
    preferred_term: short-rib thoracic dysplasia 9 with or without polydactyly
    term:
      id: MONDO:0009964
      label: short-rib thoracic dysplasia 9 with or without polydactyly
  description: >-
    The systemic pole of the spectrum: a skeletal "conorenal" ciliopathy
    overlapping Mainzer-Saldino syndrome and Jeune asphyxiating thoracic
    dystrophy, with the cardinal triad of phalangeal cone-shaped epiphyses,
    progressive chronic kidney disease, and severe retinal dystrophy.
    MONDO:0009964 (short-rib thoracic dysplasia 9 with or without polydactyly) is
    the leaf term for this pole and now anchors it; this entry previously recorded
    that no such term had been identified. The "with or without polydactyly"
    qualifier in that term records the same variability captured by the Polydactyly
    phenotype below.
  genes:
  - preferred_term: IFT140
    term:
      id: hgnc:29077
      label: IFT140
  evidence:
  - reference: PMID:22503633
    reference_title: "Mainzer-Saldino syndrome is a ciliopathy caused by IFT140 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mainzer-Saldino syndrome (MSS) is a rare disorder characterized by phalangeal
      cone-shaped epiphyses, chronic renal failure, and early-onset, severe retinal
      dystrophy.
    explanation: >-
      Defines the syndromic conorenal triad (skeletal cone-shaped epiphyses, renal
      failure, retinal dystrophy) that distinguishes this pole from isolated RP80.
pathophysiology:
- name: IFT-A Retrograde Intraflagellar Transport Failure
  conforms_to: "ciliopathy_dysfunction#Basal Body and Transition Zone Dysfunction"
  description: >
    Biallelic IFT140 mutations disrupt the intraflagellar transport complex A
    (IFT-A), which drives retrograde (tip-to-base) protein transport along the
    ciliary axoneme. Loss of IFT140 function alters the ciliary abundance and
    localization of the transport machinery, impairing primary cilium assembly,
    maintenance, and signaling competence in ciliated cells. This molecular lesion
    is the shared upstream event from which the organ-specific renal, retinal, and
    skeletal phenotypes diverge.
  genes:
  - preferred_term: IFT140
    term:
      id: hgnc:29077
      label: IFT140
  biological_processes:
  - preferred_term: Retrograde Intraflagellar Transport
    term:
      id: GO:0035721
      label: intraciliary retrograde transport
  - preferred_term: Intraflagellar Transport
    term:
      id: GO:0042073
      label: intraciliary transport
  - preferred_term: Cilium Assembly
    term:
      id: GO:0060271
      label: cilium assembly
  cellular_components:
  - preferred_term: Primary Cilium
    term:
      id: GO:0005929
      label: cilium
  evidence:
  - reference: PMID:22503633
    reference_title: "Mainzer-Saldino syndrome is a ciliopathy caused by IFT140 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      IFT140 is one of the six currently known components of the intraflagellar
      transport complex A (IFT-A) that regulates retrograde protein transport in
      ciliated cells.
    explanation: >-
      Establishes IFT140 as an IFT-A subunit governing retrograde ciliary
      transport, the molecular basis of this ciliopathy.
  - reference: PMID:22503633
    reference_title: "Mainzer-Saldino syndrome is a ciliopathy caused by IFT140 mutations."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Ciliary abundance and localization of anterograde IFTs were altered in
      fibroblasts of affected individuals, a result that supports the pivotal role
      of IFT140 in proper development and function of ciliated cells.
    explanation: >-
      Patient fibroblasts show disrupted ciliary transport machinery, demonstrating
      the functional consequence of IFT140 loss on the primary cilium.
  downstream:
  - target: Photoreceptor Connecting Cilium Degeneration
  - target: Renal Tubular Cystic and Fibrotic Disease
  - target: Skeletal Dysplasia with Thoracic Constriction
- name: Photoreceptor Connecting Cilium Degeneration
  conforms_to: "ciliopathy_dysfunction#Photoreceptor Connecting Cilium Degeneration"
  description: >
    The photoreceptor connecting cilium is a specialized primary cilium that
    transports phototransduction proteins to the outer segment. IFT-A retrograde
    transport failure compromises this conduit, producing an early-onset, severe
    congenital retinal dystrophy that can occur in isolation (non-syndromic
    retinitis pigmentosa, RP80) or as part of the systemic conorenal phenotype.
