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Classifications

ISDS Skeletal Nosology

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Inheritance

1

Autosomal recessive inheritance HP:0000007

Biallelic KIAA0753 variants, homozygous in consanguineous families and compound heterozygous elsewhere. Most reported alleles predict premature truncation, but splice-altering and missense alleles occur, including a synonymous change that creates a cryptic splice site.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:34523780 SUPPORT Human clinical

"The majority of reported KIAA0753 variants predict premature truncation of the KIAA0753 protein."

Describes the predominant allele class across reported patients.

PMID:29138412 SUPPORT Human clinical

"We report biallelic pathogenic variants in KIAA0753 in four patients with short-rib type skeletal dysplasia."

Establishes the biallelic requirement in the skeletal cases.

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Discussions and Knowledge Gaps

4

What determines whether biallelic KIAA0753 variants produce a short-rib skeletal ciliopathy, Joubert syndrome, or orofaciodigital syndrome type 6, given that all three arise from the same class of truncating allele and that individual patients carry features of more than one?

KNOWLEDGE GAP OPEN gap_srtd21_which_phenotype

Attached to

genetic#KIAA0753 pathophysiology#Defective Basal Body Docking and Ciliogenesis pathophysiology#Cerebellar and CNS Involvement

The three labels were assigned by which organ system dominated in the first patients described under each, not by an allele-level or mechanistic distinction. Truncating variants appear in all three groups. Two of the four patients in the skeletal discovery series had the molar tooth sign, which is the defining feature of the second label; the report of the eighth patient said outright that this gene shows how one locus presents as apparently distinct syndromes. Variant-level functional testing has been done, and it finds that every patient allele tested is deficient in supporting ciliogenesis - which explains why they all cause disease but not why they cause different diseases. With thirteen reported individuals across all three phenotypes there is no prospect of a genotype-phenotype analysis powered to settle it. The practical consequence for this knowledge base is that a citation about this gene must be checked for which presentation it describes.

Show evidence (2 references)

PMID:31816441 SUPPORT Human clinical

"This case provides confirmation of an additional molecular basis for skeletal dysplasia and illustrates how ciliopathies due to mutations in a single gene may present as apparently distinct syndromes."

States the problem the gap describes.

PMID:34523780 SUPPORT Human clinical

"The phenotypic spectrum associated with biallelic pathogenic variants in KIAA0753 is broad and not well-characterized."

The authors' own assessment that the spectrum is not characterised.

Does the Hedgehog signalling defect measured in KIAA0753 patient fibroblasts represent what happens in the growth-plate chondrocyte, the cell in which the disease actually manifests?

HUMAN MODEL MISMATCH OPEN gap_srtd21_chondrocyte_model

Attached to

pathophysiology#Impaired Hedgehog Signal Transduction pathophysiology#Growth Plate Zonal Disorganisation

Every functional measurement for this disorder was made in fibroblasts or in immortalised human cell lines. The disease is a chondrodysplasia, and the one direct observation in the affected tissue - the disorganised proliferative zone and broadened hypertrophic zone in a single fetus - is histology, not a signalling measurement. The gap is not that the fibroblast result is unreliable; it is that Hedgehog signalling in the growth plate has a different ligand source, a different receiving cell and a different transcriptional output, and no chondrocyte or cartilage model carrying a KIAA0753 genotype has been reported. Neither animal model closes the gap. The zebrafish shows altered cartilage patterning in an animal with no mammalian endochondral growth plate, and dies early. The Mnr-null mouse does have the mammalian skeleton, and it does show the Hedgehog defect directly - but it was characterised at E8.5 to E9.5, before the skeleton forms, and that measurement was again made in fibroblasts. Until a chondrocyte model exists, or the mouse is taken to a skeletal timepoint, the step from measured signalling defect to observed growth plate lesion is an inference. The Inskeep signaling experiments used fibroblasts from Joubert-presenting patient 1, not the skeletal-presenting patient 3, adding a presentation mismatch to the tissue mismatch.

Show evidence (2 references)

PMID:34523780 SUPPORT In vitro / ex vivo

"Correspondingly, KIAA0753 patient fibroblasts have a deficit in primary ciliation and improper SHH and WNT signaling, with a particularly blunted response to SHH pathway stimulation."

Names the cell type in which the signalling defect was actually measured.

PMID:29138412 SUPPORT Human clinical

"We demonstrate that KIAA0753 is expressed in normal fetal human growth plate and show that the affected fetus, with a compound heterozygous frameshift and a nonsense mutation in KIAA0753, has an abnormal proliferative zone and a broad hypertrophic zone."

The single direct observation in the affected tissue, which is histological rather than functional.

How much of the developmental impairment in discovery-series P1 and P2 is due to KIAA0753 versus their additional SLC13A5 diagnosis?

KNOWLEDGE GAP OPEN srtd21_slc13a5_confounded_findings

Attached to

phenotypes#Global developmental delay phenotypes#Delayed speech and language development phenotypes#Delayed gross motor development

Both cousins carry homozygous SLC13A5 p.Thr142Met as well as KIAA0753 variants. The authors assign their seizures and teeth hypoplasia to SLC13A5, so neither is curated here as a KIAA0753 phenotype. Developmental and speech delay remain associated with the skeletal presentation through independent patients, but the cousins cannot establish a KIAA0753-specific frequency or severity.

Show evidence (1 reference)

PMID:29138412 SUPPORT Human clinical

"We thus conclude that the seizures and teeth hypoplasia in P1 and P2 are due to the homozygous SLC13A5 variant, while the developmental and speech delay is an overlapping feature and could be inferable to either one of the congenital conditions."

Explicit attribution of dental hypoplasia and seizures to the second diagnosis, with developmental attribution unresolved.

Which mechanisms explain the remaining craniofacial, neurologic, sensory, genital and associated skeletal findings in the KIAA0753 skeletal presentation?

KNOWLEDGE GAP OPEN srtd21_unresolved_clinical_routes

Attached to

phenotypes#Trident pelvis phenotypes#Feeding difficulties phenotypes#Global developmental delay phenotypes#Hypotonia phenotypes#Molar tooth sign on MRI phenotypes#Delayed speech and language development phenotypes#Delayed gross motor development phenotypes#Flexion contracture phenotypes#Protuberant abdomen phenotypes#Hypoplasia of the corpus callosum phenotypes#Ventriculomegaly phenotypes#Small pituitary gland phenotypes#Macrocephaly phenotypes#Frontal bossing phenotypes#Flat face phenotypes#Depressed nasal bridge phenotypes#Pectus carinatum phenotypes#Pectus excavatum phenotypes#Cervical spinal canal stenosis phenotypes#Hepatomegaly phenotypes#Pulmonary hypertension phenotypes#Low-set ears phenotypes#Anteverted nares phenotypes#Micrognathia phenotypes#Wide nasal bridge phenotypes#Long philtrum phenotypes#Ankyloglossia phenotypes#Micropenis phenotypes#Hypospadias phenotypes#Cryptorchidism phenotypes#Cone-rod dystrophy phenotypes#Nystagmus phenotypes#Conductive hearing impairment phenotypes#Leg-length discrepancy phenotypes#Developmental regression phenotypes#Respiratory ciliary dyskinesia

Case reports establish these findings but do not resolve feature-specific causal routes. The broad CNS node and the mouse granule-neuron study do not explain every brain-imaging, developmental or sensory finding. In particular, motor and speech findings in two cousins are confounded by SLC13A5, while regression, hearing loss and motile-cilia dyskinesia come from a later single case. Thoracic restriction does not by itself establish the cause of feeding difficulty, pulmonary hypertension, hepatomegaly, pectus deformity or abdominal prominence. These are clinical gaps, not laboratory readouts; occurrence alone does not justify a causal arrow.

Show evidence (2 references)

PMID:34523780 SUPPORT Human clinical

"The phenotypic spectrum associated with biallelic pathogenic variants in KIAA0753 is broad and not well-characterized."

The clinical spectrum and its mechanistic subdivision remain incompletely characterized.

PMID:34016807 SUPPORT Human clinical

"Our case is the eldest woman reported to date (aged ten years) and the only known case to report associated hearing loss, leg-length discrepancy, pectus carinatum, respiratory ciliary dyskinesia and late-onset (9 years old) neuro-degenerative regression."

The later skeletal case adds uncommon multisystem findings without identifying their individual mechanisms.

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Pathophysiology

8

Biallelic KIAA0753 Loss-of-Function Variants

Nonsense, frameshift and splice-altering variants on both KIAA0753 alleles. Truncating alleles predominate. Splice-altering alleles are easy to miss: two Pakistani families sharing an 85 kb homozygous block carried a synonymous c.810C>T change that turned out to activate abnormal splicing, which was only demonstrated by sequencing cDNA.

KIAA0753 hgnc:29110

Downstream

Defective Basal Body Docking and Ciliogenesis Loss of the protein removes the recruitment platform at the distal centriole on which cilium assembly depends.

Show evidence (2 references)

PMID:34523780 SUPPORT Human clinical

"The majority of reported KIAA0753 variants predict premature truncation of the KIAA0753 protein."

Establishes the predominant class of disease allele.

PMID:33875766 SUPPORT Human clinical

"Four variants located in non-canonical splice sites of DYNC2H1, EVC, and KIAA0753 led to aberrant splicing that was shown by sequencing of cDNA."

Documents splice-altering KIAA0753 alleles confirmed at the transcript level.

Defective Basal Body Docking and Ciliogenesis

KIAA0753 forms a ternary complex with OFD1 and FOPNL (FOR20) at centrosomes and pericentriolar satellites, and it acts upstream of them: mammalian centrioles need Moonraker to recruit OFD1, FOPNL and CEP90, which then place the distal appendage proteins CEP83, CEP89 and CEP164. Distal appendages are what dock the basal body to the plasma membrane, the step that permits a cilium to be built at all. The protein also has microtubule-stabilising activity. In patients the result is a measurable deficit in ciliation: fibroblasts from affected individuals make fewer primary cilia, and ablating the gene in vitro blocks ciliogenesis outright. This node substitutes a docking and appendage-assembly defect for the module's generic basal body lesion. Intraflagellar transport is not the primary lesion here, which is what separates this disorder from the IFT and dynein-2 forms of short-rib thoracic dysplasia.

cilium assembly GO:0060271 ↓ DECREASED protein localization to cilium GO:0061512 ⚠ ABNORMAL

centriolar satellite GO:0034451 ciliary basal body GO:0036064

Experimental models

KIAA0753 patient fibroblasts and knockout cell lines PRIMARY CELL CULTURE Patient fibroblasts carry the actual disease genotypes and show the ciliation deficit directly; depleting any member of the ternary complex in RPE1 cells reproduces the recruitment failure.

Animal models

Mnr-null mouse (Kiaa0753 knockout) Mouse recapitulates Loss of Mnr abolishes ciliogenesis in vivo and in embryo-derived fibroblasts, which is the same lesion patient fibroblasts show.

Downstream

Impaired Hedgehog Signal Transduction Without a competent primary cilium the Hedgehog pathway cannot be transduced.

Cerebellar and CNS Involvement Mouse cerebellar experiments implicate centriolar KIAA0753 recruitment in granule-neuron progenitor differentiation. Translation to individual brain abnormalities in skeletal patients is unresolved; this supports a CNS developmental branch without explaining every clinical finding.

Show evidence (3 references)

PMID:26643951 SUPPORT In vitro / ex vivo

"We show that the KIAA0753/OFIP protein, whose sequence is conserved in ciliated species, associates with centrosome/centriole and pericentriolar satellites in human cells and forms a complex with FOR20 and OFD1."

Establishes the localisation and the ternary complex this node is built on.

PMID:36070319 SUPPORT In vitro / ex vivo

"Finally, we show that mammalian centrioles require another component, Moonraker (MNR), to recruit OFD1, FOPNL, and CEP90, which will then recruit the distal appendage proteins CEP83, CEP89, and CEP164."

Places KIAA0753/Moonraker upstream of the distal appendage assembly cascade, which is the specific mechanism this node asserts.

PMID:34523780 SUPPORT In vitro / ex vivo

"Ablation of KIAA0753 in vitro blocks primary ciliogenesis and SHH pathway activity."

KIAA0753 ablation abolishes primary ciliogenesis in mouse NIH3T3 fibroblasts, a cell-culture experiment.

Impaired Hedgehog Signal Transduction

KIAA0753-null mouse NIH3T3 cells fail to induce Gli1 after Smoothened agonist treatment. Fibroblasts from the Joubert-presenting patient 1 in the Inskeep series show reduced ciliation and a blunted SHH response with altered aspects of WNT signaling. These results support gene function but are not direct measurements in skeletal-patient growth plates.

smoothened signaling pathway GO:0007224 ↓ DECREASED Wnt signaling pathway GO:0016055 ⚠ ABNORMAL

Experimental models

KIAA0753 patient fibroblasts and knockout cell lines PRIMARY CELL CULTURE Hedgehog pathway output is measured directly in patient fibroblasts and in KIAA0753-ablated cells.

Animal models

Mnr-null mouse (Kiaa0753 knockout) Mouse recapitulates Fibroblasts from Mnr-null embryos fail to induce the Hedgehog target genes Gli1 and Ptch1 in response to a Smoothened agonist.

Downstream

Growth Plate Zonal Disorganisation Hedgehog signalling controls chondrocyte proliferation and the timing of hypertrophy in the growth plate.

Show evidence (1 reference)

PMID:34523780 SUPPORT In vitro / ex vivo

"Correspondingly, KIAA0753 patient fibroblasts have a deficit in primary ciliation and improper SHH and WNT signaling, with a particularly blunted response to SHH pathway stimulation."

Measures both signalling defects in cells carrying patient genotypes, and records that the Hedgehog response is the more severely affected.

Growth Plate Zonal Disorganisation

The distal femoral growth plate of the affected fetus had disorganized proliferative columns and a broad hypertrophic zone, with absent KIAA0753 staining in proliferative chondrocytes. The authors infer that impaired ciliary and centrosomal function disrupts growth-plate organization and causes abnormal skeletal growth. The contribution of Hedgehog signaling is inferred from other tissues and experimental systems.

chondrocyte CL:0000138 hypertrophic chondrocyte CL:0000743

growth plate cartilage development GO:0003417 ⚠ ABNORMAL

epiphyseal plate UBERON:0002516

Animal models

kiaa0753 nonsense zebrafish Zebrafish partially recapitulates The embryos have abnormal cartilage patterning and abnormal head morphology, establishing that the gene is required for cartilage development.

Downstream

Short Ribs and Thoracic Constriction Disordered endochondral growth shortens the ribs and the tubular bones.

Short long bone Abnormal growth-plate organization impairs longitudinal endochondral growth and bone shape; the exact route to this individual radiographic feature has not been separately measured.

Metaphyseal irregularity Abnormal growth-plate organization impairs longitudinal endochondral growth and bone shape; the exact route to this individual radiographic feature has not been separately measured.

Cone-shaped epiphysis Abnormal growth-plate organization impairs longitudinal endochondral growth and bone shape; the exact route to this individual radiographic feature has not been separately measured.

Brachydactyly Abnormal growth-plate organization impairs longitudinal endochondral growth and bone shape; the exact route to this individual radiographic feature has not been separately measured.

Rhizomelia Abnormal growth-plate organization impairs longitudinal endochondral growth and bone shape; the exact route to this individual radiographic feature has not been separately measured.

Disproportionate short-limb short stature Abnormal growth-plate organization impairs longitudinal endochondral growth and bone shape; the exact route to this individual radiographic feature has not been separately measured.

Bowing of the long bones Abnormal growth-plate organization impairs longitudinal endochondral growth and bone shape; the exact route to this individual radiographic feature has not been separately measured.

Genu varum Abnormal growth-plate organization produces limb deformity. Varus angulation is one reported manifestation, although its regional growth dynamics were not measured.

Show evidence (1 reference)

PMID:29138412 SUPPORT Human clinical

"We demonstrate that KIAA0753 is expressed in normal fetal human growth plate and show that the affected fetus, with a compound heterozygous frameshift and a nonsense mutation in KIAA0753, has an abnormal proliferative zone and a broad hypertrophic zone."

The direct histological observation this node records, in human tissue.

Short Ribs and Thoracic Constriction

Short, broad ribs with cupped anterior ends give a narrow thorax; the tubular bones are short with metaphyseal irregularity and cone-shaped epiphyses, and the pelvis shows the trident appearance characteristic of the group. This node substitutes the polydactyly-free presentation for the module's generic skeletal node: polydactyly is in the module's node name and is absent here, which is what the disorder's own name records.

rib UBERON:0002228 thoracic rib cage UBERON:0003252

Downstream

Respiratory Insufficiency from Thoracic Restriction A thorax too small to expand adequately restricts ventilation from birth.

Pulmonary Hypoplasia A thorax that never reaches normal volume constrains lung growth in utero, so the lungs are underdeveloped at birth rather than merely poorly ventilated.

Short ribs Clinical expression of the short-rib thoracic skeletal lesion described in this node.

Narrow chest Clinical expression of the short-rib thoracic skeletal lesion described in this node.

Thoracic hypoplasia Clinical expression of the short-rib thoracic skeletal lesion described in this node.

Show evidence (1 reference)

PMID:31816441 SUPPORT Human clinical

"On skeletal survey, short tubular bones (height - 5,5 SD) and a trident appearance of the pelvis were seen."

Records the short tubular bones and trident pelvis in a KIAA0753 patient.

Pulmonary Hypoplasia

Underdeveloped lungs at birth, the developmental consequence of a thorax that is too small during fetal lung growth. It sits between the skeletal lesion and the respiratory failure and is what distinguishes this disorder's respiratory course from simple mechanical restriction of normal lungs: in the one skeletally-presenting patient reported in detail it required NICU management from birth alongside pulmonary hypertension, and he died at two weeks.

lung UBERON:0002048

Downstream

Respiratory Insufficiency from Thoracic Restriction Lungs that never developed to normal volume cannot meet postnatal gas exchange demand, compounding the mechanical restriction.

Pulmonary hypoplasia Clinical manifestation of the pulmonary developmental lesion documented in the skeletal-presenting infant.

Show evidence (2 references)

PMID:34523780 SUPPORT Human clinical

"He had macrocephaly (head circumference 37 cm, > 2 SD). He was admitted to the NICU for management of pulmonary hypoplasia and pulmonary hypertension."

Records pulmonary hypoplasia requiring neonatal intensive care in the skeletal presentation.

PMID:34523780 SUPPORT Human clinical

"He died at 2 weeks of age due to severe pulmonary hypertension."

The outcome in the same patient, which is why this node is curated as the lethal step rather than an incidental finding.

Respiratory Insufficiency from Thoracic Restriction

Thoracic restriction and pulmonary hypoplasia contribute to respiratory insufficiency from birth in severe cases. Reported outcomes also include respiratory failure after infection and neonatal death due to pulmonary hypertension, so thoracic size alone does not establish the terminal mechanism. One skeletal patient additionally had confirmed respiratory ciliary dyskinesia with recurrent chest infections, a separate route to respiratory disease.

Downstream

Respiratory insufficiency Restricted thoracic expansion and reduced lung volume account for respiratory insufficiency in the severe skeletal presentation.

Show evidence (2 references)

PMID:31816441 SUPPORT Human clinical

"This 4 year-old boy with narrow thorax, short limbs, severe respiratory and feeding difficulties from birth on had a history of hypotonia and developmental delay."

Documents the respiratory phenotype from birth.

PMID:34016807 SUPPORT INDIRECT Human clinical

"Our case is the eldest woman reported to date (aged ten years) and the only known case to report associated hearing loss, leg-length discrepancy, pectus carinatum, respiratory ciliary dyskinesia and late-onset (9 years old) neuro-degenerative regression."

Supports the second, motile-cilia route named in this node's description rather than the thoracic-restriction route: confirmed respiratory ciliary dyskinesia with recurrent chest infections. The quoted sentence states in the same breath that this has been seen in one patient only, so it does not generalise.

Cerebellar and CNS Involvement

KIAA0753 depletion in mouse cerebellar granule-neuron progenitors impairs differentiation and germinal-zone exit. The authors propose that this contributes to cerebellar hypoplasia in Joubert syndrome. Inferior vermis hypoplasia/dysplasia and molar tooth sign also occur in skeletal patients, supporting an overlapping cerebellar developmental branch. Callosal, ventricular and pituitary anomalies, hypotonia and developmental delay are associated clinical findings whose individual causal routes remain unresolved.

cerebellar vermis UBERON:0004720

Downstream

Cerebellar vermis hypoplasia Defective cerebellar neurogenesis provides a literature-supported candidate route to vermian underdevelopment in skeletal/Joubert overlap patients; human tissue confirmation is lacking.

Show evidence (3 references)

PMID:29138412 SUPPORT Human clinical

"In addition two of our patients showed brain abnormalities consistent with JBTS."

Records the CNS involvement within the skeletal case series, and its frequency there.

PMID:34016807 SUPPORT Human clinical

"We describe a ninth case that expands the phenotype; a 10-year-old girl with rhizomelic short stature (-5.6 SD), macrocephaly, developmental delay, CNS anomalies (thin corpus callosum, bilateral ventriculomegaly), cone-rod dystrophy, nystagmus, mild conductive hearing loss and recurrent chest..."

Documents the structural CNS findings alongside the skeletal phenotype in one patient.

PMID:34711653 SUPPORT INDIRECT Model organism

"Together, our data reveal a close interplay between CEP120 and KIAA0753 for the germinal zone exit and timely neuronal differentiation of GNPs during cerebellar development, and mutations in CEP120 and KIAA0753 may participate in the heterotopia and cerebellar hypoplasia observed in JS patients."

The authors interpret mouse neuronal-development experiments as a possible explanation for human cerebellar hypoplasia. Extension to the vermian hypoplasia of skeletal/Joubert overlap patients remains indirect.

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Pathograph

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Phenotypes

51

Cardiovascular 1

Pulmonary hypertension Pulmonary arterial hypertension HP:0002092

The Inskeep skeletal infant also carried a RUNX2 in-frame deletion classified as a variant of uncertain significance, inherited from his phenotypically normal father; the authors identified biallelic truncating KIAA0753 variants as the diagnosis.

Show evidence (1 reference)

PMID:34523780 SUPPORT Human clinical

"He died at 2 weeks of age due to severe pulmonary hypertension."

Documents this finding in a molecularly confirmed skeletal presentation; no disease-wide frequency is inferred.

Digestive 3

Feeding difficulties HP:0011968

Show evidence (1 reference)

PMID:31816441 SUPPORT Human clinical

"This 4 year-old boy with narrow thorax, short limbs, severe respiratory and feeding difficulties from birth on had a history of hypotonia and developmental delay."

Records severe feeding difficulties from birth alongside the respiratory ones.

Protuberant abdomen 3/4 HP:0001538

Show evidence (1 reference)

PMID:29138412 SUPPORT Human clinical

"He had disproportionate short stature (Supplementary Table S1), speech delay, pectus carinatum, narrow chest, protuberant abdomen and short limbs (Figs 1e and 2g,h,k, Table 1)."

The clinical description directly records a protuberant abdomen in P3; Table 1 also records this in P1 and P4.

Hepatomegaly HP:0002240

Show evidence (1 reference)

PMID:31816441 SUPPORT Human clinical

"Renal function was normal and moderate hepatomegaly was noted."

Documents this finding in a molecularly confirmed skeletal presentation; no disease-wide frequency is inferred.

Ear 2

Low-set ears HP:0000369

Show evidence (1 reference)

PMID:34523780 SUPPORT Human clinical

"Physical exam was notable for frontal bossing, low-set ears, anteverted nares, and macrocephaly."

Documents this finding in a molecularly confirmed skeletal presentation; no disease-wide frequency is inferred.

Conductive hearing impairment HP:0000405

Show evidence (1 reference)

PMID:34016807 SUPPORT Human clinical

"We describe a ninth case that expands the phenotype; a 10-year-old girl with rhizomelic short stature (-5.6 SD), macrocephaly, developmental delay, CNS anomalies (thin corpus callosum, bilateral ventriculomegaly), cone-rod dystrophy, nystagmus, mild conductive hearing loss and recurrent chest..."

Documents this finding in a molecularly confirmed skeletal presentation; no disease-wide frequency is inferred.

Endocrine 1

Small pituitary gland HP:0012506

Show evidence (1 reference)

PMID:29138412 SUPPORT Human clinical

"Brain magnetic resonance imaging (MRI) showed hypoplasia of the corpus callosum, small pituitary gland, inferior vermis dysplasia, “molar tooth” sign (MTS) and mildly dilated third ventricle (Supplementary Fig. S1)."

Records the small pituitary gland alongside the other CNS findings.

Eye 2

Cone-rod dystrophy Cone/cone-rod dystrophy HP:0000548

Show evidence (1 reference)

PMID:34016807 SUPPORT Human clinical

"We describe a ninth case that expands the phenotype; a 10-year-old girl with rhizomelic short stature (-5.6 SD), macrocephaly, developmental delay, CNS anomalies (thin corpus callosum, bilateral ventriculomegaly), cone-rod dystrophy, nystagmus, mild conductive hearing loss and recurrent chest..."

Documents this finding in a molecularly confirmed skeletal presentation; no disease-wide frequency is inferred.

Nystagmus HP:0000639

Show evidence (1 reference)

PMID:34016807 SUPPORT Human clinical

"We describe a ninth case that expands the phenotype; a 10-year-old girl with rhizomelic short stature (-5.6 SD), macrocephaly, developmental delay, CNS anomalies (thin corpus callosum, bilateral ventriculomegaly), cone-rod dystrophy, nystagmus, mild conductive hearing loss and recurrent chest..."

Documents this finding in a molecularly confirmed skeletal presentation; no disease-wide frequency is inferred.

Genitourinary 3

Micropenis HP:0000054

Show evidence (1 reference)

PMID:29138412 SUPPORT Human clinical

"The parents chose to terminate the pregnancy and the fetal autopsy showed macrocephaly, wide open anterior and posterior fontanels, high forehead with frontal bossing, micrognathia, low-set and posteriorly rotated left ear, small nose with a broad nasal bridge, long philtrum, normal lips and..."

Documents this finding in a molecularly confirmed skeletal presentation; no disease-wide frequency is inferred.

Hypospadias HP:0000047

Show evidence (1 reference)

PMID:29138412 SUPPORT Human clinical

"The parents chose to terminate the pregnancy and the fetal autopsy showed macrocephaly, wide open anterior and posterior fontanels, high forehead with frontal bossing, micrognathia, low-set and posteriorly rotated left ear, small nose with a broad nasal bridge, long philtrum, normal lips and..."

Documents this finding in a molecularly confirmed skeletal presentation; no disease-wide frequency is inferred.

Cryptorchidism HP:0000028

The Inskeep skeletal infant also carried a RUNX2 in-frame deletion classified as a variant of uncertain significance, inherited from his phenotypically normal father; the authors identified biallelic truncating KIAA0753 variants as the diagnosis.

Show evidence (1 reference)

PMID:34523780 SUPPORT Human clinical

"He had a narrow chest, short limbs, brachydactyly, penoscrotal hypospadias and cryptorchidism."

Documents this finding in a molecularly confirmed skeletal presentation; no disease-wide frequency is inferred.

Head and Neck 9

Macrocephaly HP:0000256

The Inskeep skeletal infant also carried a RUNX2 in-frame deletion classified as a variant of uncertain significance, inherited from his phenotypically normal father; the authors identified biallelic truncating KIAA0753 variants as the diagnosis.

Show evidence (1 reference)

PMID:34523780 SUPPORT Human clinical

"He had macrocephaly (head circumference 37 cm, > 2 SD). He was admitted to the NICU for management of pulmonary hypoplasia and pulmonary hypertension."

Records the head circumference measurement at birth in the SRTD-presenting patient.

Frontal bossing HP:0002007

Show evidence (1 reference)

PMID:34523780 SUPPORT Human clinical

"Physical exam was notable for frontal bossing, low-set ears, anteverted nares, and macrocephaly."

Independent frontal bossing in the skeletal-presenting infant, beyond the discovery series.

Flat face HP:0012368

Show evidence (1 reference)

PMID:29138412 SUPPORT Human clinical

"Craniofacial anomaliesFrontal bossing (HP:0002007), flat face (HP:0012368), depressed nasal bridge (HP:0005280), teeth hypoplasia (HP:0000685)Frontal bossing (HP:0002007), flat face (HP:0012368), depressed nasal bridge (HP:0005280), teeth hypoplasia (HP:0000685)Frontal bossing (HP:0002007), flat..."

The same craniofacial row. Flat face follows frontal bossing in each of the P1, P2 and P3 columns.

