Cleft Palate, Proliferative Retinopathy, and Developmental Delay

Mendelian MONDO:0033641 Pathograph 18 Show in embeddings browser Syndromic cleft palate Inherited vitreoretinopathies Disorders of TGF-beta signaling

An ultra-rare autosomal recessive syndrome caused by biallelic loss-of-function variants in LRRC32, which encodes GARP (glycoprotein A repetitions predominant), the cell-surface docking receptor that tethers and presents latent TGF-beta. Affected individuals have cleft palate, a childhood-onset progressive proliferative vitreoretinopathy, and developmental delay, with growth restriction, microcephaly, and facial dysmorphism variably present. Only four patients from three families, all ascertained in Israel, had been published as of the most recent report; the gene-disease relationship rests on that small series plus a Garp-null mouse whose palate phenotype is a close match. The proximate steps linking deficient local TGF-beta activation to the retinal and neurodevelopmental arms are not established in humans.

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Mappings
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Inheritance
7
Pathophys.
16
Phenotypes
4
Gaps
18
Pathograph
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Genes
2
Variants
5
Medical Actions
3
Differentials
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Models
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References
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Deep Research
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Classifications

Harrison's Part
GENETICS ENVIRONMENT DISEASE
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Mappings

MONDO
MONDO:0033641 cleft palate, proliferative retinopathy, and developmental delay
skos:exactMatch MONDO
MONDO:0033641 carries the CPPRDD synonym and the OMIM:619074 cross-reference that define this entry, and MONDO records LRRC32 as its causal gene.
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Inheritance

1
Autosomal recessive inheritance HP:0000007
All four published patients were homozygous for an LRRC32 variant and born to consanguineous or closely related parents; heterozygous parents and siblings are unaffected.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:35656379 SUPPORT Human Clinical
"A single report, published in 2019, described three children with a novel autosomal recessive syndrome, characterized by cleft palate, developmental delay and proliferative retinopathy (OMIM # 619074) due to a single homozygous non-sense mutation in the LRRC32 gene"
The 2022 report characterises the previously published series as autosomal recessive with a homozygous nonsense genotype.
PMID:35656379 SUPPORT Human Clinical
"The variant was inherited from both parents and family segregation confirmed that the variant was not found in the homozygous state in any of the patient’s five phenotypically normal siblings."
Biparental inheritance with unaffected heterozygous relatives is the segregation pattern expected of recessive disease.
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Discussions and Knowledge Gaps

4
Does GARP loss cause the human vitreoretinopathy, given that the Garp-null mouse has no retinal phenotype but dies within 24 hours of birth?
HUMAN MODEL MISMATCH OPEN cpprdd_mouse_no_retinal_phenotype
Attached to
pathophysiology#Disordered Vitreoretinal Development animal_models#Mouse
The retinal arm of this syndrome has no animal counterpart. The only published GARP loss-of-function animal, the constitutive knockout mouse, dies within a day of birth with an isolated palatal defect and no reported retinal abnormality. The human vitreoretinopathy is childhood-onset and progressive, so the mouse is censored before the phenotype would appear. The negative result therefore neither supports nor refutes a GARP-dependent retinal mechanism, and the retinal arm of the pathophysiology rests on human observation in four patients plus the general requirement for TGF-beta in retinal development shown in ligand-knockout mice. The mismatch runs in both directions and the reverse half is the more interesting one: the mouse null is neonatally lethal and the patients are not, so either the human alleles are hypomorphic rather than null, or human development depends less absolutely on GARP than mouse development does. Whichever it is bears directly on how much of the mouse mechanism transfers.
Proposed experiments
Postnatal and retina-restricted Lrrc32 deletion
exp_cpprdd_conditional_lrrc32_retina
Bypass the neonatal lethality with a conditional Lrrc32 allele deleted either postnatally or in retinal and vitreous-associated lineages, then follow the eyes longitudinally with fundus imaging, optical coherence tomography, and fluorescein angiography into adulthood, scoring for persistent hyaloid vasculature, vitreous condensation, vitreoretinal traction, and retinal tears. A knock-in of the human p.(Arg544Ter) allele would test the patients' genotype rather than complete loss.
Would support
pathophysiology#Disordered Vitreoretinal Development
Supporting outcome
  • Conditional or knock-in animals surviving past the neonatal period develop a persistent hyaloid remnant and peripheral vitreoretinal traction resembling the human disease.
Refuting outcome
  • Animals surviving to adulthood have normal retinal and vitreous anatomy on serial imaging and histology, which would place the human retinal phenotype outside a direct GARP-dependent mechanism.
Show evidence (3 references)
PMID:35656379 SUPPORT Other
"Nevertheless, in the garp deficient murine model, retinal impairment was not observed (23). This may be explained by early lethality of the mice, which precludes later evolution of vitreoretinopathy."
States the mismatch and the authors' own explanation for it.
PMID:28912269 SUPPORT Model Organism
"Unexpectedly, the GARP KO mice died within 24 h after birth and exhibited defective palatogenesis without apparent abnormalities in other major organs."
Establishes both the neonatal lethality that censors the model and the absence of other reported organ phenotypes.
PMID:31053781 SUPPORT Other
"Fourth, the current study also suggests that loss of GARP function does not cause acute lethality."
States the reverse half of the mismatch: the human patients survive where the mouse null does not, which the commentary reads as a substantive finding about GARP rather than an incidental difference.
How does a lesion that reduces local TGF-beta activation produce a proliferative vitreoretinopathy, when TGF-beta is elevated in the vitreous of patients with the common proliferative vitreoretinal diseases?
KNOWLEDGE GAP OPEN cpprdd_tgfbeta_direction_paradox
Attached to
pathophysiology#Disordered Vitreoretinal Development pathophysiology#Deficient Local Activation of TGF-beta
The mechanism curated here is deficient GARP-dependent activation of latent TGF-beta, so the expected ocular consequence is a developmental one. The clinical picture, however, is described as proliferative and is fibrocontractile: a thickened adherent vitreous exerting traction. In acquired proliferative vitreoretinopathy and proliferative diabetic retinopathy, TGF-beta is overexpressed in the vitreous and drives the contraction of preretinal membranes, the opposite direction of change. Either the lesion here is developmental and only resembles the acquired proliferative diseases superficially, or a local deficit of TGF-beta provokes a compensatory or dysregulated response elsewhere in the eye. The published material does not decide between these, and no vitreous TGF-beta measurement has ever been made in an LRRC32 patient.
Proposed experiments
TGF-beta isoform profiling of vitreous and preretinal membranes
exp_cpprdd_vitreous_tgfbeta
In any LRRC32 patient coming to vitrectomy, assay vitreous concentrations of active and total TGF-beta1, -beta2, and -beta3 alongside age-matched non-proliferative controls and acquired proliferative vitreoretinopathy controls, and stain any excised preretinal tissue for alpha-smooth muscle actin and phospho-SMAD2.
Would support
pathophysiology#Deficient Local Activation of TGF-beta
Supporting outcome
  • Vitreous active TGF-beta is low or normal rather than elevated, and excised tissue shows no phospho-SMAD2-positive myofibroblastic reaction, placing the lesion outside the acquired proliferative mechanism.
Refuting outcome
  • Vitreous active TGF-beta is elevated to the range seen in acquired proliferative vitreoretinopathy, which would mean the ocular disease is not a straightforward consequence of deficient TGF-beta activation.
Show evidence (2 references)
PMID:18952846 SUPPORT Human Clinical
"TGF-beta is overexpressed in the vitreous of patients with proliferative vitreoretinal diseases and is also detectable in the contractile membranes."
Establishes the direction of TGF-beta change in the acquired proliferative vitreoretinal diseases, which is what makes this mechanism counterintuitive. The paper is about proliferative diabetic retinopathy and acquired proliferative vitreoretinopathy, not about LRRC32 disease.
PMID:35656379 SUPPORT Human Clinical
"A thickened vitreous firmly attached to the retinal periphery was noted, with traction and secondary retinal tears."
Describes the fibrocontractile character of the human ocular lesion that sits awkwardly with a loss-of-TGF-beta mechanism.
Is p.(Arg544Ter) a true null, and does it release a soluble GARP ectodomain that retains any ability to bind and activate latent TGF-beta?
KNOWLEDGE GAP OPEN cpprdd_truncated_garp_residual_function
Attached to
pathophysiology#GARP Loss of Function genetic#Biallelic LRRC32 loss-of-function variants
The whole entry rests on GARP loss of function, and neither published allele has been assayed. The nonsense allele truncates before the transmembrane domain and would be predicted to yield a soluble ectodomain rather than no protein, and soluble GARP is not inert. The missense allele is supported only by structural modelling and remains a variant of uncertain significance. A related observation sharpens the question: no autoimmune disease was reported in the patients, despite GARP's established role in regulatory T cell TGF-beta presentation and immune tolerance, which is compatible with residual function, with redundancy from the related milieu molecule LRRC33, or with the immune phenotype simply not having been looked for.
Proposed experiments
Functional characterisation of the two published LRRC32 alleles
exp_cpprdd_allele_function
Express the p.(Arg544Ter) and p.Ile327Thr alleles in a GARP-null cell background alongside wild type, and measure GARP protein abundance, surface versus secreted distribution, co-immunoprecipitation with latency-associated peptide, surface latent TGF-beta1 by flow cytometry, and integrin-alphaVbeta8-dependent release of active TGF-beta in a reporter assay. Test patient-derived cells where available, and phenotype regulatory T cell surface latent TGF-beta in surviving patients.
Would support
pathophysiology#GARP Loss of Function
Supporting outcome
  • Both alleles abolish or sharply reduce surface presentation of latent TGF-beta and integrin-dependent activation relative to wild type.
Refuting outcome
  • Either allele supports near-normal surface presentation and activation, which would mean the curated mechanism is not the operative one for that genotype.
Show evidence (2 references)
PMID:35656379 SUPPORT Human Clinical
"However, the proposed mechanism for a missense variant leading to loss of function effect would require further functional validation."
The authors of the second allele say explicitly that the loss-of-function mechanism is unvalidated.
PMID:30361387 SUPPORT In Vitro
"Regulatory T cells (Tregs) suppress immune cells within close proximity by activating latent TGF-β1 presented by GARP (glycoprotein A repetitions predominant) to integrin αVβ8 on their surface."
Names the regulatory T cell function that makes the absence of a reported immune phenotype in these patients worth explaining.
Is the published four-patient series the whole phenotypic spectrum of LRRC32-related disease, and do LRRC32 variants found in unselected cleft palate cohorts represent the same entity?
KNOWLEDGE GAP OPEN cpprdd_case_count_and_spectrum
Attached to
genetic#Biallelic LRRC32 loss-of-function variants prevalence#Published literature worldwide
Four patients from three families, all ascertained in Israel and reported by two overlapping groups, define this disease. That is enough to make the gene-disease relationship credible and not enough to describe a spectrum: it is not known whether milder alleles produce isolated cleft palate or isolated vitreoretinopathy, whether the growth restriction and dysmorphism are constant, or what the natural history of the eye disease is beyond adolescence. An exome study of consanguineous Kuwaiti cleft lip and palate families subsequently reported a novel LRRC32 variant in a syndromic case, which is a lead worth following rather than a confirmed additional patient: that report does not state the zygosity, does not describe a retinopathy, and does not claim this diagnosis.
Proposed experiments
Targeted LRRC32 screening of syndromic cleft palate and paediatric vitreoretinopathy cohorts
exp_cpprdd_lrrc32_cohort_screen
Screen LRRC32 in two independent, deliberately different ascertainment frames, syndromic isolated cleft palate cohorts and unexplained paediatric vitreoretinopathy cohorts, and phenotype any biallelic carriers for the full triad, so the spectrum is described from both ends rather than from the craniofacial end alone.
Would support
genetic#Biallelic LRRC32 loss-of-function variants
Supporting outcome
  • Biallelic LRRC32 carriers are found in both frames and show overlapping but non-identical combinations of the triad, defining a spectrum.
Refuting outcome
  • No further biallelic carriers are found in either frame, leaving the entity confined to the reported Israeli families.
Show evidence (2 references)
PMID:41041957 SUPPORT Human Clinical
"Seven rare gene variants were identified across all cases, including one novel variant (LRRC32) in a syndromic case"
Reports an LRRC32 variant in an independent syndromic cleft cohort. It establishes that LRRC32 recurs in this ascertainment frame; it does not state zygosity, does not report retinopathy, and does not make this diagnosis, which is why it is recorded as a lead rather than as a fifth case.
PMID:35656379 SUPPORT Human Clinical
"Table 1 summarizes the clinical, radiological and genetic features of all four cases reported so far."
Fixes the size of the published series that this gap is about.
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Pathophysiology

