Odontochondrodysplasia

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Classifications

ISDS Skeletal Nosology

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Inheritance

1

Autosomal Recessive HP:0000007

ODCD is autosomal recessive. Every reported patient carries a TRIP11-null allele in trans with a splice variant that retains partial function; two null alleles instead produce achondrogenesis type 1A. Because the penetrance of the mis-splicing varies between individuals, recurrence risk counselling cannot predict which end of the severity spectrum a subsequent affected child will occupy.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:30728324 SUPPORT Human Clinical

"all ODCD patients, in addition to aTRIP11-null allele, carry compound heterozygous splice variants, which are translated into low-abundance GMAP proteins"

Establishes the compound heterozygous null-plus-hypomorph allele structure that defines the recessive genotype of ODCD.

PMID:30728324 SUPPORT Human Clinical

"Thus, our results make the prediction of clinical outcome solely based on genotype difficult in genetic counselling and clinical care."

The authors state directly that genotype does not predict outcome, which is the counselling-relevant consequence of variable splicing penetrance.

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Discussions and Knowledge Gaps

3

Can the late-onset renal, cerebral, and pulmonary disease of ODCD be studied at all, given that every existing Trip11 knockout mouse dies perinatally?

HUMAN MODEL MISMATCH OPEN odcd_no_viable_animal_model

Attached to

pathophysiology#Extraskeletal Golgi-Related Organ Disease

The available Trip11-knockout models are null models, and nulls in humans are embryonic-lethal, so the mouse reproduces achondrogenesis 1A rather than ODCD. The authors state that perinatal lethality in these models precludes recognition and analysis of later-onset phenotypes — which is exactly the class the extraskeletal features of ODCD fall into. The cystic renal disease in particular emerged only on longitudinal clinical follow-up, and there is no system in which to test whether it arises through impaired ciliary export of IFT20 or through the Golgi defect directly.

Proposed experiments

Hypomorphic Trip11 knock-in model reproducing the human splice allele

exp_odcd_hypomorphic_knockin_model

Generate a knock-in mouse carrying the human exon-4-skipping allele rather than a null, so that residual GMAP protein permits postnatal survival, and follow the animals for renal cystic disease, hydrocephaly, and lung development. Compare against conditional Ift20 deletion to separate a ciliary from a Golgi route to the renal phenotype.

Would support

pathophysiology#Extraskeletal Golgi-Related Organ Disease

Would refute

pathophysiology#Reduced GMAP-210 Abundance at the cis-Golgi

Supporting outcome

Postnatally viable hypomorphic animals developing cystic kidneys and hydrocephaly would establish that the extraskeletal disease is a direct consequence of reduced GMAP dose rather than of an unrelated modifier.

Refuting outcome

Normal kidneys and ventricles in animals with the same residual GMAP dose that causes human disease would argue that the human extraskeletal features require something beyond the Golgi lesion.

Show evidence (1 reference)

PMID:30728324 SUPPORT Model Organism

"These models all bear the disadvantage of perinatal lethality, precluding the recognition and analysis of later-onset phenotypes"

The authors name perinatal lethality of the existing models as the barrier to studying the later-onset organ disease.

Why does a reported adult with two potentially null TRIP11 alleles have the mildest odontochondrodysplasia phenotype described, when the residual-activity model predicts the most severe?

KNOWLEDGE GAP OPEN gap_odcd_null_alleles_mild_phenotype

Attached to

pathophysiology#Aberrant TRIP11 Splicing with a Null Allele in Trans pathophysiology#Block in Hypertrophic Chondrocyte Differentiation

The whole genotype-severity account of the TRIP11 series rests on residual GMAP-210 activity: splice alleles leave some, nulls leave none, and that is offered as the reason patients have ODCD rather than achondrogenesis. One reported adult contradicts it directly. Either the alleles are not the nulls they appear to be - as already happened with the recurrent c.586C>T allele, which mRNA study showed produces an in-frame deletion - or something other than residual GMAP-210 abundance modifies severity. Resolving this would change how a TRIP11 genotype is counselled prenatally, which is the setting where the ODCD-versus-lethal distinction actually has to be made.

Show evidence (1 reference)

PMID:33746040 SUPPORT Human Clinical

"However, adult patient 4 has two potentially null alleles and it remains unknown why she has very mild clinical features."

The reported counterexample, with the authors' own statement that it is unexplained.

What determines the penetrance of TRIP11 mis-splicing between individuals, and could it be measured prenatally to predict outcome?

KNOWLEDGE GAP OPEN odcd_splicing_penetrance_modifier

Attached to

progression#Variable outcome from perinatal lethality to adult survival

Siblings carrying identical TRIP11 alleles have received radiographic diagnoses of achondrogenesis 1A and of ODCD respectively. The proposed explanation is that splicing of TRIP11 is cell-type dependent and incompletely penetrant, so residual GMAP protein settles at constitutively different levels in different individuals. Nothing is known about what sets that level. If it were measurable in accessible fetal or neonatal material it would convert an unanswerable counselling question into a quantitative one, which is why this gap has direct clinical weight rather than only mechanistic interest.

Proposed experiments

Quantify residual GMAP protein against clinical severity across the allelic series

exp_odcd_residual_gmap_quantification

Measure TRIP11 transcript isoform ratios and GMAP protein levels in matched accessible tissue from patients across the full severity range, and test whether residual protein level predicts radiographic severity independently of genotype.

Would support

pathophysiology#Reduced GMAP-210 Abundance at the cis-Golgi

Would refute

pathophysiology#Reduced GMAP-210 Abundance at the cis-Golgi

Supporting outcome

A monotonic relationship between residual GMAP protein and severity across individuals sharing alleles would confirm protein dose as the operative variable and make it a candidate prognostic measurement.

Refuting outcome

Comparable residual GMAP levels in siblings with lethal and surviving disease would move the explanation to a modifier outside TRIP11 altogether.

Show evidence (1 reference)

PMID:30728324 SUPPORT Human Clinical

"A radiographic diagnosis of ACG1A and ODCD in different children originating from the same parents may be primarily due to variable penetrance ofTRIP11missplicing between individuals, resulting in constitutively different amounts of residual GMAP protein."

States the variable-splicing-penetrance hypothesis for the intrafamilial severity difference, as a proposal rather than a demonstrated mechanism.

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Pathophysiology

6

Aberrant TRIP11 Splicing with a Null Allele in Trans

A TRIP11-null allele in trans with a recurrent splice allele. The splice allele yields low-abundance GMAP proteins identical to, or overlapping with, natural isoforms; the null allele contributes nothing. Two null alleles instead cause achondrogenesis type 1A, so this genotype defines the non-lethal end of one allelic series.

TRIP11 hgnc:12305

Downstream

Reduced GMAP-210 Abundance at the cis-Golgi All disease-associated TRIP11 alleles reduce GMAP-210 protein abundance sharply in patient-derived primary cells, leaving only trace amounts of the shortened variants.

Show evidence (1 reference)

PMID:30728324 SUPPORT Human Clinical

"whereas recurrent splice mutations are associated with a milder but variable spectrum of postnatal clinical phenotypes"

Introduces the dose relationship in which complete loss is lethal and residual function permits survival; the sentence continues to name early embryonic lethality in ACG1A versus a milder postnatal spectrum.

Reduced GMAP-210 Abundance at the cis-Golgi

GMAP-210 is the cis-Golgi vesicle tether. In ODCD its abundance is sharply reduced but not abolished, and the residual variants retain enough tethering capacity to hold the Golgi together. This is the node at which ODCD and achondrogenesis 1A diverge: what is preserved here is what makes ODCD survivable.

Golgi organization GO:0007030 ↓ DECREASED

Golgi apparatus GO:0005794

Downstream

Defective Golgi Glycan Processing and Proteoglycan Secretion Bulk secretory traffic survives the reduction in GMAP-210, but glycan processing does not. Glycosylation of LAMP1 and LAMP2, which depends on efficient intra-Golgi trafficking of processing enzymes, is used as the readout, and procollagen type I secretion is reduced relative to control while remaining above the achondrogenesis 1A level.

Extraskeletal Golgi-Related Organ Disease The lung, kidney, and brain manifestations of ODCD are attributed to reduced GMAP-210 dose rather than to a separate lesion, but the route from the Golgi defect to each organ has not been established. The authors' own fibroblast data argue against a ciliary intermediate, and no viable model exists in which to test the alternatives, so the intermediates are left unspecified.

Show evidence (2 references)

PMID:30728324 SUPPORT Other

"TRIP11 encodes Golgi-associated microtubule-binding protein 210 (GMAP-210), an essential tether protein of the Golgi apparatus that physically interacts with intraflagellar transport 20 (IFT20), a component of the ciliary intraflagellar transport complex B."

Establishes the gene product and the two candidate compartments, Golgi and cilium, that the mechanism had to be assigned between.

PMID:30728324 SUPPORT In Vitro

"In spite of reduced abundance, residual GMAP variants maintain partial Golgi integrity, normal global protein secretion, and subcellular distribution of IFT20 in ODCD."

Defines exactly what the hypomorphic alleles preserve, and by contrast what the null alleles of achondrogenesis 1A lose.

Defective Golgi Glycan Processing and Proteoglycan Secretion

Post-translational glycan processing and secretion of extracellular matrix proteoglycans are impaired while bulk protein export is normal. The authors propose that a limited set of secreted developmental regulators with key roles in early chondrogenesis — decorin among them — are the cargoes that matter, by analogy with achondrogenesis type 1B, in which aberrant glycan processing produces a closely similar skeletal phenotype.

glycoprotein biosynthetic process GO:0009101 ⚠ ABNORMAL Golgi vesicle transport GO:0048193 ⚠ ABNORMAL proteoglycan biosynthetic process GO:0030166 ⚠ ABNORMAL

Downstream

Block in Hypertrophic Chondrocyte Differentiation The differentiation block is the shared cellular endpoint of ODCD and achondrogenesis 1A, differing between them only in degree. Fibroblasts transdifferentiated to chondrocytes form fewer and smaller chondrogenic nodules with reduced matrix synthesis, and proliferation and viability are unaffected, so this is a differentiation defect and not cell loss.