Depressed nasal bridge HP:0005280

Show evidence (1 reference)

PMID:29138412 SUPPORT Human clinical

"At 20 months of age, she had disproportional short stature with severe genu varum, relatively large head, depressed nasal bridge and low set ears."

Direct examination of P1 reports depressed nasal bridge. The craniofacial table also records this in P2.

Anteverted nares HP:0000463

The Inskeep skeletal infant also carried a RUNX2 in-frame deletion classified as a variant of uncertain significance, inherited from his phenotypically normal father; the authors identified biallelic truncating KIAA0753 variants as the diagnosis.

Show evidence (1 reference)

PMID:34523780 SUPPORT Human clinical

"Physical exam was notable for frontal bossing, low-set ears, anteverted nares, and macrocephaly."

Documents this finding in a molecularly confirmed skeletal presentation; no disease-wide frequency is inferred.

Micrognathia HP:0000347

Show evidence (1 reference)

PMID:29138412 SUPPORT Human clinical

"The parents chose to terminate the pregnancy and the fetal autopsy showed macrocephaly, wide open anterior and posterior fontanels, high forehead with frontal bossing, micrognathia, low-set and posteriorly rotated left ear, small nose with a broad nasal bridge, long philtrum, normal lips and..."

Documents this finding in a molecularly confirmed skeletal presentation; no disease-wide frequency is inferred.

Wide nasal bridge HP:0000431

Show evidence (1 reference)

PMID:29138412 SUPPORT Human clinical

"The parents chose to terminate the pregnancy and the fetal autopsy showed macrocephaly, wide open anterior and posterior fontanels, high forehead with frontal bossing, micrognathia, low-set and posteriorly rotated left ear, small nose with a broad nasal bridge, long philtrum, normal lips and..."

Documents this finding in a molecularly confirmed skeletal presentation; no disease-wide frequency is inferred.

Long philtrum HP:0000343

Show evidence (1 reference)

PMID:29138412 SUPPORT Human clinical

"The parents chose to terminate the pregnancy and the fetal autopsy showed macrocephaly, wide open anterior and posterior fontanels, high forehead with frontal bossing, micrognathia, low-set and posteriorly rotated left ear, small nose with a broad nasal bridge, long philtrum, normal lips and..."

Documents this finding in a molecularly confirmed skeletal presentation; no disease-wide frequency is inferred.

Ankyloglossia HP:0010296

Show evidence (1 reference)

PMID:29138412 SUPPORT Human clinical

"The parents chose to terminate the pregnancy and the fetal autopsy showed macrocephaly, wide open anterior and posterior fontanels, high forehead with frontal bossing, micrognathia, low-set and posteriorly rotated left ear, small nose with a broad nasal bridge, long philtrum, normal lips and..."

Documents this finding in a molecularly confirmed skeletal presentation; no disease-wide frequency is inferred.

Immune 1

Recurrent chest infections Recurrent lower respiratory tract infections HP:0002783

Show evidence (1 reference)

PMID:34016807 SUPPORT Human clinical

"We describe a ninth case that expands the phenotype; a 10-year-old girl with rhizomelic short stature (-5.6 SD), macrocephaly, developmental delay, CNS anomalies (thin corpus callosum, bilateral ventriculomegaly), cone-rod dystrophy, nystagmus, mild conductive hearing loss and recurrent chest..."

Documents this finding in a molecularly confirmed skeletal presentation; no disease-wide frequency is inferred.

Limbs 5

Metaphyseal irregularity HP:0003025

Show evidence (2 references)

PMID:29138412 SUPPORT Human clinical

"Short ilia, sclerotic iliac crest, narrow sciatic notch, horizontal acetabular roof, metaphyseal irregularities and sclerosis, metaphyseal flaring of the long tubular bones, short and curved tibia are seen"

The radiographic description of the metaphyseal changes in the discovery series.

PMID:29138412 SUPPORT Human clinical

"The manifestations in our patients are variable and ranging from fetal lethal to viable and moderate skeletal dysplasia with narrow thorax and abnormal metaphyses."

Records the metaphyseal abnormality across the whole reported severity range.

Trident pelvis HP:0034044

Show evidence (1 reference)

PMID:31816441 SUPPORT Human clinical

"On skeletal survey, short tubular bones (height - 5,5 SD) and a trident appearance of the pelvis were seen."

Records the trident pelvis in a KIAA0753 patient.

Brachydactyly 4/4 HP:0001156

Show evidence (1 reference)

PMID:29138412 SUPPORT Human clinical

"In P4, the condition was lethal with skeletal changes including thorax hypoplasia and bowed limbs, while in the other three patients (P1-3), the phenotype included short stature, metaphyseal dysplasia with limb deformities, brachydactyly, developmental disability and features of Joubert syndrome."

The discussion records brachydactyly in P1-P3; the fetal autopsy and Table 1 also document it in P4.

Bowing of the long bones HP:0006487

Show evidence (1 reference)

PMID:34523780 SUPPORT Human clinical

"Plain films demonstrated skeletal abnormalities including short ribs, trident ilia, broad metaphyses, short and bowed tubular bones, and short metacarpals."

Documents this finding in a molecularly confirmed skeletal presentation; no disease-wide frequency is inferred.

Genu varum HP:0002970

Show evidence (1 reference)

PMID:29138412 SUPPORT Human clinical

"She had disproportionate short stature with genu varum at 24 months of age."

Documents this finding in a molecularly confirmed skeletal presentation; no disease-wide frequency is inferred.

Musculoskeletal 10

Narrow chest HP:0000774

Show evidence (1 reference)

PMID:29138412 SUPPORT Human clinical

"The manifestations in our patients are variable and ranging from fetal lethal to viable and moderate skeletal dysplasia with narrow thorax and abnormal metaphyses."

Records the narrow thorax across the reported severity range.

Short long bone HP:0003026

Show evidence (1 reference)

PMID:31816441 SUPPORT Human clinical

"On skeletal survey, short tubular bones (height - 5,5 SD) and a trident appearance of the pelvis were seen."

Records short tubular bones with the associated height deficit.

Hypotonia HP:0001252

The Faudi skeletal case provides independent evidence. Hypotonia in discovery-series P1 co-occurs with an additional SLC13A5 diagnosis.

Show evidence (1 reference)

PMID:31816441 SUPPORT Human clinical

"This 4 year-old boy with narrow thorax, short limbs, severe respiratory and feeding difficulties from birth on had a history of hypotonia and developmental delay."

Records hypotonia in a KIAA0753 skeletal patient.

Cone-shaped epiphysis HP:0010579

Show evidence (1 reference)

PMID:29138412 SUPPORT Human clinical

"Skeletal survey showed severe metaphyseal dysplasia and cone-shaped epiphyses of the proximal tibia and distal femur embedded in cup-shaped metaphyses (Fig. 2a–c)."

The radiographic description in the discovery series.

Short ribs HP:0000773

Show evidence (1 reference)

PMID:34523780 SUPPORT Human clinical

"Plain films demonstrated skeletal abnormalities including short ribs, trident ilia, broad metaphyses, short and bowed tubular bones, and short metacarpals."

The skeletal-presenting infant has short ribs on plain films.

Thoracic hypoplasia 4/4 HP:0005257

Show evidence (1 reference)

PMID:29138412 SUPPORT Human clinical

"In P4, the condition was lethal with skeletal changes including thorax hypoplasia and bowed limbs, while in the other three patients (P1-3), the phenotype included short stature, metaphyseal dysplasia with limb deformities, brachydactyly, developmental disability and features of Joubert syndrome."

The discussion directly records fetal thorax hypoplasia; Table 1 records thoracic hypoplasia in all four skeletal patients.

Flexion contracture 2/3 HP:0001371

Show evidence (1 reference)

PMID:29138412 SUPPORT Human clinical

"P2 has severe flexion contractures of the elbows, hips and knees, as well as genu varum."

The figure caption directly describes the contractures; Table 1 records them in P1 and P2, with P3 negative and P4 unassessed.

Pectus carinatum HP:0000768

Show evidence (1 reference)

PMID:29138412 SUPPORT Human clinical

"He had disproportionate short stature (Supplementary Table S1), speech delay, pectus carinatum, narrow chest, protuberant abdomen and short limbs (Figs 1e and 2g,h,k, Table 1)."

Documents this finding in a molecularly confirmed skeletal presentation; no disease-wide frequency is inferred.

Pectus excavatum HP:0000767

Show evidence (1 reference)

PMID:29138412 SUPPORT Human clinical

"On follow-up at 6 years she had teeth hypoplasia, pectus excavatum, rhizomelic shortening of the limbs and flexion contractures of the elbows, knee and hips (Fig. 1c)."

Documents this finding in a molecularly confirmed skeletal presentation; no disease-wide frequency is inferred.

Cervical spinal canal stenosis HP:0008445

Show evidence (1 reference)

PMID:31816441 SUPPORT Human clinical

"Brain MRI showed cervical canal stenosis."

Documents this finding in a molecularly confirmed skeletal presentation; no disease-wide frequency is inferred.

Nervous System 8

Global developmental delay HP:0001263

Show evidence (3 references)

PMID:31816441 SUPPORT Human clinical

"This 4 year-old boy with narrow thorax, short limbs, severe respiratory and feeding difficulties from birth on had a history of hypotonia and developmental delay."

Records developmental delay alongside the skeletal phenotype.

PMID:29138412 SUPPORT Human clinical

"He had disproportionate short stature (Supplementary Table S1), speech delay, pectus carinatum, narrow chest, protuberant abdomen and short limbs (Figs 1e and 2g,h,k, Table 1)."

The independent skeletal patient P3 has speech delay; Table 1 also records gross motor delay.

PMID:29138412 SUPPORT Human clinical

"We thus conclude that the seizures and teeth hypoplasia in P1 and P2 are due to the homozygous SLC13A5 variant, while the developmental and speech delay is an overlapping feature and could be inferable to either one of the congenital conditions."

The two cousins cannot establish a gene-specific developmental severity or frequency.

Molar tooth sign on MRI HP:0002419

Show evidence (2 references)

PMID:29138412 SUPPORT Human clinical

"Brain magnetic resonance imaging (MRI) showed hypoplasia of the corpus callosum, small pituitary gland, inferior vermis dysplasia, “molar tooth” sign (MTS) and mildly dilated third ventricle (Supplementary Fig. S1)."

Names the molar tooth sign directly, in the first patient of the discovery series.

PMID:29138412 SUPPORT Human clinical

"In addition two of our patients showed brain abnormalities consistent with JBTS."

Two patients had Joubert-like brain abnormalities; the source does not report four comparable MRI assessments.

Delayed speech and language development HP:0000750

Show evidence (2 references)

PMID:29138412 SUPPORT Human clinical

"He had disproportionate short stature (Supplementary Table S1), speech delay, pectus carinatum, narrow chest, protuberant abdomen and short limbs (Figs 1e and 2g,h,k, Table 1)."

Speech delay in P3 provides evidence independent of the SLC13A5-confounded cousins.

PMID:29138412 SUPPORT Human clinical

"We thus conclude that the seizures and teeth hypoplasia in P1 and P2 are due to the homozygous SLC13A5 variant, while the developmental and speech delay is an overlapping feature and could be inferable to either one of the congenital conditions."

The authors explicitly leave the developmental and speech contribution of the two diagnoses unresolved.

Delayed gross motor development HP:0002194

Table 1 records motor delay in all three children, but P1 and P2 also have biallelic SLC13A5 disease. The reported 3/3 is therefore not a KIAA0753-specific frequency. The milestone example is from P1.

Show evidence (2 references)

PMID:29138412 SUPPORT Human clinical

"She had delayed motor development (sitting unaided at 1 year; walking at 3 years of age)."

P1 has delayed motor milestones but also SLC13A5-related disease. Table 1 separately records gross motor delay in P3, who lacks this second diagnosis.

PMID:29138412 SUPPORT Human clinical

"We thus conclude that the seizures and teeth hypoplasia in P1 and P2 are due to the homozygous SLC13A5 variant, while the developmental and speech delay is an overlapping feature and could be inferable to either one of the congenital conditions."

Explains why the clinical count cannot be attributed exclusively to KIAA0753.

Hypoplasia of the corpus callosum HP:0002079

Show evidence (1 reference)

PMID:29138412 SUPPORT Human clinical

"Brain magnetic resonance imaging (MRI) showed hypoplasia of the corpus callosum, small pituitary gland, inferior vermis dysplasia, “molar tooth” sign (MTS) and mildly dilated third ventricle (Supplementary Fig. S1)."

The brain MRI findings in the first patient of the discovery series.

Ventriculomegaly HP:0002119

Show evidence (1 reference)

PMID:29138412 SUPPORT Human clinical

"Fetal ultrasound at 19 weeks gestation showed short limbs, narrow chest, prominent abdomen, cerebral ventriculomegaly, suspected defect in the cerebellar vermis and mild pelviectasis."

Records ventriculomegaly, and the rest of the prenatal picture, in the affected fetus.

Developmental regression HP:0002376

Show evidence (1 reference)

PMID:34016807 SUPPORT Human clinical

"Our case is the eldest woman reported to date (aged ten years) and the only known case to report associated hearing loss, leg-length discrepancy, pectus carinatum, respiratory ciliary dyskinesia and late-onset (9 years old) neuro-degenerative regression."

Documents this finding in a molecularly confirmed skeletal presentation; no disease-wide frequency is inferred.

Cerebellar vermis hypoplasia HP:0001320

Show evidence (1 reference)

PMID:29138412 SUPPORT Human clinical

"Brain MRI showed hypoplasia of the corpus callosum, a small pituitary gland, inferior vermis hypoplasia, MTS and mildly dilated lateral ventricles (Supplementary Fig."

Documents this finding in a molecularly confirmed skeletal presentation; no disease-wide frequency is inferred.

Respiratory 3

Respiratory insufficiency HP:0002093

Show evidence (1 reference)

PMID:31816441 SUPPORT Human clinical

"This 4 year-old boy with narrow thorax, short limbs, severe respiratory and feeding difficulties from birth on had a history of hypotonia and developmental delay."

Records severe respiratory difficulty from birth.

Pulmonary hypoplasia HP:0002089

The Inskeep skeletal infant also carried a RUNX2 in-frame deletion classified as a variant of uncertain significance, inherited from his phenotypically normal father; the authors identified biallelic truncating KIAA0753 variants as the diagnosis.

Show evidence (1 reference)

PMID:34523780 SUPPORT Human clinical

"He had macrocephaly (head circumference 37 cm, > 2 SD). He was admitted to the NICU for management of pulmonary hypoplasia and pulmonary hypertension."

Records pulmonary hypoplasia in the SRTD-presenting patient of this series.

Respiratory ciliary dyskinesia HP:0012265

Sequelae: Recurrent chest infections

Show evidence (1 reference)

PMID:34016807 SUPPORT Human clinical

"We describe a ninth case that expands the phenotype; a 10-year-old girl with rhizomelic short stature (-5.6 SD), macrocephaly, developmental delay, CNS anomalies (thin corpus callosum, bilateral ventriculomegaly), cone-rod dystrophy, nystagmus, mild conductive hearing loss and recurrent chest..."

Documents this finding in a molecularly confirmed skeletal presentation; no disease-wide frequency is inferred.

Growth 3

Rhizomelia HP:0008905

Show evidence (1 reference)

PMID:34016807 SUPPORT Human clinical

"We describe a ninth case that expands the phenotype; a 10-year-old girl with rhizomelic short stature (-5.6 SD), macrocephaly, developmental delay, CNS anomalies (thin corpus callosum, bilateral ventriculomegaly), cone-rod dystrophy, nystagmus, mild conductive hearing loss and recurrent chest..."

Records rhizomelic short stature and its severity.

Disproportionate short-limb short stature HP:0008873

Show evidence (1 reference)

PMID:29138412 SUPPORT Human clinical

"He had disproportionate short stature (Supplementary Table S1), speech delay, pectus carinatum, narrow chest, protuberant abdomen and short limbs (Figs 1e and 2g,h,k, Table 1)."

Documents this finding in a molecularly confirmed skeletal presentation; no disease-wide frequency is inferred.

Leg-length discrepancy Lower limb asymmetry HP:0100559

Show evidence (1 reference)

PMID:34016807 SUPPORT Human clinical

"Our case is the eldest woman reported to date (aged ten years) and the only known case to report associated hearing loss, leg-length discrepancy, pectus carinatum, respiratory ciliary dyskinesia and late-onset (9 years old) neuro-degenerative regression."

Documents this finding in a molecularly confirmed skeletal presentation; no disease-wide frequency is inferred.

🧬

Genetic Associations

1

KIAA0753 (Causal biallelic variant)

Gene: KIAA0753 hgnc:29110 gene page

Show evidence (2 references)

PMID:34523780 SUPPORT Human clinical

"To date, there have been 8 patients with biallelic pathogenic variants in KIAA0753 reported in the literature(5–8): two are described as having JS, one with OFD, and six with SRPS (Table 1)."

The breakdown of reported patients by clinical label, which is the three-phenotype split this note describes.

PMID:31816441 SUPPORT Human clinical

"This case provides confirmation of an additional molecular basis for skeletal dysplasia and illustrates how ciliopathies due to mutations in a single gene may present as apparently distinct syndromes."

The authors' statement that the three labels are apparent rather than separable entities.

Variants (5)

c.970C>T (p.Arg324*) Pathogenic

Gene: KIAA0753 hgnc:29110 nonsense

A nonsense variant, homozygous in three affected individuals across two separate families of the discovery series, which makes it the one recurrent allele of this disorder. Carrier frequency in gnomAD is 4 in 245,846 heterozygotes, minor allele frequency 1.627e-5, in South Asian and non-Finnish European populations.

Show evidence (1 reference)

PMID:29138412 SUPPORT Human clinical

"In family 1 and 2, all three affected patients were homozygous for a nonsense mutation, c.970 C > T (p.Arg324*); and in family 3, the affected fetus was compound heterozygous for a nonsense variant c.943 C > T (p.Gln315*) and a 1-bp deletion, c.1271del (p.Pro424Hisfs*9)."

The sequencing results directly identify the variants and zygosity in the discovery families.

c.943C>T (p.Gln315*) Pathogenic

Gene: KIAA0753 hgnc:29110 nonsense

A nonsense variant carried in trans with c.1271del by the affected fetus of the discovery series, and reported homozygous in an unrelated patient with the Jeune presentation. gnomAD carrier frequency 6 in 276,744, minor allele frequency 2.168e-5, non-Finnish European.

Show evidence (2 references)

PMID:29138412 SUPPORT Human clinical

"In family 1 and 2, all three affected patients were homozygous for a nonsense mutation, c.970 C > T (p.Arg324*); and in family 3, the affected fetus was compound heterozygous for a nonsense variant c.943 C > T (p.Gln315*) and a 1-bp deletion, c.1271del (p.Pro424Hisfs*9)."

The sequencing results directly identify the variants and zygosity in the discovery families.

PMID:31816441 SUPPORT Human clinical

"A homozygous c.943C > T mutation in KIAA0753 was identified on whole exome sequencing, resulting in Gln315Ter premature termination of the corresponding protein."

The same allele found homozygous in an unrelated patient, establishing it as recurrent rather than private.

c.1271del (p.Pro424Hisfs*9) Pathogenic

Gene: KIAA0753 hgnc:29110 frameshift

A single-base deletion causing a frameshift, in trans with c.943C>T in the affected fetus. Absent from gnomAD.

Show evidence (1 reference)

PMID:29138412 SUPPORT Human clinical

"in family 3, the affected fetus was compound heterozygous for a nonsense variant c.943 C > T (p.Gln315*) and a 1-bp deletion, c.1271del (p.Pro424Hisfs*9)"

Identifies the frameshift allele and its compound-heterozygous partner.

c.810C>T (synonymous, splice-altering) Pathogenic

Gene: KIAA0753 hgnc:29110 synonymous

A synonymous change that in silico tools did not flag and that turned out to activate abnormal splicing, demonstrated by cDNA sequencing. Two apparently unrelated Pakistani families share it within an 85 kb homozygous block, indicating a common ancestor. It is the reason a negative first-pass panel does not exclude this diagnosis.

Show evidence (2 references)

PMID:33875766 SUPPORT Human clinical

"WGS of all known skeletal ciliopathy and dysplasia genes did not reveal any known disease-causing variants, but a very rare homozygous synonymous variant in KIAA0753 (c.810 C > T, p.=) was identified."

Documents the synonymous allele and that conventional analysis missed it.

PMID:33875766 SUPPORT Human clinical

"Both families were of Pakistani origin, but according to the family history they were not related. These families share a homozygous block of 85 kb on chromosome 17p13.1, including the KIAA0753 gene, indicating a common ancestor."

Establishes the shared haplotype behind the recurrence of this allele.

c.2656C>T (p.Arg886*) Pathogenic

Gene: KIAA0753 hgnc:29110 nonsense

A nonsense variant carried in trans with c.943C>T by the skeletally-presenting patient of the KIAA0753 heterogeneity series, who was managed in neonatal intensive care for pulmonary hypoplasia and died at two weeks of severe pulmonary hypertension. Its partner allele is curated above, so leaving this one out would make the allele list read as complete when it is not.

Show evidence (1 reference)

PMID:34523780 SUPPORT Human clinical

"Rapid whole exome sequencing (GeneDx) identified biallelic truncating variants in KIAA0753 (c.943C>T/c.2656C>T; p. Gln315*/p.R886*)."

Reports both alleles of the skeletal-presentation patient, including this one.

💊

Medical Actions

1

Respiratory support and thoracic management

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Platform: Other

No disease-modifying treatment exists. Management is supportive and is dominated by the thorax: ventilatory support for the restrictive insufficiency, nutritional support for the feeding difficulties, and orthopaedic follow-up for the limb and spinal consequences of the skeletal dysplasia. Thoracic expansion surgery is used in the short-rib dysplasias generally; no KIAA0753 patient has been reported to have undergone it, so it is not curated here as a treatment for this disorder.

Target Phenotypes: Respiratory insufficiency HP:0002093

Show evidence (1 reference)

PMID:31816441 SUPPORT Human clinical

"This 4 year-old boy with narrow thorax, short limbs, severe respiratory and feeding difficulties from birth on had a history of hypotonia and developmental delay."

Establishes the respiratory and feeding problems that supportive management addresses.

🔬

Diagnosis

4

Skeletal survey

Radiographs establish the diagnosis within the short-rib group: short broad ribs with cupped anterior ends, short tubular bones with metaphyseal irregularity and cone-shaped epiphyses, and a trident pelvis. Absence of polydactyly is part of the description of this entity.

X-ray imaging NCIT:C38101

Results: Narrow thorax with short ribs, short tubular bones, metaphyseal irregularity and cone-shaped epiphyses, trident pelvis.

Show evidence (1 reference)

PMID:29138412 SUPPORT Human clinical

"Skeletal survey showed severe metaphyseal dysplasia and cone-shaped epiphyses of the proximal tibia and distal femur embedded in cup-shaped metaphyses (Fig. 2a–c)."

Documents the radiographic route to the diagnosis.

Prenatal ultrasound

In the affected fetus of the discovery series the diagnosis was suspected prenatally: fetal ultrasound at 19 weeks showed the whole picture at once - short limbs, a narrow chest, a prominent abdomen, cerebral ventriculomegaly and a suspected cerebellar vermis defect. Both the skeletal and the CNS branches of this disorder are visible before birth.

fetal ultrasound imaging NCIT:C222238

Results: Short limbs with a narrow chest, prominent abdomen, cerebral ventriculomegaly and suspected cerebellar vermis defect.

Show evidence (1 reference)

PMID:29138412 SUPPORT Human clinical

"Fetal ultrasound at 19 weeks gestation showed short limbs, narrow chest, prominent abdomen, cerebral ventriculomegaly, suspected defect in the cerebellar vermis and mild pelviectasis."

The prenatal findings in the one fetus in whom they were recorded.

Brain MRI

Brain imaging is not optional in a patient with this skeletal phenotype. Two of the four patients of the discovery series had the molar tooth sign, and the reported findings also include corpus callosum hypoplasia, ventriculomegaly and a small pituitary gland - the last of which matters because growth hormone deficiency is documented in the Joubert presentation of this same gene.

magnetic resonance imaging NCIT:C16809

Results: Inferior vermis dysplasia with the molar tooth sign, corpus callosum hypoplasia, ventricular dilatation and a small pituitary gland.

Show evidence (1 reference)

PMID:29138412 SUPPORT Human clinical

"Brain magnetic resonance imaging (MRI) showed hypoplasia of the corpus callosum, small pituitary gland, inferior vermis dysplasia, “molar tooth” sign (MTS) and mildly dilated third ventricle (Supplementary Fig. S1)."

The brain MRI findings that make imaging part of the assessment.

KIAA0753 sequencing with transcript analysis

Exome or genome sequencing on a skeletal-dysplasia or ciliopathy panel. Transcript analysis matters more than usual here: a synonymous KIAA0753 variant that in silico tools did not flag turned out to activate abnormal splicing, and was only resolved by sequencing cDNA. A negative panel result on a patient with this phenotype is therefore worth reanalysing.

genetic testing NCIT:C15709

Results: Biallelic KIAA0753 variants, with cDNA confirmation for splice-altering alleles.

Show evidence (2 references)

PMID:33875766 SUPPORT Human clinical

"Four variants located in non-canonical splice sites of DYNC2H1, EVC, and KIAA0753 led to aberrant splicing that was shown by sequencing of cDNA."

Establishes cDNA sequencing as the step that resolved the splice-altering alleles, including in KIAA0753.

PMID:34016807 SUPPORT Human clinical

"Whole-exome sequencing, aged eight, via skeletal dysplasia panel analysis and subsequent whole-genome sequencing (via the 100,000 genomes project) found no cause. WGS data reanalysis using exomiser uncovered compound heterozygous pathogenic KIAA0753 variants (frameshift and splice site)."

A worked example of the diagnosis being missed by first-pass panel and genome analysis and found only on reanalysis.

📈

Progression

2

Perinatal lethal end of the range

The 2021 count pools all KIAA0753 presentations rather than SRTD21 alone. Skeletal cases include respiratory failure after infection at seven years and neonatal death from severe pulmonary hypertension with pulmonary hypoplasia; a single exclusive route to death is not established.

Show evidence (1 reference)

PMID:33875766 SUPPORT Human clinical

"Altogether, there are 13 individuals reported with pathogenic variants in KIAA0753, out of them two pregnancies were terminated, three patients died before three months of age, one patient deceased at seven years of age, and seven patients are to our knowledge alive"

Quantifies the early-lethal fraction of reported cases.

Surviving childhood

Survivors have moderate skeletal dysplasia with disproportionate short stature, narrow thorax and metaphyseal change, alongside developmental delay and hypotonia. The oldest reported patient at the time of her report was ten years old and had accumulated cone-rod dystrophy, conductive hearing loss and a late neurodegenerative regression, so the phenotype is not static in survivors.

Show evidence (2 references)

PMID:29138412 SUPPORT Human clinical

"The manifestations in our patients are variable and ranging from fetal lethal to viable and moderate skeletal dysplasia with narrow thorax and abnormal metaphyses."

States the range from lethal to moderate viable disease.

PMID:34016807 SUPPORT Human clinical

"Our case is the eldest woman reported to date (aged ten years) and the only known case to report associated hearing loss, leg-length discrepancy, pectus carinatum, respiratory ciliary dyskinesia and late-onset (9 years old) neuro-degenerative regression."

Documents the accumulating features in the oldest reported survivor, and is careful to note they are so far unique to that case.

📊

Prevalence

1

Worldwide

Cases/families reported in the literature Ultra-rare

No population estimate exists. A 2021 skeletal-ciliopathy cohort counted 13 individuals reported with pathogenic KIAA0753 variants in total, across all three phenotypes the gene causes, not the skeletal presentation alone.

Show evidence (1 reference)

PMID:33875766 SUPPORT Human clinical

"Altogether, there are 13 individuals reported with pathogenic variants in KIAA0753, out of them two pregnancies were terminated, three patients died before three months of age, one patient deceased at seven years of age, and seven patients are to our knowledge alive"

The total reported case count and its outcome breakdown, standing in for a population estimate that has never been made.

🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Short-rib thoracic dysplasia 21 without polydactyly:

Joubert syndrome MONDO:0018772

Overlapping Features The same gene causes Joubert syndrome, and the boundary is soft: two of the four patients in the skeletal discovery series had brain abnormalities consistent with Joubert syndrome. The distinction as used in the literature is which system dominates - a molar tooth sign with hypotonia, developmental delay and abnormal eye movements and no significant skeletal disease is called Joubert syndrome; short ribs with a narrow thorax is called this disorder, whether or not a molar tooth sign is also present.

