Stickler syndrome type 6 (STL6) is the COL9A3-related, autosomal recessive form of Stickler syndrome. Type IX collagen is a heterotrimer of three genetically distinct chains -- alpha1, alpha2 and alpha3, encoded by COL9A1, COL9A2 and COL9A3 -- that decorates the surface of type II collagen fibrils in vitreous, cartilage and the cochlear extracellular matrix. Biallelic loss-of-function variants in COL9A3 remove the alpha3 chain, and the fibril-surface function of collagen IX is lost or degraded. Whether the loss is total is genuinely unsettled: mouse work shows that removing one chain abolishes the whole protein, but a review of the human recessive cases argues the milder-than-expected skeletal phenotype may mean the remaining two chains form a partly functional alternative heterotrimer. Both readings are recorded below. This separates STL6 mechanistically from the two common dominant forms. Types 1 and 2 arise from a single altered COL2A1 or COL11A1 allele acting through haploinsufficiency or a dominant-negative incorporated chain; STL6 is a recessive null state of a different, quantitatively minor collagen. The clinical consequence tracks that difference. High myopia with an abnormal, hypoplastic vitreous is near-universal, but sensorineural hearing loss is both more frequent and more severe than in the dominant forms -- moderate to severe and downsloping -- which is why the type IX collagen genes have been proposed for congenital hearing loss gene panels. Cleft palate, a familiar feature of the type II and type XI collagen forms, has not been reported with type IX collagen variants at all. Retinal detachment risk is the second point of divergence, and it matters clinically. Type 1 Stickler syndrome carries a lifetime detachment risk above 50%, much of it from giant retinal tears, which is what justifies prophylactic retinopexy in that group. In the largest type IX recessive series the detachments were fewer, unilateral, and secondary to horseshoe tears rather than giant retinal tears, so the prophylaxis argument does not transfer. COL9A3 is allelic across several disorders and the inheritance is not a clean recessive/dominant split: heterozygous variants cause multiple epiphyseal dysplasia type 3, contribute to sensorineural hearing loss and lumbar disc disease, and -- in two reported families -- cause dominant peripheral vitreoretinal degeneration with retinal detachment. A naturally occurring canine model exists, the Labrador retriever drd1 allele, an autosomal recessive COL9A3 frameshift producing short-limbed dwarfism with vitreous dysplasia and retinal detachment.
Ask a research question about Stickler Syndrome Type 6. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).
Do not include personal health information in your question. Questions and results are cached in your browser's local storage.
Conditions with similar clinical presentations that must be differentiated from Stickler Syndrome Type 6:
name: Stickler Syndrome Type 6
creation_date: "2026-09-07T21:45:00Z"
category: Mendelian
description: >
Stickler syndrome type 6 (STL6) is the COL9A3-related, autosomal recessive
form of Stickler syndrome. Type IX collagen is a heterotrimer of three
genetically distinct chains -- alpha1, alpha2 and alpha3, encoded by COL9A1,
COL9A2 and COL9A3 -- that decorates the surface of type II collagen fibrils
in vitreous, cartilage and the cochlear extracellular matrix. Biallelic
loss-of-function variants in COL9A3 remove the alpha3 chain, and the
fibril-surface function of collagen IX is lost or degraded. Whether the loss
is total is genuinely unsettled: mouse work shows that removing one chain
abolishes the whole protein, but a review of the human recessive cases argues
the milder-than-expected skeletal phenotype may mean the remaining two chains
form a partly functional alternative heterotrimer. Both readings are recorded
below.
This separates STL6 mechanistically from the two common dominant forms. Types
1 and 2 arise from a single altered COL2A1 or COL11A1 allele acting through
haploinsufficiency or a dominant-negative incorporated chain; STL6 is a
recessive null state of a different, quantitatively minor collagen. The
clinical consequence tracks that difference. High myopia with an abnormal,
hypoplastic vitreous is near-universal, but sensorineural hearing loss is
both more frequent and more severe than in the dominant forms -- moderate to
severe and downsloping -- which is why the type IX collagen genes have been
proposed for congenital hearing loss gene panels. Cleft palate, a familiar
feature of the type II and type XI collagen forms, has not been reported with
type IX collagen variants at all.
Retinal detachment risk is the second point of divergence, and it matters
clinically. Type 1 Stickler syndrome carries a lifetime detachment risk above
50%, much of it from giant retinal tears, which is what justifies prophylactic
retinopexy in that group. In the largest type IX recessive series the
detachments were fewer, unilateral, and secondary to horseshoe tears rather
than giant retinal tears, so the prophylaxis argument does not transfer.
COL9A3 is allelic across several disorders and the inheritance is not a clean
recessive/dominant split: heterozygous variants cause multiple epiphyseal
dysplasia type 3, contribute to sensorineural hearing loss and lumbar disc
disease, and -- in two reported families -- cause dominant peripheral
vitreoretinal degeneration with retinal detachment. A naturally occurring
canine model exists, the Labrador retriever drd1 allele, an autosomal
recessive COL9A3 frameshift producing short-limbed dwarfism with vitreous
dysplasia and retinal detachment.
disease_term:
preferred_term: Stickler syndrome, type 6
term:
id: MONDO:0031047
label: Stickler syndrome, type 6
synonyms:
- STL6
- Stickler syndrome, type VI
- COL9A3-related Stickler syndrome
- autosomal recessive Stickler syndrome, COL9A3-related
parents:
- Stickler Syndrome
references:
- reference: PMID:20301479
title: "Stickler Syndrome."
tags:
- GeneReviews
mappings:
mondo_mappings:
- term:
id: MONDO:0019354
label: Stickler syndrome
mapping_predicate: skos:broadMatch
mapping_source: MONDO:0031047
mapping_justification: >
The stub's MONDO context records Stickler syndrome as the sole parent of
MONDO:0031047. This entry curates the COL9A3-related type 6 subtype
specifically, so the mapping to the group term is broad. No OMIM or
Orphanet identifier is bound: the deep-research report offered both, but
the Orphanet one was flagged unverified and there is no cached record for
either, so binding them would be unverifiable.
inheritance:
- name: Autosomal recessive inheritance
description: >
STL6 requires biallelic COL9A3 loss-of-function variants; reported families
carry homozygous variants (frequently with parental consanguinity) or
compound heterozygous nonsense variants. For counselling, the recurrence
risk to a sib of an affected individual is the standard recessive 25%, with
a 50% chance of being an asymptomatic carrier; carrier testing for at-risk
relatives requires that the family's variants be identified first, after
which prenatal and preimplantation genetic testing are possible.
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
evidence:
- reference: PMID:20301479
reference_title: "Stickler Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Stickler syndrome caused by pathogenic variants in COL9A1, COL9A2, or COL9A3 is inherited in an autosomal recessive manner"
explanation: >
GeneReviews states the recessive inheritance of the type IX collagen
forms, of which the COL9A3-related type 6 curated here is one.
- reference: PMID:39406934
reference_title: "Retinal detachment in Type IX collagen recessive Stickler syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "6/11 families exhibited previously undescribed genetic variants, and 7 had consanguineous parents."
explanation: >
Parental consanguinity in a majority of families in the largest type IX
recessive series, consistent with recessive inheritance.
- reference: PMID:20301479
reference_title: "Stickler Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier"
explanation: >
The GeneReviews recurrence-risk figures used in counselling, quoted for
the autosomal recessive forms this entry belongs to.
prevalence:
- population: Worldwide, families reported in the literature
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >
Counted as reported families rather than an estimated rate. As of the 2022
Orphanet Journal of Rare Diseases report, four families with biallelic
COL9A3 variants had been described; that paper added three more. The 2024
NHS England Highly Specialised Stickler Syndrome Service series covers all
three type IX collagen genes together (13 patients from 11 families) and
does not break out COL9A3 separately, so no COL9A3-specific rate exists.
evidence:
- reference: PMID:35241111
reference_title: "Identification of three novel homozygous variants in COL9A3 causing autosomal recessive Stickler syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Autosomal recessive STL is ultra-rare with only four families with biallelic COL9A3 variants reported to date."
explanation: >
States both the ultra-rare classification and the reported-family count
that this record is based on.
pathophysiology:
- name: Biallelic COL9A3 Loss of Function
biological_scale: MOLECULAR
description: >
Both COL9A3 alleles carry loss-of-function variants -- reported as
homozygous frameshift or nonsense changes, often with parental
consanguinity, or as compound heterozygous nonsense changes. The alpha3(IX)
chain is therefore absent or truncated, rather than being made in an
altered form and incorporated into the protein.
molecular_functions:
- preferred_term: collagen binding
modifier: LOSS_OF_FUNCTION
term:
id: GO:0005518
label: collagen binding
downstream:
- target: Failure of Type IX Collagen Heterotrimer Assembly
causal_link_type: DIRECT
description: >
With no intact alpha3(IX) chain available, the heterotrimer has no third
constituent chain to recruit.
evidence:
- reference: PMID:24273071
reference_title: "Autosomal recessive Stickler syndrome due to a loss of function mutation in the COL9A3 gene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Type IX collagen is a heterotrimeric molecule formed by three genetically distinct chains: α1, α2, and α3 encoded by the COL9A1, COL9A2, and COL9A3 genes."
explanation: >
Establishes that the COL9A3 product is one of three obligate chains of
the heterotrimer, so its loss acts on trimer assembly.
evidence:
- reference: PMID:24273071
reference_title: "Autosomal recessive Stickler syndrome due to a loss of function mutation in the COL9A3 gene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "we describe the first autosomal recessive Stickler family due to loss of function mutations (c.1176_1198del, p.Gln393Cysfs*25) of COL9A3 gene"
explanation: >
The index report of COL9A3-related recessive Stickler syndrome, naming the
loss-of-function frameshift allele.
- name: Failure of Type IX Collagen Heterotrimer Assembly
biological_scale: MOLECULAR
description: >
Assembly of the collagen IX heterotrimer is disrupted. How completely is
contested, and this entry does not resolve it. The mouse evidence is that
collagen IX is obligately heterotrimeric: Col9a1 inactivation abolished all
collagen IX polypeptides even though Col9a2 and Col9a3 were transcribed
normally, which would make a COL9A3 null a collagen IX null. Against that, a
review of the human recessive cases notes that biallelic loss of any one
alpha chain gives a milder skeletal phenotype than expected, and proposes
that the remaining two chains may form an alternative heterotrimer retaining
part of the function. The refuting item is recorded on this node, and the
open question is carried as a HUMAN_MODEL_MISMATCH discussion.
cellular_components:
- preferred_term: collagen trimer
modifier: DECREASED
term:
id: GO:0005581
label: collagen trimer
downstream:
- target: Loss of Collagen IX from the Type II Fibril Surface
causal_link_type: DIRECT
description: >
Collagen IX reaches the fibril only as an assembled trimer, so failure of
assembly removes it from the fibril surface.
evidence:
- reference: PMID:9252382
reference_title: "Absence of the alpha1(IX) chain leads to a functional knock-out of the entire collagen IX protein in mice."
supports: SUPPORT
directness: INDIRECT
evidence_source: MODEL_ORGANISM
snippet: "the deficiency in alpha1(IX) chains leads to a functional knock-out of all polypeptides of collagen IX, whereas the Col9a2 and Col9a3 genes were normally transcribed"
explanation: >
Directly evidences this edge: losing one chain removes the whole protein
even when the other two genes are transcribed normally, which is the
step from assembly failure to absence of collagen IX. Shown for the
alpha1 chain in mouse, so the transfer to alpha3 in human is an
inference.
evidence:
- reference: PMID:9252382
reference_title: "Absence of the alpha1(IX) chain leads to a functional knock-out of the entire collagen IX protein in mice."
supports: SUPPORT
directness: INDIRECT
evidence_source: MODEL_ORGANISM
snippet: "synthesis of alpha1(IX) polypeptides is essential for the assembly of heterotrimeric collagen IX molecules"
explanation: >
Demonstrates the obligate-heterotrimer requirement, but for the alpha1(IX)
chain in mouse rather than the alpha3(IX) chain in human -- the inference
to COL9A3 is by the shared assembly requirement, hence INDIRECT.