Dentinogenesis Imperfecta Odontoblasts secrete a collagenous, proteoglycan-rich dentine matrix through the same Golgi route, so defective glycan processing and matrix secretion is the natural explanation for the dental defect that names the disorder. The step has not been demonstrated in odontoblasts, and MIA3/TANGO1 — the other odontochondrodysplasia gene — acts on the immediately upstream export step, which is the main circumstantial support for a shared secretory mechanism.

Show evidence (2 references)

PMID:30728324 SUPPORT In Vitro

"This association and extraskeletal disease manifestations in ODCD point to a cilium-dependent pathogenesis. However, our functional studies in patient-derived primary cells clearly support a Golgi-based disease mechanism."

States the competing hypothesis and the experimental result that settles it in favour of the Golgi.

PMID:30728324 SUPPORT INDIRECT In Vitro

"The etiology of the differentiation defect remains currently unclear, but we hypothesize that aberrant posttranslational processing and secretion of a limited number of secreted developmental regulators with key importance for early chondrogenesis, like decorin"

The specific cargo identity is an explicit hypothesis of the authors, not a demonstrated result, which is why this is graded INDIRECT.

Block in Hypertrophic Chondrocyte Differentiation

Chondrocytes fail to progress to the hypertrophic stage, so the growth plate loses the cells that synthesise the key cartilage matrix proteins, COL10A1 among them. Histology in achondrogenesis 1A fetuses shows reduced total epiphyseal cartilage with absent columnar chondrocytes in the prehypertrophic and hypertrophic zones; ODCD is the attenuated version of the same lesion.

chondrocyte CL:0000138 hypertrophic chondrocyte CL:0000743

chondrocyte differentiation GO:0002062 ↓ DECREASED extracellular matrix organization GO:0030198 ⚠ ABNORMAL

Experimental models

TRIP11-mutant patient fibroblast-derived chondrocytes PRIMARY CELL CULTURE Patient-derived chondrogenic cells reproduce the differentiation block and the matrix-synthesis defect, and separate them from any effect on cell number.

Downstream

Spondylometaphyseal Dysplasia with Mesomelic Shortening Failure of the hypertrophic transition disorders endochondral growth at both the vertebral and the metaphyseal growth plates, producing the combined radiographic pattern that places ODCD in the spondylometaphyseal group.

Show evidence (1 reference)

PMID:30728324 SUPPORT In Vitro

"A block in cellular differentiation impairs the evolution of hypertrophic chondrocytes, which synthesize key cartilage matrix proteins in the growth plate, including COL10A1."

States the cellular lesion and why it matters for growth-plate matrix production.

Spondylometaphyseal Dysplasia with Mesomelic Shortening

The skeletal phenotype: short stature, narrow chest, mesomelic limb shortening, brachydactyly, and joint laxity, on a radiographic background of platyspondyly with coronal clefts and metaphyseal irregularity. Short plump tubular bones with cupped metaphyses flanked by longitudinal spurs, short ribs, and a trident pelvis are shared with achondrogenesis 1A and are the features that first suggested the two disorders were allelic.

Downstream

Short Stature Disordered endochondral growth at every growth plate reduces stature.

Mesomelic Limb Shortening Shortening falls predominantly on the middle limb segments, the pattern that distinguishes the disorder from the rhizomelic dysplasias.

Brachydactyly Short digits with cone-shaped epiphyses, the distal expression of the same growth-plate lesion.

Platyspondyly with Coronal Clefts The vertebral growth plates are affected alongside the appendicular ones, which is what makes the disorder spondylometaphyseal rather than metaphyseal.

Coronal Cleft Vertebrae Coronal clefting is a normal transient fetal finding that persists abnormally where vertebral endochondral ossification is disordered.

Metaphyseal Irregularity Cupped, irregular metaphyses flanked by longitudinal spurs — the direct radiographic read-out of the failed hypertrophic transition.

Narrow Chest Short ribs produce a narrow thorax, which together with the pulmonary dysplasia accounts for the deaths at the lethal end of the spectrum.

Joint Laxity Ligamentous laxity accompanies the skeletal dysplasia. Whether it reflects the same defective matrix secretion acting on ligament and capsule, or a separate consequence of GMAP-210 loss, has not been established.

Show evidence (1 reference)

PMID:30728324 SUPPORT Human Clinical

"Key clinical findings are short stature, narrow chest, mesomelic limb shortening, brachydactyly, joint laxity, and dental anomalies"

The clinical core of the disorder as defined at entity recognition.

Extraskeletal Golgi-Related Organ Disease

Pulmonary dysplasia, cystic renal disease, and nonobstructive hydrocephaly occur in ODCD and implicate GMAP-210 in renal and cerebral development beyond the skeleton. The authors could not attribute these to a ciliary mechanism — cilia in GMAP-210-deficient fibroblasts were of normal length and structure, and ciliary targeting of IFT20 was preserved — but note that conditional Ift20 deletion during renal development causes polycystic kidney disease in mice, so a cilium-based route to the late renal disease remains open.

Downstream

Cystic Renal Disease Late-onset cystic renal degeneration. The authors suggest it may be the one manifestation that genuinely runs through impaired ciliary transport of IFT20, by analogy with conditional Ift20 deletion causing polycystic kidney disease in neonatal mice — but their own fibroblast data found ciliary IFT20 targeting intact, so the route is unresolved.

Nonobstructive Hydrocephaly Communicating hydrocephalus without an obstructive lesion, implicating GMAP-210 in cerebral development by a mechanism that has not been worked out.

Pulmonary Dysplasia Abnormal lung development, distinct from the mechanical restriction imposed by the narrow thorax though clinically inseparable from it.

Show evidence (2 references)

PMID:30728324 SUPPORT Human Clinical

"Second, additional extraskeletal disease manifestations of ODCD included pulmonary dysplasia, cystic renal disease, and nonobstructive hydrocephaly."

Documents the extraskeletal organ involvement in the assembled series.

PMID:30728324 REFUTE In Vitro

"Our studies did not provide support for a cilium-dependent pathogenesis inTRIP11-related disorders"

A negative result against the ciliopathy hypothesis in patient fibroblasts, which is why the extraskeletal node is not curated as a ciliary mechanism.

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Pathograph

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Phenotypes

12

Genitourinary 1

Cystic Renal Disease OCCASIONAL Multiple renal cysts HP:0005562

Show evidence (1 reference)

PMID:30728324 SUPPORT Human Clinical

"Second, additional extraskeletal disease manifestations of ODCD included pulmonary dysplasia, cystic renal disease, and nonobstructive hydrocephaly."

Documents cystic renal disease among the extraskeletal features, together with the pulmonary and cerebral findings recorded below.

Head and Neck 1

Dentinogenesis Imperfecta VERY_FREQUENT HP:0000703

Show evidence (1 reference)

PMID:40119123 SUPPORT Human Clinical

"Odontochondrodysplasia (ODCD) is a rare skeletal dysplasia characterized by short stature, skeletal deformities, and dentinogenesis imperfecta (DI)."

Dentinogenesis imperfecta is one of the three defining features.

Limbs 2

Metaphyseal Irregularity VERY_FREQUENT HP:0003025

Show evidence (1 reference)

PMID:30728324 SUPPORT Human Clinical

"some alterations such as short, plump tubular bones with cupped metaphyses flanked by longitudinal spurs, short ribs, and a trident pelvis"

Describes the metaphyseal morphology in detail.

Brachydactyly FREQUENT HP:0001156

Show evidence (1 reference)

PMID:30728324 SUPPORT Human Clinical

"the combination of thoracic dystrophy, brachydactyly with cone-shaped epiphyses, and a trident pelvis"

Describes the brachydactyly with its cone-shaped epiphyses, part of the ciliopathy-like radiographic gestalt of the disorder.

Musculoskeletal 4

Platyspondyly with Coronal Clefts VERY_FREQUENT HP:0000926

Show evidence (1 reference)

PMID:30728324 SUPPORT Human Clinical

"Radiographic features include platyspondyly with coronal clefts and metaphyseal irregularities of the tubular bones"

Names platyspondyly with coronal clefts as a defining radiographic feature.

Coronal Cleft Vertebrae FREQUENT HP:0003417

Show evidence (1 reference)

PMID:30728324 SUPPORT Human Clinical

"Radiographic features include platyspondyly with coronal clefts and metaphyseal irregularities of the tubular bones"

Coronal clefting is named directly among the radiographic features.

Joint Laxity FREQUENT Joint hypermobility HP:0001382

Show evidence (1 reference)

PMID:30728324 SUPPORT Human Clinical

"Key clinical findings are short stature, narrow chest, mesomelic limb shortening, brachydactyly, joint laxity, and dental anomalies"

Joint laxity is named among the key clinical findings.

Narrow Chest FREQUENT HP:0000774

Show evidence (1 reference)

PMID:30728324 SUPPORT Human Clinical

"Key clinical findings are short stature, narrow chest, mesomelic limb shortening, brachydactyly, joint laxity, and dental anomalies"

Narrow chest is named among the key clinical findings.

Nervous System 1

Nonobstructive Hydrocephaly OCCASIONAL Hydrocephalus HP:0000238

Show evidence (1 reference)

PMID:30728324 SUPPORT Human Clinical

"Second, additional extraskeletal disease manifestations of ODCD included pulmonary dysplasia, cystic renal disease, and nonobstructive hydrocephaly."

Hydrocephaly is named among the extraskeletal manifestations.

Growth 1

Short Stature VERY_FREQUENT HP:0004322

Show evidence (1 reference)

PMID:30728324 SUPPORT Human Clinical

"Key clinical findings are short stature, narrow chest, mesomelic limb shortening, brachydactyly, joint laxity, and dental anomalies"

Short stature heads the list of key clinical findings, supporting this and the four phenotype records that follow.

Other 2

Mesomelic Limb Shortening VERY_FREQUENT Mesomelia HP:0003027

Show evidence (1 reference)

PMID:40119123 SUPPORT Human Clinical

"a very rare form of SMD characterized by mesomelic shortening of the tubular bones, scoliosis, ligamentous laxity, cone-shaped epiphyses, and dentinogenesis imperfecta (DI)"

Characterises ODCD by mesomelic shortening and, in the same sentence, supports the joint laxity and dentinogenesis imperfecta records.