Distinguishing Features

Cerebellar and brainstem malformation dominates rather than skeletal disease
No short ribs or thoracic constriction
Growth hormone deficiency reported in the KIAA0753 Joubert siblings

Show evidence (1 reference)

PMID:28220259 SUPPORT Human clinical

"Here, we present 2 siblings with Joubert syndrome associated with growth hormone deficiency. Whole exome sequencing of the family identified compound heterozygous mutations in KIAA0753, i.e., a missense mutation (p.Arg257Gly) and an intronic mutation (c.2359-1G>C)."

Establishes the Joubert presentation of the same gene, in siblings without a skeletal ciliopathy label.

Orofaciodigital syndrome type 6 Not Yet Curated MONDO:0010176

Overlapping Features The third KIAA0753 phenotype. It is defined by oral, facial and digital anomalies - hypertelorism, cleft palate, tongue lobulation, digital abnormalities - and the index KIAA0753 patient also had a molar tooth sign. Note that the dismech entry Orofaciodigital_Syndrome_17 is a different disorder, caused by INTU; it names KIAA0753 only inside a quoted list of genes from the paper that identified both.

Distinguishing Features

Oral, facial and digital anomalies rather than short ribs
No thoracic constriction or respiratory insufficiency

Show evidence (1 reference)

PMID:26643951 SUPPORT Human clinical

"We report here causal compound heterozygous mutations of KIAA0753/OFIP in a patient with an OFD VI syndrome."

Establishes the orofaciodigital presentation of the same gene.

Jeune asphyxiating thoracic dystrophy MONDO:0018770

Overlapping Features The clinical group this disorder sits inside, and the label under which several KIAA0753 patients were reported. The other genetically defined forms are intraflagellar-transport and dynein-2 defects; this one is a basal body docking defect, which is the mechanistic reason it is curated separately rather than as a subtype.

Distinguishing Features

Caused by IFT or dynein-2 components rather than a centriolar docking protein
Polydactyly occurs in several of the IFT-related forms

Show evidence (1 reference)

PMID:31816441 SUPPORT Human clinical

"Mutations in at least 23 genes are likely to correspond to this clinical presentation: IFT43/52/80/81/122/140/172, WDR19/34/35/60, DYNC2H1, DYNC2LI1, CEP120, NEK1, TTC21B, TCTEX1D2, INTU, TCTN3, EVC 1/2 and KIAA0586."

Lists the genes of the clinical group, which are dominated by intraflagellar-transport and dynein-2 components and do not include KIAA0753.

🧫

Experimental Models

1

KIAA0753 patient fibroblasts and knockout cell lines PRIMARY_CELL_CULTURE

Dermal fibroblasts from Joubert-presenting patient 1 of the Inskeep series, mouse NIH3T3 knockout and variant-rescue cells, and human RPE1 cells used in studies of the centriolar complex. These systems establish ciliation, SHH/WNT response and protein-recruitment defects; none directly measures the growth plate of a skeletal patient.

Cell source

Joubert-patient dermal fibroblasts, mouse NIH3T3 cells and human RPE1 cells

Culture

Two-dimensional culture with serum starvation to induce ciliogenesis, plus siRNA or knockout depletion and variant reconstitution

Publication

PMID:34523780

Pathograph links

Defective Basal Body Docking and Ciliogenesis recapitulates fidelity: high Patient fibroblasts carry the actual disease genotypes and show the ciliation deficit directly; depleting any member of the ternary complex in RPE1 cells reproduces the recruitment failure.

Limitations: Fibroblasts are not chondrocytes. The cell type in which the disease manifests is the growth-plate chondrocyte, and no chondrocyte or cartilage model of this genotype has been reported, so the ciliation and signalling measurements are made in a proxy tissue. In the Inskeep series the fibroblast donor had a Joubert presentation; the ablation/rescue experiments used mouse NIH3T3 cells.

Readouts

Proportion of ciliated cells after serum starvation

Direction: DECREASED

Interpretation: Direct measurement of the ciliogenesis defect in cells carrying patient genotypes.

Show evidence (1 reference)

PMID:34523780 SUPPORT In vitro / ex vivo

"Correspondingly, KIAA0753 patient fibroblasts have a deficit in primary ciliation and improper SHH and WNT signaling, with a particularly blunted response to SHH pathway stimulation."

The ciliation measurement in patient cells.

Show evidence (1 reference)

PMID:26643951 SUPPORT In vitro / ex vivo

"The decreased expression of any component of this ternary complex in RPE1 cells causes a defective recruitment onto centrosomes and satellites."

Establishes that the recruitment failure is a property of the complex, reproducible by depleting any member.

Impaired Hedgehog Signal Transduction recapitulates fidelity: moderate Hedgehog pathway output is measured directly in patient fibroblasts and in KIAA0753-ablated cells.

Limitations: Hedgehog signalling in fibroblasts is a surrogate for Hedgehog signalling in the growth plate, where the ligand source, the receiving cell type and the transcriptional output all differ. The blunting is quantitative rather than absolute, and nothing links the size of the in vitro defect to skeletal severity in the corresponding patient. In the Inskeep series the fibroblast donor had a Joubert presentation; the ablation/rescue experiments used mouse NIH3T3 cells.

Readouts

Hedgehog pathway response to stimulation

Direction: DECREASED

Interpretation: The signalling step that connects the ciliary lesion to the skeletal phenotype.

Show evidence (1 reference)

PMID:34523780 SUPPORT In vitro / ex vivo

"Ablation of KIAA0753 in vitro blocks primary ciliogenesis and SHH pathway activity."

The Hedgehog output measurement on gene ablation.

Show evidence (1 reference)

PMID:34523780 SUPPORT In vitro / ex vivo

"Our work expands the phenotypic spectrum of KIAA0753 ciliopathies and demonstrates the utility of patient-focused functional assays for proving causality of genetic variants."

States the purpose the system was used for, which is establishing causality of individual patient variants.

🐁

Animal Models

2

kiaa0753 nonsense zebrafish

Zebrafish embryos homozygous for a nonsense variant in kiaa0753, made alongside the human skeletal cases to test whether the gene is needed for skeletal development. It is the only animal model in which a skeletal readout was taken; the Mnr-null mouse below dies too early in gestation for the skeleton to be assessed.

Species

Zebrafish

Genotype

kiaa0753 homozygous nonsense

Publication

PMID:29138412

Pathograph links

Growth Plate Zonal Disorganisation partially recapitulates fidelity: low The embryos have abnormal cartilage patterning and abnormal head morphology, establishing that the gene is required for cartilage development.

Limitations: Zebrafish cartilage patterning is not a growth plate. The fish have no endochondral growth plate of the mammalian kind, so the model cannot address the proliferative and hypertrophic zone abnormality that is the human lesion, and it cannot model a narrow thorax at all. Lethality at early developmental stages further limits what can be asked of it. The model establishes gene requirement, not disease mechanism.

Readouts

Craniofacial cartilage patterning

Direction: ALTERED

Interpretation: Cartilage development requires the gene, which is the claim this model supports.

Show evidence (1 reference)

PMID:29138412 SUPPORT Model organism

"Zebrafish knockout model with homozygous nonsense variants in the kiaa0753 gene show classic ciliopathy phenotype with cartilage abnormalities and curved body seen in other ciliopathy models15 and abnormal head morphology due to altered cartilage patterning and lethality at early developmental stages."

The cartilage and morphology measurements in the model, together with the early lethality that bounds its usefulness.

Show evidence (1 reference)

PMID:29138412 SUPPORT Model organism

"The importance of KIAA0753 for normal skeletal development is further confirmed by our findings that zebrafish embryos homozygous for a nonsense mutation in kiaa0753 display altered cartilage patterning."

The authors' own statement of what the model establishes, which is gene requirement for skeletal development.

Mnr-null mouse (Kiaa0753 knockout)

A mouse null for Mnr, the mouse orthologue of KIAA0753, obtained from the International Mouse Phenotyping Consortium and characterised alongside a Cep90-null mouse as part of the work that defined the distal centriole complex. Embryos have no cilia in the E9.5 neural tube, and fibroblasts derived from them make no cilia and cannot induce Hedgehog target genes.

Species

Mouse

Genotype

Mnr (Kiaa0753) homozygous null, IMPC-derived allele

Publication

PMID:34241634

Pathograph links

Defective Basal Body Docking and Ciliogenesis recapitulates fidelity: moderate Loss of Mnr abolishes ciliogenesis in vivo and in embryo-derived fibroblasts, which is the same lesion patient fibroblasts show.

Limitations: The mouse is a complete null, whereas patients carry truncating and splice-altering alleles some of which retain partial function, and the mouse phenotype is correspondingly more severe: cilia are absent rather than reduced in number. Embryos were characterised at E8.5 to E9.5, before the skeleton forms, so this model has not been used to ask any skeletal question.

Readouts

Cilia in the E9.5 neural tube

Direction: ABOLISHED

Interpretation: Ciliogenesis fails in vivo when the gene is absent.

Show evidence (1 reference)

PMID:34241634 SUPPORT Model organism

"Similarly, cilia detected by ARL13B staining were absent in neural tube sections from E9.5 Mnr−/− embryos (Fig. 4 f)."

The in vivo ciliation measurement in the model.

Show evidence (1 reference)

PMID:34241634 SUPPORT Model organism

"Cells and mice lacking CEP90 or MNR do not generate cilia, fail to assemble distal appendages, and do not transduce Hedgehog signals."

States the model phenotype, including the distal appendage failure that is the specific mechanism this node asserts.

Impaired Hedgehog Signal Transduction recapitulates fidelity: moderate Fibroblasts from Mnr-null embryos fail to induce the Hedgehog target genes Gli1 and Ptch1 in response to a Smoothened agonist.

Limitations: The response is abrogated in the mouse null, whereas in patient fibroblasts it is blunted rather than absent, so the model exaggerates the severity of the signalling defect. The measurement is in embryonic fibroblasts, not in growth-plate chondrocytes.

Readouts

SAG-induced Gli1 and Ptch1 expression in embryo-derived fibroblasts

Direction: DECREASED

Interpretation: Direct transcriptional readout of Hedgehog pathway output in the model.

Show evidence (1 reference)

PMID:34241634 SUPPORT Model organism

"Furthermore, qRT-PCR analysis confirmed that induction of the Hedgehog target genes Gli1 and Ptch1 in response to the Hedgehog pathway activator Smoothened agonist (SAG) was abrogated in Cep90−/− or Mnr−/− MEFs (Fig. 4, i and l)."

The Hedgehog target-gene measurement in Mnr-null fibroblasts.

Show evidence (1 reference)

PMID:34241634 SUPPORT Model organism

"Thus, CEP90 and MNR are both required for vertebrate development, ciliogenesis, and Hedgehog signaling."

The authors' summary of what the mouse establishes.

{ }

Source YAML

click to show

name: Short-rib thoracic dysplasia 21 without polydactyly
creation_date: "2026-08-29T00:00:00Z"
category: Mendelian
synonyms:
- SRTD21
- KIAA0753-related skeletal ciliopathy
- MNR-related short-rib thoracic dysplasia
- Moonraker-related skeletal ciliopathy
description: >-
  Short-rib thoracic dysplasia 21 without polydactyly is the skeletal
  presentation of biallelic KIAA0753 variants. KIAA0753 - also called
  Moonraker and OFIP - is a centriolar and pericentriolar-satellite protein.
  It sits at the top of a recruitment cascade at the distal end of the
  centriole: Moonraker brings in OFD1, FOPNL and CEP90, which in turn place
  the distal appendage proteins that dock the basal body to the plasma
  membrane so a cilium can be built. Losing it therefore removes the cilium's
  foundation rather than its transport machinery, which distinguishes this
  disorder mechanistically from the intraflagellar-transport and dynein-2
  forms of short-rib thoracic dysplasia. Hedgehog signalling failure is a
  proposed contributor to the growth-plate lesion. Chondrocyte proliferation
  in the growth plate depends on cilium-transduced Hedgehog signals;
  Joubert-patient fibroblasts are deficient in primary cilia and show
  a blunted response to Hedgehog pathway stimulation, and the growth plate of
  an affected fetus had a disorganised proliferative zone with a broadened
  hypertrophic zone. Clinically this gives short ribs, a narrow thorax and
  short tubular bones, with respiratory insufficiency and pulmonary vascular
  complications contributing to severe outcomes. Two things make this entity
  awkward and both are recorded explicitly below. First, it is one of three
  phenotypes caused by the same gene: KIAA0753 also causes Joubert syndrome
  and orofaciodigital syndrome type 6, and the literature on the gene mixes
  all three. Second, the separation between them is not clean in individual
  patients - several people counted as skeletal cases also have the molar
  tooth sign, and the report of the eighth patient concluded that this gene
  shows how one locus can present as apparently distinct syndromes.
disease_term:
  preferred_term: short-rib thoracic dysplasia 21 without polydactyly
  term:
    id: MONDO:0030356
    label: short-rib thoracic dysplasia 21 without polydactyly
parents:
- Ciliopathies
- Short-Rib Dysplasias
references:
- reference: PMID:29138412
  title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
- reference: PMID:31816441
  title: A new case of KIAA0753-related variant of Jeune asphyxiating thoracic dystrophy.
- reference: PMID:34016807
  title: "KIAA0753-related skeletal ciliopathy: a ninth case, extending the phenotype and reporting a novel variant."
- reference: PMID:34523780
  title: Genetic and phenotypic heterogeneity in KIAA0753-related ciliopathies.
- reference: PMID:33875766
  title: High diagnostic yield in skeletal ciliopathies using massively parallel genome sequencing, structural variant screening and RNA analyses.
- reference: PMID:26643951
  title: OFIP/KIAA0753 forms a complex with OFD1 and FOR20 at pericentriolar satellites and centrosomes and is mutated in one individual with oral-facial-digital syndrome.
- reference: PMID:36070319
  title: "The evolutionary conserved proteins CEP90, FOPNL, and OFD1 recruit centriolar distal appendage proteins to initiate their assembly."
- reference: PMID:28220259
  title: Mutations in KIAA0753 cause Joubert syndrome associated with growth hormone deficiency.
- reference: PMID:34241634
  title: A ciliopathy complex builds distal appendages to initiate ciliogenesis.
- reference: PMID:34711653
  title: CEP120-mediated KIAA0753 recruitment onto centrioles is required for timely neuronal differentiation and germinal zone exit in the developing cerebellum.
classifications:
  isds_skeletal_category:
  - classification_value: ciliopathies_with_major_skeletal_involvement
    notes: >-
      ISDS Nosology group "Ciliopathies with major skeletal involvement".
      Assigned on the disorder's own radiographic definition - short ribs with
      thoracic hypoplasia and short tubular bones - and on the discovery paper's
      framing of these patients as short-rib type skeletal dysplasia arising
      from a ciliary gene.
    evidence:
    - reference: PMID:29138412
      reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We report biallelic pathogenic variants in KIAA0753 in four patients with short-rib type skeletal dysplasia.
      explanation: >-
        Places these patients in the short-rib skeletal dysplasia group.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic KIAA0753 variants, homozygous in consanguineous families and
    compound heterozygous elsewhere. Most reported alleles predict premature
    truncation, but splice-altering and missense alleles occur, including a
    synonymous change that creates a cryptic splice site.
  evidence:
  - reference: PMID:34523780
    reference_title: Genetic and phenotypic heterogeneity in KIAA0753-related ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The majority of reported KIAA0753 variants predict premature truncation of the KIAA0753 protein.
    explanation: >-
      Describes the predominant allele class across reported patients.
  - reference: PMID:29138412
    reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report biallelic pathogenic variants in KIAA0753 in four patients with short-rib type skeletal dysplasia.
    explanation: >-
      Establishes the biallelic requirement in the skeletal cases.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No population estimate exists. A 2021 skeletal-ciliopathy cohort counted 13
    individuals reported with pathogenic KIAA0753 variants in total, across all
    three phenotypes the gene causes, not the skeletal presentation alone.
  evidence:
  - reference: PMID:33875766
    reference_title: High diagnostic yield in skeletal ciliopathies using massively parallel genome sequencing, structural variant screening and RNA analyses.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Altogether, there are 13 individuals reported with pathogenic variants in KIAA0753, out of them two pregnancies were terminated, three patients died before three months of age, one patient deceased at seven years of age, and seven patients are to our knowledge alive
    explanation: >-
      The total reported case count and its outcome breakdown, standing in for a
      population estimate that has never been made.
progression:
- phase: Perinatal lethal end of the range
  notes: >-
    The 2021 count pools all KIAA0753 presentations rather than SRTD21 alone.
    Skeletal cases include respiratory failure after infection at seven years
    and neonatal death from severe pulmonary hypertension with pulmonary
    hypoplasia; a single exclusive route to death is not established.
  evidence:
  - reference: PMID:33875766
    reference_title: High diagnostic yield in skeletal ciliopathies using massively parallel genome sequencing, structural variant screening and RNA analyses.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Altogether, there are 13 individuals reported with pathogenic variants in KIAA0753, out of them two pregnancies were terminated, three patients died before three months of age, one patient deceased at seven years of age, and seven patients are to our knowledge alive
    explanation: >-
      Quantifies the early-lethal fraction of reported cases.
- phase: Surviving childhood
  notes: >-
    Survivors have moderate skeletal dysplasia with disproportionate short
    stature, narrow thorax and metaphyseal change, alongside developmental delay
    and hypotonia. The oldest reported patient at the time of her report was ten
    years old and had accumulated cone-rod dystrophy, conductive hearing loss and
    a late neurodegenerative regression, so the phenotype is not static in
    survivors.
  evidence:
  - reference: PMID:29138412
    reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The manifestations in our patients are variable and ranging from fetal lethal to viable and moderate skeletal dysplasia with narrow thorax and abnormal metaphyses.
    explanation: >-
      States the range from lethal to moderate viable disease.
  - reference: PMID:34016807
    reference_title: "KIAA0753-related skeletal ciliopathy: a ninth case, extending the phenotype and reporting a novel variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our case is the eldest woman reported to date (aged ten years) and the only known case to report associated hearing loss, leg-length discrepancy, pectus carinatum, respiratory ciliary dyskinesia and late-onset (9 years old) neuro-degenerative regression.
    explanation: >-
      Documents the accumulating features in the oldest reported survivor, and
      is careful to note they are so far unique to that case.
pathophysiology:
- name: Biallelic KIAA0753 Loss-of-Function Variants
  biological_scale: MOLECULAR
  description: >-
    Nonsense, frameshift and splice-altering variants on both KIAA0753 alleles.
    Truncating alleles predominate. Splice-altering alleles are easy to miss:
    two Pakistani families sharing an 85 kb homozygous block carried a
    synonymous c.810C>T change that turned out to activate abnormal splicing,
    which was only demonstrated by sequencing cDNA.
  genes:
  - preferred_term: KIAA0753
    term:
      id: hgnc:29110
      label: KIAA0753
  evidence:
  - reference: PMID:34523780
    reference_title: Genetic and phenotypic heterogeneity in KIAA0753-related ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The majority of reported KIAA0753 variants predict premature truncation of the KIAA0753 protein.
    explanation: >-
      Establishes the predominant class of disease allele.
  - reference: PMID:33875766
    reference_title: High diagnostic yield in skeletal ciliopathies using massively parallel genome sequencing, structural variant screening and RNA analyses.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Four variants located in non-canonical splice sites of DYNC2H1, EVC, and KIAA0753 led to aberrant splicing that was shown by sequencing of cDNA.
    explanation: >-
      Documents splice-altering KIAA0753 alleles confirmed at the transcript
      level.
  downstream:
  - target: Defective Basal Body Docking and Ciliogenesis
    description: >-
      Loss of the protein removes the recruitment platform at the distal
      centriole on which cilium assembly depends.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34523780
      reference_title: Genetic and phenotypic heterogeneity in KIAA0753-related ciliopathies.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We report in vitro results assessing the function of each variant indicating that mutant proteins are not fully competent to promote primary ciliogenesis.
      explanation: >-
        Tests the patient alleles themselves and shows each is deficient in
        supporting ciliogenesis.
- name: Defective Basal Body Docking and Ciliogenesis
  conforms_to: "ciliopathy_dysfunction#Basal Body and Transition Zone Dysfunction"
  biological_scale: CELLULAR
  description: >-
    KIAA0753 forms a ternary complex with OFD1 and FOPNL (FOR20) at centrosomes
    and pericentriolar satellites, and it acts upstream of them: mammalian
    centrioles need Moonraker to recruit OFD1, FOPNL and CEP90, which then place
    the distal appendage proteins CEP83, CEP89 and CEP164. Distal appendages are
    what dock the basal body to the plasma membrane, the step that permits a
    cilium to be built at all. The protein also has microtubule-stabilising
    activity. In patients the result is a measurable deficit in ciliation:
    fibroblasts from affected individuals make fewer primary cilia, and
    ablating the gene in vitro blocks ciliogenesis outright.