7
GARP Loss of Function
Biallelic LRRC32 variants remove or destabilise GARP, a type I transmembrane leucine-rich-repeat protein whose large ectodomain docks latent TGF-beta at the cell surface. The discovery families carry a homozygous stop-gain, p.(Arg544Ter), which truncates the protein before the transmembrane domain; the fourth patient carries a homozygous missense substitution, p.Ile327Thr, predicted on the GARP:latent-TGF-beta1 crystal structure to destabilise the leucine-rich-repeat solenoid. Neither allele has been shown biochemically to abolish GARP function, so loss of function is inferred from genotype, structure, and phenotype rather than demonstrated directly.
LRRC32 hgnc:4161 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves LRRC32 (hgnc:4161). hgnc:4161 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context LRRC32 hgnc:4161 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns LRRC32 (hgnc:4161). hgnc:4161 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Homozygous germline LRRC32 alleles: the nonsense p.(Arg544Ter) in the discovery families and the missense p.Ile327Thr in the fourth patient.
transforming growth factor beta binding GO:0050431 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased transforming growth factor beta binding (GO:0050431). GO:0050431 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Failure of Latent TGF-beta Tethering at the Cell Surface GARP is the anchor itself, so losing it removes the tether rather than acting through an intermediate.
Show evidence (2 references)
PMID:30976112 SUPPORT Human Clinical
"We identified a homozygous stop-gain variant in LRRC32 (c.1630C>T; p.(Arg544Ter)) in two families with developmental delay, cleft palate, and proliferative retinopathy."
The discovery report establishes the homozygous truncating LRRC32 genotype in the affected families.
PMID:35656379 SUPPORT Computational
"The p.327Ile > Thr is likely to destabilize the LRR structure, both by introducing a polar residue into a hydrophobic pocket and by, at the same time, introducing an unoccupied cavity that destabilizes the structure."
Structural modelling on the GARP crystal structure predicts destabilisation of the leucine-rich-repeat ectodomain by the missense allele; this is a prediction, not a measured loss of function.
Failure of Latent TGF-beta Tethering at the Cell Surface
GARP binds the latency-associated peptide of pro-TGF-beta through intermolecular disulphide bonds and holds the resulting latent complex on the plasma membrane. Without GARP the latent complex is not presented at the cell surface. This step was worked out in regulatory T cells and platelets; the same requirement was later shown for membrane-associated latent TGF-beta3 in the palatal epithelium.
protein localization to plasma membrane GO:0072659 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein localization to plasma membrane (GO:0072659). GO:0072659 is a biological process from the Gene Ontology. ↓ DECREASED
transforming growth factor beta binding GO:0050431 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased transforming growth factor beta binding (GO:0050431). GO:0050431 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Deficient Local Activation of TGF-beta Latent TGF-beta must be held at the surface in the correct orientation for integrin-mediated release of the active cytokine, so failure of tethering is failure of the activation step.
Show evidence (2 references)
PMID:19651619 SUPPORT In Vitro
"We show that GARP or LRRC32, a leucine-rich repeat molecule of unknown function, is critical for tethering TGF-beta to the cell surface."
Establishes the tethering function that is lost when GARP is absent.
PMID:28912269 SUPPORT In Vitro
"In vitro studies confirmed that GARP and TGFβ3 directly interact and that GARP is indispensable for the surface expression of membrane-associated latent TGFβ3."
Extends the tethering requirement to TGF-beta3, the isoform that matters for palatal fusion.
Deficient Local Activation of TGF-beta
With latent TGF-beta no longer presented at the cell surface, the integrin alphaVbeta6/alphaVbeta8-dependent release of active cytokine cannot proceed where GARP-expressing cells would normally supply it. The defect is in local, cell-contact-dependent availability of active TGF-beta rather than in synthesis of the cytokine or in the receptor-SMAD machinery itself.
transforming growth factor beta receptor signaling pathway GO:0007179 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased transforming growth factor beta receptor signaling pathway (GO:0007179). GO:0007179 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Reduced SMAD2 Phosphorylation in Palatal Medial Edge Epithelium In the Garp-null mouse, absent GARP is accompanied by reduced SMAD2 phosphorylation specifically in the medial edge epithelium of the palatal shelf, the readout of TGF-beta receptor signalling in that tissue.
Disordered Vitreoretinal Development The retinal arm is inferred from the requirement for TGF-beta in retinal development and from the human phenotype; the intervening cellular steps have not been identified, and the Garp-null mouse cannot supply them.
Impaired Central Nervous System Development Developmental delay is a constant feature of the syndrome, but no GARP-dependent step in human brain development has been identified, and the mouse literature had not implicated GARP in the central nervous system before these patients were reported.
Show evidence (2 references)
PMID:35656379 SUPPORT Other
"Taken together, LRRC32 loss of function variants result in GARP dysfunction and consequently abnormal maturation and inactivation of TGF-β."
The authors state the mechanistic conclusion that the disease-causing step is failure of TGF-beta maturation and activation.
PMID:30361387 SUPPORT In Vitro
"Regulatory T cells (Tregs) suppress immune cells within close proximity by activating latent TGF-β1 presented by GARP (glycoprotein A repetitions predominant) to integrin αVβ8 on their surface."
Names the integrin-dependent activation step that GARP presentation enables; loss of GARP removes the substrate for that step.
Reduced SMAD2 Phosphorylation in Palatal Medial Edge Epithelium
Fusion of the secondary palate requires TGF-beta3 signalling in the medial edge epithelium, whose cells normally undergo programmed cell death and epithelial-mesenchymal transformation to remove the midline epithelial seam. In GARP-null mouse embryos both SMAD2 phosphorylation and apoptosis in this cell population are reduced at embryonic day 14.5. This node is characterised entirely in the mouse; no human palatal tissue has been examined.
medial edge epithelial cell of the palatal shelf CL:0000066 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves medial edge epithelial cell of the palatal shelf, annotated with epithelial cell (CL:0000066). CL:0000066 is a cell type from the Cell Ontology.
SMAD protein signal transduction GO:0060395 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased SMAD protein signal transduction (GO:0060395). GO:0060395 is a biological process from the Gene Ontology. ↓ DECREASED apoptotic process GO:0006915 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased apoptotic process (GO:0006915). GO:0006915 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Garp (Lrrc32) knockout mouse Mouse recapitulates The node is defined by measurements made in this model: reduced SMAD2 phosphorylation and reduced apoptosis in the palatal medial edge epithelium at E14.5.
Downstream
Failure of Palatal Shelf Fusion The palatal phenotype of the GARP knockout copies that of the TGF-beta3 knockout, including the reduction in SMAD phosphorylation, which is the argument that the signalling defect is what causes the fusion failure.
Show evidence (1 reference)
PMID:28912269 SUPPORT Model Organism
"Furthermore, we observed decreased apoptosis and SMAD2 phosphorylation in the medial edge epithelial cells of the palatal shelf of GARP KO embryos at embryonic day 14.5 (E14.5), indicating a defect in the TGFβ signaling pathway in the GARP-null developing palates."
The two measurements that define this node, made in the GARP knockout mouse.
Failure of Palatal Shelf Fusion
The secondary palatal shelves grow out from the maxillary prominences, elevate above the tongue, appose at the midline, and fuse. Loss of the TGF-beta signal in the medial edge epithelium leaves the midline seam intact and the shelves unfused, producing an isolated cleft of the secondary palate without cleft lip.
secondary palate development GO:0062009 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased secondary palate development (GO:0062009). GO:0062009 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Garp (Lrrc32) knockout mouse Mouse recapitulates GARP-null mice fail to develop the secondary palate, the same anatomical lesion seen in patients, and the defect is isolated to the palate among major organs.
Downstream
Cleft palate An unfused secondary palate is the cleft.
Show evidence (2 references)
PMID:28912269 SUPPORT Model Organism
"Unexpectedly, the GARP KO mice died within 24 h after birth and exhibited defective palatogenesis without apparent abnormalities in other major organs."
Establishes that removing GARP is by itself sufficient to break palatogenesis in vivo.
PMID:22186724 SUPPORT Other
"the embryonic primary and secondary palatal shelves develop as outgrowths from the medial nasal and maxillary prominences, respectively, remodel and fuse to form the intact roof of the oral cavity"
A developmental-biology review describing the normal process whose failure this node names.
Disordered Vitreoretinal Development
TGF-beta isoforms are expressed in the developing retina and are required for normal retinal morphogenesis; combined Tgfb2/Tgfb3 deficiency in mice produces gross retinal, lens, and corneal abnormality with retinal detachment. In CPPRDD the ocular disease is a progressive, childhood-onset vitreoretinopathy with a persistent hyaloid remnant, straightened retinal vessels, a thickened vitreous adherent to the peripheral retina, and traction with secondary retinal tears. How deficient GARP-dependent TGF-beta activation produces this specific vitreoretinal picture is not established.
retina development in camera-type eye GO:0060041 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased retina development in camera-type eye (GO:0060041). GO:0060041 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Garp (Lrrc32) knockout mouse Mouse fails to recapitulate No retinal abnormality was observed in the GARP-deficient mouse, so the model does not reproduce the ocular arm of the human syndrome.
Downstream
Vitreoretinopathy The clinical vitreoretinopathy is the observed consequence; the cellular steps between abnormal retinal development and the proliferative vitreoretinal picture have not been characterised.
Show evidence (3 references)
PMID:30976112 SUPPORT Human Clinical
"The transforming growth factor-beta (TGFβ) signaling pathway is essential for palatogenesis and retinal development."
States the premise on which the retinal arm of this syndrome is interpreted.
PMID:12838410 SUPPORT Model Organism
"We report now that eyes of Tgfbeta2/Tgfbeta3 double-deficient mice display severe alterations in the morphology of the retina, lens, and cornea."
Independent evidence that loss of TGF-beta ligand disrupts retinal morphogenesis, supporting the direction of this node although the model removes the ligands rather than the GARP tether.
PMID:12838410 SUPPORT Model Organism
"In Tgfbeta2(-/-) Tgfbeta3(-/-) and Tgfbeta2(-/-) Tgfbeta3(+/-) littermates the retina was consistently detached from the underlying pigment epithelium."
Retinal detachment in TGF-beta-deficient mice is the closest model counterpart to the tractional retinal complications seen in patients.
Impaired Central Nervous System Development
Developmental delay is present in every published patient, and brain imaging in the discovery series showed ventriculomegaly and corpus callosum abnormalities. No GARP-dependent step in brain development has been identified, in mouse or in human tissue; the Garp-null mouse dies within a day of birth and no neurodevelopmental phenotype has been reported in it.
central nervous system development GO:0007417 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased central nervous system development (GO:0007417). GO:0007417 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Global developmental delay The clinical consequence, with no established intervening mechanism.
Show evidence (1 reference)
PMID:31053781 SUPPORT Other
"First, mouse studies have uncovered roles of GARP only in palatogenesis, immune tolerance and cancer immune evasion (Fig. 1), but these three cases suggest that GARP may play other roles including in development of the central nervous system and the retina."
The commentary explicitly identifies a central nervous system role for GARP as a possibility raised by the patients and not previously demonstrated.
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Pathograph