Pulmonary Dysplasia OCCASIONAL Abnormal lung morphology HP:0002088

Show evidence (1 reference)

PMID:30728324 SUPPORT Human Clinical

"Second, additional extraskeletal disease manifestations of ODCD included pulmonary dysplasia, cystic renal disease, and nonobstructive hydrocephaly."

Pulmonary dysplasia is named among the extraskeletal manifestations.

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Genetic Associations

1

Biallelic Hypomorphic TRIP11 Variants (Causative)

Gene: TRIP11 hgnc:12305 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (7 references)

PMID:30728324 SUPPORT Human Clinical

"Here, we show that ODCD is caused by hypomorphic TRIP11 mutations, and we identify ODCD as the nonlethal counterpart to achondrogenesis 1A (ACG1A), the known null phenotype in humans."

Establishes the gene, the hypomorphic mechanism, and the allelic relationship with achondrogenesis 1A.

PMID:30728324 SUPPORT In Vitro

"However, we were surprised to find that the mutation, instead, abrogates a splice donor site, causing complete in-frame skipping of exon 4"

Shows that an apparently null nonsense allele actually behaves as a splice hypomorph, which is why the genotype is not readable from the coding annotation alone.

PMID:30728324 SUPPORT Human Clinical

"Our findings establish that ODCD is genetically homogeneous and that hypomorphic mutations ofTRIP11are the genetic basis for a range of ODCD phenotypes."

Supports treating ODCD as a single-locus disorder rather than a radiographically defined category.

+ 4 more references

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Medical Actions

3

Supportive and Multidisciplinary Management

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

No disease-modifying therapy exists. Management is supportive: respiratory support for the narrow thorax and pulmonary dysplasia in infancy, orthopaedic care for the limb and spinal deformity, renal surveillance for the late cystic disease, and neurosurgical assessment where hydrocephaly is present.

Restorative Dental Care

Action: Therapeutic Procedure NCIT:C49236

Dentinogenesis imperfecta requires early and continuing restorative dentistry to preserve the dentition. Two of the reporting centres in the founding series are dedicated rare oral and dental disease referral centres, which reflects how central the dental burden is to long-term care.

Show evidence (2 references)

PMID:30728324 SUPPORT Human Clinical

"Odontochondrodysplasia (ODCD) is an unresolved genetic disorder of skeletal and dental development."

Establishes the two organ systems management must address; no disease-modifying therapy is reported anywhere in this literature.

PMID:40119123 SUPPORT INDIRECT Human Clinical

"Odontochondrodysplasia (ODCD) is a rare skeletal dysplasia characterized by short stature, skeletal deformities, and dentinogenesis imperfecta (DI)."

Establishes dentinogenesis imperfecta as a defining feature and therefore a standing care need; it does not evidence a specific dental protocol, hence INDIRECT.

Genetic Counseling

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Recurrence risk is 25 percent, but the counselling problem is severity rather than recurrence: the same parental alleles have produced early-lethal achondrogenesis 1A in one child and surviving ODCD in a sibling, and no genotype-based prediction of outcome is currently possible.

Show evidence (1 reference)

PMID:30728324 SUPPORT Human Clinical

"Thus, our results make the prediction of clinical outcome solely based on genotype difficult in genetic counselling and clinical care."

The authors name genetic counselling as the setting in which the unpredictable genotype-phenotype relationship bites.

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Diagnosis

2

Radiographic and Dental Recognition

The combination of platyspondyly with coronal clefts, metaphyseal irregularity, mesomelic shortening, and dentinogenesis imperfecta is distinctive enough to direct testing. Because the radiographic gestalt overlaps the skeletal ciliopathies — thoracic dystrophy, brachydactyly with cone-shaped epiphyses, a trident pelvis — a ciliopathy panel is a common first and unrewarding step.

X-ray imaging NCIT:C38101

Results: Vertebral and metaphyseal changes with defective dentine.

Show evidence (2 references)

PMID:31903676 SUPPORT Human Clinical

"hypomorphic mutations in that gene have been linked to odontochondrodysplasia (ODCD), a nonlethal skeletal dysplasia characterized by skeletal changes in the spine and in the metaphyseal regions, associated with dentinogenesis imperfecta"

The diagnostic triad on which the clinical diagnosis rests.

PMID:30728324 SUPPORT Human Clinical

"radiographic features of ACG1A and ODCD are characteristic of skeletal ciliopathies"

Explains why ODCD is mistaken for a skeletal ciliopathy on imaging, the main diagnostic pitfall.

TRIP11 Sequencing with RNA Confirmation

Biallelic TRIP11 variants confirm the diagnosis, but coding annotation alone is misleading: the recurrent c.586C>T allele is annotated as a nonsense change yet behaves as an in-frame exon-skipping hypomorph. RNA analysis of patient fibroblasts is what distinguishes a true null genotype — predicting achondrogenesis 1A — from the hypomorphic genotype of ODCD.

genetic testing NCIT:C15709

Results: Biallelic TRIP11 variants, typically a null allele with a splice variant.

Show evidence (1 reference)

PMID:30728324 SUPPORT In Vitro

"Taken together, the experimental evidence shows aberrant splicing ofTRIP11in all ODCD cases investigated"

RNA analysis demonstrated aberrant splicing in every ODCD case investigated, which is why transcript-level confirmation is part of the diagnostic pathway.

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Progression

1

Variable outcome from perinatal lethality to adult survival

Outcome ranges from early lethal disease to long-term survival with short stature, and both extremes occur within a single family carrying the same alleles. A radiographic diagnosis of achondrogenesis 1A in one child and ODCD in a sibling is attributed to variable penetrance of TRIP11 mis-splicing between individuals, giving constitutively different residual GMAP levels. There is no marker that predicts which course an affected fetus will take.

Show evidence (2 references)

PMID:30728324 SUPPORT Human Clinical

"Third, it became evident that disease manifestations may range from early lethal to long-term survival with short stature"

States the range of outcomes directly from the assembled case series.

PMID:30728324 SUPPORT Human Clinical

"there is considerable clinical variability inTRIP11-related disorders, with early lethality and milder postnatal phenotypes occurring within the same family"

Introduces the observation of early lethality and milder postnatal phenotypes occurring within the same family.

📊

Prevalence

1

Worldwide

Cases In Literature 0.0 per 100,000 Ultra Rare

Sixteen patients from twelve unrelated families with TRIP11 variants had been published by 2025, three decades after Goldblatt recognised the entity in 1991. No population-based prevalence estimate exists; rate_per_100000 is recorded as 0.0 only to mark that the true rate is far below the resolution of any published survey.

Show evidence (2 references)

PMID:33746040 SUPPORT Human Clinical

"Subsequently, we review the clinical and radiological findings of the 14 reported ODCD patients."

The published case count standing in for a population estimate that does not exist.

PMID:40119123 SUPPORT Human Clinical

"To date, 16 patients from 12 unrelated families with TRIP11 variants have been described in the literature"

Gives the published caseload for the TRIP11-related form.

🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Odontochondrodysplasia:

Skeletal Ciliopathies

Overlapping Features Cranioectodermal dysplasia (Sensenbrenner syndrome) and the short-rib thoracic dysplasias share the thoracic dystrophy, cone-shaped epiphyses, trident pelvis, and the dental, renal, and cerebral organ pattern. GMAP-210 binds IFT20, which made a ciliary mechanism plausible, but cilia and ciliary IFT20 targeting were normal in ODCD patient fibroblasts.

Show evidence (1 reference)

PMID:30728324 SUPPORT Human Clinical

"The same organs are affected in an overlapping condition known as cranioectodermal dysplasia, or Sensenbrenner syndrome"

Names the specific ciliopathy with which ODCD is most readily confused.

🧫

Experimental Models

1

TRIP11-mutant patient fibroblast-derived chondrocytes PRIMARY_CELL_CULTURE

Primary dermal fibroblasts from ODCD and achondrogenesis 1A patients, transdifferentiated into mature chondrocytes on an aggrecan-coated surface and assessed for chondrogenic nodule number and size, matrix synthesis, proliferation, and viability against controls. This system carries the entire cellular mechanism for the disorder, since no viable animal model exists.

Cell source

Patient-derived (skin biopsy)

Culture

Fibroblast transdifferentiation to chondrocytes on aggrecan-coated surface

Pathograph links

Block in Hypertrophic Chondrocyte Differentiation recapitulates fidelity: moderate Patient-derived chondrogenic cells reproduce the differentiation block and the matrix-synthesis defect, and separate them from any effect on cell number.

Limitations: Transdifferentiated dermal fibroblasts are not growth-plate chondrocytes, and the system cannot reproduce the spatial organisation of the growth plate in which the hypertrophic transition normally occurs. The histological comparison the authors draw on comes from achondrogenesis 1A fetuses rather than ODCD.

Readouts

Chondrogenic nodule number and size

Direction: DECREASED

Interpretation: Fewer and smaller chondrogenic nodules index the failure of chondrogenic differentiation in TRIP11-mutant cells.

Cell proliferation and viability during chondrogenesis

Direction: UNCHANGED

Interpretation: Normal proliferation and viability establish that the reduced matrix output is a differentiation defect rather than a consequence of cell loss. A deliberate negative result.

Show evidence (1 reference)

PMID:30728324 SUPPORT In Vitro

"we found that proliferation was not impaired during chondrogenesis"

The negative control that rules out reduced cell number as the explanation for reduced matrix synthesis.

Show evidence (1 reference)

PMID:30728324 SUPPORT In Vitro

"However, our functional studies in patient-derived primary cells clearly support a Golgi-based disease mechanism."

The authors treat the patient-derived primary cell system as the decisive evidence for the mechanism, which is what makes this model informative for the node.