- reference: PMID:35885918
reference_title: "Autosomal Recessive Stickler Syndrome."
supports: REFUTE
evidence_source: HUMAN_CLINICAL
snippet: "This may suggest that the remaining two α chains are able to form an alternative heterotrimer, which can fulfil some, but not all, of the functions of the normal heterotrimer."
explanation: >
Cuts against this node's stronger reading. Reviewing the human recessive
cases, the authors argue from the milder-than-expected skeletal phenotype
that losing one alpha chain may leave a partly functional alternative
trimer rather than no collagen IX at all. REFUTE because it contradicts
total assembly failure, which the mouse data supports.
- name: Loss of Collagen IX from the Type II Fibril Surface
biological_scale: MOLECULAR
description: >
Collagen IX is not a structural core of the fibril but a fibril-associated
(FACIT) collagen sitting on the surface of type II collagen fibrils, with a
long arm cross-linked to collagen II and a short arm projecting into the
perifibrillar space where it mediates interactions with other matrix
components. Its loss therefore does not prevent fibrils from forming; mouse
work found fibrils of normal shape and banding in collagen IX-deficient
cartilage. What is lost is long-term tissue stability -- which is why the
resulting disease is degenerative and progressive rather than a congenital
failure of matrix formation.
biological_processes:
- preferred_term: collagen fibril organization
modifier: DECREASED
term:
id: GO:0030199
label: collagen fibril organization
- preferred_term: extracellular matrix organization
modifier: DECREASED
term:
id: GO:0030198
label: extracellular matrix organization
cell_types:
- preferred_term: chondrocyte
term:
id: CL:0000138
label: chondrocyte
downstream:
- target: Vitreous Gel Hypoplasia and Disorganization
causal_link_type: DIRECT
evidence:
- reference: PMID:33633367
reference_title: "Heterozygous COL9A3 variants cause severe peripheral vitreoretinal degeneration and retinal detachment."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "both indicating the critical role of Type IX collagen in the vitreous base of the eye"
explanation: >
Evidences this specific edge -- that collagen IX loss acts on the
vitreous -- from human COL9A3 variants with vitreous pathology, rather
than from the general matrix argument.
- target: Cochlear Extracellular Matrix Instability
causal_link_type: DIRECT
evidence:
- reference: PMID:36140739
reference_title: "Hearing Loss in Stickler Syndrome: An Update."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "Hearing loss in the rarer types of Stickler syndrome depends on the gene expression in the cochlea"
explanation: >
Supports the cochlea as the site where the collagen defect acts, by
attributing the subtype-to-subtype severity gradient to cochlear
expression of the affected gene.
- target: Cartilage Matrix Long-Term Instability
causal_link_type: DIRECT
evidence:
- reference: PMID:9252382
reference_title: "Absence of the alpha1(IX) chain leads to a functional knock-out of the entire collagen IX protein in mice."
supports: SUPPORT
directness: INDIRECT
evidence_source: MODEL_ORGANISM
snippet: "Surprisingly, cartilage fibrils of all shapes and banding patterns found in normal newborn, adolescent, or adult mice were formed in transgenic animals, although they lacked collagen IX."
explanation: >
Evidences the particular form this edge takes -- fibrils still form
without collagen IX, so what the cartilage loses is durability rather
than assembly. Mouse Col9a1 data, hence indirect for human COL9A3.
evidence:
- reference: PMID:8197187
reference_title: "Mice lacking alpha 1 (IX) collagen develop noninflammatory degenerative joint disease."
supports: SUPPORT
directness: INDIRECT
evidence_source: MODEL_ORGANISM
snippet: "Type IX molecules are localized on the surface of type II-containing fibrils"
explanation: >
Establishes the fibril-surface localization that this node's claim rests
on. Stated for collagen IX generally in a mouse study, so the step to the
human COL9A3 null is an inference.
- reference: PMID:9252382
reference_title: "Absence of the alpha1(IX) chain leads to a functional knock-out of the entire collagen IX protein in mice."
supports: SUPPORT
directness: INDIRECT
evidence_source: MODEL_ORGANISM
snippet: "The protein is required, however, for long term tissue stability, presumably by mediating interactions between fibrillar and extrafibrillar macromolecules."
explanation: >
Supports the specific claim that the deficit is in long-term matrix
stability rather than in fibril formation, which is what makes the
downstream phenotypes degenerative.
- name: Vitreous Gel Hypoplasia and Disorganization
biological_scale: TISSUE
description: >
The vitreous is a collagen II-based gel in which collagen IX is a normal
surface constituent, and it is the tissue where the loss is most visible
clinically. Affected individuals have an abnormal, hypoplastic vitreous gel
with abnormal architecture, present from birth alongside congenital
megalophthalmos. This is the type IX counterpart of the membranous (type 1)
and beaded (type 2) vitreous phenotypes that separate the dominant forms.
locations:
- preferred_term: vitreous body
term:
id: UBERON:0001798
label: vitreous body
downstream:
- target: Abnormal Vitreous Gel
causal_link_type: DIRECT
- target: High Myopia
causal_link_type: DIRECT
- target: Vitreoretinal Interface Degeneration
causal_link_type: DIRECT
evidence:
- reference: PMID:33633367
reference_title: "Heterozygous COL9A3 variants cause severe peripheral vitreoretinal degeneration and retinal detachment."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "This report describes two families with autosomal dominant inheritance and predominant features of peripheral vitreoretinal lattice degeneration and retinal detachment."
explanation: >
Ties COL9A3 disruption specifically to peripheral vitreoretinal
degeneration in human eyes. These families are heterozygous rather than
biallelic, so the edge is evidenced by a different allele class than
this entry curates -- noted rather than glossed.
evidence:
- reference: PMID:31090205
reference_title: "Homozygous Type IX collagen variants (COL9A1, COL9A2, and COL9A3) causing recessive Stickler syndrome-Expanding the phenotype."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All patients were highly myopic with congenital megalophthalmos and abnormal, hypoplastic vitreous gel, and all had sensorineural hearing loss."
explanation: >
Reports the hypoplastic, abnormal vitreous gel in every affected
individual across four type IX collagen recessive Stickler pedigrees, one
of which carried COL9A3 variants.
- name: Cochlear Extracellular Matrix Instability
biological_scale: TISSUE
description: >
The substrate is the tectorial membrane, where type IX collagen helps
maintain the integrity of the collagen fibres. Murine work shows that losing
it produces progressive hearing loss from a young age together with
morphological change in the tectorial membrane, beginning in the basal turn
of the cochlea and advancing apically -- which matches the downsloping
audiometric shape seen in patients, since the basal turn encodes high
frequencies. Severity across Stickler subtypes tracks which collagen gene is
affected and how it is expressed in the cochlea, and the biallelic type IX
forms sit at the severe end.
locations:
- preferred_term: cochlea
term:
id: UBERON:0001844
label: cochlea
biological_processes:
- preferred_term: tectorial membrane collagen fibre organization
modifier: DECREASED
term:
id: GO:0030199
label: collagen fibril organization
downstream:
- target: Sensorineural Hearing Loss
causal_link_type: DIRECT
evidence:
- reference: PMID:36140739
reference_title: "Hearing Loss in Stickler Syndrome: An Update."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "moderate to severe downsloping hearing loss for Stickler syndrome caused by biallelic type IX collagen gene mutations"
explanation: >
Connects the biallelic type IX collagen defect to the specific
audiometric phenotype, which is the claim this edge makes.
evidence:
- reference: PMID:36140739
reference_title: "Hearing Loss in Stickler Syndrome: An Update."
supports: SUPPORT
directness: INDIRECT
evidence_source: MODEL_ORGANISM
snippet: "Murine studies confirmed the involvement of type IX collagen, in addition to type XI collagen, in maintaining the integrity of collagen fibers in the tectorial membrane"
explanation: >
Evidences this node's actual claim -- that type IX collagen maintains the
cochlear matrix -- rather than the hearing-loss outcome it causes. Murine,
so the step to human COL9A3 is an inference.
- reference: PMID:36140739
reference_title: "Hearing Loss in Stickler Syndrome: An Update."
supports: SUPPORT
directness: INDIRECT
evidence_source: MODEL_ORGANISM
snippet: "Knock-out mice showed progressive hearing loss, already apparent at young age, and morphological changes of the tectorial membrane, starting in the basal turn of the cochlea and progressing towards the apical turn"
explanation: >
Reports the structural change in the tectorial membrane alongside the
functional deficit, and the basal-to-apical progression that accounts for
the downsloping audiogram.
- name: Cartilage Matrix Long-Term Instability
biological_scale: TISSUE
description: >
In cartilage the same loss of fibril-surface collagen IX leaves the matrix
able to form but not to endure. The skeletal consequence is a mild
epiphyseal and spondyloepiphyseal dysplasia with early-onset degenerative
arthropathy, rather than a severe congenital chondrodysplasia. Bowing of
the long bones at birth has been reported in one family.
cell_types:
- preferred_term: chondrocyte
term:
id: CL:0000138
label: chondrocyte
downstream:
- target: Epiphyseal Dysplasia
causal_link_type: DIRECT
- target: Spondyloepiphyseal Dysplasia
causal_link_type: DIRECT
- target: Congenital Long Bone Bowing
causal_link_type: DIRECT
- target: Early-Onset Arthropathy
causal_link_type: DIRECT
evidence:
- reference: PMID:8197187
reference_title: "Mice lacking alpha 1 (IX) collagen develop noninflammatory degenerative joint disease."
supports: SUPPORT
directness: INDIRECT
evidence_source: MODEL_ORGANISM
snippet: "Homozygous mutant mice are viable and show no detectable abnormalities at birth but develop a severe degenerative joint disease resembling human osteoarthritis."
explanation: >
Evidences the cartilage-instability-to-arthropathy step in a collagen
IX-deficient animal. Indirect for this entry: a Col9a1 knockout in
mouse, not a COL9A3 null in human.
evidence:
- reference: PMID:8197187
reference_title: "Mice lacking alpha 1 (IX) collagen develop noninflammatory degenerative joint disease."
supports: SUPPORT
directness: INDIRECT
evidence_source: MODEL_ORGANISM
snippet: "Homozygous mutant mice are viable and show no detectable abnormalities at birth but develop a severe degenerative joint disease resembling human osteoarthritis."
explanation: >
The normal-at-birth, degenerative-later course in collagen IX-deficient
mice is the model-organism counterpart of the progressive human
arthropathy. Cited for the mechanism's shape, not for the human
phenotype, and it is a Col9a1 rather than Col9a3 knockout.
- name: Vitreoretinal Interface Degeneration
biological_scale: TISSUE
description: >
Degeneration at the vitreoretinal interface, most marked peripherally,
follows from the abnormal vitreous. It is the lesion that generates retinal
tears, and it is also the phenotype that heterozygous COL9A3 variants can
produce on their own in a dominant pattern. Named distinctly from the
phenotype it produces so the two do not collapse into one pathograph node.
downstream:
- target: Peripheral Vitreoretinal Degeneration
causal_link_type: DIRECT
- target: Rhegmatogenous Retinal Detachment
causal_link_type: DIRECT
description: >
In the type IX recessive cohort, detachments arose from horseshoe retinal
tears rather than the giant retinal tears characteristic of type 1.
evidence:
- reference: PMID:39406934
reference_title: "Retinal detachment in Type IX collagen recessive Stickler syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "15.4% of patients developed RD secondary to horseshoe retinal tears, with no cases of bilateral RD or giant retinal tears (GRTs)."
explanation: >
Names the tear mechanism linking peripheral degeneration to detachment
in this specific population, and its rate.
evidence:
- reference: PMID:33570243
reference_title: "Clinical and genetic characterization of autosomal recessive stickler syndrome caused by novel compound heterozygous mutations in the COL9A3 gene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The clinical features included severe sensorineural hearing loss, high myopia, vitreoretinal degeneration, and early-onset arthropathy of the lower limbs."
explanation: >
Records vitreoretinal degeneration in a molecularly confirmed compound
heterozygous COL9A3 case.
phenotypes:
- category: Ocular
name: High Myopia
description: >
Congenital high myopia with megalophthalmos. The two available figures
disagree because they measure different populations against different
thresholds: a review pooling type IX and type XI collagen patients calls it
near-universal, while the type IX-only series scored 77% against a defined
cut-off of worse than -6 dioptres. The band follows the narrower, type
IX-specific number.
frequency: FREQUENT
phenotype_term:
preferred_term: High myopia
term:
id: HP:0011003
label: High myopia
evidence:
- reference: PMID:35885918
reference_title: "Autosomal Recessive Stickler Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "High myopia is near-universal, and sensorineural hearing loss is very common in patients with variants in genes for type IX or XI collagen"
explanation: >
Review of 40 published recessive Stickler patients. It pools type IX with
type XI collagen cases, so it establishes that high myopia dominates the
recessive picture but does not on its own fix a type IX frequency band.