  cell_types:
  - preferred_term: Photoreceptor Cell
    term:
      id: CL:0000210
      label: photoreceptor cell
  cellular_components:
  - preferred_term: Photoreceptor Connecting Cilium
    term:
      id: GO:0005929
      label: cilium
  evidence:
  - reference: PMID:26359340
    reference_title: "The ophthalmic phenotype of IFT140-related ciliopathy ranges from isolated to syndromic congenital retinal dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recessive IFT140 mutations cause a severe congenital retinal dystrophy with
      high hyperopia and often early photophilia.
    explanation: >-
      Documents the retinal-degeneration arm of the IFT140 ciliopathy spectrum
      arising from photoreceptor ciliary dysfunction.
  - reference: PMID:22503633
    reference_title: "Mainzer-Saldino syndrome is a ciliopathy caused by IFT140 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mainzer-Saldino syndrome (MSS) is a rare disorder characterized by phalangeal
      cone-shaped epiphyses, chronic renal failure, and early-onset, severe retinal
      dystrophy.
    explanation: >-
      Severe early-onset retinal dystrophy is a cardinal feature of the syndromic
      IFT140 phenotype.
  downstream:
  - target: Retinal Dystrophy
  - target: Nystagmus
- name: Renal Tubular Cystic and Fibrotic Disease
  conforms_to: "ciliopathy_dysfunction#Renal Tubular Cystic and Fibrotic Disease"
  description: >
    Primary cilia on renal tubular epithelial cells sense luminal flow and maintain
    tubular architecture. IFT140 deficiency disrupts this ciliary signaling, driving
    a nephronophthisis-like tubulointerstitial process with cystic and fibrotic
    change that progresses to end-stage renal disease, typically within the first
    decade of life. The severity mirrors the cystic kidney phenotype of Ift140
    conditional knockout mice and the high renal expression of IFT140.
  cell_types:
  - preferred_term: Renal Tubular Epithelial Cell
    term:
      id: CL:1000507
      label: kidney tubule cell
  cellular_components:
  - preferred_term: Primary Cilium
    term:
      id: GO:0005929
      label: cilium
  evidence:
  - reference: PMID:23418020
    reference_title: "Combined NGS approaches identify mutations in the intraflagellar transport gene IFT140 in skeletal ciliopathies with early progressive kidney Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      IFT140 patients presented with mild chest narrowing, but all had end-stage
      renal failure under 13 years of age and retinal dystrophy when examined for
      ocular dysfunction.
    explanation: >-
      Establishes early progressive renal failure as a near-universal, highly
      penetrant feature of IFT140-related ciliopathy.
  - reference: PMID:23418020
    reference_title: "Combined NGS approaches identify mutations in the intraflagellar transport gene IFT140 in skeletal ciliopathies with early progressive kidney Disease."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      This is consistent with the severe cystic phenotype of Ift140 conditional
      knockout mice
    explanation: >-
      A conditional Ift140 mouse knockout recapitulates the cystic renal phenotype,
      supporting the causal ciliary mechanism in the kidney.
  downstream:
  - target: Stage 5 Chronic Kidney Disease
- name: Skeletal Dysplasia with Thoracic Constriction
  conforms_to: "ciliopathy_dysfunction#Skeletal Dysplasia with Polydactyly and Thoracic Constriction"
  description: >
    Primary cilia transduce Hedgehog signaling required for endochondral
    ossification and growth-plate chondrocyte proliferation. IFT-A dysfunction
    perturbs ciliary Hedgehog signaling in chondrocytes, producing the skeletal
    features of the conorenal/Mainzer-Saldino spectrum, including phalangeal
    cone-shaped epiphyses and a constricted thorax. Thoracic narrowing is usually
    milder in IFT140 disease than in other short-rib skeletal ciliopathies.
  cell_types:
  - preferred_term: Chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  biological_processes:
  - preferred_term: Hedgehog Signaling
    term:
      id: GO:0007224
      label: smoothened signaling pathway
  evidence:
  - reference: PMID:22503633
    reference_title: "Mainzer-Saldino syndrome is a ciliopathy caused by IFT140 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mainzer-Saldino syndrome (MSS) is a rare disorder characterized by phalangeal
      cone-shaped epiphyses, chronic renal failure, and early-onset, severe retinal
      dystrophy.
    explanation: >-
      Phalangeal cone-shaped epiphyses are the cardinal skeletal manifestation of
      the syndromic IFT140 phenotype.