    This node substitutes a docking and appendage-assembly defect for the
    module's generic basal body lesion. Intraflagellar transport is not the
    primary lesion here, which is what separates this disorder from the IFT and
    dynein-2 forms of short-rib thoracic dysplasia.
  cellular_components:
  - preferred_term: centriolar satellite
    term:
      id: GO:0034451
      label: centriolar satellite
  - preferred_term: ciliary basal body
    term:
      id: GO:0036064
      label: ciliary basal body
  biological_processes:
  - preferred_term: cilium assembly
    modifier: DECREASED
    term:
      id: GO:0060271
      label: cilium assembly
  - preferred_term: protein localization to cilium
    modifier: ABNORMAL
    term:
      id: GO:0061512
      label: protein localization to cilium
  evidence:
  - reference: PMID:26643951
    reference_title: OFIP/KIAA0753 forms a complex with OFD1 and FOR20 at pericentriolar satellites and centrosomes and is mutated in one individual with oral-facial-digital syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We show that the KIAA0753/OFIP protein, whose sequence is conserved in ciliated species, associates with centrosome/centriole and pericentriolar satellites in human cells and forms a complex with FOR20 and OFD1.
    explanation: >-
      Establishes the localisation and the ternary complex this node is built
      on.
  - reference: PMID:36070319
    reference_title: "The evolutionary conserved proteins CEP90, FOPNL, and OFD1 recruit centriolar distal appendage proteins to initiate their assembly."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Finally, we show that mammalian centrioles require another component, Moonraker (MNR), to recruit OFD1, FOPNL, and CEP90, which will then recruit the distal appendage proteins CEP83, CEP89, and CEP164.
    explanation: >-
      Places KIAA0753/Moonraker upstream of the distal appendage assembly
      cascade, which is the specific mechanism this node asserts.
  - reference: PMID:34523780
    reference_title: Genetic and phenotypic heterogeneity in KIAA0753-related ciliopathies.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Ablation of KIAA0753 in vitro blocks primary ciliogenesis and SHH pathway activity.
    explanation: >-
      KIAA0753 ablation abolishes primary ciliogenesis in mouse NIH3T3
      fibroblasts, a cell-culture experiment.
  downstream:
  - target: Impaired Hedgehog Signal Transduction
    description: >-
      Without a competent primary cilium the Hedgehog pathway cannot be
      transduced.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34523780
      reference_title: Genetic and phenotypic heterogeneity in KIAA0753-related ciliopathies.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Correspondingly, KIAA0753 patient fibroblasts have a deficit in primary ciliation and improper SHH and WNT signaling, with a particularly blunted response to SHH pathway stimulation.
      explanation: >-
        Couples the ciliation deficit to the Hedgehog signalling defect in cells
        carrying patient genotypes.
  - target: Cerebellar and CNS Involvement
    description: >-
      Mouse cerebellar experiments implicate centriolar KIAA0753 recruitment in
      granule-neuron progenitor differentiation. Translation to individual brain
      abnormalities in skeletal patients is unresolved; this supports a CNS
      developmental branch without explaining every clinical finding.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34711653
      reference_title: CEP120-mediated KIAA0753 recruitment onto centrioles is required for timely neuronal differentiation and germinal zone exit in the developing cerebellum.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Surprisingly, we found that CEP120 recruits KIAA0753 to centrioles, and that loss of this interaction induces accumulation of GNPs in the germinal zone and impairs neuronal differentiation.
      explanation: >-
        Mouse depletion/rescue experiments support a role in cerebellar development;
        they do not directly demonstrate the cause of callosal, ventricular or
        pituitary findings in SRTD21.
      directness: INDIRECT
- name: Impaired Hedgehog Signal Transduction
  conforms_to: "ciliopathy_dysfunction#Impaired Hedgehog Signal Transduction"
  biological_scale: CELLULAR
  description: >-
    KIAA0753-null mouse NIH3T3 cells fail to induce Gli1 after Smoothened
    agonist treatment. Fibroblasts from the Joubert-presenting patient 1 in the
    Inskeep series show reduced ciliation and a blunted SHH response with
    altered aspects of WNT signaling. These results support gene function but
    are not direct measurements in skeletal-patient growth plates.
  biological_processes:
  - preferred_term: smoothened signaling pathway
    modifier: DECREASED
    term:
      id: GO:0007224
      label: smoothened signaling pathway
  - preferred_term: Wnt signaling pathway
    modifier: ABNORMAL
    term:
      id: GO:0016055
      label: Wnt signaling pathway
  evidence:
  - reference: PMID:34523780
    reference_title: Genetic and phenotypic heterogeneity in KIAA0753-related ciliopathies.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Correspondingly, KIAA0753 patient fibroblasts have a deficit in primary ciliation and improper SHH and WNT signaling, with a particularly blunted response to SHH pathway stimulation.
    explanation: >-
      Measures both signalling defects in cells carrying patient genotypes, and
      records that the Hedgehog response is the more severely affected.
  downstream:
  - target: Growth Plate Zonal Disorganisation
    description: >-
      Hedgehog signalling controls chondrocyte proliferation and the timing of
      hypertrophy in the growth plate.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:29138412
      reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We demonstrate that KIAA0753 is expressed in normal fetal human growth plate and show that the affected fetus, with a compound heterozygous frameshift and a nonsense mutation in KIAA0753, has an abnormal proliferative zone and a broad hypertrophic zone.
      explanation: >-
        Establishes both that the gene is expressed where the lesion appears and
        what the lesion looks like. The intervening steps between the signalling
        defect and the histology were not measured in the same tissue, which is
        why this edge is indirect with unknown intermediates.
- name: Growth Plate Zonal Disorganisation
  conforms_to: "growth_plate_chondrocyte_failure#Loss of Growth Plate Zonal Organisation"
  biological_scale: TISSUE
  description: >-
    The distal femoral growth plate of the affected fetus had disorganized
    proliferative columns and a broad hypertrophic zone, with absent KIAA0753
    staining in proliferative chondrocytes. The authors infer that impaired
    ciliary and centrosomal function disrupts growth-plate organization and
    causes abnormal skeletal growth. The contribution of Hedgehog signaling is
    inferred from other tissues and experimental systems.
  cell_types:
  - preferred_term: chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  - preferred_term: hypertrophic chondrocyte
    term:
      id: CL:0000743
      label: hypertrophic chondrocyte
  locations:
  - preferred_term: epiphyseal plate
    term:
      id: UBERON:0002516
      label: epiphyseal plate
  biological_processes:
  - preferred_term: growth plate cartilage development
    modifier: ABNORMAL
    term:
      id: GO:0003417
      label: growth plate cartilage development
  evidence:
  - reference: PMID:29138412
    reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We demonstrate that KIAA0753 is expressed in normal fetal human growth plate and show that the affected fetus, with a compound heterozygous frameshift and a nonsense mutation in KIAA0753, has an abnormal proliferative zone and a broad hypertrophic zone.
    explanation: >-
      The direct histological observation this node records, in human tissue.
  downstream:
  - target: Short Ribs and Thoracic Constriction
    description: >-
      Disordered endochondral growth shortens the ribs and the tubular bones.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:29138412
      reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Our results indicate that the effect that the KIAA0753 mutations have on cilia and centrosomes are sufficient to affect the growth plate organization, leading to severe postnatal short stature and bone deformities.
      explanation: >-
        The authors link disordered growth-plate organization to short stature and
        skeletal deformities.
      directness: INDIRECT
  - target: Short long bone
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Abnormal growth-plate organization impairs longitudinal endochondral growth
      and bone shape; the exact route to this individual radiographic feature has
      not been separately measured.
    evidence:
    - reference: PMID:29138412
      reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Our results indicate that the effect that the KIAA0753 mutations have on cilia and centrosomes are sufficient to affect the growth plate organization, leading to severe postnatal short stature and bone deformities.
      explanation: >-
        The authors interpret the affected growth plate as causing short stature and
        bone deformities. This is a tissue-to-skeletal inference, not a
        feature-specific experimental demonstration.
      directness: INDIRECT
  - target: Metaphyseal irregularity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Abnormal growth-plate organization impairs longitudinal endochondral growth
      and bone shape; the exact route to this individual radiographic feature has
      not been separately measured.
    evidence:
    - reference: PMID:29138412
      reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Our results indicate that the effect that the KIAA0753 mutations have on cilia and centrosomes are sufficient to affect the growth plate organization, leading to severe postnatal short stature and bone deformities.
      explanation: >-
        The authors interpret the affected growth plate as causing short stature and
        bone deformities. This is a tissue-to-skeletal inference, not a
        feature-specific experimental demonstration.
      directness: INDIRECT
  - target: Cone-shaped epiphysis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Abnormal growth-plate organization impairs longitudinal endochondral growth
      and bone shape; the exact route to this individual radiographic feature has
      not been separately measured.
    evidence:
    - reference: PMID:29138412
      reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Our results indicate that the effect that the KIAA0753 mutations have on cilia and centrosomes are sufficient to affect the growth plate organization, leading to severe postnatal short stature and bone deformities.
      explanation: >-
        The authors interpret the affected growth plate as causing short stature and
        bone deformities. This is a tissue-to-skeletal inference, not a
        feature-specific experimental demonstration.
      directness: INDIRECT
  - target: Brachydactyly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Abnormal growth-plate organization impairs longitudinal endochondral growth
      and bone shape; the exact route to this individual radiographic feature has
      not been separately measured.
    evidence:
    - reference: PMID:29138412
      reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Our results indicate that the effect that the KIAA0753 mutations have on cilia and centrosomes are sufficient to affect the growth plate organization, leading to severe postnatal short stature and bone deformities.
      explanation: >-
        The authors interpret the affected growth plate as causing short stature and
        bone deformities. This is a tissue-to-skeletal inference, not a
        feature-specific experimental demonstration.
      directness: INDIRECT
  - target: Rhizomelia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Abnormal growth-plate organization impairs longitudinal endochondral growth
      and bone shape; the exact route to this individual radiographic feature has
      not been separately measured.
    evidence:
    - reference: PMID:29138412
      reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Our results indicate that the effect that the KIAA0753 mutations have on cilia and centrosomes are sufficient to affect the growth plate organization, leading to severe postnatal short stature and bone deformities.
      explanation: >-
        The authors interpret the affected growth plate as causing short stature and
        bone deformities. This is a tissue-to-skeletal inference, not a
        feature-specific experimental demonstration.
      directness: INDIRECT
  - target: Disproportionate short-limb short stature
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Abnormal growth-plate organization impairs longitudinal endochondral growth
      and bone shape; the exact route to this individual radiographic feature has
      not been separately measured.
    evidence:
    - reference: PMID:29138412
      reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Our results indicate that the effect that the KIAA0753 mutations have on cilia and centrosomes are sufficient to affect the growth plate organization, leading to severe postnatal short stature and bone deformities.
      explanation: >-
        The authors interpret the affected growth plate as causing short stature and
        bone deformities. This is a tissue-to-skeletal inference, not a
        feature-specific experimental demonstration.
      directness: INDIRECT
  - target: Bowing of the long bones
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Abnormal growth-plate organization impairs longitudinal endochondral growth
      and bone shape; the exact route to this individual radiographic feature has
      not been separately measured.
    evidence:
    - reference: PMID:29138412
      reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Our results indicate that the effect that the KIAA0753 mutations have on cilia and centrosomes are sufficient to affect the growth plate organization, leading to severe postnatal short stature and bone deformities.
      explanation: >-
        The authors interpret the affected growth plate as causing short stature and
        bone deformities. This is a tissue-to-skeletal inference, not a
        feature-specific experimental demonstration.
      directness: INDIRECT
  - target: Genu varum
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Abnormal growth-plate organization produces limb deformity. Varus angulation
      is one reported manifestation, although its regional growth dynamics were
      not measured.
    evidence:
    - reference: PMID:29138412
      reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Our results indicate that the effect that the KIAA0753 mutations have on cilia and centrosomes are sufficient to affect the growth plate organization, leading to severe postnatal short stature and bone deformities.
      explanation: >-
        The authors interpret the affected growth plate as causing short stature and
        bone deformities. This is a tissue-to-skeletal inference, not a
        feature-specific experimental demonstration.
      directness: INDIRECT
- name: Short Ribs and Thoracic Constriction
  conforms_to: "ciliopathy_dysfunction#Skeletal Dysplasia with Polydactyly and Thoracic Constriction"
  biological_scale: ORGANISM
  description: >-
    Short, broad ribs with cupped anterior ends give a narrow thorax; the
    tubular bones are short with metaphyseal irregularity and cone-shaped
    epiphyses, and the pelvis shows the trident appearance characteristic of the
    group. This node substitutes the polydactyly-free presentation for the
    module's generic skeletal node: polydactyly is in the module's node name and
    is absent here, which is what the disorder's own name records.
  locations:
  - preferred_term: rib
    term:
      id: UBERON:0002228
      label: rib
  - preferred_term: thoracic rib cage
    term:
      id: UBERON:0003252
      label: thoracic rib cage
  evidence:
  - reference: PMID:31816441
    reference_title: A new case of KIAA0753-related variant of Jeune asphyxiating thoracic dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      On skeletal survey, short tubular bones (height - 5,5 SD) and a trident appearance of the pelvis were seen.
    explanation: >-
      Records the short tubular bones and trident pelvis in a KIAA0753 patient.
  downstream:
  - target: Respiratory Insufficiency from Thoracic Restriction
    description: >-
      A thorax too small to expand adequately restricts ventilation from birth.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31816441
      reference_title: A new case of KIAA0753-related variant of Jeune asphyxiating thoracic dystrophy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        This 4 year-old boy with narrow thorax, short limbs, severe respiratory and feeding difficulties from birth on had a history of hypotonia and developmental delay.
      explanation: >-
        Pairs the narrow thorax with severe respiratory difficulty from birth in
        the same patient.
  - target: Pulmonary Hypoplasia
    description: >-
      A thorax that never reaches normal volume constrains lung growth in
      utero, so the lungs are underdeveloped at birth rather than merely
      poorly ventilated.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34523780
      reference_title: Genetic and phenotypic heterogeneity in KIAA0753-related ciliopathies.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        He had macrocephaly (head circumference 37 cm, > 2 SD). He was admitted to the NICU for management of pulmonary hypoplasia and pulmonary hypertension.
      explanation: >-
        Pulmonary hypoplasia in the skeletally-presenting patient of this
        series, who was also recorded with a narrow chest and short ribs.
  - target: Short ribs
    causal_link_type: DIRECT
    description: >-
      Clinical expression of the short-rib thoracic skeletal lesion described in
      this node.
  - target: Narrow chest
    causal_link_type: DIRECT
    description: >-
      Clinical expression of the short-rib thoracic skeletal lesion described in
      this node.
  - target: Thoracic hypoplasia
    causal_link_type: DIRECT
    description: >-
      Clinical expression of the short-rib thoracic skeletal lesion described in
      this node.
- name: Pulmonary Hypoplasia
  biological_scale: TISSUE
  description: >-
    Underdeveloped lungs at birth, the developmental consequence of a thorax
    that is too small during fetal lung growth. It sits between the skeletal
    lesion and the respiratory failure and is what distinguishes this disorder's
    respiratory course from simple mechanical restriction of normal lungs: in
    the one skeletally-presenting patient reported in detail it required NICU
    management from birth alongside pulmonary hypertension, and he died at two
    weeks.
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  evidence:
  - reference: PMID:34523780
    reference_title: Genetic and phenotypic heterogeneity in KIAA0753-related ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He had macrocephaly (head circumference 37 cm, > 2 SD). He was admitted to the NICU for management of pulmonary hypoplasia and pulmonary hypertension.
    explanation: >-
      Records pulmonary hypoplasia requiring neonatal intensive care in the
      skeletal presentation.
  - reference: PMID:34523780
    reference_title: Genetic and phenotypic heterogeneity in KIAA0753-related ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He died at 2 weeks of age due to severe pulmonary hypertension.
    explanation: >-
      The outcome in the same patient, which is why this node is curated as the
      lethal step rather than an incidental finding.
  downstream:
  - target: Respiratory Insufficiency from Thoracic Restriction
    description: >-
      Lungs that never developed to normal volume cannot meet postnatal gas
      exchange demand, compounding the mechanical restriction.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34523780
      reference_title: Genetic and phenotypic heterogeneity in KIAA0753-related ciliopathies.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        He had macrocephaly (head circumference 37 cm, > 2 SD). He was admitted to the NICU for management of pulmonary hypoplasia and pulmonary hypertension.
      explanation: >-
        The hypoplastic lungs are what the neonatal respiratory management in
        this patient was directed at.
  - target: Pulmonary hypoplasia
    causal_link_type: DIRECT
    description: >-
      Clinical manifestation of the pulmonary developmental lesion documented in
      the skeletal-presenting infant.
- name: Respiratory Insufficiency from Thoracic Restriction
  biological_scale: ORGANISM
  description: >-
    Thoracic restriction and pulmonary hypoplasia contribute to respiratory
    insufficiency from birth in severe cases. Reported outcomes also include
    respiratory failure after infection and neonatal death due to pulmonary
    hypertension, so thoracic size alone does not establish the terminal
    mechanism. One skeletal patient additionally had confirmed respiratory
    ciliary dyskinesia with recurrent chest infections, a separate route to
    respiratory disease.
  evidence:
  - reference: PMID:31816441
    reference_title: A new case of KIAA0753-related variant of Jeune asphyxiating thoracic dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This 4 year-old boy with narrow thorax, short limbs, severe respiratory and feeding difficulties from birth on had a history of hypotonia and developmental delay.
    explanation: >-
      Documents the respiratory phenotype from birth.
  - reference: PMID:34016807
    reference_title: "KIAA0753-related skeletal ciliopathy: a ninth case, extending the phenotype and reporting a novel variant."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our case is the eldest woman reported to date (aged ten years) and the only known case to report associated hearing loss, leg-length discrepancy, pectus carinatum, respiratory ciliary dyskinesia and late-onset (9 years old) neuro-degenerative regression.
    explanation: >-
      Supports the second, motile-cilia route named in this node's description
      rather than the thoracic-restriction route: confirmed respiratory ciliary
      dyskinesia with recurrent chest infections. The quoted sentence states in
      the same breath that this has been seen in one patient only, so it does
      not generalise.
  downstream:
  - target: Respiratory insufficiency
    causal_link_type: DIRECT
    description: >-
      Restricted thoracic expansion and reduced lung volume account for
      respiratory insufficiency in the severe skeletal presentation.
- name: Cerebellar and CNS Involvement
  conforms_to: "ciliopathy_dysfunction#Cerebellar and CNS Malformation"
  biological_scale: ORGANISM
  description: >-
    KIAA0753 depletion in mouse cerebellar granule-neuron progenitors impairs
    differentiation and germinal-zone exit. The authors propose that this
    contributes to cerebellar hypoplasia in Joubert syndrome. Inferior vermis
    hypoplasia/dysplasia and molar tooth sign also occur in skeletal patients,
    supporting an overlapping cerebellar developmental branch. Callosal,
    ventricular and pituitary anomalies, hypotonia and developmental delay are
    associated clinical findings whose individual causal routes remain
    unresolved.
  locations:
  - preferred_term: cerebellar vermis
    term:
      id: UBERON:0004720
      label: cerebellar vermis
  evidence:
  - reference: PMID:29138412
    reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition two of our patients showed brain abnormalities consistent with JBTS.
    explanation: >-
      Records the CNS involvement within the skeletal case series, and its
      frequency there.
  - reference: PMID:34016807
    reference_title: "KIAA0753-related skeletal ciliopathy: a ninth case, extending the phenotype and reporting a novel variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe a ninth case that expands the phenotype; a 10-year-old girl with rhizomelic short stature (-5.6 SD), macrocephaly, developmental delay, CNS anomalies (thin corpus callosum, bilateral ventriculomegaly), cone-rod dystrophy, nystagmus, mild conductive hearing loss and recurrent chest infections secondary to confirmed ciliary dyskinesia.
    explanation: >-
      Documents the structural CNS findings alongside the skeletal phenotype in
      one patient.
  - reference: PMID:34711653
    reference_title: CEP120-mediated KIAA0753 recruitment onto centrioles is required for timely neuronal differentiation and germinal zone exit in the developing cerebellum.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Together, our data reveal a close interplay between CEP120 and KIAA0753 for the germinal zone exit and timely neuronal differentiation of GNPs during cerebellar development, and mutations in CEP120 and KIAA0753 may participate in the heterotopia and cerebellar hypoplasia observed in JS patients.
    explanation: >-
      The authors interpret mouse neuronal-development experiments as a possible
      explanation for human cerebellar hypoplasia. Extension to the vermian
      hypoplasia of skeletal/Joubert overlap patients remains indirect.
  downstream:
  - target: Cerebellar vermis hypoplasia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Defective cerebellar neurogenesis provides a literature-supported candidate
      route to vermian underdevelopment in skeletal/Joubert overlap patients;
      human tissue confirmation is lacking.
    evidence:
    - reference: PMID:34711653
      reference_title: CEP120-mediated KIAA0753 recruitment onto centrioles is required for timely neuronal differentiation and germinal zone exit in the developing cerebellum.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Together, our data reveal a close interplay between CEP120 and KIAA0753 for the germinal zone exit and timely neuronal differentiation of GNPs during cerebellar development, and mutations in CEP120 and KIAA0753 may participate in the heterotopia and cerebellar hypoplasia observed in JS patients.
      explanation: >-
        The authors interpret mouse neuronal-development experiments as a possible
        explanation for human cerebellar hypoplasia. Extension to the vermian
        hypoplasia of skeletal/Joubert overlap patients remains indirect.
phenotypes:
- name: Narrow chest
  category: Skeletal
  diagnostic: true
  description: >-
    A narrow thorax associated with short ribs is a defining skeletal feature.
    Thoracic severity contributes to respiratory risk, alongside pulmonary
    hypoplasia and other respiratory complications.
  phenotype_term:
    preferred_term: Narrow chest
    term:
      id: HP:0000774
      label: Narrow chest
  evidence:
  - reference: PMID:29138412
    reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The manifestations in our patients are variable and ranging from fetal lethal to viable and moderate skeletal dysplasia with narrow thorax and abnormal metaphyses.
    explanation: >-
      Records the narrow thorax across the reported severity range.
- name: Short long bone
  category: Skeletal
  diagnostic: true
  description: >-
    Short tubular bones with rhizomelic limb shortening, severe enough in
    reported patients to give heights around five standard deviations below the
    mean.
  phenotype_term:
    preferred_term: Short long bone
    term:
      id: HP:0003026
      label: Short long bone
  evidence:
  - reference: PMID:31816441
    reference_title: A new case of KIAA0753-related variant of Jeune asphyxiating thoracic dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      On skeletal survey, short tubular bones (height - 5,5 SD) and a trident appearance of the pelvis were seen.
    explanation: >-
      Records short tubular bones with the associated height deficit.
- name: Metaphyseal irregularity
  category: Skeletal
  diagnostic: true
  description: >-
    Metaphyseal irregularity and sclerosis with metaphyseal flaring of the long
    tubular bones.
  phenotype_term:
    preferred_term: Metaphyseal irregularity
    term:
      id: HP:0003025
      label: Metaphyseal irregularity
  evidence:
  - reference: PMID:29138412
    reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Short ilia, sclerotic iliac crest, narrow sciatic notch, horizontal acetabular roof, metaphyseal irregularities and sclerosis, metaphyseal flaring of the long tubular bones, short and curved tibia are seen
    explanation: >-
      The radiographic description of the metaphyseal changes in the discovery
      series.
  - reference: PMID:29138412
    reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The manifestations in our patients are variable and ranging from fetal lethal to viable and moderate skeletal dysplasia with narrow thorax and abnormal metaphyses.
    explanation: >-
      Records the metaphyseal abnormality across the whole reported severity
      range.
- name: Trident pelvis
  category: Skeletal
  description: >-
    The trident acetabular appearance characteristic of the short-rib
    dysplasias.
  phenotype_term:
    preferred_term: Trident pelvis
    term:
      id: HP:0034044
      label: Trident pelvis
  evidence:
  - reference: PMID:31816441
    reference_title: A new case of KIAA0753-related variant of Jeune asphyxiating thoracic dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      On skeletal survey, short tubular bones (height - 5,5 SD) and a trident appearance of the pelvis were seen.
    explanation: >-
      Records the trident pelvis in a KIAA0753 patient.
- name: Respiratory insufficiency
  category: Respiratory
  diagnostic: true
  description: >-
    Respiratory insufficiency accompanies the severe skeletal presentation, with
    thoracic restriction and pulmonary hypoplasia as contributing mechanisms.
    Respiratory infection and pulmonary hypertension also complicate reported
    cases.
  phenotype_term:
    preferred_term: Respiratory insufficiency
    term:
      id: HP:0002093
      label: Respiratory insufficiency
  evidence:
  - reference: PMID:31816441
    reference_title: A new case of KIAA0753-related variant of Jeune asphyxiating thoracic dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This 4 year-old boy with narrow thorax, short limbs, severe respiratory and feeding difficulties from birth on had a history of hypotonia and developmental delay.
    explanation: >-
      Records severe respiratory difficulty from birth.
- name: Feeding difficulties
  category: Gastrointestinal
  description: >-
    Severe feeding difficulties from birth were reported alongside respiratory
    difficulties in the four-year-old skeletal case. The relative contributions
    of respiratory compromise and neurologic dysfunction are unresolved.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:31816441
    reference_title: A new case of KIAA0753-related variant of Jeune asphyxiating thoracic dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This 4 year-old boy with narrow thorax, short limbs, severe respiratory and feeding difficulties from birth on had a history of hypotonia and developmental delay.
    explanation: >-
      Records severe feeding difficulties from birth alongside the respiratory
      ones.
- name: Global developmental delay
  category: Neurologic
  description: >-
    Developmental delay occurs in the skeletal presentation. Motor and speech
    delays are reported in the discovery series; developmental impairment in P1
    and P2 may arise from either KIAA0753 or their additional SLC13A5 diagnosis.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:31816441
    reference_title: A new case of KIAA0753-related variant of Jeune asphyxiating thoracic dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This 4 year-old boy with narrow thorax, short limbs, severe respiratory and feeding difficulties from birth on had a history of hypotonia and developmental delay.
    explanation: >-
      Records developmental delay alongside the skeletal phenotype.
  - reference: PMID:29138412
    reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He had disproportionate short stature (Supplementary Table S1), speech delay, pectus carinatum, narrow chest, protuberant abdomen and short limbs (Figs 1e and 2g,h,k, Table 1).
    explanation: >-
      The independent skeletal patient P3 has speech delay; Table 1 also records
      gross motor delay.
  - reference: PMID:29138412
    reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We thus conclude that the seizures and teeth hypoplasia in P1 and P2 are due to the homozygous SLC13A5 variant, while the developmental and speech delay is an overlapping feature and could be inferable to either one of the congenital conditions.
    explanation: >-
      The two cousins cannot establish a gene-specific developmental severity or
      frequency.
- name: Hypotonia
  category: Neurologic
  description: >-
    Hypotonia, one of the features shared with the Joubert presentation of the
    same gene.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:31816441
    reference_title: A new case of KIAA0753-related variant of Jeune asphyxiating thoracic dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This 4 year-old boy with narrow thorax, short limbs, severe respiratory and feeding difficulties from birth on had a history of hypotonia and developmental delay.
    explanation: >-
      Records hypotonia in a KIAA0753 skeletal patient.
  notes: >-
    The Faudi skeletal case provides independent evidence. Hypotonia in
    discovery-series P1 co-occurs with an additional SLC13A5 diagnosis.
- name: Molar tooth sign on MRI
  category: Neurologic
  description: >-
    Molar tooth sign was confirmed by MRI in P1 and P2 of the discovery series.
    P3 had an unremarkable CT but no MRI, and the fetus had vermian
    abnormalities without a reported molar tooth sign; the two positive scans
    therefore do not establish a 2/4 frequency among adequately assessed
    patients.
  phenotype_term:
    preferred_term: Molar tooth sign on MRI
    term:
      id: HP:0002419
      label: Molar tooth sign on MRI
  evidence:
  - reference: PMID:29138412
    reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain magnetic resonance imaging (MRI) showed hypoplasia of the corpus callosum, small pituitary gland, inferior vermis dysplasia, “molar tooth” sign (MTS) and mildly dilated third ventricle (Supplementary Fig. S1).
    explanation: >-
      Names the molar tooth sign directly, in the first patient of the discovery
      series.
  - reference: PMID:29138412
    reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition two of our patients showed brain abnormalities consistent with JBTS.
    explanation: >-
      Two patients had Joubert-like brain abnormalities; the source does not
      report four comparable MRI assessments.
- name: Cone-shaped epiphysis
  category: Skeletal
  description: >-
    Cone-shaped epiphyses embedded in cup-shaped metaphyses at the knee, and in
    the phalanges and metacarpals.
  phenotype_term:
    preferred_term: Cone-shaped epiphysis
    term:
      id: HP:0010579
      label: Cone-shaped epiphysis
  evidence:
  - reference: PMID:29138412
    reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Skeletal survey showed severe metaphyseal dysplasia and cone-shaped epiphyses of the proximal tibia and distal femur embedded in cup-shaped metaphyses (Fig. 2a–c).
    explanation: >-
      The radiographic description in the discovery series.
- name: Short ribs
  category: Skeletal
  diagnostic: true
  description: >-
    Short, broad ribs with cupped anterior ends. They are the feature the
    disorder is named for and the proximate cause of the narrow thorax.
  phenotype_term:
    preferred_term: Short ribs
    term:
      id: HP:0000773
      label: Short ribs
  evidence:
  - reference: PMID:34523780
    reference_title: Genetic and phenotypic heterogeneity in KIAA0753-related ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Plain films demonstrated skeletal abnormalities including short ribs, trident ilia, broad metaphyses, short and bowed tubular bones, and short metacarpals.
    explanation: >-
      The skeletal-presenting infant has short ribs on plain films.
- name: Thoracic hypoplasia
  category: Skeletal
  frequency: 4/4
  diagnostic: true
  description: >-
    Thoracic hypoplasia was recorded in all four discovery-series skeletal
    patients. This selected case-series count is not a population penetrance
    estimate.
  phenotype_term:
    preferred_term: Thoracic hypoplasia
    term:
      id: HP:0005257
      label: Thoracic hypoplasia
  evidence:
  - reference: PMID:29138412
    reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In P4, the condition was lethal with skeletal changes including thorax hypoplasia and bowed limbs, while in the other three patients (P1-3), the phenotype included short stature, metaphyseal dysplasia with limb deformities, brachydactyly, developmental disability and features of Joubert syndrome.
    explanation: >-
      The discussion directly records fetal thorax hypoplasia; Table 1 records
      thoracic hypoplasia in all four skeletal patients.
- name: Brachydactyly
  category: Skeletal
  frequency: 4/4
  description: >-
    Short phalanges and metacarpals in all four patients of the discovery
    series. In the same table, the previously reported orofaciodigital patient
    with this gene had polydactyly instead, which is the contrast the disorder
    name records.
  phenotype_term:
    preferred_term: Brachydactyly
    term:
      id: HP:0001156