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

16
Cardiovascular 1
Abnormal retinal vascular morphology HP:0008046 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Straightened retinal vessels, annotated with Abnormal retinal vascular morphology (HP:0008046). HP:0008046 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35656379 SUPPORT Human Clinical
"Fundoscopic examination showed bilateral pink optic discs with Bergmeister’s papillae (tufts of fibrous tissue that indicate a remnant of hyaloid artery, which is usually completely regressed before birth) and straightened retinal vessels"
Documents the abnormal retinal vessel course.
Ear 1
Posteriorly rotated ears HP:0000358 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Posteriorly rotated ears (HP:0000358). HP:0000358 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35656379 SUPPORT Human Clinical
"microcephaly with dysmorphic facial features including triangular face, micrognathia, posteriorly rotated ears, a high protruding nasal bridge; and mild to moderate global developmental delay"
Documents posteriorly rotated ears in the fourth patient.
Eye 3
Vitreoretinopathy HP:0007773 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Progressive proliferative vitreoretinopathy, annotated with Vitreoretinopathy (HP:0007773). HP:0007773 is a phenotype from the Human Phenotype Ontology.
Sequelae: Retinal perforation
Show evidence (2 references)
PMID:35656379 SUPPORT Human Clinical
"Taken together, the ophthalmological findings are consistent with early onset progressive vitreoretinopathy."
The ophthalmologic conclusion in the fourth patient.
PMID:30976112 SUPPORT Human Clinical
"We identified a homozygous stop-gain variant in LRRC32 (c.1630C>T; p.(Arg544Ter)) in two families with developmental delay, cleft palate, and proliferative retinopathy."
Proliferative retinopathy is one of the three defining features of the discovery series.
Retinal perforation HP:0011958 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Secondary retinal tear from vitreoretinal traction, annotated with Retinal perforation (HP:0011958). HP:0011958 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35656379 SUPPORT Human Clinical
"A thickened vitreous firmly attached to the retinal periphery was noted, with traction and secondary retinal tears."
Documents the tears and the traction that produced them.
Vascular remnant arising from the disk HP:0009922 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bergmeister papilla, annotated with Vascular remnant arising from the disk (HP:0009922). HP:0009922 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35656379 SUPPORT Human Clinical
"Fundoscopic examination showed bilateral pink optic discs with Bergmeister’s papillae (tufts of fibrous tissue that indicate a remnant of hyaloid artery, which is usually completely regressed before birth) and straightened retinal vessels"
Names the finding and its identity as a persistent hyaloid remnant.
Head and Neck 6
Cleft palate HP:0000175 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cleft palate (HP:0000175). HP:0000175 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30976112 SUPPORT Human Clinical
"We identified a homozygous stop-gain variant in LRRC32 (c.1630C>T; p.(Arg544Ter)) in two families with developmental delay, cleft palate, and proliferative retinopathy."
Cleft palate is one of the three defining features of the discovery series.
PMID:35656379 SUPPORT Human Clinical
"Additionally, he had cleft palate that was corrected surgically at age 1 year."
Documents the cleft palate and its surgical repair in the fourth patient.
Microcephaly HP:0000252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcephaly (HP:0000252). HP:0000252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35656379 SUPPORT Human Clinical
"microcephaly with dysmorphic facial features including triangular face, micrognathia, posteriorly rotated ears, a high protruding nasal bridge; and mild to moderate global developmental delay"
Documents microcephaly in the fourth patient.
Abnormal facial shape HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysmorphic facial features, annotated with Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35656379 SUPPORT Human Clinical
"In addition, we emphasize the associated facial dysmorphism to be dominated by triangular face, micrognathia and high protruding nasal bridge."
Names the dysmorphic pattern the authors put forward.
Triangular face HP:0000325 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Triangular face (HP:0000325). HP:0000325 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35656379 SUPPORT Human Clinical
"In addition, we emphasize the associated facial dysmorphism to be dominated by triangular face, micrognathia and high protruding nasal bridge."
Explicitly lists triangular face.
Micrognathia HP:0000347 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Micrognathia (HP:0000347). HP:0000347 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35656379 SUPPORT Human Clinical
"In addition, we emphasize the associated facial dysmorphism to be dominated by triangular face, micrognathia and high protruding nasal bridge."
Explicitly lists micrognathia.
Prominent nasal bridge HP:0000426 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is High protruding nasal bridge, annotated with Prominent nasal bridge (HP:0000426). HP:0000426 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35656379 SUPPORT Human Clinical
"In addition, we emphasize the associated facial dysmorphism to be dominated by triangular face, micrognathia and high protruding nasal bridge."
Explicitly lists the high protruding nasal bridge.
Nervous System 3
Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30976112 SUPPORT Human Clinical
"We identified a homozygous stop-gain variant in LRRC32 (c.1630C>T; p.(Arg544Ter)) in two families with developmental delay, cleft palate, and proliferative retinopathy."
Developmental delay is one of the three defining features of the discovery series.
PMID:35656379 SUPPORT Human Clinical
"microcephaly with dysmorphic facial features including triangular face, micrognathia, posteriorly rotated ears, a high protruding nasal bridge; and mild to moderate global developmental delay"
Grades the delay in the fourth patient.
Ventriculomegaly HP:0002119 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ventriculomegaly (HP:0002119). HP:0002119 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35656379 SUPPORT Human Clinical
"Finally, MRI changes in our patient showed decreased white matter volume in contrast with ventriculomegaly and corpus callosum abnormalities that were seen in the previously reported patients."
Attributes ventriculomegaly to the previously reported patients and explicitly contrasts it with the fourth patient's imaging.
Abnormal corpus callosum morphology HP:0001273 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Corpus callosum abnormality, annotated with Abnormal corpus callosum morphology (HP:0001273). HP:0001273 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35656379 SUPPORT Human Clinical
"Finally, MRI changes in our patient showed decreased white matter volume in contrast with ventriculomegaly and corpus callosum abnormalities that were seen in the previously reported patients."
Attributes corpus callosum abnormalities to the previously reported patients.
Growth 2
Intrauterine growth retardation HP:0001511 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intrauterine growth retardation (HP:0001511). HP:0001511 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35656379 SUPPORT Human Clinical
"His pregnancy was remarkable for symmetric intrauterine growth restriction."
Directly documents prenatal growth restriction.
Failure to thrive HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Severe failure to thrive, annotated with Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:35656379 SUPPORT Human Clinical
"His first 2 years of life were marked by severe failure to thrive, with growth indices (weight and height) ranging 3–4 standard deviations below the mean"
Quantifies the postnatal growth failure.
PMID:35656379 SUPPORT Human Clinical
"Previous patients had modest decrease of height and weight z-scores, whereas our patient had severe restriction of both his height and weight"
Records the severity range across published patients rather than generalising the most severe case.
🧬

Genetic Associations

1
Biallelic LRRC32 loss-of-function variants
Gene: LRRC32 hgnc:4161 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is LRRC32 (hgnc:4161). hgnc:4161 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (3 references)
PMID:30976112 SUPPORT Human Clinical
"Our study establishes LRRC32 as a candidate disease-associated gene in humans and lends further support to the role of the TGFβ pathway in palatogenesis and retinal development."
The discovery report itself calls LRRC32 a candidate disease gene, which is the strength of claim this entry records.
PMID:35656379 SUPPORT Human Clinical
"In addition, we identified the homozygous c.980T > C variant in the LRRC32 gene, which was not found in known databases."
Documents the second published allele.
PMID:35656379 SUPPORT Human Clinical
"The variant was classified variant of uncertain significance (VUS) according to ACMG classification (PM2, PP3, PP4) (27)."
Records that the second allele has not reached pathogenic classification, which bounds the strength of the gene-disease claim.
Variants (2)
c.1630C>T p.(Arg544Ter)
Homozygous stop-gain in LRRC32 identified in two families in the discovery series.
c.980T>C p.Ile327Thr
Homozygous missense in LRRC32 in the fourth patient, substituting a conserved isoleucine between leucine-rich repeats R11 and R12; classified a variant of uncertain significance.
💊

Medical Actions

5
Palatoplasty
Category: Therapeutic Action: cleft palate repairNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is cleft palate repair, annotated with Palatorrhaphy (NCIT:C168380). NCIT:C168380 is a clinical intervention from the NCI Thesaurus. Ontology label: Palatorrhaphy NCIT:C168380
Platform: Surgery
Surgical repair of the cleft secondary palate, performed in infancy in the reported patients. This corrects the anatomical defect; it does not address the underlying signalling lesion.
Target Phenotypes: Cleft palate HP:0000175 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Cleft palate (HP:0000175). HP:0000175 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35656379 SUPPORT Human Clinical
"Additionally, he had cleft palate that was corrected surgically at age 1 year."
Documents surgical repair of the cleft palate in a reported patient.
Retinal Laser Photocoagulation
Category: Therapeutic Action: argon laser photocoagulationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is argon laser photocoagulation, annotated with Laser Photocoagulation (NCIT:C217424). NCIT:C217424 is a clinical intervention from the NCI Thesaurus. Ontology label: Laser Photocoagulation NCIT:C217424
Platform: Device
Prophylactic argon laser photocoagulation of the peripheral retina to wall off tractional lesions and prevent retinal detachment. The reported patient required a second treatment a year later when a new vitreoretinal traction appeared. This is a single-patient experience, not evidence of efficacy in this syndrome.
Mechanism Target:
Vitreoretinopathy — Laser treats the tractional and proliferative consequence in the retina; it does not act on the GARP-TGF-beta lesion upstream of it.
Target Phenotypes: Progressive proliferative vitreoretinopathy HP:0007773 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Progressive proliferative vitreoretinopathy, annotated with Vitreoretinopathy (HP:0007773). HP:0007773 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:35656379 SUPPORT Human Clinical
"The patient underwent preventive argon laser photocoagulation in both eyes"
Documents the intervention used in the one patient with detailed ophthalmic follow-up.
PMID:35656379 SUPPORT Human Clinical
"A second laser photocoagulation treatment was done to prevent retinal detachment."
Records the repeat treatment and its stated aim, and with it the progressive course that made a second treatment necessary.
Serial Ophthalmologic Surveillance
Category: Monitoring Action: fundus examination and optical coherence tomographyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is fundus examination and optical coherence tomography, annotated with Eye Examination (NCIT:C38060). NCIT:C38060 is a clinical intervention from the NCI Thesaurus. Ontology label: Eye Examination NCIT:C38060
Repeated fundus examination and optical coherence tomography. The one patient followed in detail developed a new peripheral vitreoretinal traction within a year of his first laser treatment, which is the observation that motivates surveillance rather than one-off assessment. No screening interval has been established for this syndrome.
Show evidence (1 reference)
PMID:35656379 SUPPORT Human Clinical
"One year later, on follow up examination, a new large vitreoretinal traction on the peripheral retinal region of the left eye was seen"
Demonstrates that a new sight-threatening lesion appeared between examinations, which is the case for continued surveillance.
Developmental and Rehabilitative Support
Category: Therapeutic Action: developmental rehabilitationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is developmental rehabilitation, annotated with Rehabilitation (NCIT:C15315). NCIT:C15315 is a clinical intervention from the NCI Thesaurus. Ontology label: Rehabilitation NCIT:C15315
Platform: Behavioral / lifestyle
Early intervention and rehabilitation for the global developmental delay. Nothing specific to this syndrome has been published; the sources establish that delay is present in every patient, not what should be done about it.
Target Phenotypes: Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Genetic Counseling
Category: Counseling / Informational Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Autosomal recessive recurrence risk counselling for the family, with carrier testing where an allele is known. Both published kindreds were consanguineous, and segregation testing in the 2022 family returned the expected mix of heterozygous and non-carrier siblings, which is the concrete question carrier testing is offered to answer. The diagnostic testing that makes counselling possible is curated under `diagnosis:` rather than here.
Show evidence (1 reference)
PMID:35656379 SUPPORT Human Clinical
"Two siblings (III-1 and III-5) were heterozygous and three siblings (III-3, III-4, and III-6) did not carry the variant"
Sibling carrier testing in the reported kindred, which is the counselling action offered to at-risk relatives once an allele is known.
🔬