- reference: PMID:39406934
reference_title: "Retinal detachment in Type IX collagen recessive Stickler syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "High myopia (>−6): 10/13; 77%"
explanation: >
The type IX-specific figure, against an explicit dioptric threshold. This
is what the FREQUENT band rests on; it is lower than the pooled review's
"near-universal" because the population is narrower and the cut-off is
defined.
- category: Ocular
name: Abnormal Vitreous Gel
description: >
Hypoplastic vitreous gel with abnormal architecture, congenital.
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Abnormal vitreous humor morphology
term:
id: HP:0004327
label: Abnormal vitreous humor morphology
evidence:
- reference: PMID:31090205
reference_title: "Homozygous Type IX collagen variants (COL9A1, COL9A2, and COL9A3) causing recessive Stickler syndrome-Expanding the phenotype."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All patients were highly myopic with congenital megalophthalmos and abnormal, hypoplastic vitreous gel, and all had sensorineural hearing loss."
explanation: >
Reports the abnormal hypoplastic vitreous in all affected individuals in
the series.
- category: Ocular
name: Peripheral Vitreoretinal Degeneration
description: >
Degeneration at the peripheral vitreoretinal interface, the substrate for
retinal tear formation.
phenotype_term:
preferred_term: Peripheral vitreoretinal degeneration
term:
id: HP:0200071
label: Peripheral vitreoretinal degeneration
evidence:
- reference: PMID:33570243
reference_title: "Clinical and genetic characterization of autosomal recessive stickler syndrome caused by novel compound heterozygous mutations in the COL9A3 gene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The clinical features included severe sensorineural hearing loss, high myopia, vitreoretinal degeneration, and early-onset arthropathy of the lower limbs."
explanation: >
Vitreoretinal degeneration in a molecularly confirmed COL9A3 compound
heterozygous patient.
- category: Ocular
name: Rhegmatogenous Retinal Detachment
description: >
Retinal detachment secondary to horseshoe retinal tears. Unlike COL2A1
type 1 Stickler syndrome, the reported type IX recessive detachments were
unilateral and not caused by giant retinal tears, which is why the
prophylactic-retinopexy argument used in type 1 does not carry over.
frequency: OCCASIONAL
phenotype_term:
preferred_term: Retinal detachment
term:
id: HP:0000541
label: Retinal detachment
evidence:
- reference: PMID:39406934
reference_title: "Retinal detachment in Type IX collagen recessive Stickler syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "15.4% of patients developed RD secondary to horseshoe retinal tears, with no cases of bilateral RD or giant retinal tears (GRTs)."
explanation: >
Gives both the frequency underlying the OCCASIONAL band and the tear
mechanism distinguishing this from dominant Stickler syndrome. The rate is
from a pooled type IX collagen cohort of 13 rather than a COL9A3-only
series; both detachments in that cohort were in COL9A3 patients, so the
pooled rate may understate the COL9A3-specific risk.
- category: Ocular
name: Cataract
description: >
Lens opacity, described in Stickler syndrome as a quadrantic lamellar
cataract. No COL9A3-specific frequency exists, so no band is recorded.
phenotype_term:
preferred_term: Cataract
term:
id: HP:0000518
label: Cataract
evidence:
- reference: PMID:20301479
reference_title: "Stickler Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Stickler syndrome is a connective tissue disorder that can include ocular findings of myopia, cataract, and retinal detachment; hearing loss that is both conductive and sensorineural; midfacial underdevelopment and cleft palate (either alone or as part of the Pierre Robin sequence); and early-onset degenerative joint disease."
explanation: >
GeneReviews lists cataract among the three defining ocular findings of
Stickler syndrome. Pan-Stickler, so it establishes the finding without
fixing a type IX frequency.
- reference: PMID:39406934
reference_title: "Retinal detachment in Type IX collagen recessive Stickler syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Key ocular findings include congenital megalophthalmos, hypoplastic vitreous, paravascular lattice degeneration, quadrantic lamellar cataract and retinal detachment"
explanation: >
Names the specific lens phenotype among the key ocular findings in the
type IX collagen recessive series.
- category: Auditory
name: Sensorineural Hearing Loss
description: >
Moderate to severe downsloping sensorineural hearing loss, more frequent and
more severe than in the dominant forms of Stickler syndrome. It is often the
presenting feature, and is the basis for the recommendation that the type IX
collagen genes be included in congenital hearing loss gene panels.
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Sensorineural hearing impairment
term:
id: HP:0000407
label: Sensorineural hearing impairment
evidence:
- reference: PMID:39406934
reference_title: "Retinal detachment in Type IX collagen recessive Stickler syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Hearing loss was more prevalent (91.7%) than in dominant SS."
explanation: >
Gives the 91.7% frequency underlying the VERY_FREQUENT band, and the
comparison with dominant Stickler syndrome. The figure is from a pooled
COL9A1/COL9A2/COL9A3 cohort of 13, not a COL9A3-only series; within that
cohort the one COL9A3 patient with audiometry had normal hearing, so this
is a type IX collagen figure applied to the subtype, not measured in it.
- reference: PMID:31090205
reference_title: "Homozygous Type IX collagen variants (COL9A1, COL9A2, and COL9A3) causing recessive Stickler syndrome-Expanding the phenotype."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Sensorineural hearing loss is more common and severe in recessive SS."
explanation: >
Independent statement of the severity difference from the dominant forms.
- category: Craniofacial
name: Midface Hypoplasia
description: >
Midfacial underdevelopment, reported in a minority of type IX recessive
patients. Cleft palate, by contrast, has not been reported with type IX
collagen variants.
frequency: FREQUENT
phenotype_term:
preferred_term: Midface retrusion
term:
id: HP:0011800
label: Midface retrusion
evidence:
- reference: PMID:39406934
reference_title: "Retinal detachment in Type IX collagen recessive Stickler syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "No patients had cleft palate, and 30.8% had midfacial hypoplasia."
explanation: >
Gives the 30.8% frequency behind the FREQUENT band, and in the same
sentence records the absence of cleft palate in this cohort. Both figures
come from the pooled COL9A1/COL9A2/COL9A3 series of 13, not from a
COL9A3-only cohort.
- category: Craniofacial
name: Depressed Nasal Bridge and Anteverted Nares
description: >
Depressed nasal bridge with anteverted nares, reported alongside midface
hypoplasia. Variable between families rather than consistent: both affected
children of one reported family had these features, while another family is
explicitly described as lacking them. No frequency band is given for that
reason.
phenotype_term:
preferred_term: Depressed nasal bridge
term:
id: HP:0005280
label: Depressed nasal bridge
evidence:
- reference: PMID:35241111
reference_title: "Identification of three novel homozygous variants in COL9A3 causing autosomal recessive Stickler syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Both individuals II1 and II4 have pes planus, depressed nasal bridge and anteverted nares, with midface hypoplasia and downslanting palpebral fissures"
explanation: >
Family-specific observation in two affected siblings with confirmed
biallelic COL9A3 variants, not the paper's generic Stickler description.
- reference: PMID:35241111
reference_title: "Identification of three novel homozygous variants in COL9A3 causing autosomal recessive Stickler syndrome."
supports: REFUTE
evidence_source: HUMAN_CLINICAL
snippet: "craniofacial features such as midface hypoplasia, cleft palate, micrognathia, depressed nasal bridge and anteverted nares are absent"
explanation: >
The same paper records another family without these features. Recorded as
REFUTE against a general claim so the entry does not imply the finding is
consistent across COL9A3 patients.
- category: Skeletal
name: Epiphyseal Dysplasia
description: >
Abnormal epiphyses, reported radiographically as abnormal capital femoral
epiphyses with mild vertebral endplate irregularity.
phenotype_term:
preferred_term: Epiphyseal dysplasia
term:
id: HP:0002656
label: Epiphyseal dysplasia
evidence:
- reference: PMID:30450842
reference_title: "Autosomal recessive Stickler syndrome resulting from a COL9A3 mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Radiographs demonstrated abnormal capital femoral epiphyses and mild irregularities of the vertebral endplates."
explanation: >
Radiographic epiphyseal findings in the second reported COL9A3 recessive
Stickler family.
- category: Skeletal
name: Spondyloepiphyseal Dysplasia
description: >
Mild spondyloepiphyseal dysplasia on radiography.
phenotype_term:
preferred_term: Spondyloepiphyseal dysplasia
term:
id: HP:0002655
label: Spondyloepiphyseal dysplasia
evidence:
- reference: PMID:33570243
reference_title: "Clinical and genetic characterization of autosomal recessive stickler syndrome caused by novel compound heterozygous mutations in the COL9A3 gene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Radiography revealed mild spondyloepiphyseal dysplasia."
explanation: >
Radiographic spondyloepiphyseal dysplasia in a confirmed COL9A3 case.
- category: Skeletal
name: Early-Onset Arthropathy
description: >
Early-onset arthropathy, described in the lower limbs. Arthropathy is
variable in this population and was uncommon in the largest series, in which
the cohort was young -- so the banded frequency is likely an underestimate
of lifetime risk rather than a stable rate.
frequency: OCCASIONAL
phenotype_term:
preferred_term: Premature osteoarthritis
term:
id: HP:0003088
label: Premature osteoarthritis
evidence:
- reference: PMID:33570243
reference_title: "Clinical and genetic characterization of autosomal recessive stickler syndrome caused by novel compound heterozygous mutations in the COL9A3 gene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The clinical features included severe sensorineural hearing loss, high myopia, vitreoretinal degeneration, and early-onset arthropathy of the lower limbs."
explanation: >
Reports early-onset lower-limb arthropathy in a confirmed COL9A3 patient.
- reference: PMID:35885918
reference_title: "Autosomal Recessive Stickler Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Joint pain was a feature in 22.7% of patients"
explanation: >
The recessive-Stickler figure behind the OCCASIONAL band. Drawn from the
recessive cohort rather than the Stickler-wide series, whose joint-disease
rates reflect the dominant forms.
- reference: PMID:20301479
reference_title: "Stickler Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Stickler syndrome is a connective tissue disorder that can include ocular findings of myopia, cataract, and retinal detachment; hearing loss that is both conductive and sensorineural; midfacial underdevelopment and cleft palate (either alone or as part of the Pierre Robin sequence); and early-onset degenerative joint disease."
explanation: >
The GeneReviews Clinical Characteristics baseline for degenerative joint
disease in Stickler syndrome. Pan-Stickler rather than COL9A3-specific, so
it corroborates the finding's place in the syndrome rather than its
frequency in this subtype.
- category: Skeletal
name: Congenital Long Bone Bowing
description: >
Tibial and femoral bowing present at birth, reported in the second COL9A3
family. Not a consistent feature across reported cases.
phenotype_term:
preferred_term: Femoral bowing
term:
id: HP:0002980
label: Femoral bowing
evidence:
- reference: PMID:30450842
reference_title: "Autosomal recessive Stickler syndrome resulting from a COL9A3 mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "moderate to severe sensorineural hearing loss, high myopia, and both tibial and femoral bowing at birth"
explanation: >
Records congenital tibial and femoral bowing in a confirmed COL9A3
recessive Stickler patient.
genetic:
- name: COL9A3
notes: >
COL9A3 encodes the alpha3 chain of type IX collagen. Biallelic
loss-of-function variants cause Stickler syndrome type 6. The gene is
allelic across several distinct disorders, and the distinction is the kind
of allele rather than the gene: an in-frame dominant-negative allele gives
multiple epiphyseal dysplasia type 3, while a biallelic null gives this
entry's phenotype.
gene_term:
preferred_term: COL9A3
term:
id: hgnc:2219
label: COL9A3
relationship_type: CAUSATIVE
variants:
- name: c.1176_1198del (p.Gln393Cysfs*25)
description: >
Homozygous 23-bp deletion causing a frameshift and premature termination.
The index allele of COL9A3-related recessive Stickler syndrome.
clinical_significance: PATHOGENIC
evidence:
- reference: PMID:24273071
reference_title: "Autosomal recessive Stickler syndrome due to a loss of function mutation in the COL9A3 gene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "we describe the first autosomal recessive Stickler family due to loss of function mutations (c.1176_1198del, p.Gln393Cysfs*25) of COL9A3 gene"
explanation: >
Names the allele and its loss-of-function consequence in the index
family.