      label: Brachydactyly
  evidence:
  - reference: PMID:29138412
    reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In P4, the condition was lethal with skeletal changes including thorax hypoplasia and bowed limbs, while in the other three patients (P1-3), the phenotype included short stature, metaphyseal dysplasia with limb deformities, brachydactyly, developmental disability and features of Joubert syndrome.
    explanation: >-
      The discussion records brachydactyly in P1-P3; the fetal autopsy and Table 1
      also document it in P4.
- name: Delayed speech and language development
  category: Neurologic
  description: >-
    Speech delay is documented in the independent skeletal patient P3 of the
    discovery series. The same table reports delay in P1 and P2, who also had
    SLC13A5-related disease, so their findings cannot establish a
    KIAA0753-specific frequency.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:29138412
    reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He had disproportionate short stature (Supplementary Table S1), speech delay, pectus carinatum, narrow chest, protuberant abdomen and short limbs (Figs 1e and 2g,h,k, Table 1).
    explanation: >-
      Speech delay in P3 provides evidence independent of the SLC13A5-confounded
      cousins.
  - reference: PMID:29138412
    reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We thus conclude that the seizures and teeth hypoplasia in P1 and P2 are due to the homozygous SLC13A5 variant, while the developmental and speech delay is an overlapping feature and could be inferable to either one of the congenital conditions.
    explanation: >-
      The authors explicitly leave the developmental and speech contribution of
      the two diagnoses unresolved.
- name: Delayed gross motor development
  category: Neurologic
  description: >-
    Motor delay in all three living patients of the discovery series; one girl
    sat unaided at one year and walked at three.
  phenotype_term:
    preferred_term: Delayed gross motor development
    term:
      id: HP:0002194
      label: Delayed gross motor development
  evidence:
  - reference: PMID:29138412
    reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She had delayed motor development (sitting unaided at 1 year; walking at 3 years of age).
    explanation: >-
      P1 has delayed motor milestones but also SLC13A5-related disease. Table 1
      separately records gross motor delay in P3, who lacks this second diagnosis.
  - reference: PMID:29138412
    reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We thus conclude that the seizures and teeth hypoplasia in P1 and P2 are due to the homozygous SLC13A5 variant, while the developmental and speech delay is an overlapping feature and could be inferable to either one of the congenital conditions.
    explanation: >-
      Explains why the clinical count cannot be attributed exclusively to
      KIAA0753.
  notes: >-
    Table 1 records motor delay in all three children, but P1 and P2 also have
    biallelic SLC13A5 disease. The reported 3/3 is therefore not a
    KIAA0753-specific frequency. The milestone example is from P1.
- name: Flexion contracture
  category: Skeletal
  frequency: 2/3
  description: >-
    Flexion contractures of the elbows, hips and knees, severe in one patient.
  phenotype_term:
    preferred_term: Flexion contracture
    term:
      id: HP:0001371
      label: Flexion contracture
  evidence:
  - reference: PMID:29138412
    reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      P2 has severe flexion contractures of the elbows, hips and knees, as well as genu varum.
    explanation: >-
      The figure caption directly describes the contractures; Table 1 records them
      in P1 and P2, with P3 negative and P4 unassessed.
- name: Protuberant abdomen
  category: Gastrointestinal
  frequency: 3/4
  description: >-
    A prominent abdomen was reported in P1, P3 and the fetus in the discovery
    series. The source does not establish whether this reflects thoracic
    proportions or another mechanism.
  phenotype_term:
    preferred_term: Protuberant abdomen
    term:
      id: HP:0001538
      label: Protuberant abdomen
  evidence:
  - reference: PMID:29138412
    reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He had disproportionate short stature (Supplementary Table S1), speech delay, pectus carinatum, narrow chest, protuberant abdomen and short limbs (Figs 1e and 2g,h,k, Table 1).
    explanation: >-
      The clinical description directly records a protuberant abdomen in P3; Table
      1 also records this in P1 and P4.
- name: Hypoplasia of the corpus callosum
  category: Neurologic
  description: >-
    Corpus callosum hypoplasia on brain MRI, part of the CNS involvement that
    overlaps Joubert syndrome.
  phenotype_term:
    preferred_term: Hypoplasia of the corpus callosum
    term:
      id: HP:0002079
      label: Hypoplasia of the corpus callosum
  evidence:
  - reference: PMID:29138412
    reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain magnetic resonance imaging (MRI) showed hypoplasia of the corpus callosum, small pituitary gland, inferior vermis dysplasia, “molar tooth” sign (MTS) and mildly dilated third ventricle (Supplementary Fig. S1).
    explanation: >-
      The brain MRI findings in the first patient of the discovery series.
- name: Ventriculomegaly
  category: Neurologic
  description: >-
    Dilated cerebral ventricles, seen on brain MRI postnatally and on fetal
    ultrasound at 19 weeks in the affected fetus.
  phenotype_term:
    preferred_term: Ventriculomegaly
    term:
      id: HP:0002119
      label: Ventriculomegaly
  evidence:
  - reference: PMID:29138412
    reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fetal ultrasound at 19 weeks gestation showed short limbs, narrow chest, prominent abdomen, cerebral ventriculomegaly, suspected defect in the cerebellar vermis and mild pelviectasis.
    explanation: >-
      Records ventriculomegaly, and the rest of the prenatal picture, in the
      affected fetus.
- name: Small pituitary gland
  category: Endocrine
  description: >-
    A small pituitary gland was seen on MRI in the two cousins of the skeletal
    discovery series. Their endocrine assessment did not establish the growth
    hormone deficiency reported in separate Joubert patients.
  phenotype_term:
    preferred_term: Small pituitary gland
    term:
      id: HP:0012506
      label: Small pituitary gland
  evidence:
  - reference: PMID:29138412
    reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain magnetic resonance imaging (MRI) showed hypoplasia of the corpus callosum, small pituitary gland, inferior vermis dysplasia, “molar tooth” sign (MTS) and mildly dilated third ventricle (Supplementary Fig. S1).
    explanation: >-
      Records the small pituitary gland alongside the other CNS findings.
- name: Rhizomelia
  category: Skeletal
  description: >-
    Rhizomelic shortening of the limbs, with disproportionate short stature.
  phenotype_term:
    preferred_term: Rhizomelia
    term:
      id: HP:0008905
      label: Rhizomelia
  evidence:
  - reference: PMID:34016807
    reference_title: "KIAA0753-related skeletal ciliopathy: a ninth case, extending the phenotype and reporting a novel variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe a ninth case that expands the phenotype; a 10-year-old girl with rhizomelic short stature (-5.6 SD), macrocephaly, developmental delay, CNS anomalies (thin corpus callosum, bilateral ventriculomegaly), cone-rod dystrophy, nystagmus, mild conductive hearing loss and recurrent chest infections secondary to confirmed ciliary dyskinesia.
    explanation: >-
      Records rhizomelic short stature and its severity.
- name: Pulmonary hypoplasia
  category: Respiratory
  description: >-
    Underdeveloped lungs in the skeletally-presenting patient of the KIAA0753
    heterogeneity series, requiring neonatal intensive care from birth alongside
    pulmonary hypertension. It is the developmental step between the constricted
    thorax and the respiratory insufficiency: the small chest does not merely
    impair ventilation of normal lungs, it prevents them growing.
  phenotype_term:
    preferred_term: Pulmonary hypoplasia
    term:
      id: HP:0002089
      label: Pulmonary hypoplasia
  evidence:
  - reference: PMID:34523780
    reference_title: Genetic and phenotypic heterogeneity in KIAA0753-related ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He had macrocephaly (head circumference 37 cm, > 2 SD). He was admitted to the NICU for management of pulmonary hypoplasia and pulmonary hypertension.
    explanation: >-
      Records pulmonary hypoplasia in the SRTD-presenting patient of this
      series.
  notes: >-
    The Inskeep skeletal infant also carried a RUNX2 in-frame deletion
    classified as a variant of uncertain significance, inherited from his
    phenotypically normal father; the authors identified biallelic truncating
    KIAA0753 variants as the diagnosis.
- name: Macrocephaly
  category: Craniofacial
  description: >-
    Increased head circumference, measured at birth in the one
    skeletally-presenting patient reported in detail. Macrocephaly is also
    reported in KIAA0753 patients at the Joubert end of the spectrum, so it is
    not specific to this presentation.
  phenotype_term:
    preferred_term: Macrocephaly
    term:
      id: HP:0000256
      label: Macrocephaly
  evidence:
  - reference: PMID:34523780
    reference_title: Genetic and phenotypic heterogeneity in KIAA0753-related ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He had macrocephaly (head circumference 37 cm, > 2 SD). He was admitted to the NICU for management of pulmonary hypoplasia and pulmonary hypertension.
    explanation: >-
      Records the head circumference measurement at birth in the
      SRTD-presenting patient.
  notes: >-
    The Inskeep skeletal infant also carried a RUNX2 in-frame deletion
    classified as a variant of uncertain significance, inherited from his
    phenotypically normal father; the authors identified biallelic truncating
    KIAA0753 variants as the diagnosis.
- name: Frontal bossing
  category: Craniofacial
  description: >-
    Prominent forehead, present in all three living patients of the discovery
    series and in the skeletally-presenting patient of a later one.
  phenotype_term:
    preferred_term: Frontal bossing
    term:
      id: HP:0002007
      label: Frontal bossing
  evidence:
  - reference: PMID:34523780
    reference_title: Genetic and phenotypic heterogeneity in KIAA0753-related ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Physical exam was notable for frontal bossing, low-set ears, anteverted nares, and macrocephaly.
    explanation: >-
      Independent frontal bossing in the skeletal-presenting infant, beyond the
      discovery series.
- name: Flat face
  category: Craniofacial
  description: >-
    Flattened facial profile, recorded in all three living patients of the
    discovery series.
  phenotype_term:
    preferred_term: Flat face
    term:
      id: HP:0012368
      label: Flat face
  evidence:
  - reference: PMID:29138412
    reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Craniofacial anomaliesFrontal bossing (HP:0002007), flat face (HP:0012368), depressed nasal bridge (HP:0005280), teeth hypoplasia (HP:0000685)Frontal bossing (HP:0002007), flat face (HP:0012368), depressed nasal bridge (HP:0005280), teeth hypoplasia (HP:0000685)Frontal bossing (HP:0002007), flat face (HP:0012368), low set ears (HP:0000369)
    explanation: >-
      The same craniofacial row. Flat face follows frontal bossing in each of
      the P1, P2 and P3 columns.
- name: Depressed nasal bridge
  category: Craniofacial
  description: >-
    Depressed nasal bridge was recorded in the two cousins of the discovery
    series. Its omission from another patient description is not evidence of
    absence.
  phenotype_term:
    preferred_term: Depressed nasal bridge
    term:
      id: HP:0005280
      label: Depressed nasal bridge
  evidence:
  - reference: PMID:29138412
    reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At 20 months of age, she had disproportional short stature with severe genu varum, relatively large head, depressed nasal bridge and low set ears.
    explanation: >-
      Direct examination of P1 reports depressed nasal bridge. The craniofacial
      table also records this in P2.
- name: Disproportionate short-limb short stature
  category: Skeletal
  description: >-
    Disproportionate short stature with short limbs is reported in the
    independent skeletal patient P3.
  phenotype_term:
    preferred_term: Disproportionate short-limb short stature
    term:
      id: HP:0008873
      label: Disproportionate short-limb short stature
  evidence:
  - reference: PMID:29138412
    reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He had disproportionate short stature (Supplementary Table S1), speech delay, pectus carinatum, narrow chest, protuberant abdomen and short limbs (Figs 1e and 2g,h,k, Table 1).
    explanation: >-
      Documents this finding in a molecularly confirmed skeletal presentation; no
      disease-wide frequency is inferred.
- name: Bowing of the long bones
  category: Skeletal
  description: >-
    Short, bowed tubular bones occur in the severe skeletal presentation.
  phenotype_term:
    preferred_term: Bowing of the long bones
    term:
      id: HP:0006487
      label: Bowing of the long bones
  evidence:
  - reference: PMID:34523780
    reference_title: Genetic and phenotypic heterogeneity in KIAA0753-related ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Plain films demonstrated skeletal abnormalities including short ribs, trident ilia, broad metaphyses, short and bowed tubular bones, and short metacarpals.
    explanation: >-
      Documents this finding in a molecularly confirmed skeletal presentation; no
      disease-wide frequency is inferred.
- name: Genu varum
  category: Skeletal
  description: >-
    Genu varum is documented in the two cousins with skeletal dysplasia.
  phenotype_term:
    preferred_term: Genu varum
    term:
      id: HP:0002970
      label: Genu varum
  evidence:
  - reference: PMID:29138412
    reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She had disproportionate short stature with genu varum at 24 months of age.
    explanation: >-
      Documents this finding in a molecularly confirmed skeletal presentation; no
      disease-wide frequency is inferred.
- name: Pectus carinatum
  category: Skeletal
  description: >-
    Pectus carinatum is present in discovery-series P3 and also reported in the
    later ten-year-old skeletal case.
  phenotype_term:
    preferred_term: Pectus carinatum
    term:
      id: HP:0000768
      label: Pectus carinatum
  evidence:
  - reference: PMID:29138412
    reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He had disproportionate short stature (Supplementary Table S1), speech delay, pectus carinatum, narrow chest, protuberant abdomen and short limbs (Figs 1e and 2g,h,k, Table 1).
    explanation: >-
      Documents this finding in a molecularly confirmed skeletal presentation; no
      disease-wide frequency is inferred.
- name: Pectus excavatum
  category: Skeletal
  description: >-
    Pectus excavatum was reported in P1. The teeth hypoplasia in the same
    sentence was attributed to SLC13A5, not KIAA0753.
  phenotype_term:
    preferred_term: Pectus excavatum
    term:
      id: HP:0000767
      label: Pectus excavatum
  evidence:
  - reference: PMID:29138412
    reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      On follow-up at 6 years she had teeth hypoplasia, pectus excavatum, rhizomelic shortening of the limbs and flexion contractures of the elbows, knee and hips (Fig. 1c).
    explanation: >-
      Documents this finding in a molecularly confirmed skeletal presentation; no
      disease-wide frequency is inferred.
- name: Cervical spinal canal stenosis
  category: Skeletal
  description: >-
    Cervical canal stenosis was observed in the four-year-old boy with the Jeune
    skeletal presentation.
  phenotype_term:
    preferred_term: Cervical spinal canal stenosis
    term:
      id: HP:0008445
      label: Cervical spinal canal stenosis
  evidence:
  - reference: PMID:31816441
    reference_title: A new case of KIAA0753-related variant of Jeune asphyxiating thoracic dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain MRI showed cervical canal stenosis.
    explanation: >-
      Documents this finding in a molecularly confirmed skeletal presentation; no
      disease-wide frequency is inferred.
- name: Hepatomegaly
  category: Gastrointestinal
  description: >-
    Moderate hepatomegaly was described in the Faudi case; mild hepatomegaly was
    also found in discovery-series P3.
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  evidence:
  - reference: PMID:31816441
    reference_title: A new case of KIAA0753-related variant of Jeune asphyxiating thoracic dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Renal function was normal and moderate hepatomegaly was noted.
    explanation: >-
      Documents this finding in a molecularly confirmed skeletal presentation; no
      disease-wide frequency is inferred.
- name: Pulmonary hypertension
  category: Cardiovascular
  description: >-
    Pulmonary hypertension occurred with neonatal pulmonary hypoplasia and was
    fatal at two weeks. It was also detected by echocardiography in
    discovery-series P3.
  phenotype_term:
    preferred_term: Pulmonary hypertension
    term:
      id: HP:0002092
      label: Pulmonary arterial hypertension
  evidence:
  - reference: PMID:34523780
    reference_title: Genetic and phenotypic heterogeneity in KIAA0753-related ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He died at 2 weeks of age due to severe pulmonary hypertension.
    explanation: >-
      Documents this finding in a molecularly confirmed skeletal presentation; no
      disease-wide frequency is inferred.
  notes: >-
    The Inskeep skeletal infant also carried a RUNX2 in-frame deletion
    classified as a variant of uncertain significance, inherited from his
    phenotypically normal father; the authors identified biallelic truncating
    KIAA0753 variants as the diagnosis.
- name: Low-set ears
  category: Craniofacial
  description: >-
    Low-set ears occur in the severe skeletal presentation and in the discovery
    series.
  phenotype_term:
    preferred_term: Low-set ears
    term:
      id: HP:0000369
      label: Low-set ears
  evidence:
  - reference: PMID:34523780
    reference_title: Genetic and phenotypic heterogeneity in KIAA0753-related ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Physical exam was notable for frontal bossing, low-set ears, anteverted nares, and macrocephaly.
    explanation: >-
      Documents this finding in a molecularly confirmed skeletal presentation; no
      disease-wide frequency is inferred.
- name: Anteverted nares
  category: Craniofacial
  description: >-
    Anteverted nares were described in the skeletal-presenting infant.
  phenotype_term:
    preferred_term: Anteverted nares
    term:
      id: HP:0000463
      label: Anteverted nares
  evidence:
  - reference: PMID:34523780
    reference_title: Genetic and phenotypic heterogeneity in KIAA0753-related ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Physical exam was notable for frontal bossing, low-set ears, anteverted nares, and macrocephaly.
    explanation: >-
      Documents this finding in a molecularly confirmed skeletal presentation; no
      disease-wide frequency is inferred.
  notes: >-
    The Inskeep skeletal infant also carried a RUNX2 in-frame deletion
    classified as a variant of uncertain significance, inherited from his
    phenotypically normal father; the authors identified biallelic truncating
    KIAA0753 variants as the diagnosis.
- name: Micrognathia
  category: Craniofacial
  description: >-
    Micrognathia was documented at autopsy in the molecularly confirmed skeletal
    fetus.
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  evidence:
  - reference: PMID:29138412
    reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The parents chose to terminate the pregnancy and the fetal autopsy showed macrocephaly, wide open anterior and posterior fontanels, high forehead with frontal bossing, micrognathia, low-set and posteriorly rotated left ear, small nose with a broad nasal bridge, long philtrum, normal lips and palate, short lingual frenulum, short and bowed limbs, brachydactyly, micropenis and hypospadia (Fig. 3b,e).
    explanation: >-
      Documents this finding in a molecularly confirmed skeletal presentation; no
      disease-wide frequency is inferred.
- name: Wide nasal bridge
  category: Craniofacial
  description: >-
    A broad nasal bridge was described in the affected fetus.
  phenotype_term:
    preferred_term: Wide nasal bridge
    term:
      id: HP:0000431
      label: Wide nasal bridge
  evidence:
  - reference: PMID:29138412
    reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The parents chose to terminate the pregnancy and the fetal autopsy showed macrocephaly, wide open anterior and posterior fontanels, high forehead with frontal bossing, micrognathia, low-set and posteriorly rotated left ear, small nose with a broad nasal bridge, long philtrum, normal lips and palate, short lingual frenulum, short and bowed limbs, brachydactyly, micropenis and hypospadia (Fig. 3b,e).
    explanation: >-
      Documents this finding in a molecularly confirmed skeletal presentation; no
      disease-wide frequency is inferred.
- name: Long philtrum
  category: Craniofacial
  description: >-
    A long philtrum was described at fetal autopsy.
  phenotype_term:
    preferred_term: Long philtrum
    term:
      id: HP:0000343
      label: Long philtrum
  evidence:
  - reference: PMID:29138412
    reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The parents chose to terminate the pregnancy and the fetal autopsy showed macrocephaly, wide open anterior and posterior fontanels, high forehead with frontal bossing, micrognathia, low-set and posteriorly rotated left ear, small nose with a broad nasal bridge, long philtrum, normal lips and palate, short lingual frenulum, short and bowed limbs, brachydactyly, micropenis and hypospadia (Fig. 3b,e).
    explanation: >-
      Documents this finding in a molecularly confirmed skeletal presentation; no
      disease-wide frequency is inferred.
- name: Ankyloglossia
  category: Craniofacial
  description: >-
    A short lingual frenulum was described at fetal autopsy.
  phenotype_term:
    preferred_term: Ankyloglossia
    term:
      id: HP:0010296
      label: Ankyloglossia
  evidence:
  - reference: PMID:29138412
    reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The parents chose to terminate the pregnancy and the fetal autopsy showed macrocephaly, wide open anterior and posterior fontanels, high forehead with frontal bossing, micrognathia, low-set and posteriorly rotated left ear, small nose with a broad nasal bridge, long philtrum, normal lips and palate, short lingual frenulum, short and bowed limbs, brachydactyly, micropenis and hypospadia (Fig. 3b,e).
    explanation: >-
      Documents this finding in a molecularly confirmed skeletal presentation; no
      disease-wide frequency is inferred.
- name: Micropenis
  category: Genitourinary
  description: >-
    Micropenis was described in the affected male fetus.
  phenotype_term:
    preferred_term: Micropenis
    term:
      id: HP:0000054
      label: Micropenis
  evidence:
  - reference: PMID:29138412
    reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The parents chose to terminate the pregnancy and the fetal autopsy showed macrocephaly, wide open anterior and posterior fontanels, high forehead with frontal bossing, micrognathia, low-set and posteriorly rotated left ear, small nose with a broad nasal bridge, long philtrum, normal lips and palate, short lingual frenulum, short and bowed limbs, brachydactyly, micropenis and hypospadia (Fig. 3b,e).
    explanation: >-
      Documents this finding in a molecularly confirmed skeletal presentation; no
      disease-wide frequency is inferred.
- name: Hypospadias
  category: Genitourinary
  description: >-
    Hypospadias was described in the skeletal fetus; a later infant had
    penoscrotal hypospadias. The broad term retains the unspecified fetal
    finding.
  phenotype_term:
    preferred_term: Hypospadias
    term:
      id: HP:0000047
      label: Hypospadias
  evidence:
  - reference: PMID:29138412
    reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The parents chose to terminate the pregnancy and the fetal autopsy showed macrocephaly, wide open anterior and posterior fontanels, high forehead with frontal bossing, micrognathia, low-set and posteriorly rotated left ear, small nose with a broad nasal bridge, long philtrum, normal lips and palate, short lingual frenulum, short and bowed limbs, brachydactyly, micropenis and hypospadia (Fig. 3b,e).
    explanation: >-
      Documents this finding in a molecularly confirmed skeletal presentation; no
      disease-wide frequency is inferred.
- name: Cryptorchidism
  category: Genitourinary
  description: >-
    Cryptorchidism accompanied hypospadias in the skeletal-presenting infant.
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  evidence:
  - reference: PMID:34523780
    reference_title: Genetic and phenotypic heterogeneity in KIAA0753-related ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He had a narrow chest, short limbs, brachydactyly, penoscrotal hypospadias and cryptorchidism.
    explanation: >-
      Documents this finding in a molecularly confirmed skeletal presentation; no
      disease-wide frequency is inferred.
  notes: >-
    The Inskeep skeletal infant also carried a RUNX2 in-frame deletion
    classified as a variant of uncertain significance, inherited from his
    phenotypically normal father; the authors identified biallelic truncating
    KIAA0753 variants as the diagnosis.
- name: Cone-rod dystrophy
  category: Ophthalmologic
  description: >-
    Cone-rod dystrophy was reported in the ten-year-old girl with molecularly
    confirmed KIAA0753 skeletal ciliopathy.
  phenotype_term:
    preferred_term: Cone-rod dystrophy
    term:
      id: HP:0000548
      label: Cone/cone-rod dystrophy
  evidence:
  - reference: PMID:34016807
    reference_title: "KIAA0753-related skeletal ciliopathy: a ninth case, extending the phenotype and reporting a novel variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe a ninth case that expands the phenotype; a 10-year-old girl with rhizomelic short stature (-5.6 SD), macrocephaly, developmental delay, CNS anomalies (thin corpus callosum, bilateral ventriculomegaly), cone-rod dystrophy, nystagmus, mild conductive hearing loss and recurrent chest infections secondary to confirmed ciliary dyskinesia.
    explanation: >-
      Documents this finding in a molecularly confirmed skeletal presentation; no
      disease-wide frequency is inferred.
- name: Nystagmus
  category: Ophthalmologic
  description: >-
    Nystagmus was reported in the ten-year-old skeletal case.
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: PMID:34016807
    reference_title: "KIAA0753-related skeletal ciliopathy: a ninth case, extending the phenotype and reporting a novel variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe a ninth case that expands the phenotype; a 10-year-old girl with rhizomelic short stature (-5.6 SD), macrocephaly, developmental delay, CNS anomalies (thin corpus callosum, bilateral ventriculomegaly), cone-rod dystrophy, nystagmus, mild conductive hearing loss and recurrent chest infections secondary to confirmed ciliary dyskinesia.
    explanation: >-
      Documents this finding in a molecularly confirmed skeletal presentation; no
      disease-wide frequency is inferred.
- name: Conductive hearing impairment
  category: Auditory
  description: >-
    Mild conductive hearing loss was reported in the ten-year-old skeletal case.
  phenotype_term:
    preferred_term: Conductive hearing impairment
    term:
      id: HP:0000405
      label: Conductive hearing impairment
  evidence:
  - reference: PMID:34016807
    reference_title: "KIAA0753-related skeletal ciliopathy: a ninth case, extending the phenotype and reporting a novel variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe a ninth case that expands the phenotype; a 10-year-old girl with rhizomelic short stature (-5.6 SD), macrocephaly, developmental delay, CNS anomalies (thin corpus callosum, bilateral ventriculomegaly), cone-rod dystrophy, nystagmus, mild conductive hearing loss and recurrent chest infections secondary to confirmed ciliary dyskinesia.
    explanation: >-
      Documents this finding in a molecularly confirmed skeletal presentation; no
      disease-wide frequency is inferred.
- name: Leg-length discrepancy
  category: Skeletal
  description: >-
    Leg-length discrepancy was reported in the ten-year-old skeletal case; the
    direction and affected side were not specified in the abstract.
  phenotype_term:
    preferred_term: Leg-length discrepancy
    term:
      id: HP:0100559
      label: Lower limb asymmetry
  evidence:
  - reference: PMID:34016807
    reference_title: "KIAA0753-related skeletal ciliopathy: a ninth case, extending the phenotype and reporting a novel variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our case is the eldest woman reported to date (aged ten years) and the only known case to report associated hearing loss, leg-length discrepancy, pectus carinatum, respiratory ciliary dyskinesia and late-onset (9 years old) neuro-degenerative regression.
    explanation: >-
      Documents this finding in a molecularly confirmed skeletal presentation; no
      disease-wide frequency is inferred.
- name: Developmental regression
  category: Neurologic
  description: >-
    Late neurodegenerative regression began at nine years in the ten-year-old
    skeletal case. This single report does not establish a usual progressive
    course.
  phenotype_term:
    preferred_term: Developmental regression
    term:
      id: HP:0002376
      label: Developmental regression
  evidence:
  - reference: PMID:34016807
    reference_title: "KIAA0753-related skeletal ciliopathy: a ninth case, extending the phenotype and reporting a novel variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our case is the eldest woman reported to date (aged ten years) and the only known case to report associated hearing loss, leg-length discrepancy, pectus carinatum, respiratory ciliary dyskinesia and late-onset (9 years old) neuro-degenerative regression.
    explanation: >-
      Documents this finding in a molecularly confirmed skeletal presentation; no
      disease-wide frequency is inferred.
- name: Respiratory ciliary dyskinesia
  category: Respiratory
  description: >-
    Confirmed respiratory ciliary dyskinesia was reported in one skeletal case
    with recurrent chest infections. This clinical motile-cilia finding is
    separate from experimental primary-cilium assembly defects.
  phenotype_term:
    preferred_term: Respiratory ciliary dyskinesia
    term:
      id: HP:0012265
      label: Ciliary dyskinesia
  evidence:
  - reference: PMID:34016807
    reference_title: "KIAA0753-related skeletal ciliopathy: a ninth case, extending the phenotype and reporting a novel variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe a ninth case that expands the phenotype; a 10-year-old girl with rhizomelic short stature (-5.6 SD), macrocephaly, developmental delay, CNS anomalies (thin corpus callosum, bilateral ventriculomegaly), cone-rod dystrophy, nystagmus, mild conductive hearing loss and recurrent chest infections secondary to confirmed ciliary dyskinesia.
    explanation: >-
      Documents this finding in a molecularly confirmed skeletal presentation; no
      disease-wide frequency is inferred.
  sequelae:
  - target: Recurrent chest infections
    causal_link_type: DIRECT
    description: >-
      The case report explicitly attributes recurrent chest infections to
      confirmed respiratory ciliary dyskinesia.
    evidence:
    - reference: PMID:34016807
      reference_title: "KIAA0753-related skeletal ciliopathy: a ninth case, extending the phenotype and reporting a novel variant."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We describe a ninth case that expands the phenotype; a 10-year-old girl with rhizomelic short stature (-5.6 SD), macrocephaly, developmental delay, CNS anomalies (thin corpus callosum, bilateral ventriculomegaly), cone-rod dystrophy, nystagmus, mild conductive hearing loss and recurrent chest infections secondary to confirmed ciliary dyskinesia.
      explanation: >-
        The source specifies that the infections are secondary to ciliary
        dyskinesia.
- name: Recurrent chest infections
  category: Respiratory
  description: >-
    Recurrent chest infections were attributed to confirmed ciliary dyskinesia
    in the ten-year-old skeletal case.
  phenotype_term:
    preferred_term: Recurrent chest infections
    term:
      id: HP:0002783
      label: Recurrent lower respiratory tract infections
  evidence:
  - reference: PMID:34016807
    reference_title: "KIAA0753-related skeletal ciliopathy: a ninth case, extending the phenotype and reporting a novel variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe a ninth case that expands the phenotype; a 10-year-old girl with rhizomelic short stature (-5.6 SD), macrocephaly, developmental delay, CNS anomalies (thin corpus callosum, bilateral ventriculomegaly), cone-rod dystrophy, nystagmus, mild conductive hearing loss and recurrent chest infections secondary to confirmed ciliary dyskinesia.
    explanation: >-
      Documents this finding in a molecularly confirmed skeletal presentation; no
      disease-wide frequency is inferred.
- name: Cerebellar vermis hypoplasia
  category: Neurologic
  description: >-
    Inferior vermis hypoplasia was documented by MRI in P2, within the
    skeletal/Joubert overlap presentation.
  phenotype_term:
    preferred_term: Cerebellar vermis hypoplasia
    term:
      id: HP:0001320
      label: Cerebellar vermis hypoplasia
  evidence:
  - reference: PMID:29138412
    reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain MRI showed hypoplasia of the corpus callosum, a small pituitary gland, inferior vermis hypoplasia, MTS and mildly dilated lateral ventricles (Supplementary Fig.
    explanation: >-
      Documents this finding in a molecularly confirmed skeletal presentation; no
      disease-wide frequency is inferred.
biochemical: []
genetic:
- name: KIAA0753
  association: Causal biallelic variant
  gene_term:
    preferred_term: KIAA0753
    term:
      id: hgnc:29110
      label: KIAA0753
  notes: >-
    The same gene causes three named disorders: this skeletal ciliopathy,
    Joubert syndrome, and orofaciodigital syndrome type 6. The split is by
    clinical label rather than by allele - truncating variants appear across all
    three - and individual patients carry features of more than one, so the
    labels describe where a patient sits on a continuum rather than three
    separable diseases. Any citation about this gene must be checked for which
    presentation it describes before it is used.
  variants:
  - name: c.970C>T (p.Arg324*)
    description: >-
      A nonsense variant, homozygous in three affected individuals across two
      separate families of the discovery series, which makes it the one
      recurrent allele of this disorder. Carrier frequency in gnomAD is 4 in
      245,846 heterozygotes, minor allele frequency 1.627e-5, in South Asian and
      non-Finnish European populations.
    type: nonsense
    clinical_significance: PATHOGENIC
    gene:
      preferred_term: KIAA0753
      term:
        id: hgnc:29110
        label: KIAA0753
    evidence:
    - reference: PMID:29138412
      reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In family 1 and 2, all three affected patients were homozygous for a nonsense mutation, c.970 C > T (p.Arg324*); and in family 3, the affected fetus was compound heterozygous for a nonsense variant c.943 C > T (p.Gln315*) and a 1-bp deletion, c.1271del (p.Pro424Hisfs*9).
      explanation: >-
        The sequencing results directly identify the variants and zygosity in the
        discovery families.
  - name: c.943C>T (p.Gln315*)
    description: >-
      A nonsense variant carried in trans with c.1271del by the affected fetus
      of the discovery series, and reported homozygous in an unrelated patient
      with the Jeune presentation. gnomAD carrier frequency 6 in 276,744,
      minor allele frequency 2.168e-5, non-Finnish European.
    type: nonsense
    clinical_significance: PATHOGENIC
    gene:
      preferred_term: KIAA0753
      term:
        id: hgnc:29110
        label: KIAA0753
    evidence:
    - reference: PMID:29138412
      reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In family 1 and 2, all three affected patients were homozygous for a nonsense mutation, c.970 C > T (p.Arg324*); and in family 3, the affected fetus was compound heterozygous for a nonsense variant c.943 C > T (p.Gln315*) and a 1-bp deletion, c.1271del (p.Pro424Hisfs*9).
      explanation: >-
        The sequencing results directly identify the variants and zygosity in the
        discovery families.
    - reference: PMID:31816441
      reference_title: A new case of KIAA0753-related variant of Jeune asphyxiating thoracic dystrophy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        A homozygous c.943C > T mutation in KIAA0753 was identified on whole exome sequencing, resulting in Gln315Ter premature termination of the corresponding protein.
      explanation: >-
        The same allele found homozygous in an unrelated patient, establishing
        it as recurrent rather than private.
  - name: c.1271del (p.Pro424Hisfs*9)