{ }

Source YAML

click to show

name: Odontochondrodysplasia
creation_date: "2026-08-27T00:00:00Z"
category: Mendelian
description: >-
  Odontochondrodysplasia (ODCD, Goldblatt syndrome; OMIM #184260) is an ultra-rare
  autosomal recessive spondylometaphyseal dysplasia caused by hypomorphic
  biallelic variants in TRIP11, which encodes GMAP-210, the cis-Golgi vesicle
  tether. Affected individuals have short stature, a narrow chest, mesomelic limb
  shortening, brachydactyly, joint laxity, and dentinogenesis imperfecta;
  radiographs show platyspondyly with coronal clefts and metaphyseal irregularity.
  Extraskeletal disease — pulmonary dysplasia, cystic renal disease, and
  nonobstructive hydrocephaly — is part of the phenotype. ODCD is the non-lethal
  allelic counterpart of achondrogenesis type 1A: complete loss of TRIP11 is
  embryonic-lethal, while the recurrent splice alleles of ODCD leave trace amounts
  of shortened GMAP protein that preserve Golgi organisation, bulk secretion, and
  IFT20 Golgi anchoring. What survives that partial rescue is glycan processing and
  proteoglycan secretion, and the resulting block in hypertrophic chondrocyte
  differentiation is what both disorders share. Because splicing penetrance varies
  between individuals, the same alleles produce early-lethal disease and long-term
  survival within one family, so genotype does not predict outcome.
disease_term:
  preferred_term: odontochondrodysplasia
  term:
    id: MONDO:0100325
    label: odontochondrodysplasia 1
synonyms:
- ODCD
- ODCD1
- Odontochondrodysplasia 1
- Goldblatt syndrome
- Goldblatt chondrodysplasia
- Chondrodysplasia-dentinogenesis imperfecta-joint laxity syndrome
- Spondylometaphyseal dysplasia with dentinogenesis imperfecta
- TRIP11-related odontochondrodysplasia
parents:
- hereditary disease
classifications:
  isds_skeletal_category:
  - classification_value: spondylometaphyseal_dysplasias
    notes: >-
      ISDS Nosology of Genetic Skeletal Disorders, 2023 revision (Unger et al.,
      PMID:36779427), Table 1 group 12 "Spondylometaphyseal dysplasias (SMD)",
      entry NOS 12-0020, listed as "Odontochondrodysplasia (ODCD), TRIP11-related"
      (AR, TRIP11, MIM 184260). The nosology carries an explicit cross-reference
      from this entry to "Achondrogenesis, TRIP11-related (formerly type 1A)",
      which it places in group 14 (severe spondylodysplastic dysplasias) — the same
      gene, split across two groups by severity, which is why the group-12 tag
      belongs on the non-lethal phenotype only.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  rate_per_100000: 0.0
  notes: >-
    Sixteen patients from twelve unrelated families with TRIP11 variants had been
    published by 2025, three decades after Goldblatt recognised the entity in 1991.
    No population-based prevalence estimate exists; rate_per_100000 is recorded as
    0.0 only to mark that the true rate is far below the resolution of any
    published survey.
  evidence:
  - reference: PMID:33746040
    reference_title: >-
      Description of four patients with TRIP11 variants expand the clinical spectrum of
      odontochondroplasia (ODCD) and demonstrate the existence of common variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Subsequently, we review the clinical and radiological findings of the 14 reported ODCD patients.
    explanation: >-
      The published case count standing in for a population estimate that does not exist.
  - reference: PMID:40119123
    reference_title: Deciphering the phenotypic spectrum associated with MIA3-related odontochondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To date, 16 patients from 12 unrelated families with TRIP11 variants have
      been described in the literature
    explanation: Gives the published caseload for the TRIP11-related form.
inheritance:
- name: Autosomal Recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    ODCD is autosomal recessive. Every reported patient carries a TRIP11-null
    allele in trans with a splice variant that retains partial function; two null
    alleles instead produce achondrogenesis type 1A. Because the penetrance of the
    mis-splicing varies between individuals, recurrence risk counselling cannot
    predict which end of the severity spectrum a subsequent affected child will
    occupy.
  evidence:
  - reference: PMID:30728324
    reference_title: Hypomorphic mutations of TRIP11 cause odontochondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      all ODCD patients, in addition to aTRIP11-null allele, carry compound
      heterozygous splice variants, which are translated into low-abundance GMAP
      proteins
    explanation: >-
      Establishes the compound heterozygous null-plus-hypomorph allele structure
      that defines the recessive genotype of ODCD.
  - reference: PMID:30728324
    reference_title: Hypomorphic mutations of TRIP11 cause odontochondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thus, our results make the prediction of clinical outcome solely based on
      genotype difficult in genetic counselling and clinical care.
    explanation: >-
      The authors state directly that genotype does not predict outcome, which is
      the counselling-relevant consequence of variable splicing penetrance.
genetic:
- name: Biallelic Hypomorphic TRIP11 Variants
  gene_term:
    preferred_term: TRIP11
    term:
      id: hgnc:12305
      label: TRIP11
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  features: >-
    TRIP11 has 21 coding exons and encodes the 1,979-amino-acid GMAP-210 protein.
    ODCD patients are compound heterozygous for a null allele and a recurrent
    splice variant. The recurrent c.586C>T change is instructive: predicted to be a
    nonsense allele (p.Gln196*) subject to nonsense-mediated decay, it in fact
    abrogates a splice donor site and causes complete in-frame skipping of exon 4,
    producing a shortened but partly functional protein. Splicing is cell-type
    dependent and not fully penetrant, which is the proposed source of the
    intrafamilial variability.
  evidence:
  - reference: PMID:30728324
    reference_title: Hypomorphic mutations of TRIP11 cause odontochondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we show that ODCD is caused by hypomorphic TRIP11 mutations, and we
      identify ODCD as the nonlethal counterpart to achondrogenesis 1A (ACG1A), the
      known null phenotype in humans.
    explanation: >-
      Establishes the gene, the hypomorphic mechanism, and the allelic relationship
      with achondrogenesis 1A.
  - reference: PMID:30728324
    reference_title: Hypomorphic mutations of TRIP11 cause odontochondrodysplasia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      However, we were surprised to find that the mutation, instead, abrogates a
      splice donor site, causing complete in-frame skipping of exon 4
    explanation: >-
      Shows that an apparently null nonsense allele actually behaves as a splice
      hypomorph, which is why the genotype is not readable from the coding
      annotation alone.
  - reference: PMID:30728324
    reference_title: Hypomorphic mutations of TRIP11 cause odontochondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our findings establish that ODCD is genetically homogeneous and that
      hypomorphic mutations ofTRIP11are the genetic basis for a range of ODCD
      phenotypes.
    explanation: >-
      Supports treating ODCD as a single-locus disorder rather than a
      radiographically defined category.
  - reference: PMID:33746040
    reference_title: >-
      Description of four patients with TRIP11 variants expand the clinical spectrum of odontochondroplasia (ODCD) and demonstrate the existence of common variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The c.586C>T; p.(Gln196*) variant, previously shown by mRNA studies to result in p.Val105_Gln196del, is the most frequent variant, present in seven individuals from four families, three from different regions of the world, suggesting that it may be a variant hotspot.
    explanation: >-
      Establishes the recurrent allele as a hotspot across unrelated populations,
      and restates that its real consequence is an in-frame deletion rather than
      the nonsense change the coding annotation predicts.
  - reference: PMID:33746040
    reference_title: >-
      Description of four patients with TRIP11 variants expand the clinical spectrum of odontochondroplasia (ODCD) and demonstrate the existence of common variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The majority of ODCD patients are compound heterozygotes for TRIP11 variants, 12/14 have a null allele and a splice variant whilst one is homozygous for an in-frame splicing variant, with the splice variants resulting in residual GMAP activity and hypothesized to explain why they have ODCD and not ACG1A.
    explanation: >-
      Quantifies how consistently the null-plus-splice genotype recurs, and states
      the residual-activity hypothesis it is taken to support.
  - reference: PMID:31903676
    reference_title: >-
      Pathogenic variants in the TRIP11 gene cause a skeletal dysplasia spectrum from odontochondrodysplasia to achondrogenesis 1A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The two patients reported here represent the TRIP11 spectrum of skeletal dysplasia ranging from mild to lethal phenotypes, thereby enabling one to suggest a genotype-phenotype correlation in these diseases.
    explanation: >-
      Establishes the genotype-severity relationship across the TRIP11 allelic
      series, which is what makes allele-specific counselling necessary.
  - reference: PMID:31903676
    reference_title: >-
      Pathogenic variants in the TRIP11 gene cause a skeletal dysplasia spectrum from odontochondrodysplasia to achondrogenesis 1A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is known that null mutations in TRIP11 disrupt Golgi function and cause a lethal skeletal dysplasia known as achondrogenesis type 1A (ACG1A)
    explanation: >-
      States the consequence of complete TRIP11 loss, the contrast on which
      variant interpretation in this disorder rests.
pathophysiology:
- name: Aberrant TRIP11 Splicing with a Null Allele in Trans
  biological_scale: MOLECULAR
  description: >-
    A TRIP11-null allele in trans with a recurrent splice allele. The splice allele
    yields low-abundance GMAP proteins identical to, or overlapping with, natural
    isoforms; the null allele contributes nothing. Two null alleles instead cause
    achondrogenesis type 1A, so this genotype defines the non-lethal end of one
    allelic series.
  genes:
  - preferred_term: TRIP11
    term:
      id: hgnc:12305
      label: TRIP11
  evidence:
  - reference: PMID:30728324
    reference_title: Hypomorphic mutations of TRIP11 cause odontochondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      whereas recurrent splice mutations are associated with a milder but variable
      spectrum of postnatal clinical phenotypes
    explanation: >-
      Introduces the dose relationship in which complete loss is lethal and residual
      function permits survival; the sentence continues to name early embryonic
      lethality in ACG1A versus a milder postnatal spectrum.
  downstream:
  - target: Reduced GMAP-210 Abundance at the cis-Golgi
    causal_link_type: DIRECT
    description: >-
      All disease-associated TRIP11 alleles reduce GMAP-210 protein abundance
      sharply in patient-derived primary cells, leaving only trace amounts of the
      shortened variants.
    evidence:
    - reference: PMID:30728324
      reference_title: Hypomorphic mutations of TRIP11 cause odontochondrodysplasia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        caused a strong reduction of GMAP-210 abundance in patient-derived primary
        cells
      explanation: >-
        Quantifies the protein-level consequence shared by every disease-associated
        allele.