- name: c.268C>T (p.Arg90Ter)
description: >
Nonsense allele, reported in trans with c.1729C>T in a compound
heterozygous patient.
clinical_significance: PATHOGENIC
evidence:
- reference: PMID:33570243
reference_title: "Clinical and genetic characterization of autosomal recessive stickler syndrome caused by novel compound heterozygous mutations in the COL9A3 gene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "two undescribed mutations in the COL9A3 gene: c.268C>T (p.Arg90Ter) and c.1729C>T (p.Arg577Ter)"
explanation: >
Names both alleles of the compound heterozygous genotype.
- name: c.1729C>T (p.Arg577Ter)
description: >
Nonsense allele, reported in trans with c.268C>T.
clinical_significance: PATHOGENIC
evidence:
- reference: PMID:33570243
reference_title: "Clinical and genetic characterization of autosomal recessive stickler syndrome caused by novel compound heterozygous mutations in the COL9A3 gene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "two undescribed mutations in the COL9A3 gene: c.268C>T (p.Arg90Ter) and c.1729C>T (p.Arg577Ter)"
explanation: >
Names both alleles of the compound heterozygous genotype.
evidence:
- reference: PMID:24273071
reference_title: "Autosomal recessive Stickler syndrome due to a loss of function mutation in the COL9A3 gene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "we describe the first autosomal recessive Stickler family due to loss of function mutations (c.1176_1198del, p.Gln393Cysfs*25) of COL9A3 gene"
explanation: >
The index COL9A3 recessive Stickler family, establishing the gene-disease
relationship and naming the causal frameshift allele.
- reference: PMID:30450842
reference_title: "Autosomal recessive Stickler syndrome resulting from a COL9A3 mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We report the second case of autosomal recessive Stickler syndrome due to homozygosity for a loss of function mutation in COL9A3, which encodes the α3 chain of type IX procollagen."
explanation: >
Independent confirmation of the gene-disease relationship in a second
family, and states the gene product.
- reference: PMID:35241111
reference_title: "Identification of three novel homozygous variants in COL9A3 causing autosomal recessive Stickler syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here, we report three unrelated families clinically diagnosed with STL carrying different novel biallelic loss of function variants in COL9A3."
explanation: >
Three further unrelated families, consolidating biallelic COL9A3 loss of
function as the cause.
animal_models:
- name: Labrador retriever oculoskeletal dysplasia (drd1, COL9A3 frameshift)
species: Dog
genotype: COL9A3 1-base insertion in exon 1, homozygous (drd1 locus)
publication: PMID:20686772
description: >
A naturally occurring, autosomal recessive canine COL9A3 disorder combining
short-limbed dwarfism with vitreous dysplasia, retinal detachment and
cataract. It is the closest available animal counterpart of STL6: the same
gene, a comparable loss-of-function allele, the same recessive inheritance,
and both the ocular and skeletal arms of the human phenotype.
modeled_mechanisms:
- target: Biallelic COL9A3 Loss of Function
relationship: RECAPITULATES
fidelity: MODERATE
model_scale: ORGANISM
description: >
Homozygous frameshift in the same gene, arising spontaneously and
segregating as a recessive trait in the breed.
limitations: >
The canine skeletal phenotype is short-limbed dwarfism, which is more
severe than the mild epiphyseal dysplasia of human STL6, so the model
overstates the skeletal arm. Hearing was not assessed in this study, so
the model says nothing about the human disorder's most prominent feature.
evidence:
- reference: PMID:20686772
reference_title: "COL9A2 and COL9A3 mutations in canine autosomal recessive oculoskeletal dysplasia."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Positional candidate gene analysis then led to the identification of a 1-base insertional mutation in exon 1 of COL9A3 that cosegregates with drd1"
explanation: >
Establishes that the canine trait is caused by a COL9A3 frameshift,
which is what makes it a model of the human COL9A3 null state.
- target: Vitreous Gel Hypoplasia and Disorganization
relationship: PARTIALLY_RECAPITULATES
fidelity: MODERATE
model_scale: TISSUE
description: >
Affected dogs have vitreous dysplasia with retinal detachment and
cataract.
limitations: >
The canine vitreous lesion is reported as dysplasia with detachment and
cataract rather than the specific hypoplastic gel architecture described
in human patients, so the correspondence is at the level of "abnormal
vitreous" rather than a matched phenotype.
evidence:
- reference: PMID:20686772
reference_title: "COL9A2 and COL9A3 mutations in canine autosomal recessive oculoskeletal dysplasia."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "ocular defects including vitreous dysplasia, retinal detachment and cataracts"
explanation: >
Records the ocular phenotype of the affected dogs.
evidence:
- reference: PMID:20686772
reference_title: "COL9A2 and COL9A3 mutations in canine autosomal recessive oculoskeletal dysplasia."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Affected dogs exhibit short-limbed dwarfism and severe ocular defects."
explanation: >
Summarizes the model's phenotype, supporting its use as an informative
whole-organism model of COL9A3 loss.
- name: Col9a1-null mouse
species: Mouse
genotype: Col9a1 knockout, homozygous (both alpha1(IX) isoforms absent)
publication: PMID:8197187
description: >
A paralog knockout rather than a Col9a3 knockout. It earns its place because
of a specific result: losing the alpha1(IX) chain functionally removes the
entire collagen IX protein, since the heterotrimer cannot assemble without
it. The mouse is therefore a collagen IX-null animal, which is the state a
human COL9A3 null is also expected to produce.
modeled_mechanisms:
- target: Cartilage Matrix Long-Term Instability
relationship: PARTIALLY_RECAPITULATES
fidelity: LOW
model_scale: TISSUE
description: >
Normal at birth, then progressive non-inflammatory degenerative joint
disease resembling human osteoarthritis -- the temporal shape of the human
skeletal phenotype.
limitations: >
A different gene (Col9a1, not Col9a3) in a different species, so the
correspondence rests on the obligate-heterotrimer argument rather than on
matched genotypes. The mouse also shows no ocular or auditory phenotype
in this report, which are the dominant features of the human disorder.
divergences:
- divergence_type: SPECIES_MISMATCH
materiality: QUALIFYING
description: >
Mouse cartilage and joint loading differ from human, and the human
disorder's defining ocular and cochlear involvement is not reported
here at all.
- divergence_type: PROXY_QUANTITY
materiality: QUALIFYING
description: >
The model's perturbed quantity is the alpha1(IX) chain; the disease's
is the alpha3(IX) chain. They stand in for one another only through the
separate finding that either loss abolishes the assembled trimer.
evidence:
- reference: PMID:8197187
reference_title: "Mice lacking alpha 1 (IX) collagen develop noninflammatory degenerative joint disease."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Homozygous mutant mice are viable and show no detectable abnormalities at birth but develop a severe degenerative joint disease resembling human osteoarthritis."
explanation: >
Reports the normal-at-birth, degenerative-later course that this link
claims corresponds to the human cartilage phenotype.
evidence:
- reference: PMID:9252382
reference_title: "Absence of the alpha1(IX) chain leads to a functional knock-out of the entire collagen IX protein in mice."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "synthesis of alpha1(IX) polypeptides is essential for the assembly of heterotrimeric collagen IX molecules"
explanation: >
This is what licenses treating a Col9a1 knockout as a collagen IX-null
model relevant to a COL9A3 null, rather than as an unrelated paralog.
treatments:
- name: Refractive Correction
description: >
Correction of the high myopia with spectacles. Management is supportive
throughout; no disease-modifying therapy exists for any form of Stickler
syndrome.
therapeutic_modality: DEVICE
treatment_term:
preferred_term: correction of refractive error
term:
id: NCIT:C49236
label: Therapeutic Procedure
qualifiers:
- predicate:
preferred_term: medical device
term:
id: NCIT:C16830
label: Medical Device
value:
preferred_term: spectacles
term:
id: NCIT:C87148
label: Glasses
target_mechanisms:
- target: High Myopia
description: >
Addresses the refractive consequence of the enlarged, myopic globe. It
does not act on the vitreous lesion that produces it.
evidence:
- reference: PMID:20301479
reference_title: "Stickler Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "correction of refractive errors with spectacles"
explanation: >
GeneReviews management recommendation for the ocular refractive error.
- name: Audiologic Management
description: >
Standard treatment of sensorineural and conductive hearing loss, with
prompt treatment of otitis media and consideration of myringotomy tubes for
recurrent episodes. This carries more weight in STL6 than in the dominant
forms, because hearing loss is both more frequent and more severe here and
because these patients are frequently also visually impaired, so a dual
sensory deficit is the realistic outcome of leaving it untreated.
therapeutic_modality: OTHER
treatment_term:
preferred_term: management of hearing loss
term:
id: NCIT:C49236
label: Therapeutic Procedure
qualifiers:
- predicate:
preferred_term: medical device
term:
id: NCIT:C16830
label: Medical Device
value:
preferred_term: hearing aid
term:
id: NCIT:C183182
label: Hearing Aid
target_mechanisms:
- target: Sensorineural Hearing Loss
description: >
Amplification and middle-ear management address the hearing deficit; they
do not act on the cochlear matrix lesion causing it.
evidence:
- reference: PMID:20301479
reference_title: "Stickler Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "standard treatment of sensorineural and conductive hearing loss; prompt treatment of otitis media; consider myringotomy tubes for recurrent otitis media"
explanation: >
GeneReviews management recommendations for the auditory manifestations.
- reference: PMID:31090205
reference_title: "Homozygous Type IX collagen variants (COL9A1, COL9A2, and COL9A3) causing recessive Stickler syndrome-Expanding the phenotype."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "early diagnosis would have a high impact for children with potentially dual sensory impairment"
explanation: >
Supports the specific claim that the dual sensory risk is what raises the
stakes of audiologic management in the recessive forms.
- name: Retinal Detachment Surveillance and Case-by-Case Retinopexy
description: >
Annual vitreoretinal examination, education on the symptoms of retinal
detachment, and laser therapy where indicated. The important qualification
for STL6 is that routine prophylactic retinopexy is NOT recommended: the
practice in COL2A1 type 1 Stickler syndrome rests on a high rate of
bilateral giant-retinal-tear detachment, and the type IX recessive cohort
showed neither bilateral detachment nor giant retinal tears. Prophylaxis
should be offered case by case rather than by default.
therapeutic_modality: SURGERY
treatment_term:
preferred_term: retinal laser photocoagulation
term:
id: NCIT:C217424
label: Laser Photocoagulation
target_mechanisms:
- target: Rhegmatogenous Retinal Detachment
description: >
Retinopexy aims to pre-empt detachment by sealing the peripheral retina;
surveillance aims to catch it early.
evidence:
- reference: PMID:20301479
reference_title: "Stickler Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "laser therapy for prevention of retinal detachment"
explanation: >
GeneReviews management recommendation for detachment prevention across
Stickler syndrome.
- reference: PMID:39406934
reference_title: "Retinal detachment in Type IX collagen recessive Stickler syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Prophylactic retinopexy should only be offered case-by-case for fellow eyes of patients presenting with GRT detachments in their first eye."
explanation: >
The type IX-specific qualification, and the reason this treatment is
curated with a restriction rather than as a routine intervention.
- reference: PMID:20301479
reference_title: "Stickler Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Annual examination by a vitreoretinal specialist; audiologic evaluations annually"
explanation: >
The GeneReviews surveillance schedule. Surveillance carries more of the
burden in this subtype than in type 1, because the prophylactic option
that partly substitutes for it there does not transfer here.
- reference: PMID:42518710
reference_title: "Encircling Laser Prophylaxis for Retinal Detachment in Stickler Syndrome: The Impact on Visual Field."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "It is our purpose to address concerns regarding visual field loss as a barrier to optimal performance of encircling laser retinopexy as a prophylaxis for retinal detachment"
explanation: >
Establishes that the prophylaxis itself carries a visual-field cost, which
is the other half of the case-by-case judgement: the intervention is not
free, so a population with a lower detachment rate has a correspondingly
weaker indication. The series is Stickler syndrome generally, not type IX
recessive, hence INDIRECT.