  - reference: PMID:23418020
    reference_title: "Combined NGS approaches identify mutations in the intraflagellar transport gene IFT140 in skeletal ciliopathies with early progressive kidney Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      IFT140 patients presented with mild chest narrowing, but all had end-stage
      renal failure under 13 years of age and retinal dystrophy when examined for
      ocular dysfunction.
    explanation: >-
      Documents the comparatively mild thoracic constriction characteristic of
      IFT140-related skeletal ciliopathy.
  downstream:
  - target: Cone-shaped Epiphysis
  - target: Thoracic Hypoplasia
phenotypes:
- name: Retinal Dystrophy
  description: >
    Severe, early-onset congenital retinal dystrophy with non-recordable
    electroretinography; may be isolated (non-syndromic) or syndromic.
  phenotype_term:
    preferred_term: Retinal dystrophy
    term:
      id: HP:0000556
      label: Retinal dystrophy
  evidence:
  - reference: PMID:26359340
    reference_title: "The ophthalmic phenotype of IFT140-related ciliopathy ranges from isolated to syndromic congenital retinal dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recessive IFT140 mutations cause a severe congenital retinal dystrophy with
      high hyperopia and often early photophilia.
    explanation: Severe congenital retinal dystrophy is a core feature of the IFT140 phenotype.
- name: Nystagmus
  description: >
    Nystagmus present from birth, reflecting the early, severe visual impairment.
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: PMID:26359340
    reference_title: "The ophthalmic phenotype of IFT140-related ciliopathy ranges from isolated to syndromic congenital retinal dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All had poor vision and nystagmus since birth, with visual acuity after 5
      years old of hand motions or light perception.
    explanation: Documents congenital nystagmus with profound visual loss in IFT140 patients.
- name: Stage 5 Chronic Kidney Disease
  subtype: Syndromic Conorenal
  description: >
    Progressive tubulointerstitial kidney disease reaching end-stage renal failure,
    typically within the first decade of life.
  phenotype_term:
    preferred_term: Stage 5 chronic kidney disease
    term:
      id: HP:0003774
      label: Stage 5 chronic kidney disease
  evidence:
  - reference: PMID:23418020
    reference_title: "Combined NGS approaches identify mutations in the intraflagellar transport gene IFT140 in skeletal ciliopathies with early progressive kidney Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      IFT140 patients presented with mild chest narrowing, but all had end-stage
      renal failure under 13 years of age and retinal dystrophy when examined for
      ocular dysfunction.
    explanation: Establishes early end-stage renal failure as a near-universal feature.
- name: Cone-shaped Epiphysis
  subtype: Syndromic Conorenal
  description: >
    Phalangeal cone-shaped epiphyses, the characteristic skeletal radiographic
    finding of the Mainzer-Saldino/conorenal phenotype.
  phenotype_term:
    preferred_term: Cone-shaped epiphysis
    term:
      id: HP:0010579
      label: Cone-shaped epiphysis
  evidence:
  - reference: PMID:22503633
    reference_title: "Mainzer-Saldino syndrome is a ciliopathy caused by IFT140 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mainzer-Saldino syndrome (MSS) is a rare disorder characterized by phalangeal
      cone-shaped epiphyses, chronic renal failure, and early-onset, severe retinal
      dystrophy.
    explanation: Phalangeal cone-shaped epiphyses are a cardinal feature of syndromic IFT140 disease.