Diagnosis

2
Molecular Diagnosis by Exome Sequencing (Positive)
The diagnosis is molecular. With four patients in three families there is no clinical gestalt specific enough to make it, so both published reports reached it by exome sequencing, one of them as a parent-proband trio. Sanger sequencing of the relevant LRRC32 exon then confirms the variant and establishes segregation in the family, and genome sequencing is the alternative where exome is uninformative. Because the presenting feature is usually the cleft palate, the practical route to the diagnosis is LRRC32 being on the cleft palate gene panel in the first place.
whole exome sequencing NCIT:C101295 NCI Thesaurus (NCIT)
Results: Biallelic LRRC32 variants. The two 2019 families carried the homozygous stop-gain c.1630C>T p.(Arg544Ter); the 2022 patient carried the homozygous missense c.980T>C p.(Ile327Thr). In the 2022 patient the same exome also returned a second, independent recessive diagnosis (homozygous SLC22A5 c.1354G>A, primary carnitine deficiency), which is why the cardiomyopathy in that patient is not attributed to LRRC32.
Show evidence (2 references)
PMID:35656379 SUPPORT Human Clinical
"Whole exome sequencing (WES) revealed a very rare homozygous missense variant in the LRRC32 gene"
Establishes exome sequencing as the modality that made the diagnosis in the second reported family.
PMID:35656379 SUPPORT Human Clinical
"we strongly suggest to include LRRC32 in gene panels targeted for diagnosis of patients with cleft palate"
The authors' explicit recommendation that LRRC32 be included on diagnostic gene panels for cleft palate, which is the testing route by which this syndrome is reached.
Diagnostic Ophthalmologic Evaluation (Positive)
Fundoscopy with optical coherence tomography is what converts a nonspecific developmental presentation into this syndrome, because the vitreoretinal findings are the discriminating feature against other cleft palate syndromes. It is also the examination that finds traction and retinal tears while they are still treatable by prophylactic laser, so the same modality recurs under `treatments:` as ongoing surveillance; this record is the evaluation at diagnosis rather than the surveillance interval.
ophthalmologic examination with fundoscopy and optical coherence tomography NCIT:C38060 NCI Thesaurus (NCIT)
Results: Mildly reduced visual acuity with normal ocular movements and a normal anterior segment; Bergmeister papillae and straightened retinal vessels on fundoscopy; and on optical coherence tomography a thickened vitreous firmly attached to the retinal periphery, with traction and secondary retinal tears.
Show evidence (2 references)
PMID:35656379 SUPPORT Human Clinical
"Ophthalmological evaluation at age 13 years demonstrated mildly decreased visual acuity of 20/30 in the right eye and 20/40 in the left eye."
Documents the ophthalmologic evaluation performed at diagnosis and its acuity findings.
PMID:35656379 SUPPORT Human Clinical
"These retinal abnormalities were also evident by optical coherence tomography, which revealed retinopathy mainly involving the vitreal regions"
Establishes optical coherence tomography as the imaging modality that characterised the vitreoretinal lesion.
📊

Prevalence

1
Published literature worldwide
Cases In Literature Ultra Rare
A literature head-count, not a population estimate. Three affected children from two Israeli families were reported in 2019 and a fourth unrelated Israeli patient in 2022, which the later report describes as all cases published to that point. No population-based prevalence study, Orphanet epidemiology record, or newborn-screening series was identified.
Show evidence (2 references)
PMID:35656379 SUPPORT Human Clinical
"Table 1 summarizes the clinical, radiological and genetic features of all four cases reported so far."
The most recent primary report states the total published case count as four.
PMID:35656379 SUPPORT Human Clinical
"To our knowledge, no additional patients with this syndrome have been reported since."
Confirms that no further patients had been published between the 2019 discovery series and the 2022 report.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Cleft Palate, Proliferative Retinopathy, and Developmental Delay:

Familial exudative vitreoretinopathy MONDO:0019516
Overlapping Features FEVR produces peripheral vitreoretinal traction, retinal folds, and tractional detachment that can look like the ocular arm of this syndrome, but it arises from impaired Norrin/FZD4/beta-catenin signalling in retinal vascular endothelium rather than from deficient TGF-beta activation.
Distinguishing Features
  • Cleft palate and developmental delay are not features of familial exudative vitreoretinopathy.
  • Familial exudative vitreoretinopathy is usually autosomal dominant (FZD4, LRP5, TSPAN12), with recessive and X-linked forms; this syndrome is recessive and LRRC32-related.
  • The FEVR retina has a peripheral avascular zone on fluorescein angiography, which has not been reported in this syndrome.
Stickler syndrome Not Yet Curated MONDO:0019354
Overlapping Features The closest clinical mimic. Stickler syndrome pairs cleft palate, often within a Pierre Robin sequence, with a vitreoretinopathy that leads to retinal detachment, so it reproduces two of the three defining features.
Distinguishing Features
  • Stickler syndrome adds myopia, cataract, conductive and sensorineural hearing loss, midfacial underdevelopment, and early-onset degenerative joint disease, none of which has been reported in the LRRC32 patients.
  • Stickler syndrome is a collagen disorder (COL2A1, COL11A1, COL11A2 dominant; COL9A1, COL9A2, COL9A3 recessive), so molecular testing separates the two cleanly.
  • Developmental delay is not a feature of Stickler syndrome, whereas it is one of the three defining features here.
Show evidence (2 references)
PMID:20301479 SUPPORT Other
"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..."
The GeneReviews clinical description establishes both the overlap (cleft palate with a retinal-detaching vitreoretinopathy) and the extra features that separate Stickler syndrome from this entry.
PMID:20301479 SUPPORT Other
"The diagnosis of Stickler syndrome can be established in a proband with characteristic clinical features and/or a heterozygous pathogenic variant in COL2A1, COL11A1, or COL11A2 or biallelic pathogenic variants in COL9A1, COL9A2, or COL9A3 identified by molecular genetic testing."
Names the causal genes that make the molecular distinction from LRRC32 disease decisive.
Retinopathy of prematurity MONDO:0006952
Overlapping Features This is not a theoretical confusion. The fourth published patient was born at 34 weeks and carried a diagnosis of grade I retinopathy of prematurity from the neonatal period; his later vitreoretinal disease was initially attributed to it.
Distinguishing Features
  • Retinopathy of prematurity does not progress in the way the reported patient's disease did, and the location of his lesions did not fit it.
  • Cleft palate, growth restriction, and developmental delay point to a syndromic diagnosis rather than a complication of prematurity.
Show evidence (1 reference)
PMID:35656379 SUPPORT Human Clinical
"However, the progressive nature and distinctive location of his retinopathy excluded retinopathy of prematurity as the cause of his ophthalmological disease."
The authors state the reasoning by which they separated the two diagnoses in a patient who genuinely had both risk factors.
🐁

Animal Models

1
Garp (Lrrc32) knockout mouse
A constitutive GARP knockout mouse generated to test GARP's role in organ development. Homozygous nulls die within 24 hours of birth with a cleft secondary palate and no other apparent major-organ abnormality, and show reduced SMAD2 phosphorylation and reduced apoptosis in the medial edge epithelium of the palatal shelf at E14.5. The palatal phenotype copies that of the TGF-beta3 knockout.
Species
Mouse
Genotype
Lrrc32 (Garp) constitutive knockout, homozygous null
Genes
LRRC32 hgnc:4161 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns LRRC32 (hgnc:4161). hgnc:4161 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:28912269
Pathograph links
Reduced SMAD2 Phosphorylation in Palatal Medial Edge Epithelium recapitulates fidelity: high observes: cellular The node is defined by measurements made in this model: reduced SMAD2 phosphorylation and reduced apoptosis in the palatal medial edge epithelium at E14.5.
Limitations: The corresponding human tissue has never been examined, so the cellular step is assumed rather than shown in patients.
Readouts
SMAD2 phosphorylation in palatal medial edge epithelium at E14.5
Direction: DECREASED
Interpretation: A direct readout of TGF-beta receptor signalling output in the epithelium that must fuse.
Show evidence (1 reference)
PMID:28912269 SUPPORT Model Organism
"Furthermore, we observed decreased apoptosis and SMAD2 phosphorylation in the medial edge epithelial cells of the palatal shelf of GARP KO embryos at embryonic day 14.5 (E14.5), indicating a defect in the TGFβ signaling pathway in the GARP-null developing palates."
Reports the measurement and its direction.
Apoptosis in palatal medial edge epithelium at E14.5
Direction: DECREASED
Interpretation: Programmed cell death removes the midline epithelial seam; its reduction is the cellular failure that leaves the seam intact.
Show evidence (1 reference)
PMID:28912269 SUPPORT Model Organism
"Furthermore, we observed decreased apoptosis and SMAD2 phosphorylation in the medial edge epithelial cells of the palatal shelf of GARP KO embryos at embryonic day 14.5 (E14.5), indicating a defect in the TGFβ signaling pathway in the GARP-null developing palates."
Reports the measurement and its direction.
Show evidence (1 reference)
PMID:28912269 SUPPORT Model Organism
"Our findings indicate that GARP is essential for normal morphogenesis of the palate and demonstrate that GARP plays a crucial role in regulating TGFβ3 signaling during embryogenesis."
Supports treating this model as informative for the palatal signalling node.
Failure of Palatal Shelf Fusion recapitulates fidelity: high observes: tissue GARP-null mice fail to develop the secondary palate, the same anatomical lesion seen in patients, and the defect is isolated to the palate among major organs.
Limitations: The mouse allele is a constitutive null while the human discovery allele is a late truncation that may leave a soluble product, so the mouse models the complete-loss end of the allelic series rather than the patients' genotype specifically.
Show evidence (1 reference)
PMID:28912269 SUPPORT Model Organism
"Unexpectedly, the GARP KO mice died within 24 h after birth and exhibited defective palatogenesis without apparent abnormalities in other major organs."
The model reproduces the human palatal lesion.
Disordered Vitreoretinal Development fails to recapitulate fidelity: low observes: organism No retinal abnormality was observed in the GARP-deficient mouse, so the model does not reproduce the ocular arm of the human syndrome.
Limitations: The mice die within 24 hours of birth, which precludes the postnatal window in which the human vitreoretinopathy appears and progresses; the negative result therefore cannot distinguish a species difference from a censored observation, and cannot be used to argue that the retinal arm is not GARP-dependent.
Show evidence (1 reference)
PMID:35656379 SUPPORT Other
"Nevertheless, in the garp deficient murine model, retinal impairment was not observed (23). This may be explained by early lethality of the mice, which precludes later evolution of vitreoretinopathy."
States both the negative retinal finding in the model and the lethality that limits its interpretation.
Show evidence (1 reference)
PMID:35656379 SUPPORT Other
"Accordingly, garp knockout mice had early lethality and also defective palatogenesis (23)."
The clinical report cites this mouse as the animal counterpart of the human palatal phenotype.
{ }