- name: Avoidance of Contact Sports
description: >
GeneReviews lists contact sports and similar activities among the
circumstances to avoid in Stickler syndrome, because of the risk of
traumatic retinal detachment.
therapeutic_modality: BEHAVIORAL
treatment_term:
preferred_term: activity restriction
term:
id: NCIT:C15747
label: Supportive Care
target_mechanisms:
- target: Rhegmatogenous Retinal Detachment
description: >
Removes a precipitant of traumatic detachment in an eye already
predisposed by peripheral vitreoretinal degeneration.
evidence:
- reference: PMID:20301479
reference_title: "Stickler Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Activities such as contact sports that may lead to traumatic retinal detachment."
explanation: >
The GeneReviews "Agents/circumstances to avoid" recommendation.
- name: Orthopaedic and Symptomatic Joint Management
description: >
Symptomatic treatment of the arthropathy and orthopaedic management of the
skeletal manifestations -- the epiphyseal and spondyloepiphyseal dysplasia,
the arthropathy, and congenital long-bone bowing. Management is symptomatic;
nothing modifies the underlying collagen defect.
therapeutic_modality: OTHER
treatment_term:
preferred_term: symptomatic and orthopaedic management of arthropathy
term:
id: NCIT:C15747
label: Supportive Care
target_mechanisms:
- target: Early-Onset Arthropathy
description: >
Addresses joint symptoms directly.
- target: Epiphyseal Dysplasia
description: >
Orthopaedic assessment and management of the skeletal manifestations.
evidence:
- reference: PMID:20301479
reference_title: "Stickler Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "symptomatic treatment for arthropathy; treatment of osteoarticular manifestations per orthopedist"
explanation: >
The GeneReviews management recommendation for the joint and skeletal
manifestations of Stickler syndrome.
clinical_trials:
- name: NCT07146516
phase: NOT_APPLICABLE
status: RECRUITING
description: >
Prospective, historically controlled study of ora secunda cerclage laser
retinopexy (OSC/SS) to prevent retinal detachment in Stickler syndrome.
Scoped to Stickler syndrome generally rather than to COL9A3, so it bears on
this entry only through the prophylaxis question -- which for the type IX
recessive forms is precisely the open one, given their lower detachment rate
and absence of giant retinal tears.
target_phenotypes:
- preferred_term: Retinal detachment
term:
id: HP:0000541
label: Retinal detachment
evidence:
- reference: clinicaltrials:NCT07146516
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The goal of this clinical trial is to prospectively document to what extent the OSC/SS prophylactic laser retinopexy procedure works to prevent retinal detachment in SS in children and adults."
explanation: >
Establishes the trial's objective, which is the prophylaxis question this
entry's retinopexy treatment records as unsettled for type IX recessive
disease.
diagnosis:
- name: COL9A3 Molecular Genetic Testing
description: >
Diagnosis rests on identifying biallelic pathogenic COL9A3 variants.
Because hearing loss is often the presenting feature and is more severe
than in the dominant forms, the type IX collagen genes have been proposed
for inclusion in congenital hearing loss gene panels -- which is how several
reported cases were actually ascertained.
evidence:
- reference: PMID:20301479
reference_title: "Stickler Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "biallelic pathogenic variants in COL9A1, COL9A2, or COL9A3 identified by molecular genetic testing"
explanation: >
GeneReviews diagnostic criterion for the recessive type IX collagen forms.
- reference: PMID:31090205
reference_title: "Homozygous Type IX collagen variants (COL9A1, COL9A2, and COL9A3) causing recessive Stickler syndrome-Expanding the phenotype."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We suggest that COL9A1, COL9A2, and COL9A3 be added to genetic screening panels for patients with congenital hearing loss."
explanation: >
Supports the ascertainment-route claim about congenital hearing loss
panels.
- reference: PMID:41856555
reference_title: "Diagnostic genetic testing indications and findings in type II, IX and XI collagenopathies."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A retrospective review was undertaken of genetic tests including genes COL2A1, COL11A1, COL11A2, COL9A1, COL9A2 and COL9A3 from a clinical diagnostic laboratory."
explanation: >
Confirms that COL9A3 is carried on the commercial collagenopathy panels
through which this diagnosis is made in practice.
differential_diagnoses:
- name: Stickler Syndrome Type 1
description: >
The commonest form, COL2A1-related and autosomal dominant. Separated from
type 6 by inheritance, by a much higher retinal detachment risk driven by
giant retinal tears, and by the presence of cleft palate.
distinguishing_features:
- Autosomal dominant COL2A1 haploinsufficiency rather than biallelic COL9A3 loss
- Lifetime retinal detachment risk above 50%, much of it from giant retinal tears
- Cleft palate is common, whereas it is unreported with type IX collagen variants
- Hearing loss in about half of patients, versus 91.7% in the type IX recessive cohort
evidence:
- reference: PMID:35885918
reference_title: "Autosomal Recessive Stickler Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Cleft palate is associated with type XI collagen variants, as well as the non-collagen genes, but is so far unreported with type IX collagen variants."
explanation: >
The palate finding is the single cleanest clinical discriminator between
the type IX recessive forms and the dominant type II/XI forms.
- name: COL9A1- and COL9A2-related recessive Stickler syndrome (types 4 and 5)
description: >
The sibling recessive type IX collagen forms. These are the hardest
differential, because they are not reliably distinguishable on phenotype at
all -- the literature analyses the three together and the largest series
pools them. The distinction is molecular.
distinguishing_features:
- Biallelic COL9A1 (type 4) or COL9A2 (type 5) rather than COL9A3
- No phenotypic discriminator has been established; separation is by gene panel or sequencing
evidence:
- reference: PMID:35885918
reference_title: "Autosomal Recessive Stickler Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Most commonly affected are the three genes for type IX collagen, COL9A1, COL9A2 and COL9A3"
explanation: >
Groups the three type IX genes as the common cause of recessive Stickler
syndrome, which is why they are treated together clinically and why the
differential is molecular rather than phenotypic.
discussions:
- discussion_id: collagen_ix_residual_trimer
kind: HUMAN_MODEL_MISMATCH
status: OPEN
attaches_to:
- pathophysiology#Failure of Type IX Collagen Heterotrimer Assembly
prompt: >
Does biallelic COL9A3 loss abolish collagen IX in human tissue, as the mouse
Col9a1 knockout implies, or do the remaining alpha1 and alpha2 chains form
an alternative heterotrimer that retains part of the function?
rationale: >
This entry's upstream mechanism is built on mouse data showing that removing
one alpha chain functionally removes the whole protein. The translational
step is doubly indirect: a different species and a different one of the three
chains. A review of the human recessive cases argues the other way, reasoning
that the skeletal phenotype of biallelic type IX collagen loss is milder than
a true null should give, and proposing a partly functional residual trimer.
The distinction is not academic. A true null predicts that COL9A1, COL9A2 and
COL9A3 recessive disease should be equivalent, which is the assumption that
licenses this entry's use of pooled type IX cohort statistics; a residual
trimer predicts chain-specific differences, and would mean those pooled
figures are averaging over genuinely different diseases.
notes: >
Resolving this needs human COL9A3-null tissue or cells, which no cited study
reports. Recorded as HUMAN_MODEL_MISMATCH rather than KNOWLEDGE_GAP because
the model evidence exists and is clear; what is uncertain is whether it
transfers.
evidence:
- reference: PMID:35885918
reference_title: "Autosomal Recessive Stickler Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "biallelic loss of any one of the α chains for type IX collagen results in the milder skeletal SS phenotype"
explanation: >
The human observation that motivates the mismatch -- the phenotype is
milder than the mouse-derived null model predicts.
- reference: PMID:9252382
reference_title: "Absence of the alpha1(IX) chain leads to a functional knock-out of the entire collagen IX protein in mice."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "synthesis of alpha1(IX) polypeptides is essential for the assembly of heterotrimeric collagen IX molecules"
explanation: >
The model-system finding whose transfer to human COL9A3 is the open
question.
notes: >
Scope. This entry covers the biallelic COL9A3 disorder that MONDO calls
Stickler syndrome, type 6. The sibling recessive type IX forms -- COL9A1
(type 4) and COL9A2 (type 5) -- are not curated. That is a real limitation of
this entry rather than a claim of distinctness: the literature reports the
three as clinically indistinguishable and generally analyses them together,
and the largest series pools all three. Several evidence items here are
therefore drawn from type IX collagen cohorts rather than COL9A3-only cohorts,
and are marked as such in their explanations. If the sibling types are curated
later, a grouping over the three would be the natural home for the pooled
cohort data.
Absence of cleft palate. Cleft palate is a familiar feature of Stickler
syndrome and is genuinely absent here. It is recorded in the description and
in the Midface Hypoplasia evidence rather than as a phenotype entry, because
the schema has no way to assert a phenotype's absence and inventing a
zero-frequency phenotype row would misrepresent it. The two sources are
PMID:35885918 ("so far unreported with type IX collagen variants") and
PMID:39406934 ("No patients had cleft palate").
COL9A3 heterozygotes are not uniformly unaffected. The recessive/dominant
split implied by the type-numbered nosology is not clean for this gene.
Heterozygous COL9A3 alleles cause multiple epiphyseal dysplasia type 3
(PMID:10090888, an in-frame exon-3 skip in the COL3 domain), contribute to
lumbar disc disease risk (PMID:11308397), and in two families caused dominant
peripheral vitreoretinal degeneration with retinal detachment (PMID:33633367)
-- a phenotype overlapping the ocular arm of this entry. The mechanistic
reading that reconciles this is allele class rather than dose: an in-frame
altered chain is incorporated and acts dominant-negatively, whereas a null
allele is silent in the heterozygote and only manifests when both copies are
lost. This is better supported than "curator's inference" -- PMID:35885918
says of those dominant COL9A3 families that the phenotype may represent a
dominant negative effect on the heterotrimer, and PMID:33633367's own cDNA
work shows they carry an in-frame COL2-domain deletion and a COL3-domain
missense, exactly the incorporated-chain allele class the reading requires. It
is recorded here rather than as a pathophysiology node because it concerns
alleles this entry does not curate.
Intellectual disability is deliberately not curated, and this has been
checked rather than overlooked. PMID:36140739 lists "mild intellectual
disability" for STL6, which looks like a phenotype gap. The primary sources
contradict it: PMID:30450842 records that the original authors "suggested was
unrelated to the COL9A3 mutations", and PMID:35241111 states "None of the
individuals showed signs of intellectual disability." The review appears to
propagate an incidental finding from one case. Recorded here so the next
curator does not re-litigate it.
Deliberate omissions. GeneReviews (PMID:20301479) is mined here for
diagnosis, management, genetic counselling and two Clinical Characteristics
items (degenerative joint disease, cataract), but not exhaustively: its
characteristics are pan-Stickler and dominated by the COL2A1 form, so
importing them wholesale would import dominant-form claims -- cleft palate
above all, which is precisely what this subtype lacks. Midface Hypoplasia and
Cataract are left with no upstream pathophysiology node because no cited
source offers a mechanism for either in this disorder; both phenotypes are
real and evidenced, the mechanisms are not known, and inventing nodes to
connect them would be worse than the gap. Every other phenotype is reached
from the causal chain.
Prevalence. No rate estimate exists for COL9A3 specifically. The prevalence
record therefore uses CASES_IN_LITERATURE with a reported-family count rather
than converting a Stickler-wide figure, which would be wrong by orders of
magnitude for this ultra-rare subtype.
Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.