- name: Thoracic Hypoplasia
  subtype: Syndromic Conorenal
  description: >
    Thoracic constriction from short ribs, typically milder than in other short-rib
    skeletal ciliopathies.
  phenotype_term:
    preferred_term: Thoracic hypoplasia
    term:
      id: HP:0005257
      label: Thoracic hypoplasia
  evidence:
  - reference: PMID:23418020
    reference_title: "Combined NGS approaches identify mutations in the intraflagellar transport gene IFT140 in skeletal ciliopathies with early progressive kidney Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      IFT140 patients presented with mild chest narrowing, but all had end-stage
      renal failure under 13 years of age and retinal dystrophy when examined for
      ocular dysfunction.
    explanation: Documents the comparatively mild thoracic constriction in IFT140 disease.
- name: High Hyperopia
  description: >
    High hyperopia (severe hypermetropia over +5.00 diopters) is a typical
    refractive finding in IFT140-related congenital retinal dystrophy.
  phenotype_term:
    preferred_term: High hyperopia
    term:
      id: HP:0008499
      label: High hypermetropia
  evidence:
  - reference: PMID:26359340
    reference_title: "The ophthalmic phenotype of IFT140-related ciliopathy ranges from isolated to syndromic congenital retinal dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      high hyperopia was typical, and electroretinography was
      non-recordable.
    explanation: High hyperopia is a typical refractive finding in IFT140-related retinal dystrophy.
- name: Developmental Delay
  description: >
    Developmental delay affects a majority of children with syndromic IFT140
    disease (8 of 12 in one cohort), though it is common but not universal.
  phenotype_term:
    preferred_term: Developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:26359340
    reference_title: "The ophthalmic phenotype of IFT140-related ciliopathy ranges from isolated to syndromic congenital retinal dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Eight children had developmental delay
    explanation: Developmental delay was documented in 8 of the children in the IFT140 ophthalmic cohort.
- name: Short Stature
  description: >
    Short stature is present in nearly all IFT140 patients and is likely
    secondary to renal insufficiency, contrasting with DYNC2H1-related disease.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:23418020
    reference_title: "Combined NGS approaches identify mutations in the intraflagellar transport gene IFT140 in skeletal ciliopathies with early progressive kidney Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All IFT140 patients but patient JATD2 were of short stature
    explanation: Short stature was present in all but one IFT140 patient, likely secondary to renal insufficiency.
- name: Polydactyly
  subtype: Syndromic Conorenal
  description: >
    Polydactyly occurs in this phenotype group but is not constant, which is what
    the "with or without polydactyly" qualifier in MONDO:0009964 records.
  phenotype_term:
    preferred_term: Polydactyly
    term:
      id: HP:0010442
      label: Polydactyly
  evidence:
  - reference: PMID:23418020
    reference_title: "Combined NGS approaches identify mutations in the intraflagellar transport gene IFT140 in skeletal ciliopathies with early progressive kidney Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other features that occur more variably are short long bones and polydactyly"
    explanation: Records polydactyly as a variable rather than constant feature of this phenotype group.
inheritance:
- name: Autosomal Recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >
    Autosomal recessive inheritance from biallelic (homozygous or compound
    heterozygous) IFT140 mutations.
  evidence:
  - reference: PMID:26359340
    reference_title: "The ophthalmic phenotype of IFT140-related ciliopathy ranges from isolated to syndromic congenital retinal dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Conorenal syndrome is a systemic skeletal ciliopathy characterised by skeletal
      and renal findings and caused by biallelic mutations in the gene intraflagellar
      transport 140 Chlamydomonas homologue (IFT140).
    explanation: Confirms biallelic (autosomal recessive) IFT140 inheritance.
genetic:
- name: IFT140 Biallelic Mutations
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  notes: >
    Biallelic IFT140 mutations cause a recessive ciliopathy spectrum spanning
    isolated congenital retinal dystrophy through the systemic conorenal
    (Mainzer-Saldino / Jeune-overlap) phenotype. IFT140 encodes a subunit of the
    retrograde IFT-A transport complex.
  gene_term:
    preferred_term: IFT140
    term:
      id: hgnc:29077
      label: IFT140
  evidence:
  - reference: PMID:22503633
    reference_title: "Mainzer-Saldino syndrome is a ciliopathy caused by IFT140 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Through a combination of ciliome resequencing and Sanger sequencing, we
      identified IFT140 mutations in six MSS families and in a family with the
      clinically overlapping Jeune syndrome.
    explanation: Identifies IFT140 as the causative gene across the MSS/Jeune-overlap spectrum.