    description: >-
      A single-base deletion causing a frameshift, in trans with c.943C>T in the
      affected fetus. Absent from gnomAD.
    type: frameshift
    clinical_significance: PATHOGENIC
    gene:
      preferred_term: KIAA0753
      term:
        id: hgnc:29110
        label: KIAA0753
    evidence:
    - reference: PMID:29138412
      reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        in family 3, the affected fetus was compound heterozygous for a nonsense variant c.943 C > T (p.Gln315*) and a 1-bp deletion, c.1271del (p.Pro424Hisfs*9)
      explanation: >-
        Identifies the frameshift allele and its compound-heterozygous partner.
  - name: c.810C>T (synonymous, splice-altering)
    description: >-
      A synonymous change that in silico tools did not flag and that turned out
      to activate abnormal splicing, demonstrated by cDNA sequencing. Two
      apparently unrelated Pakistani families share it within an 85 kb
      homozygous block, indicating a common ancestor. It is the reason a
      negative first-pass panel does not exclude this diagnosis.
    type: synonymous
    clinical_significance: PATHOGENIC
    gene:
      preferred_term: KIAA0753
      term:
        id: hgnc:29110
        label: KIAA0753
    evidence:
    - reference: PMID:33875766
      reference_title: High diagnostic yield in skeletal ciliopathies using massively parallel genome sequencing, structural variant screening and RNA analyses.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        WGS of all known skeletal ciliopathy and dysplasia genes did not reveal any known disease-causing variants, but a very rare homozygous synonymous variant in KIAA0753 (c.810 C > T, p.=) was identified.
      explanation: >-
        Documents the synonymous allele and that conventional analysis missed
        it.
    - reference: PMID:33875766
      reference_title: High diagnostic yield in skeletal ciliopathies using massively parallel genome sequencing, structural variant screening and RNA analyses.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Both families were of Pakistani origin, but according to the family history they were not related. These families share a homozygous block of 85 kb on chromosome 17p13.1, including the KIAA0753 gene, indicating a common ancestor.
      explanation: >-
        Establishes the shared haplotype behind the recurrence of this allele.
  - name: c.2656C>T (p.Arg886*)
    description: >-
      A nonsense variant carried in trans with c.943C>T by the
      skeletally-presenting patient of the KIAA0753 heterogeneity series, who
      was managed in neonatal intensive care for pulmonary hypoplasia and died
      at two weeks of severe pulmonary hypertension. Its partner allele is
      curated above, so leaving this one out would make the allele list read as
      complete when it is not.
    type: nonsense
    clinical_significance: PATHOGENIC
    gene:
      preferred_term: KIAA0753
      term:
        id: hgnc:29110
        label: KIAA0753
    evidence:
    - reference: PMID:34523780
      reference_title: Genetic and phenotypic heterogeneity in KIAA0753-related ciliopathies.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Rapid whole exome sequencing (GeneDx) identified biallelic truncating variants in KIAA0753 (c.943C>T/c.2656C>T; p. Gln315*/p.R886*).
      explanation: >-
        Reports both alleles of the skeletal-presentation patient, including
        this one.
  evidence:
  - reference: PMID:34523780
    reference_title: Genetic and phenotypic heterogeneity in KIAA0753-related ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To date, there have been 8 patients with biallelic pathogenic variants in KIAA0753 reported in the literature(5–8): two are described as having JS, one with OFD, and six with SRPS (Table 1).
    explanation: >-
      The breakdown of reported patients by clinical label, which is the
      three-phenotype split this note describes.
  - reference: PMID:31816441
    reference_title: A new case of KIAA0753-related variant of Jeune asphyxiating thoracic dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This case provides confirmation of an additional molecular basis for skeletal dysplasia and illustrates how ciliopathies due to mutations in a single gene may present as apparently distinct syndromes.
    explanation: >-
      The authors' statement that the three labels are apparent rather than
      separable entities.
environmental: []
treatments:
- name: Respiratory support and thoracic management
  description: >-
    No disease-modifying treatment exists. Management is supportive and is
    dominated by the thorax: ventilatory support for the restrictive
    insufficiency, nutritional support for the feeding difficulties, and
    orthopaedic follow-up for the limb and spinal consequences of the skeletal
    dysplasia. Thoracic expansion surgery is used in the short-rib dysplasias
    generally; no KIAA0753 patient has been reported to have undergone it, so
    it is not curated here as a treatment for this disorder.
  notes: >-
    The generic Supportive Care binding summarizes the respiratory and feeding
    difficulties documented in the skeletal case. Detailed airway and feeding
    interventions described in Joubert-only patients cannot establish treatment
    of thoracic restriction in SRTD21. This evidence does not establish the
    absence of such interventions in other skeletal patients.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Respiratory insufficiency
    term:
      id: HP:0002093
      label: Respiratory insufficiency
  evidence:
  - reference: PMID:31816441
    reference_title: A new case of KIAA0753-related variant of Jeune asphyxiating thoracic dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This 4 year-old boy with narrow thorax, short limbs, severe respiratory and feeding difficulties from birth on had a history of hypotonia and developmental delay.
    explanation: >-
      Establishes the respiratory and feeding problems that supportive
      management addresses.
diagnosis:
- name: Skeletal survey
  description: >-
    Radiographs establish the diagnosis within the short-rib group: short broad
    ribs with cupped anterior ends, short tubular bones with metaphyseal
    irregularity and cone-shaped epiphyses, and a trident pelvis. Absence of
    polydactyly is part of the description of this entity.
  results: >-
    Narrow thorax with short ribs, short tubular bones, metaphyseal irregularity
    and cone-shaped epiphyses, trident pelvis.
  diagnosis_term:
    preferred_term: X-ray imaging
    term:
      id: NCIT:C38101
      label: X-Ray Imaging
  evidence:
  - reference: PMID:29138412
    reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Skeletal survey showed severe metaphyseal dysplasia and cone-shaped epiphyses of the proximal tibia and distal femur embedded in cup-shaped metaphyses (Fig. 2a–c).
    explanation: >-
      Documents the radiographic route to the diagnosis.
- name: Prenatal ultrasound
  description: >-
    In the affected fetus of the discovery series the diagnosis was suspected
    prenatally: fetal ultrasound at 19 weeks showed the whole picture at once -
    short limbs, a narrow chest, a prominent abdomen, cerebral ventriculomegaly
    and a suspected cerebellar vermis defect. Both the skeletal and the CNS
    branches of this disorder are visible before birth.
  results: >-
    Short limbs with a narrow chest, prominent abdomen, cerebral
    ventriculomegaly and suspected cerebellar vermis defect.
  diagnosis_term:
    preferred_term: fetal ultrasound imaging
    term:
      id: NCIT:C222238
      label: Fetal Ultrasound Imaging
  evidence:
  - reference: PMID:29138412
    reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fetal ultrasound at 19 weeks gestation showed short limbs, narrow chest, prominent abdomen, cerebral ventriculomegaly, suspected defect in the cerebellar vermis and mild pelviectasis.
    explanation: >-
      The prenatal findings in the one fetus in whom they were recorded.
- name: Brain MRI
  description: >-
    Brain imaging is not optional in a patient with this skeletal phenotype. Two
    of the four patients of the discovery series had the molar tooth sign, and
    the reported findings also include corpus callosum hypoplasia,
    ventriculomegaly and a small pituitary gland - the last of which matters
    because growth hormone deficiency is documented in the Joubert presentation
    of this same gene.
  results: >-
    Inferior vermis dysplasia with the molar tooth sign, corpus callosum
    hypoplasia, ventricular dilatation and a small pituitary gland.
  diagnosis_term:
    preferred_term: magnetic resonance imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:29138412
    reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain magnetic resonance imaging (MRI) showed hypoplasia of the corpus callosum, small pituitary gland, inferior vermis dysplasia, “molar tooth” sign (MTS) and mildly dilated third ventricle (Supplementary Fig. S1).
    explanation: >-
      The brain MRI findings that make imaging part of the assessment.
- name: KIAA0753 sequencing with transcript analysis
  description: >-
    Exome or genome sequencing on a skeletal-dysplasia or ciliopathy panel.
    Transcript analysis matters more than usual here: a synonymous KIAA0753
    variant that in silico tools did not flag turned out to activate abnormal
    splicing, and was only resolved by sequencing cDNA. A negative panel result
    on a patient with this phenotype is therefore worth reanalysing.
  results: Biallelic KIAA0753 variants, with cDNA confirmation for splice-altering alleles.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:33875766
    reference_title: High diagnostic yield in skeletal ciliopathies using massively parallel genome sequencing, structural variant screening and RNA analyses.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Four variants located in non-canonical splice sites of DYNC2H1, EVC, and KIAA0753 led to aberrant splicing that was shown by sequencing of cDNA.
    explanation: >-
      Establishes cDNA sequencing as the step that resolved the splice-altering
      alleles, including in KIAA0753.
  - reference: PMID:34016807
    reference_title: "KIAA0753-related skeletal ciliopathy: a ninth case, extending the phenotype and reporting a novel variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole-exome sequencing, aged eight, via skeletal dysplasia panel analysis and subsequent whole-genome sequencing (via the 100,000 genomes project) found no cause. WGS data reanalysis using exomiser uncovered compound heterozygous pathogenic KIAA0753 variants (frameshift and splice site).
    explanation: >-
      A worked example of the diagnosis being missed by first-pass panel and
      genome analysis and found only on reanalysis.
differential_diagnoses:
- name: Joubert syndrome
  description: >-
    The same gene causes Joubert syndrome, and the boundary is soft: two of the
    four patients in the skeletal discovery series had brain abnormalities
    consistent with Joubert syndrome. The distinction as used in the literature
    is which system dominates - a molar tooth sign with hypotonia,
    developmental delay and abnormal eye movements and no significant skeletal
    disease is called Joubert syndrome; short ribs with a narrow thorax is
    called this disorder, whether or not a molar tooth sign is also present.
  disease_term:
    preferred_term: Joubert syndrome
    term:
      id: MONDO:0018772
      label: Joubert syndrome
  distinguishing_features:
  - Cerebellar and brainstem malformation dominates rather than skeletal disease
  - No short ribs or thoracic constriction
  - Growth hormone deficiency reported in the KIAA0753 Joubert siblings
  evidence:
  - reference: PMID:28220259
    reference_title: Mutations in KIAA0753 cause Joubert syndrome associated with growth hormone deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we present 2 siblings with Joubert syndrome associated with growth hormone deficiency. Whole exome sequencing of the family identified compound heterozygous mutations in KIAA0753, i.e., a missense mutation (p.Arg257Gly) and an intronic mutation (c.2359-1G>C).
    explanation: >-
      Establishes the Joubert presentation of the same gene, in siblings without
      a skeletal ciliopathy label.
- name: Orofaciodigital syndrome type 6
  description: >-
    The third KIAA0753 phenotype. It is defined by oral, facial and digital
    anomalies - hypertelorism, cleft palate, tongue lobulation, digital
    abnormalities - and the index KIAA0753 patient also had a molar tooth sign.
    Note that the dismech entry Orofaciodigital_Syndrome_17 is a different
    disorder, caused by INTU; it names KIAA0753 only inside a quoted list of
    genes from the paper that identified both.
  disease_term:
    preferred_term: orofaciodigital syndrome type 6
    term:
      id: MONDO:0010176
      label: orofaciodigital syndrome type 6
  distinguishing_features:
  - Oral, facial and digital anomalies rather than short ribs
  - No thoracic constriction or respiratory insufficiency
  evidence:
  - reference: PMID:26643951
    reference_title: OFIP/KIAA0753 forms a complex with OFD1 and FOR20 at pericentriolar satellites and centrosomes and is mutated in one individual with oral-facial-digital syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report here causal compound heterozygous mutations of KIAA0753/OFIP in a patient with an OFD VI syndrome.
    explanation: >-
      Establishes the orofaciodigital presentation of the same gene.
- name: Jeune asphyxiating thoracic dystrophy
  description: >-
    The clinical group this disorder sits inside, and the label under which
    several KIAA0753 patients were reported. The other genetically defined
    forms are intraflagellar-transport and dynein-2 defects; this one is a basal
    body docking defect, which is the mechanistic reason it is curated
    separately rather than as a subtype.
  disease_term:
    preferred_term: Jeune syndrome
    term:
      id: MONDO:0018770
      label: Jeune syndrome
  distinguishing_features:
  - Caused by IFT or dynein-2 components rather than a centriolar docking protein
  - Polydactyly occurs in several of the IFT-related forms
  evidence:
  - reference: PMID:31816441
    reference_title: A new case of KIAA0753-related variant of Jeune asphyxiating thoracic dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in at least 23 genes are likely to correspond to this clinical presentation: IFT43/52/80/81/122/140/172, WDR19/34/35/60, DYNC2H1, DYNC2LI1, CEP120, NEK1, TTC21B, TCTEX1D2, INTU, TCTN3, EVC 1/2 and KIAA0586.
    explanation: >-
      Lists the genes of the clinical group, which are dominated by
      intraflagellar-transport and dynein-2 components and do not include
      KIAA0753.
animal_models:
- name: kiaa0753 nonsense zebrafish
  species: Zebrafish
  genotype: kiaa0753 homozygous nonsense
  publication: PMID:29138412
  description: >-
    Zebrafish embryos homozygous for a nonsense variant in kiaa0753, made
    alongside the human skeletal cases to test whether the gene is needed for
    skeletal development. It is the only animal model in which a skeletal
    readout was taken; the Mnr-null mouse below dies too early in gestation for
    the skeleton to be assessed.
  modeled_mechanisms:
  - target: Growth Plate Zonal Disorganisation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      The embryos have abnormal cartilage patterning and abnormal head
      morphology, establishing that the gene is required for cartilage
      development.
    limitations: >-
      Zebrafish cartilage patterning is not a growth plate. The fish have no
      endochondral growth plate of the mammalian kind, so the model cannot
      address the proliferative and hypertrophic zone abnormality that is the
      human lesion, and it cannot model a narrow thorax at all. Lethality at
      early developmental stages further limits what can be asked of it. The
      model establishes gene requirement, not disease mechanism.
    readouts:
    - name: Craniofacial cartilage patterning
      target: Growth Plate Zonal Disorganisation
      direction: ALTERED
      interpretation: >-
        Cartilage development requires the gene, which is the claim this model
        supports.
      evidence:
      - reference: PMID:29138412
        reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Zebrafish knockout model with homozygous nonsense variants in the kiaa0753 gene show classic ciliopathy phenotype with cartilage abnormalities and curved body seen in other ciliopathy models15 and abnormal head morphology due to altered cartilage patterning and lethality at early developmental stages.
        explanation: >-
          The cartilage and morphology measurements in the model, together with
          the early lethality that bounds its usefulness.
    evidence:
    - reference: PMID:29138412
      reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        The importance of KIAA0753 for normal skeletal development is further confirmed by our findings that zebrafish embryos homozygous for a nonsense mutation in kiaa0753 display altered cartilage patterning.
      explanation: >-
        The authors' own statement of what the model establishes, which is gene
        requirement for skeletal development.
- name: Mnr-null mouse (Kiaa0753 knockout)
  species: Mouse
  genotype: Mnr (Kiaa0753) homozygous null, IMPC-derived allele
  publication: PMID:34241634
  description: >-
    A mouse null for Mnr, the mouse orthologue of KIAA0753, obtained from the
    International Mouse Phenotyping Consortium and characterised alongside a
    Cep90-null mouse as part of the work that defined the distal centriole
    complex. Embryos have no cilia in the E9.5 neural tube, and fibroblasts
    derived from them make no cilia and cannot induce Hedgehog target genes.
  modeled_mechanisms:
  - target: Defective Basal Body Docking and Ciliogenesis
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Loss of Mnr abolishes ciliogenesis in vivo and in embryo-derived
      fibroblasts, which is the same lesion patient fibroblasts show.
    limitations: >-
      The mouse is a complete null, whereas patients carry truncating and
      splice-altering alleles some of which retain partial function, and the
      mouse phenotype is correspondingly more severe: cilia are absent rather
      than reduced in number. Embryos were characterised at E8.5 to E9.5, before
      the skeleton forms, so this model has not been used to ask any skeletal
      question.
    readouts:
    - name: Cilia in the E9.5 neural tube
      target: Defective Basal Body Docking and Ciliogenesis
      direction: ABOLISHED
      interpretation: >-
        Ciliogenesis fails in vivo when the gene is absent.
      evidence:
      - reference: PMID:34241634
        reference_title: A ciliopathy complex builds distal appendages to initiate ciliogenesis.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Similarly, cilia detected by ARL13B staining were absent in neural tube sections from E9.5 Mnr−/− embryos (Fig. 4 f).
        explanation: >-
          The in vivo ciliation measurement in the model.
    evidence:
    - reference: PMID:34241634
      reference_title: A ciliopathy complex builds distal appendages to initiate ciliogenesis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Cells and mice lacking CEP90 or MNR do not generate cilia, fail to assemble distal appendages, and do not transduce Hedgehog signals.
      explanation: >-
        States the model phenotype, including the distal appendage failure that
        is the specific mechanism this node asserts.
  - target: Impaired Hedgehog Signal Transduction
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Fibroblasts from Mnr-null embryos fail to induce the Hedgehog target genes
      Gli1 and Ptch1 in response to a Smoothened agonist.
    limitations: >-
      The response is abrogated in the mouse null, whereas in patient
      fibroblasts it is blunted rather than absent, so the model exaggerates the
      severity of the signalling defect. The measurement is in embryonic
      fibroblasts, not in growth-plate chondrocytes.
    readouts:
    - name: SAG-induced Gli1 and Ptch1 expression in embryo-derived fibroblasts
      target: Impaired Hedgehog Signal Transduction
      direction: DECREASED
      interpretation: >-
        Direct transcriptional readout of Hedgehog pathway output in the model.
      evidence:
      - reference: PMID:34241634
        reference_title: A ciliopathy complex builds distal appendages to initiate ciliogenesis.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Furthermore, qRT-PCR analysis confirmed that induction of the Hedgehog target genes Gli1 and Ptch1 in response to the Hedgehog pathway activator Smoothened agonist (SAG) was abrogated in Cep90−/− or Mnr−/− MEFs (Fig. 4, i and l).
        explanation: >-
          The Hedgehog target-gene measurement in Mnr-null fibroblasts.
    evidence:
    - reference: PMID:34241634
      reference_title: A ciliopathy complex builds distal appendages to initiate ciliogenesis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Thus, CEP90 and MNR are both required for vertebrate development, ciliogenesis, and Hedgehog signaling.
      explanation: >-
        The authors' summary of what the mouse establishes.
experimental_models:
- name: KIAA0753 patient fibroblasts and knockout cell lines
  description: >-
    Dermal fibroblasts from Joubert-presenting patient 1 of the Inskeep series,
    mouse NIH3T3 knockout and variant-rescue cells, and human RPE1 cells used in
    studies of the centriolar complex. These systems establish ciliation,
    SHH/WNT response and protein-recruitment defects; none directly measures the
    growth plate of a skeletal patient.
  experimental_model_type: PRIMARY_CELL_CULTURE
  cell_source: Joubert-patient dermal fibroblasts, mouse NIH3T3 cells and human RPE1 cells
  culture_system: Two-dimensional culture with serum starvation to induce ciliogenesis, plus siRNA or knockout depletion and variant reconstitution
  publication: PMID:34523780
  modeled_mechanisms:
  - target: Defective Basal Body Docking and Ciliogenesis
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Patient fibroblasts carry the actual disease genotypes and show the
      ciliation deficit directly; depleting any member of the ternary complex in
      RPE1 cells reproduces the recruitment failure.
    limitations: >-
      Fibroblasts are not chondrocytes. The cell type in which the disease
      manifests is the growth-plate chondrocyte, and no chondrocyte or cartilage
      model of this genotype has been reported, so the ciliation and signalling
      measurements are made in a proxy tissue. In the Inskeep series the
      fibroblast donor had a Joubert presentation; the ablation/rescue experiments
      used mouse NIH3T3 cells.
    readouts:
    - name: Proportion of ciliated cells after serum starvation
      target: Defective Basal Body Docking and Ciliogenesis
      direction: DECREASED
      interpretation: >-
        Direct measurement of the ciliogenesis defect in cells carrying patient
        genotypes.
      evidence:
      - reference: PMID:34523780
        reference_title: Genetic and phenotypic heterogeneity in KIAA0753-related ciliopathies.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          Correspondingly, KIAA0753 patient fibroblasts have a deficit in primary ciliation and improper SHH and WNT signaling, with a particularly blunted response to SHH pathway stimulation.
        explanation: >-
          The ciliation measurement in patient cells.
    evidence:
    - reference: PMID:26643951
      reference_title: OFIP/KIAA0753 forms a complex with OFD1 and FOR20 at pericentriolar satellites and centrosomes and is mutated in one individual with oral-facial-digital syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The decreased expression of any component of this ternary complex in RPE1 cells causes a defective recruitment onto centrosomes and satellites.
      explanation: >-
        Establishes that the recruitment failure is a property of the complex,
        reproducible by depleting any member.
  - target: Impaired Hedgehog Signal Transduction
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Hedgehog pathway output is measured directly in patient fibroblasts and in
      KIAA0753-ablated cells.
    limitations: >-
      Hedgehog signalling in fibroblasts is a surrogate for Hedgehog signalling in
      the growth plate, where the ligand source, the receiving cell type and the
      transcriptional output all differ. The blunting is quantitative rather than
      absolute, and nothing links the size of the in vitro defect to skeletal
      severity in the corresponding patient. In the Inskeep series the fibroblast
      donor had a Joubert presentation; the ablation/rescue experiments used mouse
      NIH3T3 cells.
    readouts:
    - name: Hedgehog pathway response to stimulation
      target: Impaired Hedgehog Signal Transduction
      direction: DECREASED
      interpretation: >-
        The signalling step that connects the ciliary lesion to the skeletal
        phenotype.
      evidence:
      - reference: PMID:34523780
        reference_title: Genetic and phenotypic heterogeneity in KIAA0753-related ciliopathies.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          Ablation of KIAA0753 in vitro blocks primary ciliogenesis and SHH pathway activity.
        explanation: >-
          The Hedgehog output measurement on gene ablation.
    evidence:
    - reference: PMID:34523780
      reference_title: Genetic and phenotypic heterogeneity in KIAA0753-related ciliopathies.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Our work expands the phenotypic spectrum of KIAA0753 ciliopathies and demonstrates the utility of patient-focused functional assays for proving causality of genetic variants.
      explanation: >-
        States the purpose the system was used for, which is establishing causality
        of individual patient variants.
discussions:
- discussion_id: gap_srtd21_which_phenotype
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What determines whether biallelic KIAA0753 variants produce a short-rib
    skeletal ciliopathy, Joubert syndrome, or orofaciodigital syndrome type 6,
    given that all three arise from the same class of truncating allele and that
    individual patients carry features of more than one?
  attaches_to:
  - genetic#KIAA0753
  - pathophysiology#Defective Basal Body Docking and Ciliogenesis
  - pathophysiology#Cerebellar and CNS Involvement
  rationale: >-
    The three labels were assigned by which organ system dominated in the first
    patients described under each, not by an allele-level or mechanistic
    distinction. Truncating variants appear in all three groups. Two of the four
    patients in the skeletal discovery series had the molar tooth sign, which is
    the defining feature of the second label; the report of the eighth patient
    said outright that this gene shows how one locus presents as apparently
    distinct syndromes. Variant-level functional testing has been done, and it
    finds that every patient allele tested is deficient in supporting
    ciliogenesis - which explains why they all cause disease but not why they
    cause different diseases. With thirteen reported individuals across all
    three phenotypes there is no prospect of a genotype-phenotype analysis
    powered to settle it. The practical consequence for this knowledge base is
    that a citation about this gene must be checked for which presentation it
    describes.
  evidence:
  - reference: PMID:31816441
    reference_title: A new case of KIAA0753-related variant of Jeune asphyxiating thoracic dystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This case provides confirmation of an additional molecular basis for skeletal dysplasia and illustrates how ciliopathies due to mutations in a single gene may present as apparently distinct syndromes.
    explanation: >-
      States the problem the gap describes.
  - reference: PMID:34523780
    reference_title: Genetic and phenotypic heterogeneity in KIAA0753-related ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The phenotypic spectrum associated with biallelic pathogenic variants in KIAA0753 is broad and not well-characterized.
    explanation: >-
      The authors' own assessment that the spectrum is not characterised.
- discussion_id: gap_srtd21_chondrocyte_model
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Does the Hedgehog signalling defect measured in KIAA0753 patient fibroblasts
    represent what happens in the growth-plate chondrocyte, the cell in which
    the disease actually manifests?
  attaches_to:
  - pathophysiology#Impaired Hedgehog Signal Transduction
  - pathophysiology#Growth Plate Zonal Disorganisation
  rationale: >-
    Every functional measurement for this disorder was made in fibroblasts or in
    immortalised human cell lines. The disease is a chondrodysplasia, and the
    one direct observation in the affected tissue - the disorganised
    proliferative zone and broadened hypertrophic zone in a single fetus - is
    histology, not a signalling measurement. The gap is not that the fibroblast
    result is unreliable; it is that Hedgehog signalling in the growth plate has
    a different ligand source, a different receiving cell and a different
    transcriptional output, and no chondrocyte or cartilage model carrying a
    KIAA0753 genotype has been reported. Neither animal model closes the gap.
    The zebrafish shows altered cartilage patterning in an animal with no
    mammalian endochondral growth plate, and dies early. The Mnr-null mouse does
    have the mammalian skeleton, and it does show the Hedgehog defect directly -
    but it was characterised at E8.5 to E9.5, before the skeleton forms, and
    that measurement was again made in fibroblasts. Until a chondrocyte model
    exists, or the mouse is taken to a skeletal timepoint, the step from
    measured signalling defect to observed growth plate lesion is an inference.
    The Inskeep signaling experiments used fibroblasts from Joubert-presenting
    patient 1, not the skeletal-presenting patient 3, adding a presentation
    mismatch to the tissue mismatch.
  evidence:
  - reference: PMID:34523780
    reference_title: Genetic and phenotypic heterogeneity in KIAA0753-related ciliopathies.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Correspondingly, KIAA0753 patient fibroblasts have a deficit in primary ciliation and improper SHH and WNT signaling, with a particularly blunted response to SHH pathway stimulation.
    explanation: >-
      Names the cell type in which the signalling defect was actually measured.
  - reference: PMID:29138412
    reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We demonstrate that KIAA0753 is expressed in normal fetal human growth plate and show that the affected fetus, with a compound heterozygous frameshift and a nonsense mutation in KIAA0753, has an abnormal proliferative zone and a broad hypertrophic zone.
    explanation: >-
      The single direct observation in the affected tissue, which is
      histological rather than functional.
- discussion_id: srtd21_slc13a5_confounded_findings
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    How much of the developmental impairment in discovery-series P1 and P2 is
    due to KIAA0753 versus their additional SLC13A5 diagnosis?
  attaches_to:
  - phenotypes#Global developmental delay
  - phenotypes#Delayed speech and language development
  - phenotypes#Delayed gross motor development
  rationale: >-
    Both cousins carry homozygous SLC13A5 p.Thr142Met as well as KIAA0753
    variants. The authors assign their seizures and teeth hypoplasia to SLC13A5,
    so neither is curated here as a KIAA0753 phenotype. Developmental and speech
    delay remain associated with the skeletal presentation through independent
    patients, but the cousins cannot establish a KIAA0753-specific frequency or
    severity.
  evidence:
  - reference: PMID:29138412
    reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We thus conclude that the seizures and teeth hypoplasia in P1 and P2 are due to the homozygous SLC13A5 variant, while the developmental and speech delay is an overlapping feature and could be inferable to either one of the congenital conditions.
    explanation: >-
      Explicit attribution of dental hypoplasia and seizures to the second
      diagnosis, with developmental attribution unresolved.
- discussion_id: srtd21_unresolved_clinical_routes
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Which mechanisms explain the remaining craniofacial, neurologic, sensory,
    genital and associated skeletal findings in the KIAA0753 skeletal
    presentation?
  attaches_to:
  - phenotypes#Trident pelvis
  - phenotypes#Feeding difficulties
  - phenotypes#Global developmental delay
  - phenotypes#Hypotonia
  - phenotypes#Molar tooth sign on MRI
  - phenotypes#Delayed speech and language development
  - phenotypes#Delayed gross motor development
  - phenotypes#Flexion contracture
  - phenotypes#Protuberant abdomen
  - phenotypes#Hypoplasia of the corpus callosum
  - phenotypes#Ventriculomegaly
  - phenotypes#Small pituitary gland
  - phenotypes#Macrocephaly
  - phenotypes#Frontal bossing
  - phenotypes#Flat face
  - phenotypes#Depressed nasal bridge
  - phenotypes#Pectus carinatum
  - phenotypes#Pectus excavatum
  - phenotypes#Cervical spinal canal stenosis
  - phenotypes#Hepatomegaly
  - phenotypes#Pulmonary hypertension
  - phenotypes#Low-set ears
  - phenotypes#Anteverted nares
  - phenotypes#Micrognathia
  - phenotypes#Wide nasal bridge
  - phenotypes#Long philtrum
  - phenotypes#Ankyloglossia
  - phenotypes#Micropenis
  - phenotypes#Hypospadias
  - phenotypes#Cryptorchidism
  - phenotypes#Cone-rod dystrophy
  - phenotypes#Nystagmus
  - phenotypes#Conductive hearing impairment
  - phenotypes#Leg-length discrepancy
  - phenotypes#Developmental regression
  - phenotypes#Respiratory ciliary dyskinesia
  rationale: >-
    Case reports establish these findings but do not resolve feature-specific
    causal routes. The broad CNS node and the mouse granule-neuron study do not
    explain every brain-imaging, developmental or sensory finding. In
    particular, motor and speech findings in two cousins are confounded by
    SLC13A5, while regression, hearing loss and motile-cilia dyskinesia come
    from a later single case. Thoracic restriction does not by itself establish
    the cause of feeding difficulty, pulmonary hypertension, hepatomegaly,
    pectus deformity or abdominal prominence. These are clinical gaps, not
    laboratory readouts; occurrence alone does not justify a causal arrow.
  evidence:
  - reference: PMID:34523780
    reference_title: Genetic and phenotypic heterogeneity in KIAA0753-related ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The phenotypic spectrum associated with biallelic pathogenic variants in KIAA0753 is broad and not well-characterized.
    explanation: >-
      The clinical spectrum and its mechanistic subdivision remain incompletely
      characterized.
  - reference: PMID:34016807
    reference_title: "KIAA0753-related skeletal ciliopathy: a ninth case, extending the phenotype and reporting a novel variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our case is the eldest woman reported to date (aged ten years) and the only known case to report associated hearing loss, leg-length discrepancy, pectus carinatum, respiratory ciliary dyskinesia and late-onset (9 years old) neuro-degenerative regression.
    explanation: >-
      The later skeletal case adds uncommon multisystem findings without
      identifying their individual mechanisms.
clinical_trials: []
datasets: []
notes: >-
  Lump/split decision. Curated as a standalone Disease rather than as a
  has_subtypes entry on Jeune_Asphyxiating_Thoracic_Dystrophy, on two grounds.
  The mechanism differs from every subtype currently listed there: those are
  intraflagellar-transport, dynein-2 and Hedgehog-kinase defects, whereas
  KIAA0753 loss removes the recruitment platform that docks the basal body
  before any transport question arises. And the KB already curates
  Short-Rib_Thoracic_Dysplasia_6_With_Or_Without_Polydactyly as a standalone
  entry on the same reasoning, that the per-gene SRTD numbering identifies a
  single disease. The counter-argument is real and is recorded rather than
  hidden: MONDO places MONDO:0030356 under Jeune syndrome, and the reported
  patients overlap Joubert syndrome clinically. Same-gene separation. KIAA0753
  causes three named disorders and the KB already holds two of them -
  Joubert_syndrome carries it as a causal gene, and
  Orofaciodigital_Syndrome_17 mentions it only inside a quoted gene list from
  the paper that identified INTU. Clinical findings are restricted to skeletal
  presentations. PMID:28220259 supports the Joubert differential;
  PMID:26643951 supports OFIP cell biology and the OFD differential. The
  Inskeep fibroblast experiments and mouse neuronal studies inform gene
  function with explicit presentation and tissue limitations. Evidence-source
  convention: patient clinical, radiographic and genetic findings, and the
  fetal growth-plate histology, are graded HUMAN_CLINICAL; cell-line and
  patient-fibroblast work IN_VITRO; zebrafish and mouse MODEL_ORGANISM.
  Phenotype review: dental hypoplasia is excluded because the discovery paper
  assigns it to coexisting SLC13A5 disease; no independent dental-hypoplasia
  observation was identified in the subsequent skeletal reports reviewed.
  Clinical observations are kept separate from Joubert-only and OFD-only
  cases. Pulmonary hypertension retains the source wording in preferred_term;
  HP:0002092 has a broader pulmonary-hypertension definition despite its
  arterial label.