- name: Reduced GMAP-210 Abundance at the cis-Golgi
  biological_scale: MOLECULAR
  description: >-
    GMAP-210 is the cis-Golgi vesicle tether. In ODCD its abundance is sharply
    reduced but not abolished, and the residual variants retain enough tethering
    capacity to hold the Golgi together. This is the node at which ODCD and
    achondrogenesis 1A diverge: what is preserved here is what makes ODCD
    survivable.
  cellular_components:
  - preferred_term: Golgi apparatus
    term:
      id: GO:0005794
      label: Golgi apparatus
  biological_processes:
  - preferred_term: Golgi organization
    modifier: DECREASED
    term:
      id: GO:0007030
      label: Golgi organization
  evidence:
  - reference: PMID:30728324
    reference_title: >-
      Hypomorphic mutations of TRIP11 cause odontochondrodysplasia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      TRIP11 encodes Golgi-associated microtubule-binding protein 210 (GMAP-210), an essential tether protein of the Golgi apparatus that physically interacts with intraflagellar transport 20 (IFT20), a component of the ciliary intraflagellar transport complex B.
    explanation: >-
      Establishes the gene product and the two candidate compartments, Golgi and cilium, that
      the mechanism had to be assigned between.
  - reference: PMID:30728324
    reference_title: Hypomorphic mutations of TRIP11 cause odontochondrodysplasia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In spite of reduced abundance, residual GMAP variants maintain partial Golgi
      integrity, normal global protein secretion, and subcellular distribution of
      IFT20 in ODCD.
    explanation: >-
      Defines exactly what the hypomorphic alleles preserve, and by contrast what
      the null alleles of achondrogenesis 1A lose.
  downstream:
  - target: Defective Golgi Glycan Processing and Proteoglycan Secretion
    causal_link_type: DIRECT
    description: >-
      Bulk secretory traffic survives the reduction in GMAP-210, but glycan
      processing does not. Glycosylation of LAMP1 and LAMP2, which depends on
      efficient intra-Golgi trafficking of processing enzymes, is used as the
      readout, and procollagen type I secretion is reduced relative to control while
      remaining above the achondrogenesis 1A level.
    evidence:
    - reference: PMID:30728324
      reference_title: Hypomorphic mutations of TRIP11 cause odontochondrodysplasia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        ensuing from aberrant glycan processing and impaired extracellular matrix
        proteoglycan secretion by the Golgi apparatus
      explanation: >-
        Names the two Golgi functions that fail despite preserved bulk secretion.
  - target: Extraskeletal Golgi-Related Organ Disease
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The lung, kidney, and brain manifestations of ODCD are attributed to reduced
      GMAP-210 dose rather than to a separate lesion, but the route from the Golgi
      defect to each organ has not been established. The authors' own fibroblast
      data argue against a ciliary intermediate, and no viable model exists in which
      to test the alternatives, so the intermediates are left unspecified.
    evidence:
    - reference: PMID:30728324
      reference_title: Hypomorphic mutations of TRIP11 cause odontochondrodysplasia.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Second, additional extraskeletal disease manifestations of ODCD included
        pulmonary dysplasia, cystic renal disease, and nonobstructive hydrocephaly.
      explanation: >-
        Establishes that the extraskeletal organ disease belongs to the TRIP11
        hypomorph phenotype, which is what places it downstream of reduced GMAP-210
        abundance. Graded INDIRECT because the sentence documents co-occurrence in
        the series and does not itself demonstrate the causal route.
- name: Defective Golgi Glycan Processing and Proteoglycan Secretion
  biological_scale: MOLECULAR
  description: >-
    Post-translational glycan processing and secretion of extracellular matrix
    proteoglycans are impaired while bulk protein export is normal. The authors
    propose that a limited set of secreted developmental regulators with key roles
    in early chondrogenesis — decorin among them — are the cargoes that matter, by
    analogy with achondrogenesis type 1B, in which aberrant glycan processing
    produces a closely similar skeletal phenotype.
  biological_processes:
  - preferred_term: glycoprotein biosynthetic process
    modifier: ABNORMAL
    term:
      id: GO:0009101
      label: glycoprotein biosynthetic process
  - preferred_term: Golgi vesicle transport
    modifier: ABNORMAL
    term:
      id: GO:0048193
      label: Golgi vesicle transport
  - preferred_term: proteoglycan biosynthetic process
    modifier: ABNORMAL
    term:
      id: GO:0030166
      label: proteoglycan biosynthetic process
  evidence:
  - reference: PMID:30728324
    reference_title: >-
      Hypomorphic mutations of TRIP11 cause odontochondrodysplasia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      This association and extraskeletal disease manifestations in ODCD point to a cilium-dependent pathogenesis. However, our functional studies in patient-derived primary cells clearly support a Golgi-based disease mechanism.
    explanation: >-
      States the competing hypothesis and the experimental result that settles it in favour of
      the Golgi.
  - reference: PMID:30728324
    reference_title: Hypomorphic mutations of TRIP11 cause odontochondrodysplasia.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: >-
      The etiology of the differentiation defect remains currently unclear, but we
      hypothesize that aberrant posttranslational processing and secretion of a
      limited number of secreted developmental regulators with key importance for
      early chondrogenesis, like decorin
    explanation: >-
      The specific cargo identity is an explicit hypothesis of the authors, not a
      demonstrated result, which is why this is graded INDIRECT.
  downstream:
  - target: Block in Hypertrophic Chondrocyte Differentiation
    causal_link_type: DIRECT
    description: >-
      The differentiation block is the shared cellular endpoint of ODCD and
      achondrogenesis 1A, differing between them only in degree. Fibroblasts
      transdifferentiated to chondrocytes form fewer and smaller chondrogenic
      nodules with reduced matrix synthesis, and proliferation and viability are
      unaffected, so this is a differentiation defect and not cell loss.
    evidence:
    - reference: PMID:30728324
      reference_title: Hypomorphic mutations of TRIP11 cause odontochondrodysplasia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        However, a similar defect in chondrocyte maturation is observed in both
        disorders, which produces a cellular achondrogenesis phenotype of different
        severity
      explanation: >-
        Establishes the differentiation block as the common downstream endpoint of
        the allelic series.
  - target: Dentinogenesis Imperfecta
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Odontoblasts secrete a collagenous, proteoglycan-rich dentine matrix through
      the same Golgi route, so defective glycan processing and matrix secretion is
      the natural explanation for the dental defect that names the disorder. The
      step has not been demonstrated in odontoblasts, and MIA3/TANGO1 — the other
      odontochondrodysplasia gene — acts on the immediately upstream export step,
      which is the main circumstantial support for a shared secretory mechanism.
- name: Block in Hypertrophic Chondrocyte Differentiation
  biological_scale: CELLULAR
  description: >-
    Chondrocytes fail to progress to the hypertrophic stage, so the growth plate
    loses the cells that synthesise the key cartilage matrix proteins, COL10A1
    among them. Histology in achondrogenesis 1A fetuses shows reduced total
    epiphyseal cartilage with absent columnar chondrocytes in the prehypertrophic
    and hypertrophic zones; ODCD is the attenuated version of the same lesion.
  cell_types:
  - preferred_term: chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  - preferred_term: hypertrophic chondrocyte
    term:
      id: CL:0000743
      label: hypertrophic chondrocyte
  biological_processes:
  - preferred_term: chondrocyte differentiation
    modifier: DECREASED
    term:
      id: GO:0002062
      label: chondrocyte differentiation
  - preferred_term: extracellular matrix organization
    modifier: ABNORMAL
    term:
      id: GO:0030198
      label: extracellular matrix organization
  evidence:
  - reference: PMID:30728324
    reference_title: Hypomorphic mutations of TRIP11 cause odontochondrodysplasia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      A block in cellular differentiation impairs the evolution of hypertrophic
      chondrocytes, which synthesize key cartilage matrix proteins in the growth
      plate, including COL10A1.
    explanation: >-
      States the cellular lesion and why it matters for growth-plate matrix
      production.
  downstream:
  - target: Spondylometaphyseal Dysplasia with Mesomelic Shortening
    causal_link_type: DIRECT
    description: >-
      Failure of the hypertrophic transition disorders endochondral growth at both
      the vertebral and the metaphyseal growth plates, producing the combined
      radiographic pattern that places ODCD in the spondylometaphyseal group.
    evidence:
    - reference: PMID:30728324
      reference_title: Hypomorphic mutations of TRIP11 cause odontochondrodysplasia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Radiographic features include platyspondyly with coronal clefts and
        metaphyseal irregularities of the tubular bones
      explanation: Gives the vertebral-plus-metaphyseal radiographic pattern that results.
- name: Spondylometaphyseal Dysplasia with Mesomelic Shortening
  biological_scale: ORGANISM
  description: >-
    The skeletal phenotype: short stature, narrow chest, mesomelic limb shortening,
    brachydactyly, and joint laxity, on a radiographic background of platyspondyly
    with coronal clefts and metaphyseal irregularity. Short plump tubular bones with
    cupped metaphyses flanked by longitudinal spurs, short ribs, and a trident
    pelvis are shared with achondrogenesis 1A and are the features that first
    suggested the two disorders were allelic.
  evidence:
  - reference: PMID:30728324
    reference_title: Hypomorphic mutations of TRIP11 cause odontochondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Key clinical findings are short stature, narrow chest, mesomelic limb
      shortening, brachydactyly, joint laxity, and dental anomalies
    explanation: The clinical core of the disorder as defined at entity recognition.
  downstream:
  - target: Short Stature
    causal_link_type: DIRECT
    description: Disordered endochondral growth at every growth plate reduces stature.
  - target: Mesomelic Limb Shortening
    causal_link_type: DIRECT
    description: >-
      Shortening falls predominantly on the middle limb segments, the pattern that
      distinguishes the disorder from the rhizomelic dysplasias.
  - target: Brachydactyly
    causal_link_type: DIRECT
    description: >-
      Short digits with cone-shaped epiphyses, the distal expression of the same
      growth-plate lesion.
  - target: Platyspondyly with Coronal Clefts
    causal_link_type: DIRECT
    description: >-
      The vertebral growth plates are affected alongside the appendicular ones,