  - reference: PMID:23418020
    reference_title: "Combined NGS approaches identify mutations in the intraflagellar transport gene IFT140 in skeletal ciliopathies with early progressive kidney Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      IFT140 is therefore a major cause of cono-renal syndromes (JATD and MSS).
    explanation: Establishes IFT140 as a major cause of the conorenal ciliopathy spectrum.
prevalence:
- population: Published literature worldwide
  percentage: Rare; precise population prevalence not established
  notes: >-
    IFT140-related ciliopathy is reported in small consanguineous family and
    fetal/clinical series rather than population registries; a recurrent founder
    allele (c.1990G>A) is described on the Arabian Peninsula.
  evidence:
  - reference: PMID:26359340
    reference_title: "The ophthalmic phenotype of IFT140-related ciliopathy ranges from isolated to syndromic congenital retinal dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The c.1990G>A mutation represents a founder effect or mutational hotspot on
      the Arabian Peninsula.
    explanation: Supports rarity and a regional founder effect rather than a common, registry-defined disorder.
diagnosis:
- name: Clinical and Radiographic Conorenal Diagnosis
  description: >-
    The syndromic conorenal/Mainzer-Saldino pole is recognized clinically and
    radiographically by phalangeal cone-shaped epiphyses with chronic renal
    failure and early severe retinal dystrophy; Jeune-overlap cases may show
    mild chest narrowing with prominent renal and retinal disease.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  evidence:
  - reference: PMID:22503633
    reference_title: "Mainzer-Saldino syndrome is a ciliopathy caused by IFT140 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mainzer-Saldino syndrome (MSS) is a rare disorder characterized by
      phalangeal cone-shaped epiphyses, chronic renal failure, and early-onset,
      severe retinal dystrophy.
    explanation: >-
      Defines the core clinical/radiographic triad used to recognize the
      conorenal IFT140 phenotype.
  - reference: PMID:23418020
    reference_title: "Combined NGS approaches identify mutations in the intraflagellar transport gene IFT140 in skeletal ciliopathies with early progressive kidney Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      IFT140 patients presented with mild chest narrowing, but all had end-stage
      renal failure under 13 years of age and retinal dystrophy when examined for
      ocular dysfunction.
    explanation: >-
      Supports the Jeune-overlap diagnostic pattern of mild thoracic narrowing
      with early severe renal and retinal involvement.
- name: Molecular Genetic Confirmation and IFT140 Screening
  description: >-
    Molecular diagnosis is established by identifying biallelic IFT140 mutations.
    IFT140 should be prioritized in skeletal ciliopathy-spectrum patients,
    especially JATD/MSS presentations with kidney disease with or without retinal
    involvement. A single pathogenic variant on panel or exome sequencing does not
    exclude the diagnosis: a recurrent exons 27-30 tandem duplication is missed by
    both, and was found only on genome sequencing in one patient and then by
    targeted screening for that duplication in a second. In a clinically convincing
    patient with one variant, look for the second by a method that can see a
    structural change.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:22503633
    reference_title: "Mainzer-Saldino syndrome is a ciliopathy caused by IFT140 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Through a combination of ciliome resequencing and Sanger sequencing, we
      identified IFT140 mutations in six MSS families and in a family with the
      clinically overlapping Jeune syndrome.
    explanation: >-
      Supports IFT140 molecular testing as confirmatory across the
      Mainzer-Saldino/Jeune-overlap spectrum.
  - reference: PMID:23418020
    reference_title: "Combined NGS approaches identify mutations in the intraflagellar transport gene IFT140 in skeletal ciliopathies with early progressive kidney Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The present study strengthens the rationale for IFT140 screening in
      skeletal ciliopathy spectrum patients that have kidney disease and/or
      retinal dystrophy.
    explanation: >-
      Directly supports prioritizing IFT140 screening in skeletal ciliopathy
      patients with renal and/or retinal involvement.