📚

References & Deep Research

References

10

PMID:29138412

Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.

No top-level findings curated for this source.

PMID:31816441

A new case of KIAA0753-related variant of Jeune asphyxiating thoracic dystrophy.

No top-level findings curated for this source.

PMID:34016807

KIAA0753-related skeletal ciliopathy: a ninth case, extending the phenotype and reporting a novel variant.

No top-level findings curated for this source.

PMID:34523780

Genetic and phenotypic heterogeneity in KIAA0753-related ciliopathies.

No top-level findings curated for this source.

PMID:33875766

High diagnostic yield in skeletal ciliopathies using massively parallel genome sequencing, structural variant screening and RNA analyses.

No top-level findings curated for this source.

PMID:26643951

OFIP/KIAA0753 forms a complex with OFD1 and FOR20 at pericentriolar satellites and centrosomes and is mutated in one individual with oral-facial-digital syndrome.

No top-level findings curated for this source.

PMID:36070319

The evolutionary conserved proteins CEP90, FOPNL, and OFD1 recruit centriolar distal appendage proteins to initiate their assembly.

No top-level findings curated for this source.

PMID:28220259

Mutations in KIAA0753 cause Joubert syndrome associated with growth hormone deficiency.

No top-level findings curated for this source.

PMID:34241634

A ciliopathy complex builds distal appendages to initiate ciliogenesis.

No top-level findings curated for this source.

PMID:34711653

CEP120-mediated KIAA0753 recruitment onto centrioles is required for timely neuronal differentiation and germinal zone exit in the developing cerebellum.

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.

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 21 citations 2026-08-28T19:15:41.437520

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

Disease Name: short-rib thoracic dysplasia 21 without polydactyly (SRTD21, biallelic KIAA0753/MOONRAKER)
MONDO ID: MONDO:0030356 (if available)
Category: Mendelian

Research Objectives

Please provide a comprehensive research report on short-rib thoracic dysplasia 21 without polydactyly (SRTD21, biallelic KIAA0753/MOONRAKER) covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

What is the disease? Provide a concise overview.
What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
What are the common synonyms and alternative names?
Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
Risk Factors:

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Pathogenic Variants:
Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
Variant type/class (missense, frameshift, nonsense, splice-site, structural)
Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
Functional consequences (loss of function, gain of function, dominant negative)
Modifier Genes: Genes that modify disease severity or expression
Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

Search first: PubMed, Gene Ontology, Reactome
Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Molecular Profiling (if available):
Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
Advanced Technologies (if applicable):
Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

Organ Level:
Primary organs directly affected
Secondary organ involvement (complications, secondary effects)
Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

Onset:
Typical age of onset (congenital, pediatric, adult, geriatric)
Onset pattern (acute, subacute, chronic, insidious)

Search first: OMIM, Orphanet, HPO, PubMed
Progression:
Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
Progression rate (rapid, slow, variable)
Disease course pattern (episodic, relapsing-remitting, progressive, stable)
Disease duration (self-limited, chronic lifelong)

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

Epidemiology:
Prevalence (cases per 100,000 at given time)
Incidence (new cases per 100,000 per year)

Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
For Genetic Etiology:
Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
Population Demographics:
Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
Geographic distribution of specific variants
Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

Clinical Tests:
Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
Genetic Testing:

Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
Overview of recommended genetic testing approach
Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
FISH > Search first: ClinVar, cytogenetics databases, PubMed
Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
Omics-Based Diagnostics (if applicable):
RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
Clinical Criteria:
Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
Screening:
Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

Survival and Mortality:
Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
Morbidity and Function:
Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
Disease Course:
Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
Prediction:
Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

Pharmacotherapy:
Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
Advanced Therapeutics:
Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
Surgical and Interventional:
Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
Supportive and Rehabilitative:
Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
Experimental:
Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
Treatment Outcomes:
Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
Treatment Strategy:
Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

Prevention Levels:
Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
Immunization: Vaccine strategies (if applicable)

Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Screening and Early Detection:
Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
Behavioral Interventions: Lifestyle modifications to reduce risk

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

Search first: NSGC resources, ACMG guidelines, GeneReviews
Public Health:
Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
Prophylaxis: Preventive medications or procedures

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

Search first: NCBI Gene
Natural Disease:
Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
Comparative Biology:
Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
Transmission (if applicable):
Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

Model Types:
Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
Genetic Models:
Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
Model Characteristics:
Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
Applications:
Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
Resources:
Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic and clinical claims
Prioritize recent reviews and landmark papers
Include direct quotes from abstracts where possible to support key statements
Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Short-rib thoracic dysplasia 21 without polydactyly (SRTD21)

Executive summary

SRTD21 is an exceptionally rare, congenital, autosomal-recessive skeletal ciliopathy caused by biallelic pathogenic variants in KIAA0753, encoding the centrosomal protein MOONRAKER/MNR, also called OFIP. Its defining clinical pattern is a narrow, hypoplastic thorax with short ribs, shortened tubular bones, metaphyseal/pelvic abnormalities, and no polydactyly. Respiratory insufficiency is the principal immediate threat. The phenotype belongs to a wider KIAA0753-related ciliopathy continuum that can include Joubert syndrome (JS), oral-facial-digital syndrome, brain malformations, and—in noncanonical overlapping cases—polydactyly. Therefore, “SRTD21 without polydactyly” should not be treated as synonymous with every biallelic KIAA0753 disorder. The published human evidence remains a collection of small families and individual cases rather than a population-based natural-history cohort. (faudi2020anewcase pages 1-5, hammarsjo2017novelkiaa0753mutations pages 6-9, hammarsjo2017novelkiaa0753mutations pages 1-2)

Domain	Summary	Evidence strength	Key citations
Identity / identifiers	Disease: short-rib thoracic dysplasia 21 without polydactyly (SRTD21), a Mendelian skeletal ciliopathy associated with biallelic KIAA0753 variants. Gene/protein aliases: KIAA0753, MOONRAKER (MNR), OFIP. MONDO: MONDO:0030356. OMIM caution: available evidence clearly supports KIAA0753 as the causal gene and a broader KIAA0753-related ciliopathy spectrum; disease/gene OMIM distinctions should be checked in OMIM directly rather than inferred here.	Strong for disease-gene identity; moderate for exact cross-database identifier harmonization	(faudi2020anewcase pages 1-5, faudi2020anewcase pages 5-9, inskeep2022geneticandphenotypic pages 1-2, kumar2021aciliopathycomplex pages 1-2)
Inheritance	Autosomal recessive; reported affected individuals carry biallelic variants (homozygous or compound heterozygous). Several skeletal cases occurred in consanguineous families, but non-consanguineous families are also reported.	Strong	(stephen2017mutationsinkiaa0753 pages 1-3, faudi2020anewcase pages 5-9, hammarsjo2017novelkiaa0753mutations pages 5-6, hammarsjo2021highdiagnosticyield pages 2-3)
Core phenotype	Congenital/prenatal narrow thorax, short ribs, short limbs/short tubular bones, brachydactyly, abnormal pelvis including trident acetabula/ilia, neonatal or infantile respiratory distress, severe short stature, and variable developmental delay/hypotonia. Polydactyly is absent in the canonical SRTD21 designation, although some broader KIAA0753-spectrum cases reported in later literature show overlap with other ciliopathy phenotypes.	Strong for skeletal-respiratory core; moderate for full spectrum boundaries	(faudi2020anewcase pages 1-5, faudi2020anewcase pages 5-9, hammarsjo2017novelkiaa0753mutations pages 5-6, hammarsjo2017novelkiaa0753mutations pages 6-9, hammarsjo2017novelkiaa0753mutations pages 1-2)
Variants	Recurrently reported skeletal-dysplasia variants are mostly predicted loss-of-function/truncating alleles, including *c.970C>T (p.Arg324), c.943C>T (p.Gln315), and c.1271del (p.Pro424Hisfs9); one family in a later skeletal ciliopathy cohort had c.810C>T (synonymous, splice-affecting candidate)**. Reported gnomAD frequencies for some KIAA0753 ciliopathy alleles are extremely low, and homozygotes were not observed in cited reports.	Strong for recurrent truncating skeletal alleles; moderate for complete variant catalog	(faudi2020anewcase pages 5-9, inskeep2022geneticandphenotypic pages 7-8, hammarsjo2017novelkiaa0753mutations pages 5-6, hammarsjo2021highdiagnosticyield pages 2-3)
Mechanism / pathophysiology	KIAA0753/MNR is a centrosome/pericentriolar satellite and distal centriole protein required for primary ciliogenesis. It functions with OFD1, FOPNL, and CEP90 in a distal centriole module that helps establish distal appendages, recruit CEP83, support preciliary vesicle docking, and regulate centriole length. Loss impairs ciliation and downstream SHH and some WNT signaling; growth-plate and cerebellar developmental defects are consistent downstream consequences.	Strong	(inskeep2022geneticandphenotypic pages 1-2, inskeep2022geneticandphenotypic pages 8-10, kumar2021aciliopathycomplex pages 7-9, borgne2022theevolutionaryconserved pages 1-2, kumar2021aciliopathycomplex pages 1-2, kumar2021aciliopathycomplex pages 13-16, chang2021cep120mediatedkiaa0753recruitment pages 1-2)
Diagnosis	Real-world diagnosis has relied on prenatal ultrasound, fetal MRI/brain MRI, skeletal survey/radiographs, and exome or genome sequencing. Suggestive imaging includes short femurs/limbs, narrow thorax, trident pelvis, metaphyseal changes, and in some allelic-spectrum cases molar tooth sign or other CNS anomalies. Functional follow-up in research settings has used patient fibroblasts, RNA/cDNA studies, and variant rescue assays.	Strong for sequencing + imaging; moderate for functional assays as clinical tools	(stephen2017mutationsinkiaa0753 pages 1-3, faudi2020anewcase pages 1-5, inskeep2022geneticandphenotypic pages 5-7, inskeep2022geneticandphenotypic pages 8-10, hammarsjo2021highdiagnosticyield pages 2-3)
Prognosis	Highly variable. Reported outcomes range from fetal loss/neonatal death or death in childhood from respiratory failure/pulmonary complications to survival into childhood with chronic respiratory disease, growth failure, hypotonia, developmental delay, and ongoing support needs. Long-term natural history, life expectancy, and population survival statistics are not established.	Moderate for variability; weak for long-term statistics	(faudi2020anewcase pages 1-5, faudi2020anewcase pages 5-9, inskeep2022geneticandphenotypic pages 7-8, hammarsjo2017novelkiaa0753mutations pages 5-6, hammarsjo2017novelkiaa0753mutations pages 2-4)
Treatment / management	No disease-specific or disease-modifying therapy established. Management is supportive and multidisciplinary: neonatal/childhood respiratory support (e.g., tracheostomy, ventilation, CPAP), feeding support including tube feeding/gastrostomy, developmental therapies, and surveillance for renal/hepatic/neurologic complications as indicated by phenotype. No relevant interventional clinical trial was identified in the cited evidence.	Moderate for supportive care; weak for formal guidelines	(faudi2020anewcase pages 1-5, faudi2020anewcase pages 5-9)
Prevention / screening	No primary prevention known for the disease biology. For at-risk families, prevention is mainly genetic counseling, carrier testing, prenatal diagnosis by targeted familial-variant testing or exome/genome sequencing, and potentially preimplantation genetic testing if the familial variants are known. Population screening recommendations are not established.	Moderate	(stephen2017mutationsinkiaa0753 pages 1-3, faudi2020anewcase pages 1-5, hammarsjo2021highdiagnosticyield pages 2-3)
Models / comparative evidence	Experimental systems include patient fibroblasts, NIH3T3 and RPE1 KIAA0753/MNR loss-of-function cells, mouse embryos lacking Mnr with defective ciliogenesis/Hedgehog-linked development, zebrafish kiaa0753 nonsense mutants with curved body and altered cartilage patterning, and Paramecium/mammalian comparative ciliogenesis studies for conserved distal appendage assembly. A naturally occurring veterinary KIAA0753 disease homolog is not established.	Strong for engineered models; weak for natural animal disease	(inskeep2022geneticandphenotypic pages 8-10, kumar2021aciliopathycomplex pages 1-2, chang2021cep120mediatedkiaa0753recruitment pages 1-2, hammarsjo2017novelkiaa0753mutations pages 5-6, hammarsjo2017novelkiaa0753mutations pages 6-9)
Unknown / not established	Population prevalence, incidence, carrier frequency, penetrance estimates, validated modifier genes, environmental risk/protective factors, biomarker-based monitoring, and disease-specific pharmacologic/gene/RNA/cell therapies are not established in the cited evidence.	Strong for absence of established evidence	(faudi2020anewcase pages 1-5, inskeep2022geneticandphenotypic pages 1-2, hammarsjo2021highdiagnosticyield pages 2-3)

Table: This table provides a compact knowledge-base style summary of SRTD21 caused by biallelic KIAA0753 variants, covering identity, phenotype, mechanism, diagnosis, prognosis, management, prevention, and model systems. It also flags where evidence is strong versus where key aspects remain not established.

1. Disease information

Definition and nomenclature

SRTD21 is a developmental disorder of the skeleton caused by defective primary-cilium formation and signaling. The core manifestations—thoracic hypoplasia, short ribs, and short tubular bones—overlap Jeune asphyxiating thoracic dystrophy and the historical short-rib polydactyly syndromes. A 2020 case was explicitly described as a KIAA0753-related variant of Jeune asphyxiating thoracic dystrophy and fulfilled Jeune radiographic criteria while lacking both polydactyly and the molar-tooth sign. (faudi2020anewcase pages 1-5, faudi2020anewcase pages 5-9)

Suggested identifiers and names are:

MONDO: MONDO:0030356, as supplied in the target specification.
Disease name: short-rib thoracic dysplasia 21 without polydactyly; SRTD21.
Gene: KIAA0753, aliases MNR/MOONRAKER and OFIP; the literature places the locus at 17p13.1 and describes a 19-exon gene encoding a 967-amino-acid, approximately 115-kDa protein. (faudi2020anewcase pages 5-9)
OMIM: the reviewed literature cites KIAA0753-related disease/gene entry 617112. Because gene and phenotype numbers are easily conflated, the current disease-specific number should be verified directly in OMIM before database ingestion. (faudi2020anewcase pages 1-5)
Orphanet, MeSH, ICD-10/ICD-11: no specific SRTD21 code was established in the retrieved primary literature. Clinically, broader skeletal-dysplasia/short-rib thoracic-dysplasia coding may be necessary.
Alternative labels: KIAA0753-related skeletal ciliopathy; KIAA0753-related short-rib skeletal dysplasia; KIAA0753-related Jeune/asphyxiating thoracic dystrophy.

The evidence is aggregated disease-level literature derived from deeply phenotyped individual patients and families, not EHR-scale data. By 2017 four skeletal cases had been reported; the 2020 report called its subject the eighth known KIAA0753 case overall and fifth short-rib skeletal-dysplasia case. Subsequent reports broadened the allelic spectrum, so historical counts are publication-date dependent. (faudi2020anewcase pages 1-5, hammarsjo2017novelkiaa0753mutations pages 5-6)

2. Etiology, risk, and protective factors

The necessary causal factor is biallelic germline KIAA0753 dysfunction. Homozygous and compound-heterozygous truncating alleles segregate with disease, patient tissue shows deficient KIAA0753/ciliation, engineered loss abolishes ciliogenesis, and wild-type—but not patient-variant—KIAA0753 partially rescues ciliation. This provides human genetic plus functional evidence for loss of function. (inskeep2022geneticandphenotypic pages 8-10, hammarsjo2017novelkiaa0753mutations pages 5-6)

Established genetic risk is having two pathogenic alleles. Consanguinity was present in several initial skeletal families, but affected children also occurred in unrelated, nonconsanguineous families; consanguinity increases the probability of homozygosity but is not required. (stephen2017mutationsinkiaa0753 pages 3-5, faudi2020anewcase pages 5-9, hammarsjo2017novelkiaa0753mutations pages 6-9)

No reproducible susceptibility loci, validated modifier genes, protective variants, environmental triggers, infectious causes, toxic exposures, diet/lifestyle effects, or gene–environment interactions are established. Inskeep and colleagues found no simple genotype–phenotype correlation and proposed unidentified genetic or environmental modifiers as an explanation for marked variability; this is a hypothesis, not demonstrated G×E evidence. (inskeep2022geneticandphenotypic pages 10-11)

3. Phenotypes

Frequencies below are qualitative because ascertainment is sparse and phenotype definitions changed across reports.

Thoracic hypoplasia/narrow chest and short ribs—congenital, usually severe, sometimes fetal-lethal; suggested HPO: Narrow chest HP:0000774, Short ribs HP:0000773, Thoracic hypoplasia HP:0005257. This is the principal SRTD21 feature and causes restrictive respiratory disease. (faudi2020anewcase pages 1-5, hammarsjo2017novelkiaa0753mutations pages 6-9)
Short limbs/tubular bones, rhizomelia or acromesomelia, severe short stature—prenatal or congenital, persistent; HPO suggestions: Short limb HP:0009826, Rhizomelia HP:0008905, Disproportionate short stature HP:0003498. One surviving child measured −5.5 SD at four years. (faudi2020anewcase pages 1-5)
Metaphyseal and pelvic dysplasia—trident acetabula/ilia, broad or flared metaphyses, short/bowed tubular bones, cone-shaped epiphyses, pectus deformity, and short metacarpals; HPO: Metaphyseal dysplasia HP:0100255, Trident acetabulum HP:0003170, Bowing of long bones HP:0006487. (hammarsjo2017novelkiaa0753mutations pages 2-4, hammarsjo2017novelkiaa0753mutations pages 4-5)
Brachydactyly and contractures—congenital, variable; HPO: Brachydactyly HP:0001156 and Flexion contracture HP:0001371. Polydactyly is absent in canonical SRTD21, although it occurs in broader KIAA0753 JS/OFD overlap. (faudi2020anewcase pages 5-9, hammarsjo2017novelkiaa0753mutations pages 6-9)
Respiratory insufficiency—neonatal respiratory distress, pulmonary hypoplasia, recurrent acute respiratory decompensation, chronic lung disease, atelectasis, and ventilatory dependence; HPO: Neonatal respiratory distress HP:0002643, Pulmonary hypoplasia HP:0002089, Respiratory insufficiency HP:0002093. Severity ranges from chronic CPAP need to neonatal/childhood death. (faudi2020anewcase pages 1-5, inskeep2022geneticandphenotypic pages 7-8, hammarsjo2017novelkiaa0753mutations pages 2-4)
Hypotonia and developmental delay—variable, evident in infancy; HPO: Generalized hypotonia HP:0001290, Global developmental delay HP:0001263, Delayed speech and language development HP:0000750. These may reflect CNS ciliopathy, prolonged critical illness, or both. (faudi2020anewcase pages 1-5, hammarsjo2017novelkiaa0753mutations pages 2-4)
CNS abnormalities—variable and not required for narrowly defined SRTD21: ventriculomegaly, corpus-callosum hypoplasia/agenesis, cerebellar vermis dysplasia, molar-tooth sign in overlap cases, cervical canal/craniovertebral-junction stenosis, and seizures. Suggested HPO: HP:0002119, HP:0002079, HP:0001320, HP:0002419, and HP:0001250. The 2020 SRTD21-like child had no molar-tooth sign but had occipitocervical narrowing and an arachnoid cyst. (faudi2020anewcase pages 5-9, hammarsjo2017novelkiaa0753mutations pages 2-4)
Craniofacial findings—macrocephaly or prominent forehead, depressed/broad nasal bridge, anteverted nares, long philtrum, widely spaced teeth, large mouth, micrognathia, and low-set ears; individually variable. (faudi2020anewcase pages 1-5, hammarsjo2017novelkiaa0753mutations pages 5-6)
Other variable findings: feeding difficulty; hepatomegaly; micropenis, hypospadias, or cryptorchidism; dental hypoplasia. Renal ultrasound/function and fundus examination were normal in the detailed 2020 survivor, although renal/hepatic disease remains biologically plausible in a ciliopathy and should be monitored. (faudi2020anewcase pages 5-9, inskeep2022geneticandphenotypic pages 7-8)

No EQ-5D, SF-36, PROMIS, or disease-specific quality-of-life study exists. Nevertheless, reported tracheostomy, nocturnal CPAP or continuous ventilation, tube feeding, delayed walking and speech, repeated intensive-care admissions, and assistive communication indicate major effects on mobility, communication, schooling, caregiver burden, and daily living. (faudi2020anewcase pages 1-5, inskeep2022geneticandphenotypic pages 5-7)

4. Genetic and molecular information

KIAA0753 is the established causal gene. Reported SRTD/skeletal alleles include:

homozygous NM_014804.3:c.970C>T, p.(Arg324Ter) in three patients from two families;
compound heterozygous c.943C>T, p.(Gln315Ter) and c.1271del, p.(Pro424HisfsTer9) in a severely affected fetus;
homozygous c.943C>T, p.(Gln315Ter) in the 2020 survivor (ClinVar ID 428615);
compound heterozygous c.943C>T, p.(Gln315Ter) and c.2656C>T, p.(Arg886Ter) in an infant who died at two weeks;
a homozygous synonymous c.810C>T, p.(=) allele reported in two deceased siblings and investigated as splice-disrupting. (faudi2020anewcase pages 5-9, inskeep2022geneticandphenotypic pages 7-8, hammarsjo2017novelkiaa0753mutations pages 5-6, hammarsjo2021highdiagnosticyield pages 2-3)

Broader KIAA0753 ciliopathy alleles include c.769A>G, p.(Arg257Gly) plus c.2359-1G>C, p.(Lys787_Gln789del) in two JS siblings and c.1891A>T, p.(Lys631Ter) plus a frameshifting splice allele in OFD. These are relevant differential/allelic-spectrum evidence but should not automatically be annotated as SRTD21 variants. (stephen2017mutationsinkiaa0753 pages 6-8, faudi2020anewcase pages 5-9)

Where reported, alleles were absent or extremely rare in gnomAD and had no observed homozygotes. Examples from the expanded ciliopathy cohort include frequencies of 2.14×10⁻⁵ and 2.86×10⁻⁵ for p.Gln315Ter and p.Arg886Ter, respectively. (inskeep2022geneticandphenotypic pages 7-8)

Variants are germline, not somatic. Most skeletal alleles are nonsense, frameshift, or splice-disrupting loss-of-function variants. Five of six tested variant constructs generated truncated proteins, whereas p.Gln315Ter was below Western-blot detection; all six failed to rescue ciliation. A simple rule that truncating variants cause skeletal disease while distal missense variants cause JS was proposed in 2020, but the larger 2022 series found no robust genotype–phenotype correlation. (faudi2020anewcase pages 5-9, inskeep2022geneticandphenotypic pages 8-10, inskeep2022geneticandphenotypic pages 10-11)

No validated modifier gene, disease-specific epigenetic signature, recurrent pathogenic chromosomal rearrangement, or large-scale KIAA0753 structural variant has been established.

5. Environmental information

No toxin, radiation, pollution, occupational exposure, smoking, alcohol, diet, exercise pattern, or infectious agent causes or triggers SRTD21. Lifestyle modification cannot prevent an embryo with biallelic pathogenic variants from developing the disorder. Environmental factors may influence respiratory complications or general health, but this has not been studied specifically.