      which is what makes the disorder spondylometaphyseal rather than metaphyseal.
  - target: Coronal Cleft Vertebrae
    causal_link_type: DIRECT
    description: >-
      Coronal clefting is a normal transient fetal finding that persists abnormally
      where vertebral endochondral ossification is disordered.
  - target: Metaphyseal Irregularity
    causal_link_type: DIRECT
    description: >-
      Cupped, irregular metaphyses flanked by longitudinal spurs — the direct
      radiographic read-out of the failed hypertrophic transition.
  - target: Narrow Chest
    causal_link_type: DIRECT
    description: >-
      Short ribs produce a narrow thorax, which together with the pulmonary
      dysplasia accounts for the deaths at the lethal end of the spectrum.
  - target: Joint Laxity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Ligamentous laxity accompanies the skeletal dysplasia. Whether it reflects the
      same defective matrix secretion acting on ligament and capsule, or a separate
      consequence of GMAP-210 loss, has not been established.
- name: Extraskeletal Golgi-Related Organ Disease
  biological_scale: ORGANISM
  description: >-
    Pulmonary dysplasia, cystic renal disease, and nonobstructive hydrocephaly
    occur in ODCD and implicate GMAP-210 in renal and cerebral development beyond
    the skeleton. The authors could not attribute these to a ciliary mechanism —
    cilia in GMAP-210-deficient fibroblasts were of normal length and structure, and
    ciliary targeting of IFT20 was preserved — but note that conditional Ift20
    deletion during renal development causes polycystic kidney disease in mice, so a
    cilium-based route to the late renal disease remains open.
  evidence:
  - reference: PMID:30728324
    reference_title: Hypomorphic mutations of TRIP11 cause odontochondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Second, additional extraskeletal disease manifestations of ODCD included
      pulmonary dysplasia, cystic renal disease, and nonobstructive hydrocephaly.
    explanation: Documents the extraskeletal organ involvement in the assembled series.
  - reference: PMID:30728324
    reference_title: Hypomorphic mutations of TRIP11 cause odontochondrodysplasia.
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: >-
      Our studies did not provide support for a cilium-dependent pathogenesis
      inTRIP11-related disorders
    explanation: >-
      A negative result against the ciliopathy hypothesis in patient fibroblasts,
      which is why the extraskeletal node is not curated as a ciliary mechanism.
  downstream:
  - target: Cystic Renal Disease
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Late-onset cystic renal degeneration. The authors suggest it may be the one
      manifestation that genuinely runs through impaired ciliary transport of IFT20,
      by analogy with conditional Ift20 deletion causing polycystic kidney disease in
      neonatal mice — but their own fibroblast data found ciliary IFT20 targeting
      intact, so the route is unresolved.
  - target: Nonobstructive Hydrocephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Communicating hydrocephalus without an obstructive lesion, implicating GMAP-210
      in cerebral development by a mechanism that has not been worked out.
  - target: Pulmonary Dysplasia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Abnormal lung development, distinct from the mechanical restriction imposed by
      the narrow thorax though clinically inseparable from it.
phenotypes:
- category: Growth
  name: Short Stature
  frequency: VERY_FREQUENT
  description: >-
    Disproportionate short stature is a defining feature, present across the
    surviving spectrum of the disorder.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:30728324
    reference_title: Hypomorphic mutations of TRIP11 cause odontochondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Key clinical findings are short stature, narrow chest, mesomelic limb
      shortening, brachydactyly, joint laxity, and dental anomalies
    explanation: >-
      Short stature heads the list of key clinical findings, supporting this and the
      four phenotype records that follow.
- category: Skeletal
  name: Platyspondyly with Coronal Clefts
  frequency: VERY_FREQUENT
  description: >-
    Flattened vertebral bodies with coronal clefting, the vertebral half of the
    spondylometaphyseal pattern.
  phenotype_term:
    preferred_term: Platyspondyly
    term:
      id: HP:0000926
      label: Platyspondyly
  evidence:
  - reference: PMID:30728324
    reference_title: Hypomorphic mutations of TRIP11 cause odontochondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Radiographic features include platyspondyly with coronal clefts and
      metaphyseal irregularities of the tubular bones
    explanation: Names platyspondyly with coronal clefts as a defining radiographic feature.
- category: Skeletal
  name: Coronal Cleft Vertebrae
  frequency: FREQUENT
  description: >-
    Vertical clefting of the vertebral bodies in the coronal plane, a normal
    transient finding in the fetus that persists abnormally here.
  phenotype_term:
    preferred_term: Coronal cleft vertebrae
    term:
      id: HP:0003417
      label: Coronal cleft vertebrae
  evidence:
  - reference: PMID:30728324
    reference_title: Hypomorphic mutations of TRIP11 cause odontochondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Radiographic features include platyspondyly with coronal clefts and
      metaphyseal irregularities of the tubular bones
    explanation: Coronal clefting is named directly among the radiographic features.
- category: Skeletal
  name: Metaphyseal Irregularity
  frequency: VERY_FREQUENT
  description: >-
    Irregular, cupped metaphyses of the tubular bones, flanked by longitudinal
    spurs. With the platyspondyly, this is the finding that places the disorder in
    the spondylometaphyseal group.
  phenotype_term:
    preferred_term: Metaphyseal irregularity
    term:
      id: HP:0003025
      label: Metaphyseal irregularity
  evidence:
  - reference: PMID:30728324
    reference_title: Hypomorphic mutations of TRIP11 cause odontochondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      some alterations such as short, plump tubular bones with cupped metaphyses
      flanked by longitudinal spurs, short ribs, and a trident pelvis
    explanation: Describes the metaphyseal morphology in detail.
- category: Skeletal
  name: Mesomelic Limb Shortening
  frequency: VERY_FREQUENT
  description: >-
    Shortening predominantly of the middle limb segments, the forearm and lower
    leg.
  phenotype_term:
    preferred_term: Mesomelia
    term:
      id: HP:0003027
      label: Mesomelia
  evidence:
  - reference: PMID:40119123
    reference_title: Deciphering the phenotypic spectrum associated with MIA3-related odontochondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a very rare form of SMD characterized by mesomelic shortening of the tubular
      bones, scoliosis, ligamentous laxity, cone-shaped epiphyses, and
      dentinogenesis imperfecta (DI)
    explanation: >-
      Characterises ODCD by mesomelic shortening and, in the same sentence, supports
      the joint laxity and dentinogenesis imperfecta records.
- category: Dental
  name: Dentinogenesis Imperfecta
  frequency: VERY_FREQUENT
  description: >-
    Defective dentine with discoloured, fragile teeth. The dental component is what
    the "odonto-" of the disorder name records, and it distinguishes ODCD from the
    other spondylometaphyseal dysplasias at the chairside.
  phenotype_term:
    preferred_term: Dentinogenesis imperfecta
    term:
      id: HP:0000703
      label: Dentinogenesis imperfecta
  evidence:
  - reference: PMID:40119123
    reference_title: Deciphering the phenotypic spectrum associated with MIA3-related odontochondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Odontochondrodysplasia (ODCD) is a rare skeletal dysplasia characterized by
      short stature, skeletal deformities, and dentinogenesis imperfecta (DI).
    explanation: Dentinogenesis imperfecta is one of the three defining features.
- category: Skeletal
  name: Joint Laxity
  frequency: FREQUENT
  description: Generalised ligamentous laxity with hypermobile joints.
  phenotype_term:
    preferred_term: Joint hypermobility
    term:
      id: HP:0001382
      label: Joint hypermobility
  evidence:
  - reference: PMID:30728324
    reference_title: Hypomorphic mutations of TRIP11 cause odontochondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Key clinical findings are short stature, narrow chest, mesomelic limb
      shortening, brachydactyly, joint laxity, and dental anomalies
    explanation: Joint laxity is named among the key clinical findings.
- category: Skeletal
  name: Narrow Chest
  frequency: FREQUENT
  description: >-
    A narrow thorax with short ribs. Combined with pulmonary dysplasia this is the
    proximate cause of death in the early-lethal end of the spectrum.
  phenotype_term:
    preferred_term: Narrow chest
    term:
      id: HP:0000774
      label: Narrow chest
  evidence:
  - reference: PMID:30728324
    reference_title: Hypomorphic mutations of TRIP11 cause odontochondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Key clinical findings are short stature, narrow chest, mesomelic limb
      shortening, brachydactyly, joint laxity, and dental anomalies
    explanation: Narrow chest is named among the key clinical findings.
- category: Skeletal
  name: Brachydactyly
  frequency: FREQUENT
  description: Short digits, with cone-shaped epiphyses of the phalanges.
  phenotype_term:
    preferred_term: Brachydactyly
    term:
      id: HP:0001156
      label: Brachydactyly
  evidence:
  - reference: PMID:30728324
    reference_title: Hypomorphic mutations of TRIP11 cause odontochondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the combination of thoracic dystrophy, brachydactyly with cone-shaped
      epiphyses, and a trident pelvis
    explanation: >-
      Describes the brachydactyly with its cone-shaped epiphyses, part of the
      ciliopathy-like radiographic gestalt of the disorder.
- category: Renal
  name: Cystic Renal Disease
  frequency: OCCASIONAL
  description: >-
    Cystic kidney disease, of later onset than the skeletal features, recognised
    only once patients were followed longitudinally.
  phenotype_term:
    preferred_term: Cystic renal disease
    term:
      id: HP:0005562
      label: Multiple renal cysts
  evidence:
  - reference: PMID:30728324
    reference_title: Hypomorphic mutations of TRIP11 cause odontochondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Second, additional extraskeletal disease manifestations of ODCD included
      pulmonary dysplasia, cystic renal disease, and nonobstructive hydrocephaly.
    explanation: >-
      Documents cystic renal disease among the extraskeletal features, together with
      the pulmonary and cerebral findings recorded below.
- category: Neurologic
  name: Nonobstructive Hydrocephaly
  frequency: OCCASIONAL
  description: Communicating hydrocephalus without a demonstrable obstructive lesion.
  phenotype_term:
    preferred_term: Hydrocephalus
    term:
      id: HP:0000238
      label: Hydrocephalus
  evidence:
  - reference: PMID:30728324
    reference_title: Hypomorphic mutations of TRIP11 cause odontochondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Second, additional extraskeletal disease manifestations of ODCD included