  - reference: DOI:10.3390/genes14081553
    reference_title: "Rare IFT140-Associated Phenotype of Cranioectodermal Dysplasia and Features of Diagnostic Journey in Patients with Suspected Ciliopathies"
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "In both cases, at first only one pathogenic variant was detected following panel or exome NGS sequencing."
    explanation: >-
      The reason a single variant on panel or exome testing does not exclude
      IFT140 disease - in both of these patients the second allele was invisible
      to the first-line assay.
  - reference: DOI:10.3390/genes14081553
    reference_title: "Rare IFT140-Associated Phenotype of Cranioectodermal Dysplasia and Features of Diagnostic Journey in Patients with Suspected Ciliopathies"
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Further WGS was performed for one of them where tandem duplication was found."
    explanation: >-
      Names the assay that recovered the missed allele, which is what makes this
      caveat actionable rather than merely cautionary.
- name: Ophthalmic Diagnostic Evaluation
  description: >-
    Ophthalmic evaluation can identify the IFT140 retinal phenotype, including
    severe congenital retinal dystrophy with poor vision and nystagmus from
    birth, typical high hyperopia, and non-recordable electroretinography.
  diagnosis_term:
    preferred_term: ophthalmic diagnostic procedure
    term:
      id: NCIT:C38060
      label: Eye Examination
  evidence:
  - reference: PMID:26359340
    reference_title: "The ophthalmic phenotype of IFT140-related ciliopathy ranges from isolated to syndromic congenital retinal dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All had poor vision and nystagmus since birth
    explanation: >-
      Defines the early severe visual presentation that can prompt ophthalmic
      evaluation for IFT140-related retinal dystrophy.
  - reference: PMID:26359340
    reference_title: "The ophthalmic phenotype of IFT140-related ciliopathy ranges from isolated to syndromic congenital retinal dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      high hyperopia was typical, and electroretinography was non-recordable.
    explanation: >-
      Supports high hyperopia and non-recordable electroretinography as
      ophthalmic diagnostic findings in IFT140-related disease.
treatments:
- name: Renal Replacement Therapy
  description: >
    Progressive kidney disease in IFT140-related ciliopathy reaches end-stage renal
    failure in childhood, necessitating dialysis and kidney transplantation as
    definitive renal-replacement management.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: organ transplantation
    term:
      id: NCIT:C15289
      label: Organ Transplantation
  evidence:
  - reference: PMID:23418020
    reference_title: "Combined NGS approaches identify mutations in the intraflagellar transport gene IFT140 in skeletal ciliopathies with early progressive kidney Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      IFT140 patients presented with mild chest narrowing, but all had end-stage
      renal failure under 13 years of age and retinal dystrophy when examined for
      ocular dysfunction.
    explanation: >-
      Universal early end-stage renal failure establishes the indication for
      renal-replacement therapy (dialysis and transplantation).
- name: Low Vision Supportive Care
  description: >
    Severe congenital retinal dystrophy with profound visual impairment is managed
    with low-vision rehabilitation, optical correction of the typical high hyperopia,
    and educational/developmental support.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:26359340
    reference_title: "The ophthalmic phenotype of IFT140-related ciliopathy ranges from isolated to syndromic congenital retinal dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All had poor vision and nystagmus since birth, with visual acuity after 5
      years old of hand motions or light perception.
    explanation: >-
      Profound early visual loss establishes the need for low-vision supportive
      management.
- name: Genetic Counseling
  description: >
    Autosomal recessive inheritance with a 25% recurrence risk warrants genetic
    counseling, carrier/cascade testing, and discussion of reproductive options
    including prenatal and preimplantation genetic diagnosis.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:26359340
    reference_title: "The ophthalmic phenotype of IFT140-related ciliopathy ranges from isolated to syndromic congenital retinal dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Conorenal syndrome is a systemic skeletal ciliopathy characterised by skeletal
      and renal findings and caused by biallelic mutations in the gene intraflagellar
      transport 140 Chlamydomonas homologue (IFT140).
    explanation: >-
      Biallelic (autosomal recessive) inheritance underpins recurrence-risk
      counseling and cascade testing.