Source YAML

click to show 
name: Cleft Palate, Proliferative Retinopathy, and Developmental Delay
creation_date: '2026-09-07T00:00:00Z'
description: >-
  An ultra-rare autosomal recessive syndrome caused by biallelic loss-of-function
  variants in LRRC32, which encodes GARP (glycoprotein A repetitions predominant),
  the cell-surface docking receptor that tethers and presents latent TGF-beta.
  Affected individuals have cleft palate, a childhood-onset progressive
  proliferative vitreoretinopathy, and developmental delay, with growth
  restriction, microcephaly, and facial dysmorphism variably present. Only four
  patients from three families, all ascertained in Israel, had been published as
  of the most recent report; the gene-disease relationship rests on that small
  series plus a Garp-null mouse whose palate phenotype is a close match. The
  proximate steps linking deficient local TGF-beta activation to the retinal and
  neurodevelopmental arms are not established in humans.
category: Mendelian
synonyms:
- CPPRDD
- GARP deficiency
- cleft palate-retinopathy syndrome
- LRRC32-related cleft palate, retinopathy and developmental delay
disease_term:
  preferred_term: cleft palate, proliferative retinopathy, and developmental delay
  term:
    id: MONDO:0033641
    label: cleft palate, proliferative retinopathy, and developmental delay
parents:
- Syndromic cleft palate
- Inherited vitreoretinopathies
- Disorders of TGF-beta signaling
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0033641
      label: cleft palate, proliferative retinopathy, and developmental delay
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO:0033641 carries the CPPRDD synonym and the OMIM:619074
      cross-reference that define this entry, and MONDO records LRRC32 as its
      causal gene.
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      A Mendelian, autosomal recessive multiple-congenital-anomaly syndrome
      defined by its causal gene rather than by an organ system; Harrison's has
      no craniofacial or ophthalmology Part.
    evidence:
    - reference: PMID:35656379
      reference_title: A Novel Homozygous Missense Variant in the LRRC32 Gene Is Associated With a New Syndrome of Cleft Palate, Progressive Vitreoretinopathy, Growth Retardation, and Developmental Delay.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        A single report, published in 2019, described three children with a
        novel autosomal recessive syndrome, characterized by cleft palate,
        developmental delay and proliferative retinopathy (OMIM # 619074) due to
        a single homozygous non-sense mutation in the LRRC32 gene
      explanation: >-
        The source frames the entity as an autosomal recessive syndrome defined
        by a single gene, which is what places it in Harrison's genetics Part.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    All four published patients were homozygous for an LRRC32 variant and born
    to consanguineous or closely related parents; heterozygous parents and
    siblings are unaffected.
  evidence:
  - reference: PMID:35656379
    reference_title: A Novel Homozygous Missense Variant in the LRRC32 Gene Is Associated With a New Syndrome of Cleft Palate, Progressive Vitreoretinopathy, Growth Retardation, and Developmental Delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A single report, published in 2019, described three children with a novel
      autosomal recessive syndrome, characterized by cleft palate, developmental
      delay and proliferative retinopathy (OMIM # 619074) due to a single
      homozygous non-sense mutation in the LRRC32 gene
    explanation: >-
      The 2022 report characterises the previously published series as autosomal
      recessive with a homozygous nonsense genotype.
  - reference: PMID:35656379
    reference_title: A Novel Homozygous Missense Variant in the LRRC32 Gene Is Associated With a New Syndrome of Cleft Palate, Progressive Vitreoretinopathy, Growth Retardation, and Developmental Delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The variant was inherited from both parents and family segregation
      confirmed that the variant was not found in the homozygous state in any of
      the patient’s five phenotypically normal siblings.
    explanation: >-
      Biparental inheritance with unaffected heterozygous relatives is the
      segregation pattern expected of recessive disease.
prevalence:
- population: Published literature worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    A literature head-count, not a population estimate. Three affected children
    from two Israeli families were reported in 2019 and a fourth unrelated
    Israeli patient in 2022, which the later report describes as all cases
    published to that point. No population-based prevalence study, Orphanet
    epidemiology record, or newborn-screening series was identified.
  evidence:
  - reference: PMID:35656379
    reference_title: A Novel Homozygous Missense Variant in the LRRC32 Gene Is Associated With a New Syndrome of Cleft Palate, Progressive Vitreoretinopathy, Growth Retardation, and Developmental Delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Table 1 summarizes the clinical, radiological and genetic features of all
      four cases reported so far.
    explanation: >-
      The most recent primary report states the total published case count as
      four.
  - reference: PMID:35656379
    reference_title: A Novel Homozygous Missense Variant in the LRRC32 Gene Is Associated With a New Syndrome of Cleft Palate, Progressive Vitreoretinopathy, Growth Retardation, and Developmental Delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To our knowledge, no additional patients with this syndrome have been
      reported since.
    explanation: >-
      Confirms that no further patients had been published between the 2019
      discovery series and the 2022 report.
pathophysiology:
- name: GARP Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Biallelic LRRC32 variants remove or destabilise GARP, a type I transmembrane
    leucine-rich-repeat protein whose large ectodomain docks latent TGF-beta at
    the cell surface. The discovery families carry a homozygous stop-gain,
    p.(Arg544Ter), which truncates the protein before the transmembrane domain;
    the fourth patient carries a homozygous missense substitution, p.Ile327Thr,
    predicted on the GARP:latent-TGF-beta1 crystal structure to destabilise the
    leucine-rich-repeat solenoid. Neither allele has been shown biochemically to
    abolish GARP function, so loss of function is inferred from genotype,
    structure, and phenotype rather than demonstrated directly.
  genes:
  - preferred_term: LRRC32
    term:
      id: hgnc:4161
      label: LRRC32
  molecular_functions:
  - preferred_term: transforming growth factor beta binding
    term:
      id: GO:0050431
      label: transforming growth factor beta binding
    modifier: DECREASED
  genetic_context:
    gene:
      preferred_term: LRRC32
      term:
        id: hgnc:4161
        label: LRRC32
    zygosity: HOMOZYGOUS
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Homozygous germline LRRC32 alleles: the nonsense p.(Arg544Ter) in the
      discovery families and the missense p.Ile327Thr in the fourth patient.
  evidence:
  - reference: PMID:30976112
    reference_title: "Homozygous stop-gain variant in LRRC32, encoding a TGFβ receptor, associated with cleft palate, proliferative retinopathy, and developmental delay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a homozygous stop-gain variant in LRRC32 (c.1630C>T;
      p.(Arg544Ter)) in two families with developmental delay, cleft palate, and
      proliferative retinopathy.
    explanation: >-
      The discovery report establishes the homozygous truncating LRRC32 genotype
      in the affected families.
  - reference: PMID:35656379
    reference_title: A Novel Homozygous Missense Variant in the LRRC32 Gene Is Associated With a New Syndrome of Cleft Palate, Progressive Vitreoretinopathy, Growth Retardation, and Developmental Delay.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      The p.327Ile > Thr is likely to destabilize the LRR structure, both by
      introducing a polar residue into a hydrophobic pocket and by, at the same
      time, introducing an unoccupied cavity that destabilizes the structure.
    explanation: >-
      Structural modelling on the GARP crystal structure predicts destabilisation
      of the leucine-rich-repeat ectodomain by the missense allele; this is a
      prediction, not a measured loss of function.
  downstream:
  - target: Failure of Latent TGF-beta Tethering at the Cell Surface
    causal_link_type: DIRECT
    description: >-
      GARP is the anchor itself, so losing it removes the tether rather than
      acting through an intermediate.
    evidence:
    - reference: PMID:19651619
      reference_title: GARP (LRRC32) is essential for the surface expression of latent TGF-beta on platelets and activated FOXP3+ regulatory T cells.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The knockdown of GARP mRNA with siRNA prevented surface latent TGF-beta
        expression on activated Tregs and recombinant latent TGF-beta1 is able
        to bind directly with GARP.
      explanation: >-
        Removing GARP removes surface latent TGF-beta in the cell type where the
        interaction was first mapped, which is the causal step this edge asserts.
- name: Failure of Latent TGF-beta Tethering at the Cell Surface
  biological_scale: MOLECULAR
  description: >-
    GARP binds the latency-associated peptide of pro-TGF-beta through
    intermolecular disulphide bonds and holds the resulting latent complex on the
    plasma membrane. Without GARP the latent complex is not presented at the cell
    surface. This step was worked out in regulatory T cells and platelets; the
    same requirement was later shown for membrane-associated latent TGF-beta3 in
    the palatal epithelium.
  molecular_functions:
  - preferred_term: transforming growth factor beta binding
    term:
      id: GO:0050431
      label: transforming growth factor beta binding
    modifier: DECREASED
  biological_processes:
  - preferred_term: protein localization to plasma membrane
    term:
      id: GO:0072659
      label: protein localization to plasma membrane
    modifier: DECREASED
  evidence:
  - reference: PMID:19651619
    reference_title: GARP (LRRC32) is essential for the surface expression of latent TGF-beta on platelets and activated FOXP3+ regulatory T cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We show that GARP or LRRC32, a leucine-rich repeat molecule of unknown
      function, is critical for tethering TGF-beta to the cell surface.
    explanation: >-
      Establishes the tethering function that is lost when GARP is absent.
  - reference: PMID:28912269
    reference_title: Glycoprotein A repetitions predominant (GARP) positively regulates transforming growth factor (TGF) β3 and is essential for mouse palatogenesis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In vitro studies confirmed that GARP and TGFβ3 directly interact and that
      GARP is indispensable for the surface expression of membrane-associated
      latent TGFβ3.
    explanation: >-
      Extends the tethering requirement to TGF-beta3, the isoform that matters
      for palatal fusion.
  downstream:
  - target: Deficient Local Activation of TGF-beta
    causal_link_type: DIRECT
    description: >-
      Latent TGF-beta must be held at the surface in the correct orientation for
      integrin-mediated release of the active cytokine, so failure of tethering
      is failure of the activation step.
    evidence:
    - reference: PMID:30361387
      reference_title: Structural basis of latent TGF-β1 presentation and activation by GARP on human regulatory T cells.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        This finding reveals how GARP exploits an unusual medley of
        interactions, including fold complementation by the amino terminus of
        TGF-β1, to chaperone and orient the cytokine for binding and activation
        by αVβ8.
      explanation: >-
        The crystal structure shows that GARP's orientation of the latent
        complex is what permits integrin-mediated activation, making the tether
        and the activation step mechanistically inseparable.
- name: Deficient Local Activation of TGF-beta
  biological_scale: MOLECULAR
  description: >-
    With latent TGF-beta no longer presented at the cell surface, the integrin
    alphaVbeta6/alphaVbeta8-dependent release of active cytokine cannot proceed
    where GARP-expressing cells would normally supply it. The defect is in local,
    cell-contact-dependent availability of active TGF-beta rather than in
    synthesis of the cytokine or in the receptor-SMAD machinery itself.
  biological_processes:
  - preferred_term: transforming growth factor beta receptor signaling pathway
    term:
      id: GO:0007179
      label: transforming growth factor beta receptor signaling pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:35656379
    reference_title: A Novel Homozygous Missense Variant in the LRRC32 Gene Is Associated With a New Syndrome of Cleft Palate, Progressive Vitreoretinopathy, Growth Retardation, and Developmental Delay.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Taken together, LRRC32 loss of function variants result in GARP
      dysfunction and consequently abnormal maturation and inactivation of
      TGF-β.
    explanation: >-
      The authors state the mechanistic conclusion that the disease-causing step
      is failure of TGF-beta maturation and activation.
  - reference: PMID:30361387
    reference_title: Structural basis of latent TGF-β1 presentation and activation by GARP on human regulatory T cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Regulatory T cells (Tregs) suppress immune cells within close proximity by
      activating latent TGF-β1 presented by GARP (glycoprotein A repetitions
      predominant) to integrin αVβ8 on their surface.
    explanation: >-
      Names the integrin-dependent activation step that GARP presentation
      enables; loss of GARP removes the substrate for that step.
  downstream:
  - target: Reduced SMAD2 Phosphorylation in Palatal Medial Edge Epithelium