      pulmonary dysplasia, cystic renal disease, and nonobstructive hydrocephaly.
    explanation: Hydrocephaly is named among the extraskeletal manifestations.
- category: Respiratory
  name: Pulmonary Dysplasia
  frequency: OCCASIONAL
  description: >-
    Abnormal lung development, which together with the narrow thorax accounts for
    the deaths at the early-lethal end of the phenotypic range. The source says
    "pulmonary dysplasia" and does not specify hypoplasia, so the binding stays at
    the level of abnormal lung morphology rather than asserting the more specific
    developmental deficit.
  phenotype_term:
    preferred_term: Abnormal lung morphology
    term:
      id: HP:0002088
      label: Abnormal lung morphology
  evidence:
  - reference: PMID:30728324
    reference_title: Hypomorphic mutations of TRIP11 cause odontochondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Second, additional extraskeletal disease manifestations of ODCD included
      pulmonary dysplasia, cystic renal disease, and nonobstructive hydrocephaly.
    explanation: Pulmonary dysplasia is named among the extraskeletal manifestations.
progression:
- phase: Variable outcome from perinatal lethality to adult survival
  notes: >-
    Outcome ranges from early lethal disease to long-term survival with short
    stature, and both extremes occur within a single family carrying the same
    alleles. A radiographic diagnosis of achondrogenesis 1A in one child and ODCD in
    a sibling is attributed to variable penetrance of TRIP11 mis-splicing between
    individuals, giving constitutively different residual GMAP levels. There is no
    marker that predicts which course an affected fetus will take.
  evidence:
  - reference: PMID:30728324
    reference_title: Hypomorphic mutations of TRIP11 cause odontochondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Third, it became evident that disease manifestations may range from early
      lethal to long-term survival with short stature
    explanation: States the range of outcomes directly from the assembled case series.
  - reference: PMID:30728324
    reference_title: Hypomorphic mutations of TRIP11 cause odontochondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      there is considerable clinical variability inTRIP11-related disorders, with
      early lethality and milder postnatal phenotypes occurring within the same
      family
    explanation: >-
      Introduces the observation of early lethality and milder postnatal phenotypes
      occurring within the same family.
diagnosis:
- name: Radiographic and Dental Recognition
  results: >-
    Vertebral and metaphyseal changes with defective dentine.
  diagnosis_term:
    preferred_term: X-ray imaging
    term:
      id: NCIT:C38101
      label: X-Ray Imaging
  description: >-
    The combination of platyspondyly with coronal clefts, metaphyseal irregularity,
    mesomelic shortening, and dentinogenesis imperfecta is distinctive enough to
    direct testing. Because the radiographic gestalt overlaps the skeletal
    ciliopathies — thoracic dystrophy, brachydactyly with cone-shaped epiphyses, a
    trident pelvis — a ciliopathy panel is a common first and unrewarding step.
  evidence:
  - reference: PMID:31903676
    reference_title: >-
      Pathogenic variants in the TRIP11 gene cause a skeletal dysplasia spectrum from
      odontochondrodysplasia to achondrogenesis 1A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hypomorphic mutations in that gene have been linked to odontochondrodysplasia (ODCD), a nonlethal skeletal dysplasia characterized by skeletal changes in the spine and in the metaphyseal regions, associated with dentinogenesis imperfecta
    explanation: >-
      The diagnostic triad on which the clinical diagnosis rests.
  - reference: PMID:30728324
    reference_title: Hypomorphic mutations of TRIP11 cause odontochondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      radiographic features of ACG1A and ODCD are characteristic of skeletal
      ciliopathies
    explanation: >-
      Explains why ODCD is mistaken for a skeletal ciliopathy on imaging, the main
      diagnostic pitfall.
- name: TRIP11 Sequencing with RNA Confirmation
  results: >-
    Biallelic TRIP11 variants, typically a null allele with a splice variant.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    Biallelic TRIP11 variants confirm the diagnosis, but coding annotation alone is
    misleading: the recurrent c.586C>T allele is annotated as a nonsense change yet
    behaves as an in-frame exon-skipping hypomorph. RNA analysis of patient
    fibroblasts is what distinguishes a true null genotype — predicting
    achondrogenesis 1A — from the hypomorphic genotype of ODCD.
  evidence:
  - reference: PMID:30728324
    reference_title: Hypomorphic mutations of TRIP11 cause odontochondrodysplasia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Taken together, the experimental evidence shows aberrant splicing
      ofTRIP11in all ODCD cases investigated
    explanation: >-
      RNA analysis demonstrated aberrant splicing in every ODCD case investigated,
      which is why transcript-level confirmation is part of the diagnostic pathway.
differential_diagnoses:
- name: Achondrogenesis Type 1A (TRIP11-Related)
  description: >-
    The allelic null phenotype: complete loss of TRIP11 causes early embryonic
    lethality with a closely similar but more severe skeletal picture. The ISDS
    nosology places it in group 14 (severe spondylodysplastic dysplasias), so the
    same gene appears in two groups separated by severity. Distinguishing them
    matters for counselling because they are not different diseases at the molecular
    level, only different residual GMAP doses.
  evidence:
  - reference: PMID:30728324
    reference_title: Hypomorphic mutations of TRIP11 cause odontochondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although our functional data corroborate that ODCD is the milder allelic form
      of ACG1A, clinical variability associated with hypomorphicTRIP11mutations is
      too high for a reliable genotype-phenotype correlation, at present.
    explanation: >-
      States the allelic relationship and, in the same sentence, that the variability
      defeats a reliable genotype-phenotype correlation.
- name: MIA3/TANGO1-Related Odontochondrodysplasia
  description: >-
    Biallelic MIA3 (TANGO1) variants produce an odontochondrodysplasia phenotype
    that at its severe end closely resembles the TRIP11 disorder — MIA3 and TRIP11
    act at consecutive steps of collagen and matrix export from the endoplasmic
    reticulum and Golgi. Extraskeletal features differ: the originally reported MIA3
    family had insulin-dependent diabetes, hearing loss, obesity, and intellectual
    disability, none of which is typical of TRIP11 disease. MIA3-related ODCD is not
    listed in the 2023 ISDS nosology and is therefore not assigned an ISDS group
    here.
  evidence:
  - reference: PMID:40119123
    reference_title: Deciphering the phenotypic spectrum associated with MIA3-related odontochondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, they had more severe skeletal deformities closely resembling those
      observed in patients with TRIP11 variants.
    explanation: >-
      Documents the radiographic convergence between the MIA3 and TRIP11 forms that
      makes this a genuine differential.
- name: Skeletal Ciliopathies
  description: >-
    Cranioectodermal dysplasia (Sensenbrenner syndrome) and the short-rib thoracic
    dysplasias share the thoracic dystrophy, cone-shaped epiphyses, trident pelvis,
    and the dental, renal, and cerebral organ pattern. GMAP-210 binds IFT20, which
    made a ciliary mechanism plausible, but cilia and ciliary IFT20 targeting were
    normal in ODCD patient fibroblasts.
  evidence:
  - reference: PMID:30728324
    reference_title: Hypomorphic mutations of TRIP11 cause odontochondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The same organs are affected in an overlapping condition known as
      cranioectodermal dysplasia, or Sensenbrenner syndrome
    explanation: Names the specific ciliopathy with which ODCD is most readily confused.
treatments:
- name: Supportive and Multidisciplinary Management
  description: >-
    No disease-modifying therapy exists. Management is supportive: respiratory
    support for the narrow thorax and pulmonary dysplasia in infancy, orthopaedic
    care for the limb and spinal deformity, renal surveillance for the late cystic
    disease, and neurosurgical assessment where hydrocephaly is present.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  therapeutic_modality: OTHER
  notes: >-
    Curated without an evidence item because no management study of ODCD has been
    published; the record states the absence of disease-specific therapy rather
    than asserting a supported intervention. The organ systems listed are those the
    case series documents as involved.
- name: Restorative Dental Care
  description: >-
    Dentinogenesis imperfecta requires early and continuing restorative dentistry to
    preserve the dentition. Two of the reporting centres in the founding series are
    dedicated rare oral and dental disease referral centres, which reflects how
    central the dental burden is to long-term care.
  treatment_term:
    preferred_term: Therapeutic Procedure
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
  therapeutic_modality: OTHER
  evidence:
  - reference: PMID:30728324
    reference_title: >-
      Hypomorphic mutations of TRIP11 cause odontochondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Odontochondrodysplasia (ODCD) is an unresolved genetic disorder of skeletal and dental development.
    explanation: >-
      Establishes the two organ systems management must address; no disease-modifying therapy is
      reported anywhere in this literature.
  - reference: PMID:40119123
    reference_title: Deciphering the phenotypic spectrum associated with MIA3-related odontochondrodysplasia.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Odontochondrodysplasia (ODCD) is a rare skeletal dysplasia characterized by
      short stature, skeletal deformities, and dentinogenesis imperfecta (DI).
    explanation: >-
      Establishes dentinogenesis imperfecta as a defining feature and therefore a
      standing care need; it does not evidence a specific dental protocol, hence
      INDIRECT.
- name: Genetic Counseling
  description: >-
    Recurrence risk is 25 percent, but the counselling problem is severity rather
    than recurrence: the same parental alleles have produced early-lethal
    achondrogenesis 1A in one child and surviving ODCD in a sibling, and no
    genotype-based prediction of outcome is currently possible.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  therapeutic_modality: OTHER
  evidence:
  - reference: PMID:30728324
    reference_title: Hypomorphic mutations of TRIP11 cause odontochondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thus, our results make the prediction of clinical outcome solely based on
      genotype difficult in genetic counselling and clinical care.
    explanation: >-
      The authors name genetic counselling as the setting in which the unpredictable
      genotype-phenotype relationship bites.
experimental_models:
- name: TRIP11-mutant patient fibroblast-derived chondrocytes
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: >-
    Primary dermal fibroblasts from ODCD and achondrogenesis 1A patients,
    transdifferentiated into mature chondrocytes on an aggrecan-coated surface and