animal_models:
- name: Cauli mouse (Ift140 ENU allele)
  species: Mouse
  genotype: Ift140 ENU-induced mutation, homozygous
  publication: PMID:24009529
  description: >-
    An ENU-induced Ift140 allele causing mid-gestation embryonic lethality in
    homozygotes, presented by its authors as a model of Jeune syndrome. The same
    report identified a homozygous recessive IFT140 variant in a Jeune syndrome
    patient.
  modeled_mechanisms:
  - target: IFT-A Retrograde Intraflagellar Transport Failure
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Mutant embryos show craniofacial dysmorphism, digit anomalies, cardiac anomalies
      and somite patterning defects, a number of which the authors attribute to altered
      Hedgehog signalling.
    limitations: >-
      Homozygotes die in mid-gestation with neural tube defects and cardiac anomalies
      that are not features of the human disease, so the model cannot report on the
      postnatal renal and retinal course that dominates human management. The authors
      also state that signalling systems other than Hedgehog are likely involved.
    evidence:
    - reference: PMID:24009529
      reference_title: "Cauli: a mouse strain with an Ift140 mutation that results in a skeletal ciliopathy modelling Jeune syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "A number of these phenotypes can be attributed to alterations in Hedgehog signalling, although additional signalling systems are also likely to be involved."
      explanation: Supports treating this model as informative for the transport-failure node while recording that Hedgehog is not the whole mechanism.
  evidence:
  - reference: PMID:24009529
    reference_title: "Cauli: a mouse strain with an Ift140 mutation that results in a skeletal ciliopathy modelling Jeune syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We have identified a novel ENU mutant allele of Ift140, which causes a mid-gestation embryonic lethal phenotype in homozygous mutant mice."
    explanation: Establishes the model's genotype and its lethality, which bounds what it can be used for.
discussions:
- discussion_id: ift140_biallelic_vs_monoallelic_adpkd
  kind: INTERPRETATION
  attaches_to:
  - disease#
  - genetic#IFT140 Biallelic Mutations
  prompt: >-
    How should this biallelic IFT140 ciliopathy be kept separate from the monoallelic
    IFT140 cystic kidney phenotype?
  rationale: >-
    Monoallelic IFT140 loss of function causes a mild autosomal dominant polycystic
    kidney phenotype that is common enough to rank behind only PKD1 and PKD2 among
    cystic kidney disease probands. It shares a gene with this entry but is a
    different disease with different inheritance, severity and organ involvement, and
    the two are easy to conflate in a gene-first search. This entry is the biallelic
    recessive ciliopathy only. IFT140 also sits about 0.5 Mb from PKD1 at 16p13.3,
    which is a recognised source of diagnostic confusion, and PKD1 variants may modify
    the IFT140 phenotype.
  evidence:
  - reference: PMID:34890546
    reference_title: "Monoallelic IFT140 pathogenic variants are an important cause of the autosomal dominant polycystic kidney-spectrum phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "bi-allelic IFT140 variants cause the syndromic ciliopathy, short-rib thoracic dysplasia (SRTD9)"
    explanation: States the biallelic requirement for the syndromic ciliopathy and distinguishes it from the monoallelic phenotype described in the same paper.
  - reference: PMID:34890546
    reference_title: "Monoallelic IFT140 pathogenic variants are an important cause of the autosomal dominant polycystic kidney-spectrum phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The distinctive monoallelic phenotype is mild PKD with large cysts, limited kidney insufficiency, and few liver cysts."
    explanation: Characterises the separate monoallelic phenotype that must not be merged into this entry.
  - reference: PMID:34890546
    reference_title: "Monoallelic IFT140 pathogenic variants are an important cause of the autosomal dominant polycystic kidney-spectrum phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The proximity of IFT140 to PKD1 (∼0.5 Mb) in 16p13.3 can cause diagnostic confusion, and PKD1 variants could modify the IFT140 phenotype."
    explanation: Documents the locus proximity that creates diagnostic confusion and a possible modifier effect.