    causal_link_type: DIRECT
    description: >-
      In the Garp-null mouse, absent GARP is accompanied by reduced SMAD2
      phosphorylation specifically in the medial edge epithelium of the palatal
      shelf, the readout of TGF-beta receptor signalling in that tissue.
    evidence:
    - reference: PMID:28912269
      reference_title: Glycoprotein A repetitions predominant (GARP) positively regulates transforming growth factor (TGF) β3 and is essential for mouse palatogenesis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Furthermore, we observed decreased apoptosis and SMAD2 phosphorylation
        in the medial edge epithelial cells of the palatal shelf of GARP KO
        embryos at embryonic day 14.5 (E14.5), indicating a defect in the TGFβ
        signaling pathway in the GARP-null developing palates.
      explanation: >-
        Directly links loss of GARP to a measured drop in TGF-beta pathway output
        in the tissue that fails.
  - target: Disordered Vitreoretinal Development
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The retinal arm is inferred from the requirement for TGF-beta in retinal
      development and from the human phenotype; the intervening cellular steps
      have not been identified, and the Garp-null mouse cannot supply them.
    evidence:
    - reference: PMID:30976112
      reference_title: "Homozygous stop-gain variant in LRRC32, encoding a TGFβ receptor, associated with cleft palate, proliferative retinopathy, and developmental delay."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Our study establishes LRRC32 as a candidate disease-associated gene in
        humans and lends further support to the role of the TGFβ pathway in
        palatogenesis and retinal development.
      explanation: >-
        The discovery report advances the retinal arm as support for a TGF-beta
        role in retinal development, and its own hedged wording places the causal
        step short of demonstrated.
  - target: Impaired Central Nervous System Development
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Developmental delay is a constant feature of the syndrome, but no
      GARP-dependent step in human brain development has been identified, and the
      mouse literature had not implicated GARP in the central nervous system
      before these patients were reported.
    evidence:
    - reference: PMID:31053781
      reference_title: Truncation of TGF-β docking receptor GARP is linked to human disease.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        First, mouse studies have uncovered roles of GARP only
        in palatogenesis, immune tolerance and cancer immune
        evasion (Fig. 1), but these three cases suggest that GARP
        may play other roles including in development of the
        central nervous system and the retina.
      explanation: >-
        The commentary states that a central nervous system role for GARP is
        suggested by the patients rather than demonstrated, which is the claim
        this edge makes.
- name: Reduced SMAD2 Phosphorylation in Palatal Medial Edge Epithelium
  biological_scale: CELLULAR
  description: >-
    Fusion of the secondary palate requires TGF-beta3 signalling in the medial
    edge epithelium, whose cells normally undergo programmed cell death and
    epithelial-mesenchymal transformation to remove the midline epithelial seam.
    In GARP-null mouse embryos both SMAD2 phosphorylation and apoptosis in this
    cell population are reduced at embryonic day 14.5. This node is characterised
    entirely in the mouse; no human palatal tissue has been examined.
  cell_types:
  - preferred_term: medial edge epithelial cell of the palatal shelf
    term:
      id: CL:0000066
      label: epithelial cell
  biological_processes:
  - preferred_term: SMAD protein signal transduction
    term:
      id: GO:0060395
      label: SMAD protein signal transduction
    modifier: DECREASED
  - preferred_term: apoptotic process
    term:
      id: GO:0006915
      label: apoptotic process
    modifier: DECREASED
  evidence:
  - reference: PMID:28912269
    reference_title: Glycoprotein A repetitions predominant (GARP) positively regulates transforming growth factor (TGF) β3 and is essential for mouse palatogenesis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Furthermore, we observed decreased apoptosis and SMAD2 phosphorylation in
      the medial edge epithelial cells of the palatal shelf of GARP KO embryos at
      embryonic day 14.5 (E14.5), indicating a defect in the TGFβ signaling
      pathway in the GARP-null developing palates.
    explanation: >-
      The two measurements that define this node, made in the GARP knockout
      mouse.
  downstream:
  - target: Failure of Palatal Shelf Fusion
    causal_link_type: DIRECT
    description: >-
      The palatal phenotype of the GARP knockout copies that of the TGF-beta3
      knockout, including the reduction in SMAD phosphorylation, which is the
      argument that the signalling defect is what causes the fusion failure.
    evidence:
    - reference: PMID:28912269
      reference_title: Glycoprotein A repetitions predominant (GARP) positively regulates transforming growth factor (TGF) β3 and is essential for mouse palatogenesis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Of note, the failure to develop the secondary palate and concurrent
        reduction of SMAD phosphorylation without other defects in GARP KO mice
        phenocopied TGFβ3 KO mice, although GARP has not been suggested
        previously to interact with TGFβ3.
      explanation: >-
        The phenocopy argument ties the reduced SMAD signal to the fusion failure
        rather than leaving the two as parallel observations.
- name: Failure of Palatal Shelf Fusion
  biological_scale: TISSUE
  description: >-
    The secondary palatal shelves grow out from the maxillary prominences,
    elevate above the tongue, appose at the midline, and fuse. Loss of the
    TGF-beta signal in the medial edge epithelium leaves the midline seam intact
    and the shelves unfused, producing an isolated cleft of the secondary palate
    without cleft lip.
  biological_processes:
  - preferred_term: secondary palate development
    term:
      id: GO:0062009
      label: secondary palate development
    modifier: DECREASED
  evidence:
  - reference: PMID:28912269
    reference_title: Glycoprotein A repetitions predominant (GARP) positively regulates transforming growth factor (TGF) β3 and is essential for mouse palatogenesis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Unexpectedly, the GARP KO mice died within 24 h after birth and exhibited
      defective palatogenesis without apparent abnormalities in other major
      organs.
    explanation: >-
      Establishes that removing GARP is by itself sufficient to break
      palatogenesis in vivo.
  - reference: PMID:22186724
    reference_title: "Palatogenesis: morphogenetic and molecular mechanisms of secondary palate development."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the embryonic primary and secondary palatal shelves develop as outgrowths
      from
      the medial nasal and maxillary prominences, respectively, remodel and fuse
      to
      form the intact roof of the oral cavity
    explanation: >-
      A developmental-biology review describing the normal process whose failure
      this node names.
  downstream:
  - target: Cleft palate
    causal_link_type: DIRECT
    description: >-
      An unfused secondary palate is the cleft.
- name: Disordered Vitreoretinal Development
  biological_scale: TISSUE
  description: >-
    TGF-beta isoforms are expressed in the developing retina and are required for
    normal retinal morphogenesis; combined Tgfb2/Tgfb3 deficiency in mice
    produces gross retinal, lens, and corneal abnormality with retinal
    detachment. In CPPRDD the ocular disease is a progressive, childhood-onset
    vitreoretinopathy with a persistent hyaloid remnant, straightened retinal
    vessels, a thickened vitreous adherent to the peripheral retina, and traction
    with secondary retinal tears. How deficient GARP-dependent TGF-beta
    activation produces this specific vitreoretinal picture is not established.
  biological_processes:
  - preferred_term: retina development in camera-type eye
    term:
      id: GO:0060041
      label: retina development in camera-type eye
    modifier: DECREASED
  evidence:
  - reference: PMID:30976112
    reference_title: "Homozygous stop-gain variant in LRRC32, encoding a TGFβ receptor, associated with cleft palate, proliferative retinopathy, and developmental delay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The transforming growth factor-beta (TGFβ) signaling pathway is essential
      for palatogenesis and retinal development.
    explanation: >-
      States the premise on which the retinal arm of this syndrome is
      interpreted.
  - reference: PMID:12838410
    reference_title: Reduced programmed cell death in the retina and defects in lens and cornea of Tgfbeta2(-/-) Tgfbeta3(-/-) double-deficient mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We report now that eyes of Tgfbeta2/Tgfbeta3 double-deficient mice display
      severe alterations in the morphology of the retina, lens, and cornea.
    explanation: >-
      Independent evidence that loss of TGF-beta ligand disrupts retinal
      morphogenesis, supporting the direction of this node although the model
      removes the ligands rather than the GARP tether.
  - reference: PMID:12838410
    reference_title: Reduced programmed cell death in the retina and defects in lens and cornea of Tgfbeta2(-/-) Tgfbeta3(-/-) double-deficient mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In Tgfbeta2(-/-) Tgfbeta3(-/-) and Tgfbeta2(-/-) Tgfbeta3(+/-) littermates
      the retina was consistently detached from the underlying pigment
      epithelium.
    explanation: >-
      Retinal detachment in TGF-beta-deficient mice is the closest model
      counterpart to the tractional retinal complications seen in patients.
  downstream:
  - target: Vitreoretinopathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The clinical vitreoretinopathy is the observed consequence; the cellular
      steps between abnormal retinal development and the proliferative
      vitreoretinal picture have not been characterised.
- name: Impaired Central Nervous System Development
  biological_scale: ORGANISM
  description: >-
    Developmental delay is present in every published patient, and brain imaging
    in the discovery series showed ventriculomegaly and corpus callosum
    abnormalities. No GARP-dependent step in brain development has been
    identified, in mouse or in human tissue; the Garp-null mouse dies within a
    day of birth and no neurodevelopmental phenotype has been reported in it.
  biological_processes:
  - preferred_term: central nervous system development
    term:
      id: GO:0007417
      label: central nervous system development
    modifier: DECREASED
  evidence:
  - reference: PMID:31053781
    reference_title: Truncation of TGF-β docking receptor GARP is linked to human disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      First, mouse studies have uncovered roles of GARP only
      in palatogenesis, immune tolerance and cancer immune
      evasion (Fig. 1), but these three cases suggest that GARP
      may play other roles including in development of the
      central nervous system and the retina.
    explanation: >-
      The commentary explicitly identifies a central nervous system role for GARP
      as a possibility raised by the patients and not previously demonstrated.
  downstream:
  - target: Global developmental delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The clinical consequence, with no established intervening mechanism.
phenotypes:
- name: Cleft palate
  category: Craniofacial
  description: >-
    Cleft of the secondary palate, present in all published patients and repaired
    surgically. Cleft lip is not part of the reported phenotype.
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  evidence:
  - reference: PMID:30976112
    reference_title: "Homozygous stop-gain variant in LRRC32, encoding a TGFβ receptor, associated with cleft palate, proliferative retinopathy, and developmental delay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a homozygous stop-gain variant in LRRC32 (c.1630C>T;
      p.(Arg544Ter)) in two families with developmental delay, cleft palate, and
      proliferative retinopathy.
    explanation: >-
      Cleft palate is one of the three defining features of the discovery series.
  - reference: PMID:35656379
    reference_title: A Novel Homozygous Missense Variant in the LRRC32 Gene Is Associated With a New Syndrome of Cleft Palate, Progressive Vitreoretinopathy, Growth Retardation, and Developmental Delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additionally, he had cleft palate that was corrected surgically at age 1
      year.
    explanation: >-
      Documents the cleft palate and its surgical repair in the fourth patient.
- name: Vitreoretinopathy
  category: Ocular
  description: >-
    A childhood-onset, progressive proliferative vitreoretinopathy. Reported
    findings include a thickened vitreous firmly adherent to the peripheral
    retina with traction, secondary retinal tears, a persistent hyaloid remnant
    at the disc, and straightened retinal vessels. In the fourth patient the
    progressive course and peripheral location were what excluded retinopathy of
    prematurity, for which he also had risk factors.
  phenotype_term:
    preferred_term: Progressive proliferative vitreoretinopathy
    term:
      id: HP:0007773
      label: Vitreoretinopathy
  evidence:
  - reference: PMID:35656379
    reference_title: A Novel Homozygous Missense Variant in the LRRC32 Gene Is Associated With a New Syndrome of Cleft Palate, Progressive Vitreoretinopathy, Growth Retardation, and Developmental Delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Taken together, the ophthalmological findings are consistent with early
      onset progressive vitreoretinopathy.
    explanation: >-
      The ophthalmologic conclusion in the fourth patient.
  - reference: PMID:30976112