    assessed for chondrogenic nodule number and size, matrix synthesis,
    proliferation, and viability against controls. This system carries the entire
    cellular mechanism for the disorder, since no viable animal model exists.
  cell_source: Patient-derived (skin biopsy)
  culture_system: Fibroblast transdifferentiation to chondrocytes on aggrecan-coated surface
  modeled_mechanisms:
  - target: Block in Hypertrophic Chondrocyte Differentiation
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Patient-derived chondrogenic cells reproduce the differentiation block and
      the matrix-synthesis defect, and separate them from any effect on cell number.
    limitations: >-
      Transdifferentiated dermal fibroblasts are not growth-plate chondrocytes, and
      the system cannot reproduce the spatial organisation of the growth plate in
      which the hypertrophic transition normally occurs. The histological comparison
      the authors draw on comes from achondrogenesis 1A fetuses rather than ODCD.
    readouts:
    - name: Chondrogenic nodule number and size
      target: Block in Hypertrophic Chondrocyte Differentiation
      direction: DECREASED
      interpretation: >-
        Fewer and smaller chondrogenic nodules index the failure of chondrogenic
        differentiation in TRIP11-mutant cells.
    - name: Cell proliferation and viability during chondrogenesis
      target: Block in Hypertrophic Chondrocyte Differentiation
      direction: UNCHANGED
      interpretation: >-
        Normal proliferation and viability establish that the reduced matrix output
        is a differentiation defect rather than a consequence of cell loss. A
        deliberate negative result.
      evidence:
      - reference: PMID:30728324
        reference_title: Hypomorphic mutations of TRIP11 cause odontochondrodysplasia.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          we found that proliferation was not impaired during chondrogenesis
        explanation: >-
          The negative control that rules out reduced cell number as the explanation
          for reduced matrix synthesis.
    evidence:
    - reference: PMID:30728324
      reference_title: Hypomorphic mutations of TRIP11 cause odontochondrodysplasia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        However, our functional studies in patient-derived primary cells clearly
        support a Golgi-based disease mechanism.
      explanation: >-
        The authors treat the patient-derived primary cell system as the decisive
        evidence for the mechanism, which is what makes this model informative for
        the node.
discussions:
- discussion_id: odcd_no_viable_animal_model
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Extraskeletal Golgi-Related Organ Disease
  prompt: >-
    Can the late-onset renal, cerebral, and pulmonary disease of ODCD be studied at
    all, given that every existing Trip11 knockout mouse dies perinatally?
  rationale: >-
    The available Trip11-knockout models are null models, and nulls in humans are
    embryonic-lethal, so the mouse reproduces achondrogenesis 1A rather than ODCD.
    The authors state that perinatal lethality in these models precludes recognition
    and analysis of later-onset phenotypes — which is exactly the class the
    extraskeletal features of ODCD fall into. The cystic renal disease in particular
    emerged only on longitudinal clinical follow-up, and there is no system in which
    to test whether it arises through impaired ciliary export of IFT20 or through
    the Golgi defect directly.
  evidence:
  - reference: PMID:30728324
    reference_title: Hypomorphic mutations of TRIP11 cause odontochondrodysplasia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These models all bear the disadvantage of perinatal lethality, precluding the
      recognition and analysis of later-onset phenotypes
    explanation: >-
      The authors name perinatal lethality of the existing models as the barrier to
      studying the later-onset organ disease.
  proposed_experiments:
  - experiment_id: exp_odcd_hypomorphic_knockin_model
    name: Hypomorphic Trip11 knock-in model reproducing the human splice allele
    description: >-
      Generate a knock-in mouse carrying the human exon-4-skipping allele rather
      than a null, so that residual GMAP protein permits postnatal survival, and
      follow the animals for renal cystic disease, hydrocephaly, and lung
      development. Compare against conditional Ift20 deletion to separate a ciliary
      from a Golgi route to the renal phenotype.
    would_support:
    - pathophysiology#Extraskeletal Golgi-Related Organ Disease
    supporting_outcome:
    - >-
      Postnatally viable hypomorphic animals developing cystic kidneys and
      hydrocephaly would establish that the extraskeletal disease is a direct
      consequence of reduced GMAP dose rather than of an unrelated modifier.
    would_refute:
    - pathophysiology#Reduced GMAP-210 Abundance at the cis-Golgi
    refuting_outcome:
    - >-
      Normal kidneys and ventricles in animals with the same residual GMAP dose that
      causes human disease would argue that the human extraskeletal features require
      something beyond the Golgi lesion.
- discussion_id: gap_odcd_null_alleles_mild_phenotype
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Why does a reported adult with two potentially null TRIP11 alleles have the
    mildest odontochondrodysplasia phenotype described, when the
    residual-activity model predicts the most severe?
  attaches_to:
  - pathophysiology#Aberrant TRIP11 Splicing with a Null Allele in Trans
  - pathophysiology#Block in Hypertrophic Chondrocyte Differentiation
  rationale: >-
    The whole genotype-severity account of the TRIP11 series rests on residual
    GMAP-210 activity: splice alleles leave some, nulls leave none, and that is
    offered as the reason patients have ODCD rather than achondrogenesis. One
    reported adult contradicts it directly. Either the alleles are not the nulls
    they appear to be - as already happened with the recurrent c.586C>T allele,
    which mRNA study showed produces an in-frame deletion - or something other
    than residual GMAP-210 abundance modifies severity. Resolving this would
    change how a TRIP11 genotype is counselled prenatally, which is the setting
    where the ODCD-versus-lethal distinction actually has to be made.
  evidence:
  - reference: PMID:33746040
    reference_title: >-
      Description of four patients with TRIP11 variants expand the clinical spectrum of odontochondroplasia (ODCD) and demonstrate the existence of common variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, adult patient 4 has two potentially null alleles and it remains unknown why she has very mild clinical features.
    explanation: >-
      The reported counterexample, with the authors' own statement that it is
      unexplained.
- discussion_id: odcd_splicing_penetrance_modifier
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - progression#Variable outcome from perinatal lethality to adult survival
  prompt: >-
    What determines the penetrance of TRIP11 mis-splicing between individuals, and
    could it be measured prenatally to predict outcome?
  rationale: >-
    Siblings carrying identical TRIP11 alleles have received radiographic diagnoses
    of achondrogenesis 1A and of ODCD respectively. The proposed explanation is that
    splicing of TRIP11 is cell-type dependent and incompletely penetrant, so
    residual GMAP protein settles at constitutively different levels in different
    individuals. Nothing is known about what sets that level. If it were measurable
    in accessible fetal or neonatal material it would convert an unanswerable
    counselling question into a quantitative one, which is why this gap has direct
    clinical weight rather than only mechanistic interest.
  evidence:
  - reference: PMID:30728324
    reference_title: Hypomorphic mutations of TRIP11 cause odontochondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A radiographic diagnosis of ACG1A and ODCD in different children originating
      from the same parents may be primarily due to variable penetrance
      ofTRIP11missplicing between individuals, resulting in constitutively different
      amounts of residual GMAP protein.
    explanation: >-
      States the variable-splicing-penetrance hypothesis for the intrafamilial
      severity difference, as a proposal rather than a demonstrated mechanism.
  proposed_experiments:
  - experiment_id: exp_odcd_residual_gmap_quantification
    name: Quantify residual GMAP protein against clinical severity across the allelic series
    description: >-
      Measure TRIP11 transcript isoform ratios and GMAP protein levels in matched
      accessible tissue from patients across the full severity range, and test
      whether residual protein level predicts radiographic severity independently of
      genotype.
    would_support:
    - pathophysiology#Reduced GMAP-210 Abundance at the cis-Golgi
    supporting_outcome:
    - >-
      A monotonic relationship between residual GMAP protein and severity across
      individuals sharing alleles would confirm protein dose as the operative
      variable and make it a candidate prognostic measurement.
    would_refute:
    - pathophysiology#Reduced GMAP-210 Abundance at the cis-Golgi
    refuting_outcome:
    - >-
      Comparable residual GMAP levels in siblings with lethal and surviving disease
      would move the explanation to a modifier outside TRIP11 altogether.
clinical_trials: []
datasets: []
notes: >-
  Curated as part of filling ISDS Nosology group 12 (Spondylometaphyseal
  dysplasias), which was unpopulated when this work began. ODCD is NOS 12-0020 in the 2023
  revision. TRIP11 appears twice in that nosology - here and, as achondrogenesis
  type 1A, in group 14 - so this entry is scoped to the non-lethal phenotype and
  the lethal null phenotype is recorded as a differential rather than as a
  subtype. Keyed on MONDO:0100325 (odontochondrodysplasia 1), the TRIP11-related
  entity, rather than the MONDO:0031169 parent - MONDO:0031010
  odontochondrodysplasia 2 is MIA3-related with hearing loss and diabetes and is
  a different disease that the 2023 nosology does not place in this row. The
  MIA3/TANGO1 form is deliberately left unclassified: it is not listed in the
  2023 nosology, and the schema's own guidance is that this classification is a
  transcription of an expert nosology and should not be extended to entities the
  committee did not list.

  This entry is the merge of two independently curated entries for
  MONDO:0100325 that reached the repository at the same time - one on main under
  this filename, and one on the ISDS group-12 branch as
  Odontochondrodysplasia_TRIP11-Related.yaml. The surviving file keeps main's
  name and filename and takes the branch entry's content, which was the fuller of
  the two, together with the null-allele counterexample gap and the
  PMID:33746040 and PMID:31903676 evidence that only main's entry carried. The
  superseded history records were moved into this slug directory with
  target.superseded_by blocks.
references:
- reference: PMID:36779427
  title: "Nosology of genetic skeletal disorders: 2023 revision."
  findings: []

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References & Deep Research

References

1

PMID:36779427

Nosology of genetic skeletal disorders: 2023 revision.

No top-level findings curated for this source.

Odontochondrodysplasia

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