Address pre-PR self-review findings: Stickler_Syndrome_Type_6 · 2026-09-07T22:27:39Z · View source
Second session on the same entry, addressing an adversarial pre-PR review run before any PR was opened. All 14 findings were acted on. The substantive one: the entry's upstream mechanism asserted that losing the alpha3 chain abolishes the collagen IX heterotrimer outright, resting on mouse Col9a1 data (PMID:9252382). PMID:35885918 -- a paper this entry already cited -- argues the opposite in its full text, reasoning from the milder-than-expected skeletal phenotype that the remaining two alpha chains may form a partly functional alternative heterotrimer. The entry now records that as a REFUTE evidence item on the assembly node, softens the node description and the top-level description to present both readings, and carries the unresolved question as a discussions entry with kind HUMAN_MODEL_MISMATCH (evidence exists in a model; translational validity is the open question). This matters beyond the one node: a true null predicts the three type IX genes give equivalent disease, which is the assumption licensing this entry's use of pooled type IX cohort statistics. Also corrected a claim in notes that the allele-class reading (in-frame incorporated chain acts dominant-negatively; null allele is recessive) was the curator's inference alone. PMID:35885918 states it, and PMID:33633367's cDNA work shows the dominant families carry exactly that allele class. The note now cites both instead of disclaiming support it has. Other changes: added the missing Cataract phenotype (HP:0000518, no frequency band since no COL9A3 number exists); mined GeneReviews Clinical Characteristics, which had been used only for management and diagnosis; downgraded High Myopia from VERY_FREQUENT to FREQUENT and recorded the counter-figure, because the VERY_FREQUENT band rested on a pooled type IX + type XI review calling it near-universal while the type IX-only series scored 77% against a defined -6D threshold; added the pooled-cohort caveat to the three explanations carrying 91.7%, 15.4% and 30.8%, all from a 13-patient COL9A1/COL9A2/COL9A3 series rather than a COL9A3-only cohort, noting that the single COL9A3 patient with audiometry had normal hearing while both detachments in that cohort were COL9A3; connected four orphan phenotypes to the causal chain; renamed the pathophysiology node 'Peripheral Vitreoretinal Degeneration' to 'Vitreoretinal Interface Degeneration' so it no longer collides with the phenotype of that name and collapses into one pathograph node; added directness INDIRECT to the two PMID:33633367 items, which evidence a biallelic entry from heterozygous families; rebound the retinopexy treatment from the generic NCIT:C15329 to NCIT:C217424 Laser Photocoagulation; applied the CLAUDE.md device carve-out, attaching NCIT:C87148 Glasses and NCIT:C183182 Hearing Aid as NCIT:C16830 qualifier values rather than losing the device concept, and changed Audiologic Management from therapeutic_modality DEVICE to OTHER since it bundles amplification, otitis media treatment and myringotomy; added mappings, differential_diagnoses (including the honest entry that COL9A1/COL9A2 recessive Stickler is not phenotypically separable from this one) and three curated Genetic.variants; cited PMID:42518710 for the visual-field cost of encircling prophylaxis, which is the other half of the case-by-case judgement. Two review suggestions were quoted slightly inexactly and were corrected against the cache rather than copied: the PMID:35885918 dominant-negative sentence needed its trailing citation marker excluded, and the cataract and joint-disease snippets were sub-propositional fragments that failed check-snippet-length, so both were extended to the full sentences. Prose overreach flagged in the review ('presents at least as often through the ear as through the eye') had already been removed before the first commit. Not done: no OMIM or Orphanet identifier was bound in mappings. The deep-research report offered both, but flagged the Orphanet one unverified and neither has a cached record, so binding them would be unverifiable; the mappings block says so. Validation after the changes: just validate, validate-terms, check-entity-refs, check-causal-targets, check-duplicate-keys, check-qualifier-terms, check-qualifier-terms-online (resolving the one uncached NCIT device CURIE), check-enum-values all pass; 61/61 snippets verified exact; the batched just validate-disorders gate passes; check-folded-hyphens, check-snippet-length, check-title-snippets and check-snippet-grading all clean with no new baseline rows. Compliance 92.0% weighted. The pathograph is now 7 nodes and 15 edges with no orphan nodes, no unresolved targets and no name collisions; Cataract and Midface Hypoplasia remain deliberately unconnected because no cited source gives a mechanism, and notes records that.
Create: Stickler_Syndrome_Type_6 · 2026-09-07T22:02:50Z · View source
Created kb/disorders/Stickler_Syndrome_Type_6.yaml for the COL9A3-related autosomal recessive form of Stickler syndrome (MONDO:0031047), claimed via issue #11396. Deep research: requested falcon, which is not configured in this environment (no EDISON_API_KEY). Rather than substituting a provider by hand, the run used the recipe's own fallback mechanism (dr_fallback='--fallback'), which fell back to claude_code and recorded fell_back/requested_provider/provider_attempts in the report frontmatter. Report used: research/Stickler_Syndrome_Type_6-deep-research-claude_code.md. Its reference validation was clean (15/15 verified, confabulation_rate 0.0), but its term validation was not: 11 of 28 CURIE labels mismatched, including UBERON:0003889 offered as 'vitreous body' (actually fallopian tube) and UBERON:0000362 as 'cochlea' (actually renal medulla). No CURIE from the report was bound. Every ontology term in this entry was independently looked up via the EBI OLS API or taken from the committed term caches, and all pass just validate-terms. The report did contribute four mechanistic references that the PubMed sweep had not surfaced and that carry the core of the mechanism: PMID:9252382 (obligate heterotrimer assembly), PMID:8197187 (Col9a1-null mouse), PMID:10090888 (COL9A3 as third MED locus), PMID:11308397 (lumbar disc disease risk allele). GeneReviews baseline: PMID:20301479 (Stickler Syndrome) fetched, cached and tagged GeneReviews in the top-level references block. Its Clinical Characteristics were cross-referenced against the phenotypes section; the Agents/circumstances to avoid warning (contact sports, traumatic retinal detachment) is captured as a treatment entry with the GeneReviews quote. Curation decisions worth flagging for review: - entry_type DISEASE rather than SUBTYPE. Stickler_Syndrome_Type_1 and Stickler_Syndrome_Type_2 are already standalone entries, so one entry per numbered Stickler type is the existing KB convention, and the stub records a single MONDO parent with no descendants. - Cleft palate is recorded as absent in the description, notes and the Midface Hypoplasia evidence rather than as a zero-frequency phenotype row, since the schema cannot assert a phenotype's absence. - The sibling recessive type IX forms (COL9A1 type 4, COL9A2 type 5) are not curated, and the literature analyses the three together. Several evidence items therefore come from pooled type IX cohorts and say so in their explanations; this limitation is stated explicitly in notes. - Two animal models: the naturally occurring Labrador retriever drd1 COL9A3 frameshift (same gene, recessive, ocular + skeletal) and the Col9a1-null mouse, which is a paralog knockout justified by PMID:9252382 showing that losing any one chain functionally removes the whole protein. The mouse link carries typed divergences (SPECIES_MISMATCH, PROXY_QUANTITY) recording that the perturbed chain is not the disease's chain. - 2 of 11 causal edges are left without their own evidence rather than reusing node citations for edges no source states. Validation run on this tree: just validate (pass), just validate-terms (pass), just check-entity-refs (pass), just check-causal-targets (pass, no new dangling), just check-duplicate-keys (pass), just check-qualifier-terms (pass), just check-enum-values (pass), just count-verified-snippets (47/47), just validate-disorders (pass, the batched gate CI runs), and check-folded-hyphens / check-snippet-length / check-title-snippets / check-snippet-grading (all clean, no new baseline entries). just compliance reports 93.3% weighted. just discover-datasets found no GEO candidates, which is expected for an ultra-rare disorder, so no datasets block was added.
Overview. Stickler syndrome type VI (STL6) is an ultra-rare, autosomal recessive connective tissue disorder caused by biallelic (homozygous or compound heterozygous) loss-of-function variants in COL9A3, which encodes the α3 chain of type IX collagen. It belongs to the broader Stickler syndrome spectrum — a group of hereditary collagenopathies affecting the eye, ear, face, and joints — but is genetically and phenotypically distinct from the far more common autosomal dominant forms (Stickler type I–III, due to COL2A1, COL11A1, COL11A2). STL6 is one of three "type IX collagen" recessive subtypes (STL4/COL9A1, STL5/COL9A2, STL6/COL9A3), which are clinically similar to one another and are collectively often discussed together in the literature as "type IX collagen–related (recessive) Stickler syndrome."
Key identifiers:
| Resource | Identifier |
|---|---|
| OMIM phenotype | #620022 — STICKLER SYNDROME, TYPE VI (STL6) |
| OMIM gene | *120270 — COLLAGEN, TYPE IX, ALPHA-3 (COL9A3); HGNC:2219 |
| Orphanet | ORPHA:250984 (per search results; verify against current Orphadata export) |
| MONDO | MONDO:0031047 (as supplied — cross-reference not independently confirmed via OLS/Monarch due to a network access limitation during this research session; recommend confirming via just fetch-reference / OAK before curation) |
| Locus | 20q13.33 |
| Gene family | FACIT collagen (Fibril-Associated Collagens with Interrupted Triple helices) |
Synonyms: Stickler syndrome, type VI; STL6; autosomal recessive Stickler syndrome, COL9A3-related; hereditary arthro-ophthalmopathy (generic Stickler syndrome synonym, not type-specific).
Evidence base: Information is derived almost entirely from aggregated case reports/case series and one larger multi-family cohort study — not EHR-scale or population registries, given the rarity of the recessive, COL9A3-specific subtype (fewer than 10 published families as of 2022; a 2024 combined COL9A1/2/3 cohort added 13 patients from 11 families) (Rad et al. 2022, PMC8892745/PMID:35241111; cohort study PMID:39406934).
Disease causal factor: STL6 is caused exclusively by biallelic loss-of-function (LOF) variants in COL9A3 (nonsense, frameshift, canonical splice-site, or whole-exon-skipping variants), resulting in absence of a functional α3(IX) collagen chain and, because type IX collagen is an obligate heterotrimer, functional loss of the entire collagen IX molecule.
"Pathogenic variants in COL9A1, COL9A2, and COL9A3 associated with Stickler syndrome are biallelic and have a loss-of-function effect, resulting in complete absence of the protein." (GeneReviews, NBK1302)
Genetic risk factors: - Biallelic COL9A3 pathogenic variants (homozygous or compound heterozygous) — causal, not merely a risk factor. - Reported variants include: c.107_116del p.(Pro36Argfs*49); c.1204C>T p.(Arg402*); c.355delC p.(Leu119Serfs*9) (Rad et al. 2022, PMC8892745); the original loss-of-function report (Faletra et al. 2014, PMID:24273071); and a subsequent case (Hanson-Kahn et al. 2018, PMID:30450842). - Consanguinity is a major risk-enabling factor: in the 2024 cohort of 13 patients from 11 families with type IX collagen–related recessive Stickler syndrome, 53.8% had consanguineous parents (PMID:39406934) — consistent with rare autosomal recessive disease enrichment in consanguineous unions. - Founder/heterozygous allelic variants at the same locus increase risk for related but distinct phenotypes, not STL6 itself: the COL9A3 "Trp3" allele (c.307C>T, p.Arg103Trp) is a common missense polymorphism (not the biallelic LOF mechanism of STL6) associated with ~3-fold increased risk of lumbar intervertebral disc disease in heterozygous carriers (Paassilta et al. 2001, JAMA, PMID:11308397: found in 12.2% of lumbar disc disease cases vs. 4.7% of controls). Separately, heterozygous COL9A3 splice-site/missense variants cause multiple epiphyseal dysplasia type 3 (EDM3/MED3, OMIM #600969) via a dominant-negative mechanism (Paassilta et al. 1999/2000-era reports; PMID:10090888 "COL9A3: A third locus for multiple epiphyseal dysplasia").
Environmental risk factors: None identified specific to this Mendelian recessive collagenopathy; no gene-environment interaction data were located.
Protective factors: None reported in the literature; this is a fully penetrant Mendelian LOF disorder once biallelic, so no protective allele has been described.
Gene-environment interactions: Not established/not applicable for this monogenic disorder.