    reference_title: "Homozygous stop-gain variant in LRRC32, encoding a TGFβ receptor, associated with cleft palate, proliferative retinopathy, and developmental delay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a homozygous stop-gain variant in LRRC32 (c.1630C>T;
      p.(Arg544Ter)) in two families with developmental delay, cleft palate, and
      proliferative retinopathy.
    explanation: >-
      Proliferative retinopathy is one of the three defining features of the
      discovery series.
  sequelae:
  - target: Retinal perforation
    description: >-
      Vitreoretinal traction on the peripheral retina produced secondary retinal
      tears in the fourth patient.
- name: Retinal perforation
  category: Ocular
  description: >-
    Secondary retinal tears arising from traction by a thickened vitreous
    adherent to the peripheral retina. In the reported patient these prompted
    prophylactic laser photocoagulation to avert retinal detachment.
  phenotype_term:
    preferred_term: Secondary retinal tear from vitreoretinal traction
    term:
      id: HP:0011958
      label: Retinal perforation
  evidence:
  - reference: PMID:35656379
    reference_title: A Novel Homozygous Missense Variant in the LRRC32 Gene Is Associated With a New Syndrome of Cleft Palate, Progressive Vitreoretinopathy, Growth Retardation, and Developmental Delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A thickened vitreous firmly attached to the retinal periphery was noted,
      with traction and secondary retinal tears.
    explanation: >-
      Documents the tears and the traction that produced them.
- name: Vascular remnant arising from the disk
  category: Ocular
  description: >-
    Bergmeister papillae, tufts of fibrous tissue at the optic disc representing
    a remnant of the hyaloid artery, which normally regresses before birth.
  phenotype_term:
    preferred_term: Bergmeister papilla
    term:
      id: HP:0009922
      label: Vascular remnant arising from the disk
  evidence:
  - reference: PMID:35656379
    reference_title: A Novel Homozygous Missense Variant in the LRRC32 Gene Is Associated With a New Syndrome of Cleft Palate, Progressive Vitreoretinopathy, Growth Retardation, and Developmental Delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fundoscopic examination showed bilateral pink optic discs with
      Bergmeister’s papillae (tufts of fibrous tissue that indicate a remnant of
      hyaloid artery, which is usually completely regressed before birth) and
      straightened retinal vessels
    explanation: >-
      Names the finding and its identity as a persistent hyaloid remnant.
- name: Abnormal retinal vascular morphology
  category: Ocular
  description: >-
    Straightened retinal vessels on fundoscopy, reported alongside the persistent
    hyaloid remnant.
  phenotype_term:
    preferred_term: Straightened retinal vessels
    term:
      id: HP:0008046
      label: Abnormal retinal vascular morphology
  evidence:
  - reference: PMID:35656379
    reference_title: A Novel Homozygous Missense Variant in the LRRC32 Gene Is Associated With a New Syndrome of Cleft Palate, Progressive Vitreoretinopathy, Growth Retardation, and Developmental Delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fundoscopic examination showed bilateral pink optic discs with
      Bergmeister’s papillae (tufts of fibrous tissue that indicate a remnant of
      hyaloid artery, which is usually completely regressed before birth) and
      straightened retinal vessels
    explanation: >-
      Documents the abnormal retinal vessel course.
- name: Global developmental delay
  category: Neurologic
  description: >-
    Developmental delay is present in all published patients; in the fourth
    patient it was graded mild to moderate.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:30976112
    reference_title: "Homozygous stop-gain variant in LRRC32, encoding a TGFβ receptor, associated with cleft palate, proliferative retinopathy, and developmental delay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a homozygous stop-gain variant in LRRC32 (c.1630C>T;
      p.(Arg544Ter)) in two families with developmental delay, cleft palate, and
      proliferative retinopathy.
    explanation: >-
      Developmental delay is one of the three defining features of the discovery
      series.
  - reference: PMID:35656379
    reference_title: A Novel Homozygous Missense Variant in the LRRC32 Gene Is Associated With a New Syndrome of Cleft Palate, Progressive Vitreoretinopathy, Growth Retardation, and Developmental Delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      microcephaly with dysmorphic facial features including triangular face,
      micrognathia, posteriorly rotated ears, a high protruding nasal bridge;
      and mild to moderate global developmental delay
    explanation: >-
      Grades the delay in the fourth patient.
- name: Intrauterine growth retardation
  category: Growth
  description: >-
    Symmetric intrauterine growth restriction was documented in the fourth
    patient, whose birth weight, length, and head circumference were all well
    below the mean.
  phenotype_term:
    preferred_term: Intrauterine growth retardation
    term:
      id: HP:0001511
      label: Intrauterine growth retardation
  evidence:
  - reference: PMID:35656379
    reference_title: A Novel Homozygous Missense Variant in the LRRC32 Gene Is Associated With a New Syndrome of Cleft Palate, Progressive Vitreoretinopathy, Growth Retardation, and Developmental Delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      His pregnancy was remarkable for symmetric intrauterine growth
      restriction.
    explanation: >-
      Directly documents prenatal growth restriction.
- name: Failure to thrive
  category: Growth
  description: >-
    Severe postnatal growth failure. In the fourth patient weight and height ran
    three to four standard deviations below the mean through the first two years;
    the report notes that growth restriction in this patient was more severe than
    in the previously published children, who had only modest reductions in
    height and weight z-scores.
  phenotype_term:
    preferred_term: Severe failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:35656379
    reference_title: A Novel Homozygous Missense Variant in the LRRC32 Gene Is Associated With a New Syndrome of Cleft Palate, Progressive Vitreoretinopathy, Growth Retardation, and Developmental Delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      His first 2 years of life were marked by severe failure to thrive, with
      growth indices (weight and height) ranging 3–4 standard deviations below
      the mean
    explanation: >-
      Quantifies the postnatal growth failure.
  - reference: PMID:35656379
    reference_title: A Novel Homozygous Missense Variant in the LRRC32 Gene Is Associated With a New Syndrome of Cleft Palate, Progressive Vitreoretinopathy, Growth Retardation, and Developmental Delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Previous patients had modest decrease of height and weight z-scores,
      whereas our patient had severe restriction of both his height and weight
    explanation: >-
      Records the severity range across published patients rather than
      generalising the most severe case.
- name: Microcephaly
  category: Neurologic
  description: >-
    Microcephaly was present in the fourth patient, whose head circumference at
    birth was three standard deviations below the mean.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:35656379
    reference_title: A Novel Homozygous Missense Variant in the LRRC32 Gene Is Associated With a New Syndrome of Cleft Palate, Progressive Vitreoretinopathy, Growth Retardation, and Developmental Delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      microcephaly with dysmorphic facial features including triangular face,
      micrognathia, posteriorly rotated ears, a high protruding nasal bridge;
      and mild to moderate global developmental delay
    explanation: >-
      Documents microcephaly in the fourth patient.
- name: Abnormal facial shape
  category: Craniofacial
  description: >-
    Facial dysmorphism dominated by a triangular face, micrognathia, posteriorly
    rotated ears, and a high protruding nasal bridge. The 2022 report presents
    this pattern as an addition to the syndrome's described features rather than
    as an established diagnostic gestalt.
  phenotype_term:
    preferred_term: Dysmorphic facial features
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:35656379
    reference_title: A Novel Homozygous Missense Variant in the LRRC32 Gene Is Associated With a New Syndrome of Cleft Palate, Progressive Vitreoretinopathy, Growth Retardation, and Developmental Delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition, we emphasize the associated facial dysmorphism to be
      dominated by triangular face, micrognathia and high protruding nasal
      bridge.
    explanation: >-
      Names the dysmorphic pattern the authors put forward.
- name: Triangular face
  category: Craniofacial
  description: A triangular facial shape, reported as part of the dysmorphic pattern.
  phenotype_term:
    preferred_term: Triangular face
    term:
      id: HP:0000325
      label: Triangular face
  evidence:
  - reference: PMID:35656379
    reference_title: A Novel Homozygous Missense Variant in the LRRC32 Gene Is Associated With a New Syndrome of Cleft Palate, Progressive Vitreoretinopathy, Growth Retardation, and Developmental Delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition, we emphasize the associated facial dysmorphism to be
      dominated by triangular face, micrognathia and high protruding nasal
      bridge.
    explanation: Explicitly lists triangular face.
- name: Micrognathia
  category: Craniofacial
  description: >-
    Micrognathia, reported as part of the dysmorphic pattern and clinically
    relevant because it can compound the airway and feeding difficulty of a cleft
    palate.
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  evidence:
  - reference: PMID:35656379
    reference_title: A Novel Homozygous Missense Variant in the LRRC32 Gene Is Associated With a New Syndrome of Cleft Palate, Progressive Vitreoretinopathy, Growth Retardation, and Developmental Delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition, we emphasize the associated facial dysmorphism to be
      dominated by triangular face, micrognathia and high protruding nasal
      bridge.
    explanation: Explicitly lists micrognathia.
- name: Prominent nasal bridge
  category: Craniofacial
  description: A high, protruding nasal bridge, reported as part of the dysmorphic pattern.
  phenotype_term:
    preferred_term: High protruding nasal bridge
    term:
      id: HP:0000426
      label: Prominent nasal bridge
  evidence:
  - reference: PMID:35656379
    reference_title: A Novel Homozygous Missense Variant in the LRRC32 Gene Is Associated With a New Syndrome of Cleft Palate, Progressive Vitreoretinopathy, Growth Retardation, and Developmental Delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition, we emphasize the associated facial dysmorphism to be
      dominated by triangular face, micrognathia and high protruding nasal
      bridge.
    explanation: Explicitly lists the high protruding nasal bridge.
- name: Posteriorly rotated ears
  category: Craniofacial
  description: Posteriorly rotated ears, reported in the fourth patient.
  phenotype_term:
    preferred_term: Posteriorly rotated ears
    term:
      id: HP:0000358
      label: Posteriorly rotated ears
  evidence:
  - reference: PMID:35656379
    reference_title: A Novel Homozygous Missense Variant in the LRRC32 Gene Is Associated With a New Syndrome of Cleft Palate, Progressive Vitreoretinopathy, Growth Retardation, and Developmental Delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      microcephaly with dysmorphic facial features including triangular face,
      micrognathia, posteriorly rotated ears, a high protruding nasal bridge;
      and mild to moderate global developmental delay
    explanation: Documents posteriorly rotated ears in the fourth patient.
- name: Ventriculomegaly
  category: Neurologic
  description: >-
    Ventriculomegaly on brain imaging was reported in the patients of the 2019
    discovery series. It was not present in the fourth patient, whose imaging
    instead showed reduced white matter volume in the setting of a documented
    perinatal haemorrhage.
  phenotype_term:
    preferred_term: Ventriculomegaly
    term:
      id: HP:0002119
      label: Ventriculomegaly
  evidence:
  - reference: PMID:35656379
    reference_title: A Novel Homozygous Missense Variant in the LRRC32 Gene Is Associated With a New Syndrome of Cleft Palate, Progressive Vitreoretinopathy, Growth Retardation, and Developmental Delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Finally, MRI changes in our patient showed decreased white matter volume
      in contrast with ventriculomegaly and corpus callosum abnormalities that
      were seen in the previously reported patients.
    explanation: >-
      Attributes ventriculomegaly to the previously reported patients and
      explicitly contrasts it with the fourth patient's imaging.
- name: Abnormal corpus callosum morphology
  category: Neurologic
  description: >-
    Corpus callosum abnormalities on brain imaging were reported in the patients
    of the 2019 discovery series. The specific abnormality is not resolvable from
    the sources cached for this entry.
  phenotype_term:
    preferred_term: Corpus callosum abnormality
    term:
      id: HP:0001273
      label: Abnormal corpus callosum morphology
  evidence:
  - reference: PMID:35656379
    reference_title: A Novel Homozygous Missense Variant in the LRRC32 Gene Is Associated With a New Syndrome of Cleft Palate, Progressive Vitreoretinopathy, Growth Retardation, and Developmental Delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Finally, MRI changes in our patient showed decreased white matter volume
      in contrast with ventriculomegaly and corpus callosum abnormalities that
      were seen in the previously reported patients.
    explanation: >-
      Attributes corpus callosum abnormalities to the previously reported
      patients.
genetic:
- name: Biallelic LRRC32 loss-of-function variants
  gene_term:
    preferred_term: LRRC32
    term:
      id: hgnc:4161