6. Mechanism and pathophysiology

Upstream causal chain

Biallelic loss of functional KIAA0753/MNR impairs a centrosomal/distal-centriolar scaffold.
MNR normally recruits OFD1, FOPNL, and CEP90 at the distal centriole. CEP90 then recruits CEP83 and supports construction of distal appendages required for basal-body membrane docking. (borgne2022theevolutionaryconserved pages 1-2, kumar2021aciliopathycomplex pages 13-16)
MNR loss also prevents normal removal of CP110/CEP97, reduces IFT88 and Myosin-Va-positive preciliary-vesicle recruitment, prevents vesicle docking, and dysregulates centriole length through failure to recruit OFD1. Approximately 30% of MNR-null RPE1 cells had hyperelongated centrioles. (kumar2021aciliopathycomplex pages 7-9)
Consequently, primary-cilium assembly fails or is markedly reduced. KIAA0753-null NIH3T3 cells had essentially no cilia; wild-type transfection raised ciliation from 4.4% to 28.5%, whereas six patient alleles yielded only 3.0–7.8%. Patient fibroblasts showed about a 50% reduction: approximately 15% versus 40% ciliated without stimulation and 30% versus 60% after serum starvation. (inskeep2022geneticandphenotypic pages 8-10)
Loss of the primary cilium disrupts developmental signal transduction. KIAA0753-null cells did not induce GLI1 after Smoothened-agonist stimulation; patient fibroblast RNA-seq showed a blunted SHH response and failed normal AXIN2 induction after WNT3A. (inskeep2022geneticandphenotypic pages 8-10)
In fetal growth plate, impaired ciliary signaling disrupts chondrocyte organization: the affected fetus had an abnormal proliferative zone and broad hypertrophic zone. This plausibly causes short/bowed bones, metaphyseal dysplasia, ribs too short to expand the thorax, pulmonary hypoplasia, and respiratory failure. (hammarsjo2017novelkiaa0753mutations pages 5-6, hammarsjo2017novelkiaa0753mutations pages 9-10)
In the cerebellum, CEP120-dependent recruitment of KIAA0753 to centrioles is required for granule-neuron progenitors to exit the germinal zone and differentiate. Disruption retains Ki67-positive/Tuj1-negative progenitors and provides a mechanistic route to heterotopia and vermian hypoplasia in JS-overlap disease. (chang2021cep120mediatedkiaa0753recruitment pages 1-2, chang2021cep120mediatedkiaa0753recruitment pages 10-12)

Suggested ontology annotations include GO:0060271 cilium assembly, GO:0030030 cell projection organization, GO:0007099 centriole replication, GO:0097547 proximal/distal centriole-associated processes, GO:0007224 smoothened signaling pathway, and GO:0016055 Wnt signaling pathway. Cellular-component terms include GO:0005813 centrosome, GO:0005814 centriole, GO:0036064 ciliary basal body, GO:0097542 ciliary tip/appendage-related compartment, and GO:0043596 nuclear replication fork only if specifically justified—not as a disease annotation.

Relevant cell types include growth-plate chondrocytes (CL:0000138), fibroblasts (CL:0000057), cerebellar granule-neuron progenitors and granule neurons, respiratory epithelial cells, and renal tubular epithelial cells. Direct disease evidence is strongest for chondrocytes and experimental fibroblasts; respiratory/renal cell involvement is inferred from anatomy and general ciliopathy biology.

Molecular profiling and advanced technologies

Patient-fibroblast bulk RNA-seq demonstrated abnormal SHH/WNT response. Proteomics and super-resolution microscopy defined the DISCO complex, but no SRTD21 patient-tissue proteome was identified. No disease-specific metabolomic, lipidomic, methylomic, single-cell, spatial-transcriptomic, organoid, or multi-omics dataset was found. CRISPR knockout/rescue experiments constitute the strongest functional-genomics evidence. (inskeep2022geneticandphenotypic pages 8-10, kumar2021aciliopathycomplex pages 1-2)

7. Anatomical structures affected

Primary sites are the developing appendicular and axial skeleton—ribs, thoracic cage, long bones, metaphyses, growth plates, pelvis/acetabula, vertebrae, hands, and feet—and secondarily the lungs because the small thorax constrains development and ventilation. Suggested UBERON concepts include thoracic cage, rib, long bone, growth plate cartilage, pelvis, vertebral column, lung, and primary cilium/basal body at the subcellular level. (faudi2020anewcase pages 1-5, hammarsjo2017novelkiaa0753mutations pages 4-5)

Variable secondary involvement includes cerebellar vermis/brainstem, corpus callosum, cerebral ventricles, craniovertebral junction, pituitary, liver, kidney, eye, and external genitalia. Skeletal disease is generally bilateral and symmetric; no consistent lateralization is established. (faudi2020anewcase pages 5-9, inskeep2022geneticandphenotypic pages 7-8, hammarsjo2017novelkiaa0753mutations pages 2-4)

8. Temporal development

Onset is prenatal/congenital. Prenatal ultrasound may show short femora/long bones, narrow thorax, growth restriction, ventriculomegaly, or cerebellar abnormalities. Respiratory distress commonly begins at birth or in the neonatal period. (faudi2020anewcase pages 1-5, inskeep2022geneticandphenotypic pages 5-7)

There is no validated staging system. A practical course is: prenatal skeletal malformation; neonatal respiratory-risk phase; childhood chronic skeletal, pulmonary, feeding, and neurodevelopmental morbidity among survivors. Severity ranges from termination/fetal lethality or neonatal death to survival beyond childhood. Skeletal short stature and developmental impairment are lifelong; pulmonary support requirements may improve, persist, or prove fatal. No remission pattern is known. The prenatal and early neonatal periods are critical for diagnosis, delivery planning, and respiratory intervention. (faudi2020anewcase pages 1-5, inskeep2022geneticandphenotypic pages 7-8, hammarsjo2017novelkiaa0753mutations pages 2-4)

9. Inheritance and population

Inheritance is autosomal recessive. For two confirmed heterozygous parents, each pregnancy has a theoretical 25% affected, 50% carrier, and 25% unaffected/noncarrier probability. Both sexes are affected. Penetrance for genuinely biallelic severe loss-of-function genotypes appears high, but cannot be estimated formally; expressivity is markedly variable. Anticipation is not expected, and germline mosaicism has not been demonstrated. (stephen2017mutationsinkiaa0753 pages 3-5, hammarsjo2017novelkiaa0753mutations pages 5-6)

No population prevalence, annual incidence, carrier frequency, sex ratio, geographic clustering, or validated founder effect is available. Initial families had Iranian, Indian, Italian, French, Welsh-Croatian, and German backgrounds, arguing against restriction to one ancestry. Recurrent p.Arg324Ter in consanguineous families could reflect local ancestry but is not a proven founder allele. (faudi2020anewcase pages 5-9)

10. Diagnostics

Diagnosis integrates:

Prenatal imaging: ultrasound for short long bones, small thorax, polyhydramnios and CNS malformations; fetal MRI when posterior-fossa or brainstem disease is suspected.
Postnatal skeletal survey: short/broad ribs, narrow thorax, shortened/bowed tubular bones, metaphyseal irregularity/flaring, trident ilia/acetabula, and brachydactyly.
Brain and spine MRI: assess molar-tooth sign, vermis/corpus-callosum abnormalities, ventriculomegaly, and craniocervical stenosis.
Molecular testing: a skeletal-ciliopathy/skeletal-dysplasia panel including KIAA0753, trio WES, or WGS, followed by segregation. CNV and RNA/cDNA analysis should be considered when only one allele is found or a synonymous/deep-intronic splice variant is suspected. Combined sequencing, CNV, and RNA analysis achieved a 90% diagnosis rate in a 34-person skeletal-ciliopathy cohort, although that statistic is not specific to SRTD21. (hammarsjo2021highdiagnosticyield pages 2-3)

WES identified the homozygous p.Gln315Ter case after a normal 46,XY karyotype. CMA, karyotype, and FISH can exclude alternative chromosomal disorders but do not directly test most KIAA0753 variants. Mitochondrial and repeat-expansion tests are not indicated. Patient-fibroblast ciliation, RNA-seq, or rescue assays are research-level tools for difficult variants rather than standard diagnostic criteria. (faudi2020anewcase pages 1-5, inskeep2022geneticandphenotypic pages 8-10)

Differential diagnoses include other SRTDs/Jeune syndromes due to DYNC2H1, DYNC2LI1, WDR34, WDR35, WDR60, IFT80, IFT140, IFT172, TTC21B, TCTEX1D2, CEP120, INTU, NEK1, C2CD3, Ellis–van Creveld syndrome (EVC/EVC2), cranioectodermal dysplasia, and KIAA0753-related JS/OFD. Absence of polydactyly does not identify KIAA0753 by itself; molecular confirmation is required. (faudi2020anewcase pages 1-5)

There is no population or newborn screening. Cascade carrier testing is appropriate after familial variants are established.

11. Outcome and prognosis

No five- or ten-year survival estimates, life-expectancy tables, mortality rate, validated prognostic model, or prognostic biomarker exists. Published outcomes include fetal lethality, death at two weeks from pulmonary hypertension, death at seven years from respiratory failure, and survival to four years with chronic lung disease, nocturnal CPAP, recurrent intensive-care admissions, severe short stature, and developmental delay. Thoracic size, pulmonary hypoplasia, neonatal respiratory requirement, pulmonary hypertension, and associated CNS disease are plausible prognostic factors, but none has been formally validated. (faudi2020anewcase pages 1-5, inskeep2022geneticandphenotypic pages 7-8, hammarsjo2017novelkiaa0753mutations pages 2-4)

Potential complications include restrictive respiratory failure, recurrent pulmonary decompensation, atelectasis/chronic lung disease, feeding failure, growth failure, orthopedic deformity/contracture, craniocervical stenosis, and developmental disability. Renal, hepatic, retinal, and endocrine surveillance is reasonable because of the broader allelic spectrum, but these complications are not uniformly present in SRTD21. (faudi2020anewcase pages 5-9)

12. Treatment and current applications

There is no approved disease-modifying drug, pharmacogenomic strategy, gene therapy, CRISPR therapy, RNA therapy, cell therapy, or targeted SHH/WNT treatment. No relevant interventional clinical trial was identified.

Real-world care is multidisciplinary and phenotype-directed:

neonatal respiratory stabilization, ventilation, tracheostomy when necessary, nocturnal noninvasive ventilation/CPAP, treatment of wheeze/infections, and pulmonary-hypertension assessment;
nutritional and swallowing assessment, gastrostomy or tube feeding when required;
physical, occupational, speech, developmental, and augmentative-communication therapies;
orthopedic monitoring of limb deformity, contractures, spine, and mobility;
neurosurgical review for symptomatic cervical/foramen-magnum stenosis;
periodic renal function/ultrasound, liver tests/ultrasound, ophthalmology, hearing, neurologic/developmental, and endocrine assessment when clinically indicated.

A reported child required tracheostomy and feeding tube at two months, later decannulated at 21 months, but continued nocturnal CPAP and inhaled corticosteroids for chronic pulmonary disease. This is case-specific evidence, not a treatment algorithm or response rate. (faudi2020anewcase pages 1-5, faudi2020anewcase pages 5-9)

Suggested NCIT intervention concepts include Mechanical Ventilation, Tracheostomy, Continuous Positive Airway Pressure, Gastrostomy, Physical Therapy, Occupational Therapy, Speech Therapy, and Genetic Counseling; exact NCIT codes should be validated in the current NCI Thesaurus release.

13. Prevention

There is no lifestyle, vaccine, drug, or environmental primary prevention. Prevention options are reproductive:

carrier and cascade testing in relatives;
preconception genetic counseling;
targeted prenatal testing by chorionic-villus sampling or amniocentesis when familial variants are known;
prenatal ultrasound/fetal MRI for early structural detection;
preimplantation genetic testing for monogenic disease (PGT-M).

Tertiary prevention consists of early respiratory planning, nutritional support, rehabilitation, and surveillance to reduce complications. Counseling must emphasize variable expressivity: the same gene can produce lethal skeletal disease, viable SRTD, JS, or OFD-overlap phenotypes. (inskeep2022geneticandphenotypic pages 10-11, faudi2020anewcase pages 1-5)

14. Other species and natural disease

No naturally occurring companion-animal, livestock, or wildlife syndrome definitively homologous to human SRTD21 was identified; therefore breed ontology, veterinary prevalence, zoonotic potential, and cross-species transmission are not applicable. KIAA0753 function is evolutionarily conserved, but this is comparative biology rather than infectious transmission.

15. Model organisms

Zebrafish (Danio rerio, NCBI Taxon 7955): homozygous nonsense kiaa0753 mutants developed curved bodies, altered cranial cartilage patterning, significantly shortened cranial measurements (11 mutants versus 14 controls; five of six reported measurements p<0.01), and lethality beyond the first week. This model recapitulates ciliary and cartilage-development defects but not the complete human thoracic phenotype. (hammarsjo2017novelkiaa0753mutations pages 5-6, hammarsjo2017novelkiaa0753mutations pages 6-9)
Mouse (Mus musculus, Taxon 10090): Mnr-null embryos showed defective neural-tube ciliogenesis and developmental/Hedgehog abnormalities. In vivo cerebellar electroporation established that centriolar KIAA0753 is required for timely differentiation and germinal-zone exit of granule-neuron progenitors. These models are mechanistically strong but incompletely model human SRTD survival and skeletal natural history. (kumar2021aciliopathycomplex pages 7-9, chang2021cep120mediatedkiaa0753recruitment pages 1-2, chang2021cep120mediatedkiaa0753recruitment pages 10-12)
Cellular models: CRISPR KIAA0753-null NIH3T3 fibroblasts, MNR-null human RPE1 cells, patient dermal fibroblasts, and variant-rescue assays quantify ciliation, centriole morphology, and SHH/WNT signaling. (inskeep2022geneticandphenotypic pages 8-10, kumar2021aciliopathycomplex pages 7-9)
Paramecium: comparative knockdown/localization studies demonstrate conserved CEP90–FOPNL–OFD1 distal-appendage and basal-body docking biology; mammals additionally require MNR upstream. This is valuable for organelle assembly but does not model human skeletal disease. (borgne2022theevolutionaryconserved pages 1-2)

Key primary sources and recent-research assessment

The foundational SRTD21 study is Hammarsjö et al., “Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies,” published November 2017, Scientific Reports, DOI/URL: https://doi.org/10.1038/s41598-017-15442-1. Its abstract states: “We report biallelic pathogenic variants in KIAA0753 in four patients with short-rib type skeletal dysplasia,” and documents growth-plate and zebrafish cartilage abnormalities. (hammarsjo2017novelkiaa0753mutations pages 5-6, hammarsjo2017novelkiaa0753mutations pages 1-2)

Faudi et al., published April 2020, European Journal of Medical Genetics, DOI/URL: https://doi.org/10.1016/j.ejmg.2019.103823, provided the detailed viable p.Gln315Ter homozygote and stated that the case “illustrates how ciliopathies due to mutations in a single gene may present as apparently distinct syndromes.” (faudi2020anewcase pages 1-5)

Inskeep et al., accepted August 2021 and published in the 2022 volume of American Journal of Medical Genetics A, DOI/URL: https://doi.org/10.1002/ajmg.a.62497, added four individuals and functional rescue/RNA-seq data. Its abstract reports that “Ablation of KIAA0753 in vitro blocks primary ciliogenesis and SHH pathway activity” and that patient fibroblasts show abnormal SHH and WNT signaling. (inskeep2022geneticandphenotypic pages 1-2)

Kumar et al., published July 2021, Journal of Cell Biology, DOI/URL: https://doi.org/10.1083/jcb.202011133, defined the DISCO complex and concluded that it supports ciliogenesis by “restraining centriole length and assembling distal appendages.” (kumar2021aciliopathycomplex pages 1-2)

Le Borgne et al., published September 7, 2022, PLOS Biology, DOI/URL: https://doi.org/10.1371/journal.pbio.3001782, independently placed MNR upstream of OFD1/FOPNL/CEP90 and distal-appendage proteins. (borgne2022theevolutionaryconserved pages 1-2)

No 2023–2024 primary clinical natural-history study specific to SRTD21 was retrieved. Thus, despite the requested recency priority, the most authoritative disease-specific evidence remains the 2017–2022 primary literature. The major unresolved needs are a curated international registry, standardized phenotyping, definitive prevalence/carrier estimates, longitudinal respiratory and renal/hepatic outcomes, robust genotype–phenotype analysis, and therapeutic studies.

References

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(stephen2017mutationsinkiaa0753 pages 1-3): Joshi Stephen, Thierry Vilboux, Luhe Mian, Chulaluck Kuptanon, Courtney M. Sinclair, Deniz Yildirimli, Dawn M. Maynard, Joy Bryant, Roxanne Fischer, Meghana Vemulapalli, James C. Mullikin, Marjan Huizing, William A. Gahl, May Christine V. Malicdan, and Meral Gunay-Aygun. Mutations in kiaa0753 cause joubert syndrome associated with growth hormone deficiency. Human Genetics, 136:399-408, Feb 2017. URL: https://doi.org/10.1007/s00439-017-1765-z, doi:10.1007/s00439-017-1765-z. This article has 50 citations and is from a peer-reviewed journal.
(hammarsjo2017novelkiaa0753mutations pages 5-6): A. Hammarsjö, Zheng Wang, Raquel Vaz, F. Taylan, M. Sedghi, K. Girisha, D. Chitayat, K. Neethukrishna, Patrick Shannon, Ruth Godoy, K. Gowrishankar, A. Lindstrand, Jafar Nasiri, M. Baktashian, Phillip T Newton, L. Guo, Wolfgang Hofmeister, M. Pettersson, A. Chagin, Gen Nishimura, Li Yan, Naomichi Matsumoto, Ann Nordgren, Noriko Miyake, G. Grigelioniene, and S. Ikegawa. Novel kiaa0753 mutations extend the phenotype of skeletal ciliopathies. Scientific Reports, Nov 2017. URL: https://doi.org/10.1038/s41598-017-15442-1, doi:10.1038/s41598-017-15442-1. This article has 41 citations and is from a peer-reviewed journal.
(hammarsjo2021highdiagnosticyield pages 2-3): Anna Hammarsjö, Maria Pettersson, David Chitayat, Atsuhiko Handa, Britt-Marie Anderlid, Marco Bartocci, Donald Basel, Dominyka Batkovskyte, Ana Beleza-Meireles, Peter Conner, Jesper Eisfeldt, Katta M. Girisha, Brian Hon-Yin Chung, Eva Horemuzova, Hironobu Hyodo, Liene Korņejeva, Kristina Lagerstedt-Robinson, Angela E. Lin, Måns Magnusson, Shahida Moosa, Shalini S. Nayak, Daniel Nilsson, Hirofumi Ohashi, Naoko Ohashi-Fukuda, Henrik Stranneheim, Fulya Taylan, Rasa Traberg, Ulrika Voss, Valtteri Wirta, Ann Nordgren, Gen Nishimura, Anna Lindstrand, and Giedre Grigelioniene. High diagnostic yield in skeletal ciliopathies using massively parallel genome sequencing, structural variant screening and rna analyses. Journal of Human Genetics, 66:995-1008, Apr 2021. URL: https://doi.org/10.1038/s10038-021-00925-x, doi:10.1038/s10038-021-00925-x. This article has 41 citations and is from a peer-reviewed journal.
(inskeep2022geneticandphenotypic pages 7-8): Katherine A. Inskeep, Yuri A. Zarate, Danielle Monteil, Jurgen Spranger, Dan Doherty, Rolf W. Stottmann, and K. Nicole Weaver. Genetic and phenotypic heterogeneity in kiaa0753‐related ciliopathies. American Journal of Medical Genetics Part A, 188:104-115, Sep 2022. URL: https://doi.org/10.1002/ajmg.a.62497, doi:10.1002/ajmg.a.62497. This article has 8 citations.
(inskeep2022geneticandphenotypic pages 8-10): Katherine A. Inskeep, Yuri A. Zarate, Danielle Monteil, Jurgen Spranger, Dan Doherty, Rolf W. Stottmann, and K. Nicole Weaver. Genetic and phenotypic heterogeneity in kiaa0753‐related ciliopathies. American Journal of Medical Genetics Part A, 188:104-115, Sep 2022. URL: https://doi.org/10.1002/ajmg.a.62497, doi:10.1002/ajmg.a.62497. This article has 8 citations.
(kumar2021aciliopathycomplex pages 7-9): Dhivya Kumar, Addison Rains, Vicente Herranz-Pérez, Quanlong Lu, Xiaoyu Shi, Danielle L. Swaney, Erica Stevenson, Nevan J. Krogan, Bo Huang, Christopher Westlake, Jose Manuel Garcia-Verdugo, Bradley K. Yoder, and Jeremy F. Reiter. A ciliopathy complex builds distal appendages to initiate ciliogenesis. Journal of Cell Biology, Jul 2021. URL: https://doi.org/10.1083/jcb.202011133, doi:10.1083/jcb.202011133. This article has 57 citations and is from a highest quality peer-reviewed journal.
(borgne2022theevolutionaryconserved pages 1-2): Pierrick Le Borgne, Logan Greibill, Marine Hélène Laporte, Michel Lemullois, Khaled Bouhouche, Mebarek Temagoult, Olivier Rosnet, Maeva Le Guennec, Laurent Lignières, Guillaume Chevreux, France Koll, Virginie Hamel, Paul Guichard, and Anne-Marie Tassin. The evolutionary conserved proteins cep90, fopnl, and ofd1 recruit centriolar distal appendage proteins to initiate their assembly. PLOS Biology, 20:e3001782, Sep 2022. URL: https://doi.org/10.1371/journal.pbio.3001782, doi:10.1371/journal.pbio.3001782. This article has 27 citations and is from a highest quality peer-reviewed journal.
(kumar2021aciliopathycomplex pages 13-16): Dhivya Kumar, Addison Rains, Vicente Herranz-Pérez, Quanlong Lu, Xiaoyu Shi, Danielle L. Swaney, Erica Stevenson, Nevan J. Krogan, Bo Huang, Christopher Westlake, Jose Manuel Garcia-Verdugo, Bradley K. Yoder, and Jeremy F. Reiter. A ciliopathy complex builds distal appendages to initiate ciliogenesis. Journal of Cell Biology, Jul 2021. URL: https://doi.org/10.1083/jcb.202011133, doi:10.1083/jcb.202011133. This article has 57 citations and is from a highest quality peer-reviewed journal.
(chang2021cep120mediatedkiaa0753recruitment pages 1-2): Chia-Hsiang Chang, Ting-Yu Chen, I-Ling Lu, Rong-Bin Li, Jhih-Jie Tsai, Pin-Yeh Lin, and Tang K. Tang. Cep120-mediated kiaa0753 recruitment onto centrioles is required for timely neuronal differentiation and germinal zone exit in the developing cerebellum. Genes & Development, 35:1445-1460, Oct 2021. URL: https://doi.org/10.1101/gad.348636.121, doi:10.1101/gad.348636.121. This article has 9 citations and is from a highest quality peer-reviewed journal.
(inskeep2022geneticandphenotypic pages 5-7): Katherine A. Inskeep, Yuri A. Zarate, Danielle Monteil, Jurgen Spranger, Dan Doherty, Rolf W. Stottmann, and K. Nicole Weaver. Genetic and phenotypic heterogeneity in kiaa0753‐related ciliopathies. American Journal of Medical Genetics Part A, 188:104-115, Sep 2022. URL: https://doi.org/10.1002/ajmg.a.62497, doi:10.1002/ajmg.a.62497. This article has 8 citations.
(hammarsjo2017novelkiaa0753mutations pages 2-4): A. Hammarsjö, Zheng Wang, Raquel Vaz, F. Taylan, M. Sedghi, K. Girisha, D. Chitayat, K. Neethukrishna, Patrick Shannon, Ruth Godoy, K. Gowrishankar, A. Lindstrand, Jafar Nasiri, M. Baktashian, Phillip T Newton, L. Guo, Wolfgang Hofmeister, M. Pettersson, A. Chagin, Gen Nishimura, Li Yan, Naomichi Matsumoto, Ann Nordgren, Noriko Miyake, G. Grigelioniene, and S. Ikegawa. Novel kiaa0753 mutations extend the phenotype of skeletal ciliopathies. Scientific Reports, Nov 2017. URL: https://doi.org/10.1038/s41598-017-15442-1, doi:10.1038/s41598-017-15442-1. This article has 41 citations and is from a peer-reviewed journal.
(stephen2017mutationsinkiaa0753 pages 3-5): Joshi Stephen, Thierry Vilboux, Luhe Mian, Chulaluck Kuptanon, Courtney M. Sinclair, Deniz Yildirimli, Dawn M. Maynard, Joy Bryant, Roxanne Fischer, Meghana Vemulapalli, James C. Mullikin, Marjan Huizing, William A. Gahl, May Christine V. Malicdan, and Meral Gunay-Aygun. Mutations in kiaa0753 cause joubert syndrome associated with growth hormone deficiency. Human Genetics, 136:399-408, Feb 2017. URL: https://doi.org/10.1007/s00439-017-1765-z, doi:10.1007/s00439-017-1765-z. This article has 50 citations and is from a peer-reviewed journal.
(inskeep2022geneticandphenotypic pages 10-11): Katherine A. Inskeep, Yuri A. Zarate, Danielle Monteil, Jurgen Spranger, Dan Doherty, Rolf W. Stottmann, and K. Nicole Weaver. Genetic and phenotypic heterogeneity in kiaa0753‐related ciliopathies. American Journal of Medical Genetics Part A, 188:104-115, Sep 2022. URL: https://doi.org/10.1002/ajmg.a.62497, doi:10.1002/ajmg.a.62497. This article has 8 citations.
(hammarsjo2017novelkiaa0753mutations pages 4-5): A. Hammarsjö, Zheng Wang, Raquel Vaz, F. Taylan, M. Sedghi, K. Girisha, D. Chitayat, K. Neethukrishna, Patrick Shannon, Ruth Godoy, K. Gowrishankar, A. Lindstrand, Jafar Nasiri, M. Baktashian, Phillip T Newton, L. Guo, Wolfgang Hofmeister, M. Pettersson, A. Chagin, Gen Nishimura, Li Yan, Naomichi Matsumoto, Ann Nordgren, Noriko Miyake, G. Grigelioniene, and S. Ikegawa. Novel kiaa0753 mutations extend the phenotype of skeletal ciliopathies. Scientific Reports, Nov 2017. URL: https://doi.org/10.1038/s41598-017-15442-1, doi:10.1038/s41598-017-15442-1. This article has 41 citations and is from a peer-reviewed journal.
(stephen2017mutationsinkiaa0753 pages 6-8): Joshi Stephen, Thierry Vilboux, Luhe Mian, Chulaluck Kuptanon, Courtney M. Sinclair, Deniz Yildirimli, Dawn M. Maynard, Joy Bryant, Roxanne Fischer, Meghana Vemulapalli, James C. Mullikin, Marjan Huizing, William A. Gahl, May Christine V. Malicdan, and Meral Gunay-Aygun. Mutations in kiaa0753 cause joubert syndrome associated with growth hormone deficiency. Human Genetics, 136:399-408, Feb 2017. URL: https://doi.org/10.1007/s00439-017-1765-z, doi:10.1007/s00439-017-1765-z. This article has 50 citations and is from a peer-reviewed journal.
(hammarsjo2017novelkiaa0753mutations pages 9-10): A. Hammarsjö, Zheng Wang, Raquel Vaz, F. Taylan, M. Sedghi, K. Girisha, D. Chitayat, K. Neethukrishna, Patrick Shannon, Ruth Godoy, K. Gowrishankar, A. Lindstrand, Jafar Nasiri, M. Baktashian, Phillip T Newton, L. Guo, Wolfgang Hofmeister, M. Pettersson, A. Chagin, Gen Nishimura, Li Yan, Naomichi Matsumoto, Ann Nordgren, Noriko Miyake, G. Grigelioniene, and S. Ikegawa. Novel kiaa0753 mutations extend the phenotype of skeletal ciliopathies. Scientific Reports, Nov 2017. URL: https://doi.org/10.1038/s41598-017-15442-1, doi:10.1038/s41598-017-15442-1. This article has 41 citations and is from a peer-reviewed journal.
(chang2021cep120mediatedkiaa0753recruitment pages 10-12): Chia-Hsiang Chang, Ting-Yu Chen, I-Ling Lu, Rong-Bin Li, Jhih-Jie Tsai, Pin-Yeh Lin, and Tang K. Tang. Cep120-mediated kiaa0753 recruitment onto centrioles is required for timely neuronal differentiation and germinal zone exit in the developing cerebellum. Genes & Development, 35:1445-1460, Oct 2021. URL: https://doi.org/10.1101/gad.348636.121, doi:10.1101/gad.348636.121. This article has 9 citations and is from a highest quality peer-reviewed journal.

Artifacts

Edison artifact artifact-00

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	8
Resolved	8
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	8
On topic	2
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	36
Resolved	36
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	0
Terms whose name was checked	2
Terms named correctly	1
Terms named as a different term	1

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:

MONDO:0030356 (3 mentions) - the report calls it "if available"; MONDO calls it short-rib thoracic dysplasia 21 without polydactyly

Ask OpenScientist

OpenScientist Report

Classifications

Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Progression

Prevalence

Differential Diagnoses

Experimental Models

Animal Models

Source YAML

References & Deep Research

References

Deep Research

Disease Characteristics Research Template

Target Disease

Research Objectives

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

Citation Requirements

Output Format

Short-rib thoracic dysplasia 21 without polydactyly (SRTD21)

Executive summary

1. Disease information

Definition and nomenclature

2. Etiology, risk, and protective factors

3. Phenotypes

4. Genetic and molecular information

5. Environmental information

6. Mechanism and pathophysiology

Upstream causal chain

Molecular profiling and advanced technologies

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

11. Outcome and prognosis

12. Treatment and current applications

13. Prevention

14. Other species and natural disease

15. Model organisms

Key primary sources and recent-research assessment

Artifacts

Reference Validation

Term Validation

Terms the report names something else