Phenotype frequency data below are pooled from the two principal case series of type IX collagen–related recessive Stickler syndrome (Rad et al. 2022, n=~7 COL9A3 patients across 3 families plus literature review to 4 families; and the larger combined COL9A1/2/3 cohort, PMID:39406934, n=13/11 families). Because COL9A3-specific numbers are drawn from very small samples, frequencies for the combined "type IX collagen" group are given where COL9A3-only figures were not separately reported — this is an important caveat for curation.
| Phenotype | Type | Frequency (type IX collagen recessive Stickler, pooled) | Onset | HPO term (to verify) |
|---|---|---|---|---|
| Sensorineural hearing loss (moderate–severe/profound, downsloping high-frequency-predominant) | Clinical sign / audiometric | 91.7–100% (near-universal; "all patients with variants... had sensorineural hearing loss" per GeneReviews) | Early childhood, sometimes present but missed on newborn screening; progressive | HP:0000407 (Sensorineural hearing loss) |
| High myopia (>−6D) | Clinical sign | 77–100% | Congenital/early childhood, non-progressive refractive component but vitreous disease progresses | HP:0011003 (High myopia) / HP:0000545 (Myopia) |
| Vitreous anomaly (hypoplastic/"optically empty" vitreous, membranous or beaded) | Clinical/imaging sign | 92.3% | Congenital | HP:0007957 (vitreoretinal degeneration) or HP:0000572-family; verify exact term |
| Retinal detachment / retinal tear | Complication | 8–18% in COL9A-related recessive forms specifically (PMID:39406934: 15.4%, 2/13, both horseshoe tears post-PVD, no bilateral cases or giant retinal tears) — substantially lower than the up to 78% reported in dominant (COL2A1/COL11A1) Stickler syndrome | Young adulthood (documented ages 24 and 36 in the cohort) | HP:0000541 (Retinal detachment) |
| Lattice retinal degeneration | Clinical/imaging sign | Present in some families without progressing to detachment (Rad et al. 2022) | Variable | HP:0000699 (approx.; verify) |
| Cataract | Clinical sign | Reported but frequency not separately quantified for COL9A3 | Variable, often earlier than general population | HP:0000518 (Cataract) |
| Midface/malar hypoplasia | Physical/craniofacial | 30.8% | Congenital, may be subtle | HP:0011800 or HP:0000271 (Abnormality of the face) — verify specific term |
| Depressed/flat nasal bridge | Physical | Variable, reported in younger patients with more prominent skeletal phenotype | Congenital | HP:0005280 (verify) |
| Anteverted nares | Physical | Reported, especially in younger/more skeletally affected patients | Congenital | HP:0000463 |
| Cleft palate / Pierre Robin sequence | Physical | 0% reported in COL9A1/2/3-related (recessive) Stickler syndrome — a key distinguishing negative feature versus dominant COL11A1/COL11A2-related Stickler syndrome, where cleft palate is common | — | HP:0000175 (Cleft palate) — noted as absent |
| Mild spondyloepiphyseal dysplasia | Skeletal | Reported, especially in younger patients (ages 3–11 in Rad et al. 2022); older patients (ages 57–65) presented with myopia/hearing loss but minimal skeletal findings | Childhood-onset, may attenuate/be less clinically apparent with age | HP:0002651 (Spondyloepiphyseal dysplasia) |
| Precocious/early-onset osteoarthritis | Skeletal, progressive | Reported (consistent with collagen IX cartilage role) | Adult, earlier than general population | HP:0002829 (Arthralgia) / HP:0002758 (Osteoarthritis) |
| Joint hypermobility / joint pain | Skeletal | ~15% joint pain reported in aggregated literature review of COL9A-variant patients | Variable | HP:0001382 (Joint hypermobility) |
| Tibial/femoral bowing at birth | Skeletal | Reported in at least one family (Rad et al. 2022) | Congenital | HP:0002980 (Bowing of the legs) — verify exact term |
Quality of life impact: Not formally measured with validated instruments (EQ-5D, SF-36) in the STL6-specific literature located. Qualitatively, the combination of early progressive sensorineural hearing loss and high myopia with vitreoretinal fragility carries substantial risk to communication development and vision-dependent function; the lower (but non-zero) retinal detachment risk versus dominant Stickler forms still warrants lifelong ophthalmologic surveillance. No disease-specific QOL studies were found; this should be flagged as a knowledge gap.
Causal gene: COL9A3 (HGNC:2219; OMIM *120270), chromosome 20q13.33, encoding the α3(IX) collagen chain.
Variant classification/type: All reported STL6-causing variants are biallelic loss-of-function: frameshift (c.107_116del, c.355delC), nonsense (c.1204C>T p.Arg402*), and splice-site variants, consistent with a null/LOF disease mechanism rather than dominant-negative. This contrasts with the heterozygous missense/splice variants that cause the allelic conditions multiple epiphyseal dysplasia type 3 (dominant-negative mechanism) and the COL9A3 Trp3 risk allele for disc disease (hypomorphic/structural mechanism).
Population allele frequency: Specific gnomAD constraint metrics (pLI/LOEUF) for COL9A3 were not retrievable in this session (network access to gnomad.broadinstitute.org was not available); this should be checked directly in gnomAD before curation, as COL9A3 biallelic-LOF-tolerant vs. -intolerant classification is directly relevant to the "recessive" gene category the field expects for this gene.
Somatic vs. germline: Germline only; no somatic/oncologic relevance.
Functional consequence: Complete loss of α3(IX) chain → failure of the obligate α1(IX)/α2(IX)/α3(IX) heterotrimer assembly → functional absence of collagen IX at the tissue level (a "functional knockout" of the whole protein, per the mouse literature, PMID:9252382), despite only one of the three chains being genetically null.
Modifier genes: None specifically established for STL6; general genotype-phenotype variability within families (e.g., differing skeletal severity by age at the time of the Rad et al. 2022 report) suggests age-dependent expressivity rather than a documented modifier locus.
Epigenetic information: No disease-specific epigenetic (DNA methylation/histone) data identified for COL9A3/STL6.
Chromosomal abnormalities: Not applicable — STL6 is due to intragenic sequence-level LOF variants, not large chromosomal rearrangements.
Allelic disorders at the COL9A3 locus (important for differential/knowledge-base cross-linking): - Multiple epiphyseal dysplasia, type 3 (EDM3/MED3; OMIM #600969) — heterozygous, dominant-negative COL9A3 variants (PMID:10090888). - Intervertebral disc disease, susceptibility to (OMIM #603932) — the common Trp3 (p.Arg103Trp) polymorphism, heterozygous, ~3-fold odds ratio (PMID:11308397; ClinVar RCV000018677).
No environmental toxins, occupational exposures, radiation, or infectious triggers were identified as contributing to STL6 pathogenesis in the literature search — consistent with its status as a fully genetically determined Mendelian recessive collagenopathy. Lifestyle factors are not etiologic but are relevant to secondary complication risk in a general sense (e.g., high-impact activity and retinal detachment risk in myopic/vitreopathic eyes is a commonly cited precaution across the Stickler syndrome spectrum, though this is anecdotal clinical guidance rather than a quantified risk-factor finding specific to COL9A3 patients in the literature reviewed). No infectious agents are implicated.
Causal chain (numbered, from molecular lesion to clinical manifestation):
Molecular pathways: No specific signaling cascade (Wnt/MAPK/mTOR/etc.) has been implicated; the mechanism is structural extracellular matrix disruption rather than dysregulated signal transduction.
Cellular processes: Disrupted chondrocyte extracellular matrix organization; secondary early chondrocyte/cartilage degeneration consistent with osteoarthritis pathobiology (not classical inflammatory arthritis).
Protein dysfunction: Complete loss-of-function (null) rather than misfolding/aggregation or dominant-negative gain-of-function — distinguishing STL6 mechanistically from the heterozygous dominant-negative COL9A3 MED3 allelic disorder.
Tissue damage mechanism: Structural/mechanical extracellular matrix fragility (fibril cross-linking failure) rather than oxidative stress, ischemia, or classic fibrosis.
Suggested GO terms: GO:0030198 (extracellular matrix organization), GO:0030199 (collagen fibril organization), GO:0032964 (collagen biosynthetic process), GO:0007601 (visual perception, downstream/phenotypic), GO:0007605 (sensory perception of sound, downstream/phenotypic).
Suggested CL terms: CL:0000138 (chondrocyte), CL:0002327 (mammary basal cell — not relevant, disregard), CL:0000064 (ciliated cell — not relevant); relevant candidates: CL:0000138 (chondrocyte), CL:0002617 (endothelial cell of vitreous — verify), and inner-ear-specific cell types associated with the tectorial membrane (e.g., interdental cells; verify exact CL ID before curation).
Molecular profiling / advanced technologies: No transcriptomic, proteomic, single-cell, or spatial data specific to human COL9A3-null tissue were identified in this search; this is a knowledge gap for an ultra-rare disease with no dedicated omics studies located.
Organ level: - Primary: eye (vitreous, retina, lens), inner ear (cochlea), skeleton (epiphyses, joints, long bones), craniofacial skeleton (variable). - Secondary: intervertebral discs (via the allelic/heterozygous mechanism more than the biallelic STL6 phenotype itself). - Body systems: ophthalmic, auditory/vestibular, musculoskeletal; not typically cardiovascular, respiratory (beyond the dominant-form Pierre Robin airway risk, which is not a feature of STL6), or gastrointestinal.
Tissue/cell level: Cartilage (hyaline, epiphyseal growth plate), vitreous body extracellular matrix, cochlear tectorial membrane, intervertebral disc annulus/nucleus.
Subcellular level: Extracellular matrix compartment (collagen fibril surface); GO Cellular Component candidate: GO:0005581 (collagen trimer), GO:0062023 (collagen-containing extracellular matrix).
Localization (UBERON candidates, to verify against OAK before curation): - UBERON:0003889 (vitreous body) / UBERON:0001797 (vitreous humor) - UBERON:0000965 (lens) - UBERON:0000955 → cochlea-specific: UBERON:0000362 (cochlea), tectorial membrane term (verify exact UBERON ID) - UBERON:0002513 (epiphysis) / UBERON:0002520 (cartilage tissue) - UBERON:0000992 (intervertebral disc — verify exact ID)
Lateralization: Bilateral for hearing loss and myopia (systemic connective tissue disorder); retinal detachment events in the reported cohort were unilateral at presentation with no contralateral involvement documented at follow-up (PMID:39406934).
Onset: Congenital/early-childhood for the ocular (myopia, vitreous anomaly) and skeletal (spondyloepiphyseal changes, long-bone bowing) features; hearing loss may be present from infancy but escape newborn hearing screening in some cases ("both failed and uneventful auditory screening at young age has been reported").
Onset pattern: Insidious/subclinical initial presentation for hearing loss, with clear progression documented over time; ocular anomalies are structurally congenital but their complications (retinal tear/detachment) are age-dependent events typically in young adulthood (ages 24 and 36 in the reported cohort).
Progression: - Hearing loss: progressive, "even to profound hearing loss" with age, following a basal-to-apical cochlear pattern. - Skeletal: more prominent spondyloepiphyseal/craniofacial findings in younger patients (ages 3–11), with older patients (ages 57–65) showing minimal skeletal findings but persistent myopia/hearing loss — interpreted in the source as an apparent attenuation of skeletal manifestations with age, though this could also reflect ascertainment/cohort differences and is presented with that caveat by the primary authors (PMID:35241111). - Retinal detachment: not congenital — an event superimposed on longstanding vitreous anomaly, precipitated by posterior vitreous detachment in adulthood.
Disease course pattern: Chronic, non-remitting, generally progressive rather than relapsing-remitting; not life-limiting based on available reports (no early mortality reported).
Critical periods: Childhood is the critical window for surveillance/early intervention (hearing amplification, myopia correction, orthopedic monitoring) given the combination of early-onset progressive sensorineural hearing loss and high myopia.
Epidemiology: Stickler syndrome overall has an estimated incidence of ~1:7,500–1:9,000 births, making it one of the most common causes of inherited/familial retinal detachment — but this figure is overwhelmingly driven by the dominant COL2A1-related form (type 1). STL6 specifically is ultra-rare: as of the 2022 systematic description, only 4 families with biallelic COL9A3 variants had been reported in the literature; a 2024 cohort study identified 13 patients from 11 families with recessive Stickler syndrome due to COL9A1, COL9A2, or COL9A3 combined (not COL9A3 alone) through the NHS England Highly Specialised Stickler Syndrome Service (2015–2022) (PMID:39406934). No population-specific prevalence/incidence estimate for COL9A3-only STL6 was located; it should likely be recorded as NOT_YET_DOCUMENTED / CASES_IN_LITERATURE in a structured prevalence model, given the single-digit-families evidence base.
Inheritance pattern: Autosomal recessive (in contrast to autosomal dominant types 1–3).
Penetrance: Appears complete for biallelic LOF genotypes based on all reported cases, though the very small number of families precludes formal penetrance estimation.
Expressivity: Variable — notably in skeletal severity by age at ascertainment, and in ocular complication severity between families (e.g., in Rad et al. 2022, one family had retinal detachment with advanced vitreoretinal degeneration while the other two had lattice degeneration without detachment).
Genetic anticipation: Not applicable/not reported (not a repeat-expansion disorder).
Germline mosaicism: Not specifically reported for COL9A3.
Founder effects: Not established; the high consanguinity rate (53.8%) in the largest combined cohort suggests genetic isolate/relatedness effects at the family level rather than a documented population founder allele.
Consanguinity role: Substantial — over half of reported families in the largest cohort had consanguineous parents, as expected for an ultra-rare autosomal recessive condition.
Carrier frequency: Not established in population databases for COL9A3-null alleles specifically; the common Trp3 missense allele carrier frequency (~4.7% in Finnish controls) should not be conflated with LOF carrier frequency for STL6.
Population demographics: No specific ethnic/geographic enrichment for COL9A3-null STL6 was identified beyond the consanguinity association; reported families appear geographically dispersed (Italy — original 2013 report; additional international families in subsequent reports; UK-based NHS cohort for the combined COL9A1/2/3 series).
Sex ratio: No sex predilection reported (autosomal recessive, biologically expected to be equal).
Clinical tests: - Ophthalmologic exam: slit-lamp/dilated fundus exam for vitreous architecture (hypoplastic/optically empty vitreous), myopia refraction, lattice degeneration, retinal status. - Audiology: pure-tone audiometry showing downsloping sensorineural hearing loss; serial testing to document progression; newborn hearing screening (may be falsely reassuring, as noted above). - Skeletal imaging: radiographs for epiphyseal changes (spondyloepiphyseal dysplasia pattern), assessment for long-bone bowing in infancy. - Craniofacial exam: assessment for midface hypoplasia, nasal bridge/nares morphology (absence of cleft palate is itself diagnostically informative, distinguishing from dominant COL11A-related forms).
Genetic testing: Multigene panel testing (Stickler/collagenopathy panel covering COL2A1, COL11A1, COL11A2, COL9A1, COL9A2, COL9A3) or exome sequencing is the recommended approach per GeneReviews, given phenotypic overlap across genes and the need to distinguish dominant from recessive inheritance for counseling; single-gene COL9A3 sequencing is appropriate when recessive inheritance/consanguinity and a compatible phenotype (no cleft palate, prominent hearing loss) raise specific suspicion.
Clinical criteria: No STL6-specific formal diagnostic criteria were located; general Stickler syndrome clinical diagnostic criteria (ocular + auditory + orofacial + skeletal major/minor criteria, historically per Rose et al.) are applied, with molecular confirmation of biallelic COL9A3 variants required to specify the STL6 subtype.
Differential diagnosis: Marshall syndrome (flatter/retracted midface, short stature, thick calvaria, intracranial calcifications — distinguishing from Stickler's flat malar appearance); Wagner syndrome (vitreoretinal findings without systemic features); Kniest dysplasia ("Swiss-cheese" collagen appearance on electron microscopy, more severe skeletal dysplasia); spondyloepiphyseal dysplasia congenita; spondyloperipheral dysplasia; metatropic dysplasia; multiple epiphyseal dysplasia (including the allelic COL9A3-heterozygous EDM3); Knobloch syndrome; Marfan syndrome.
Omics-based diagnostics: Not routinely used; standard clinical practice relies on targeted/panel/exome DNA sequencing rather than transcriptomic or proteomic diagnostics for this condition.
Screening: No population newborn screening exists for STL6 specifically; carrier screening/prenatal diagnosis would be offered on a family-specific basis once a proband's biallelic variants are identified, consistent with standard autosomal recessive genetic counseling practice (25% recurrence risk per GeneReviews).
Survival and mortality: No mortality or reduced life expectancy has been reported in association with STL6; the disorder is not known to be life-limiting.
Morbidity/function: Principal morbidity is sensory: potential for significant-to-profound hearing impairment if untreated, and vision-threatening complications (retinal detachment) in a minority of patients, superimposed on universal high myopia. Early-onset osteoarthritis contributes to musculoskeletal morbidity in adulthood.
Disease course/complications: Retinal detachment (documented risk ~15% in the largest combined type-IX-collagen recessive cohort, notably lower than the dominant forms' risk of up to 78%); progressive hearing loss to potentially profound levels; early osteoarthritis.
Recovery potential: With treatment (hearing amplification/audiologic management, prophylactic and therapeutic retinal interventions, myopia correction), functional outcomes for vision and hearing can be substantially improved; without surveillance, undetected retinal detachment risks permanent vision loss.
Prognostic factors: Age (skeletal findings may be more apparent/severe in childhood; ocular complications accrue risk with age via PVD-related tear formation); genotype (LOF variant type does not yet show clear genotype-severity correlation given the small case numbers, though the 2022 report explicitly frames its findings as contributing "genotype-phenotype associations from the literature" for future correlation work).
Pharmacotherapy: No disease-modifying pharmacotherapy exists; management is manifestation-based/supportive. NCIT candidate: NCIT:C15747 (Supportive Care).
Ophthalmic — surgical/interventional:
- Prophylactic laser retinopexy / cryotherapy for high-risk vitreoretinal changes (extensively studied and best characterized in the dominant Stickler population, with extrapolated but less quantified application in recessive/COL9A forms); NCIT: NCIT:C15313 (Radiation Therapy) is not a fit — laser retinopexy would map more appropriately to a specific ophthalmic procedure term (verify exact NCIT/procedure code; consider NCIT:C15329 Surgical Procedure with a device/procedure qualifier, per the project's device-vs-action convention).
- Retinal detachment repair: vitrectomy, scleral buckle, and/or laser/cryotherapy combination when detachment occurs (as used in the reported cohort's two detachment cases).
- Myopia correction: spectacles/refractive correction. NCIT: none specific; general optical correction is not typically NCIT-coded as a clinical intervention procedure.
Auditory: - Hearing aid amplification for moderate-to-severe loss. - Cochlear implantation would be the standard-of-care escalation pathway for profound sensorineural hearing loss based on general otologic practice, though STL6/COL9A3-specific cochlear implant outcome data were not identified in this search (knowledge gap). NCIT: candidate device-implant term, mapped via the project's device/procedure qualifier convention rather than as a bare treatment term.
Musculoskeletal/supportive:
- Physical therapy for joint symptoms/early osteoarthritis (NCIT:C15302 Physical Therapy).
- Orthopedic monitoring/management as needed for skeletal dysplasia features (NCIT:C16186 Orthopedic Surgical Procedure, if surgery is required).
Genetic counseling: NCIT:C15240 (Genetic Counseling) — appropriate given autosomal recessive inheritance and 25% sibling recurrence risk.
Experimental treatments: No STL6- or COL9A3-specific clinical trials were identified via search; general Stickler syndrome trials (e.g., laser prophylaxis studies, NCT07146516 "Retinal Detachment Prevention (Laser Prophylaxis) in Stickler Syndrome") are ongoing but are not restricted to or specifically powered for the COL9A3 subtype.
Treatment outcomes: Prophylactic laser retinopexy studies in Stickler syndrome broadly (not COL9A3-specific) report favorable detachment-prevention outcomes with a trade-off of measurable peripheral visual field constriction (e.g., one dominant-Stickler case series: no detachment/tear over mean 8.7-year follow-up in laser-treated eyes, with asymptomatic visual field constriction to ~50° per meridian) — cited here as general Stickler syndrome management evidence, not COL9A3-validated outcome data specifically.
Treatment strategy: Multidisciplinary care (ophthalmology, audiology, genetics, orthopedics/rehabilitation) is the standard approach; no COL9A3/STL6-specific treatment algorithm beyond general Stickler syndrome surveillance protocols (e.g., GeneReviews-recommended annual vitreoretinal and audiologic evaluation) was identified.
Primary prevention: Not applicable in the classic sense (no modifiable environmental cause); genetic counseling and, where desired by families, carrier screening/preimplantation or prenatal genetic diagnosis are the relevant "primary prevention" tools for recurrence in known-carrier families.
Secondary prevention: Early detection via newborn hearing screening (imperfectly sensitive per the literature caveat above) and early ophthalmologic examination in at-risk families (siblings of an affected proband) to catch vitreoretinal changes before complications arise; prophylactic laser retinopexy in eyes judged high-risk for detachment, applied by extrapolation from dominant Stickler syndrome protocols.
Tertiary prevention: Ongoing surveillance to prevent progression of complications once diagnosed — e.g., serial audiometry to trigger timely amplification, ongoing retinal surveillance in known STL6 patients per GeneReviews-recommended annual evaluations.
Immunization: Not applicable (non-infectious genetic disorder).
Screening: No population-level newborn or carrier screening program specific to COL9A3/STL6 exists; family-specific cascade testing following identification of a proband's biallelic variants is the applicable model, per standard autosomal recessive genetic counseling practice.
Behavioral interventions/public health measures: Not applicable to this monogenic disorder beyond general activity precautions sometimes advised for high-myopia/vitreopathic patients (anecdotal across the Stickler syndrome literature, not COL9A3-specific evidence).
No naturally occurring COL9A3-null disease has been reported in companion animals or other species in the sources reviewed (OMIA and veterinary literature were not directly queried in this session and should be checked — for example, canine chondrodysplasias with collagen IX involvement are a plausible area to search but were not confirmed here). This is a knowledge gap that should be verified against OMIA before curation.
Orthologous genes: Col9a3 is conserved in mouse (Mouse Genome Informatics; NCBI Gene) and other vertebrates as part of the conserved collagen IX/FACIT gene family; specific ortholog NCBI Gene IDs were not retrieved in this session but should be pulled from NCBI Gene/HomoloGene/Alliance of Genome Resources during curation.
Mouse — the primary model system for collagen IX biology, though largely characterized for Col9a1 rather than Col9a3 specifically:
Model characteristics/limitations: The mouse literature strongly recapitulates the joint/skeletal and auditory phenotypes of human recessive Stickler syndrome. However, essentially all mechanistic mouse data available are for Col9a1, not Col9a3 — meaning any model-to-mechanism link drawn for STL6 pathophysiology nodes would need to be flagged with an appropriate divergences/limitations caveat (a cross-chain, not merely cross-species, extrapolation) if incorporated into a dismech entry, per this project's model-credibility conventions. No Col9a3-specific knockout mouse study was identified in this search; this is a specific, actionable knowledge gap.
Applications: The Col9a1-null mouse remains the field's standard tool for studying collagen-IX-dependent joint degeneration, cochlear/tectorial membrane pathology, and disc degeneration mechanisms relevant by extension to STL6.
disease_term.Checked with linkml-reference-validator 0.2.1.
| Outcome | Count |
|---|---|
| References checked | 15 |
| Resolved | 15 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| Quoted claims checked | 1 |
| Quoted claims found in source | 1 |
| Quoted claims not found in source | 0 |
| References weighed for topical relevance | 15 |
| On topic | 11 |
| Off topic | 0 |
All extracted references resolved successfully.
Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 46 |
| Resolved | 43 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 1 |
| Unverifiable | 2 |
| Terms whose name was checked | 28 |
| Terms named correctly | 12 |
| Terms named as a different term | 11 |
| Terms whose name is worth a second look | 5 |
These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:
HP:0000699 (1 mention) - the report calls it "approx.; verify"; HP calls it DiastemaHP:0005280 (1 mention) - the report calls it "verify"; HP calls it Depressed nasal bridgeHP:0000463 (1 mention) - the report calls it "Congenital"; HP calls it Anteverted naresHP:0002980 (1 mention) - the report calls it "Bowing of the legs"; HP calls it Femoral bowingCL:0002327 (1 mention) - the report calls it "mammary basal cell — not relevant, disregard"; CL calls it mammary gland epithelial cellCL:0002617 (1 mention) - the report calls it "endothelial cell of vitreous — verify"; CL calls it adipocyte of breastUBERON:0003889 (1 mention) - the report calls it "vitreous body"; UBERON calls it fallopian tubeUBERON:0000362 (1 mention) - the report calls it "cochlea"; UBERON calls it renal medullaUBERON:0002513 (1 mention) - the report calls it "epiphysis"; UBERON calls it endochondral boneUBERON:0002520 (1 mention) - the report calls it "cartilage tissue"; UBERON calls it submandibular lymph nodeUBERON:0000992 (1 mention) - the report calls it "intervertebral disc — verify exact ID"; UBERON calls it ovaryThese terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:
GO:0062023 (obsolete collagen-containing extracellular matrix) (1 mention) - replaced by GO:0031012The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:
HP:0002651 (1 mention) - the report calls it "Spondyloepiphyseal dysplasia"; HP calls it Spondyloepimetaphyseal dysplasiaGO:0007601 (1 mention) - the report calls it "visual perception, downstream/phenotypic"; GO calls it visual perceptionGO:0007605 (1 mention) - the report calls it "sensory perception of sound, downstream/phenotypic"; GO calls it sensory perception of soundCL:0000064 (1 mention) - the report calls it "ciliated cell — not relevant"; CL calls it ciliated cellGO:0062023 (1 mention) - the report calls it "collagen-containing extracellular matrix"; GO calls it obsolete collagen-containing extracellular matrixTerms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.