      label: LRRC32
  relationship_type: CAUSATIVE
  notes: >-
    Two alleles are published. The homozygous nonsense c.1630C>T p.(Arg544Ter)
    segregated in the two families of the 2019 discovery series; it truncates
    GARP before the transmembrane domain and is predicted to leave a soluble
    product, but neither the abundance of that product nor its residual activity
    has been measured. The homozygous missense c.980T>C p.Ile327Thr in the fourth
    patient was classified a variant of uncertain significance under ACMG
    criteria (PM2, PP3, PP4) and was supported by structural modelling rather
    than by a functional assay. No ClinGen gene-disease validity assertion for
    LRRC32 was found in the local structured-source cache. Because both reports
    come from the same country and share a senior author, the four patients are
    not four independent ascertainments in the usual sense.
  variants:
  - name: c.1630C>T p.(Arg544Ter)
    description: >-
      Homozygous stop-gain in LRRC32 identified in two families in the discovery
      series.
  - name: c.980T>C p.Ile327Thr
    description: >-
      Homozygous missense in LRRC32 in the fourth patient, substituting a
      conserved isoleucine between leucine-rich repeats R11 and R12; classified a
      variant of uncertain significance.
  evidence:
  - reference: PMID:30976112
    reference_title: "Homozygous stop-gain variant in LRRC32, encoding a TGFβ receptor, associated with cleft palate, proliferative retinopathy, and developmental delay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our study establishes LRRC32 as a candidate disease-associated gene in
      humans and lends further support to the role of the TGFβ pathway in
      palatogenesis and retinal development.
    explanation: >-
      The discovery report itself calls LRRC32 a candidate disease gene, which is
      the strength of claim this entry records.
  - reference: PMID:35656379
    reference_title: A Novel Homozygous Missense Variant in the LRRC32 Gene Is Associated With a New Syndrome of Cleft Palate, Progressive Vitreoretinopathy, Growth Retardation, and Developmental Delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition, we identified the homozygous c.980T > C variant in the LRRC32
      gene, which was not found in known databases.
    explanation: >-
      Documents the second published allele.
  - reference: PMID:35656379
    reference_title: A Novel Homozygous Missense Variant in the LRRC32 Gene Is Associated With a New Syndrome of Cleft Palate, Progressive Vitreoretinopathy, Growth Retardation, and Developmental Delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The variant was classified variant of uncertain significance (VUS)
      according to ACMG classification (PM2, PP3, PP4) (27).
    explanation: >-
      Records that the second allele has not reached pathogenic classification,
      which bounds the strength of the gene-disease claim.
animal_models:
- name: Garp (Lrrc32) knockout mouse
  species: Mouse
  genotype: Lrrc32 (Garp) constitutive knockout, homozygous null
  publication: PMID:28912269
  description: >-
    A constitutive GARP knockout mouse generated to test GARP's role in organ
    development. Homozygous nulls die within 24 hours of birth with a cleft
    secondary palate and no other apparent major-organ abnormality, and show
    reduced SMAD2 phosphorylation and reduced apoptosis in the medial edge
    epithelium of the palatal shelf at E14.5. The palatal phenotype copies that
    of the TGF-beta3 knockout.
  genes:
  - preferred_term: LRRC32
    term:
      id: hgnc:4161
      label: LRRC32
  modeled_mechanisms:
  - target: Reduced SMAD2 Phosphorylation in Palatal Medial Edge Epithelium
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: >-
      The node is defined by measurements made in this model: reduced SMAD2
      phosphorylation and reduced apoptosis in the palatal medial edge
      epithelium at E14.5.
    limitations: >-
      The corresponding human tissue has never been examined, so the cellular
      step is assumed rather than shown in patients.
    readouts:
    - name: SMAD2 phosphorylation in palatal medial edge epithelium at E14.5
      target: Reduced SMAD2 Phosphorylation in Palatal Medial Edge Epithelium
      direction: DECREASED
      interpretation: >-
        A direct readout of TGF-beta receptor signalling output in the epithelium
        that must fuse.
      evidence:
      - reference: PMID:28912269
        reference_title: Glycoprotein A repetitions predominant (GARP) positively regulates transforming growth factor (TGF) β3 and is essential for mouse palatogenesis.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Furthermore, we observed decreased apoptosis and SMAD2 phosphorylation
          in the medial edge epithelial cells of the palatal shelf of GARP KO
          embryos at embryonic day 14.5 (E14.5), indicating a defect in the TGFβ
          signaling pathway in the GARP-null developing palates.
        explanation: Reports the measurement and its direction.
    - name: Apoptosis in palatal medial edge epithelium at E14.5
      target: Reduced SMAD2 Phosphorylation in Palatal Medial Edge Epithelium
      direction: DECREASED
      interpretation: >-
        Programmed cell death removes the midline epithelial seam; its reduction
        is the cellular failure that leaves the seam intact.
      evidence:
      - reference: PMID:28912269
        reference_title: Glycoprotein A repetitions predominant (GARP) positively regulates transforming growth factor (TGF) β3 and is essential for mouse palatogenesis.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Furthermore, we observed decreased apoptosis and SMAD2 phosphorylation
          in the medial edge epithelial cells of the palatal shelf of GARP KO
          embryos at embryonic day 14.5 (E14.5), indicating a defect in the TGFβ
          signaling pathway in the GARP-null developing palates.
        explanation: Reports the measurement and its direction.
    evidence:
    - reference: PMID:28912269
      reference_title: Glycoprotein A repetitions predominant (GARP) positively regulates transforming growth factor (TGF) β3 and is essential for mouse palatogenesis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Our findings indicate that GARP is essential for normal morphogenesis of
        the palate and demonstrate that GARP plays a crucial role in regulating
        TGFβ3 signaling during embryogenesis.
      explanation: >-
        Supports treating this model as informative for the palatal signalling
        node.
  - target: Failure of Palatal Shelf Fusion
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: TISSUE
    description: >-
      GARP-null mice fail to develop the secondary palate, the same anatomical
      lesion seen in patients, and the defect is isolated to the palate among
      major organs.
    limitations: >-
      The mouse allele is a constitutive null while the human discovery allele is
      a late truncation that may leave a soluble product, so the mouse models the
      complete-loss end of the allelic series rather than the patients' genotype
      specifically.
    evidence:
    - reference: PMID:28912269
      reference_title: Glycoprotein A repetitions predominant (GARP) positively regulates transforming growth factor (TGF) β3 and is essential for mouse palatogenesis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Unexpectedly, the GARP KO mice died within 24 h after birth and
        exhibited defective palatogenesis without apparent abnormalities in other
        major organs.
      explanation: >-
        The model reproduces the human palatal lesion.
  - target: Disordered Vitreoretinal Development
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    model_scale: ORGANISM
    description: >-
      No retinal abnormality was observed in the GARP-deficient mouse, so the
      model does not reproduce the ocular arm of the human syndrome.
    limitations: >-
      The mice die within 24 hours of birth, which precludes the postnatal window
      in which the human vitreoretinopathy appears and progresses; the negative
      result therefore cannot distinguish a species difference from a censored
      observation, and cannot be used to argue that the retinal arm is not
      GARP-dependent.
    evidence:
    - reference: PMID:35656379
      reference_title: A Novel Homozygous Missense Variant in the LRRC32 Gene Is Associated With a New Syndrome of Cleft Palate, Progressive Vitreoretinopathy, Growth Retardation, and Developmental Delay.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Nevertheless, in the garp deficient murine model, retinal impairment was
        not observed (23). This may be explained by early lethality of the mice,
        which precludes later evolution of vitreoretinopathy.
      explanation: >-
        States both the negative retinal finding in the model and the lethality
        that limits its interpretation.
  evidence:
  - reference: PMID:35656379
    reference_title: A Novel Homozygous Missense Variant in the LRRC32 Gene Is Associated With a New Syndrome of Cleft Palate, Progressive Vitreoretinopathy, Growth Retardation, and Developmental Delay.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Accordingly, garp knockout mice had early lethality and also defective
      palatogenesis (23).
    explanation: >-
      The clinical report cites this mouse as the animal counterpart of the human
      palatal phenotype.
treatments:
- name: Palatoplasty
  description: >-
    Surgical repair of the cleft secondary palate, performed in infancy in the
    reported patients. This corrects the anatomical defect; it does not address
    the underlying signalling lesion.
  action_category: THERAPEUTIC
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: cleft palate repair
    term:
      id: NCIT:C168380
      label: Palatorrhaphy
  target_phenotypes:
  - preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  evidence:
  - reference: PMID:35656379
    reference_title: A Novel Homozygous Missense Variant in the LRRC32 Gene Is Associated With a New Syndrome of Cleft Palate, Progressive Vitreoretinopathy, Growth Retardation, and Developmental Delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additionally, he had cleft palate that was corrected surgically at age 1
      year.
    explanation: >-
      Documents surgical repair of the cleft palate in a reported patient.
- name: Retinal Laser Photocoagulation
  description: >-
    Prophylactic argon laser photocoagulation of the peripheral retina to wall
    off tractional lesions and prevent retinal detachment. The reported patient
    required a second treatment a year later when a new vitreoretinal traction
    appeared. This is a single-patient experience, not evidence of efficacy in
    this syndrome.
  action_category: THERAPEUTIC
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: argon laser photocoagulation
    term:
      id: NCIT:C217424
      label: Laser Photocoagulation
  target_phenotypes:
  - preferred_term: Progressive proliferative vitreoretinopathy
    term:
      id: HP:0007773
      label: Vitreoretinopathy
  target_mechanisms:
  - target: Vitreoretinopathy
    description: >-
      Laser treats the tractional and proliferative consequence in the retina; it
      does not act on the GARP-TGF-beta lesion upstream of it.
  evidence:
  - reference: PMID:35656379
    reference_title: A Novel Homozygous Missense Variant in the LRRC32 Gene Is Associated With a New Syndrome of Cleft Palate, Progressive Vitreoretinopathy, Growth Retardation, and Developmental Delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient underwent preventive argon laser photocoagulation in both eyes
    explanation: >-
      Documents the intervention used in the one patient with detailed ophthalmic
      follow-up.
  - reference: PMID:35656379
    reference_title: A Novel Homozygous Missense Variant in the LRRC32 Gene Is Associated With a New Syndrome of Cleft Palate, Progressive Vitreoretinopathy, Growth Retardation, and Developmental Delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A second laser photocoagulation treatment was done to prevent retinal
      detachment.
    explanation: >-
      Records the repeat treatment and its stated aim, and with it the
      progressive course that made a second treatment necessary.
- name: Serial Ophthalmologic Surveillance
  description: >-
    Repeated fundus examination and optical coherence tomography. The one patient
    followed in detail developed a new peripheral vitreoretinal traction within a
    year of his first laser treatment, which is the observation that motivates
    surveillance rather than one-off assessment. No screening interval has been
    established for this syndrome.
  action_category: MONITORING
  treatment_term:
    preferred_term: fundus examination and optical coherence tomography
    term:
      id: NCIT:C38060
      label: Eye Examination
  evidence:
  - reference: PMID:35656379
    reference_title: A Novel Homozygous Missense Variant in the LRRC32 Gene Is Associated With a New Syndrome of Cleft Palate, Progressive Vitreoretinopathy, Growth Retardation, and Developmental Delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One year later, on follow up examination, a new large vitreoretinal
      traction on the peripheral retinal region of the left eye was seen
    explanation: >-
      Demonstrates that a new sight-threatening lesion appeared between
      examinations, which is the case for continued surveillance.
  notes: >-
    Carries no target_phenotypes. This is a MONITORING action, and
    target_phenotypes is a treatment-style link asserting that the action acts
    on the phenotype; surveillance observes the vitreoretinopathy rather than
    treating it, so the link would misstate what the entry claims. The
    phenotype under surveillance is named in the description and in
    preferred_term instead. Enforced by
    check_non_therapeutic_actions_do_not_use_treatment_targets.
- name: Developmental and Rehabilitative Support
  description: >-
    Early intervention and rehabilitation for the global developmental delay.
    Nothing specific to this syndrome has been published; the sources establish
    that delay is present in every patient, not what should be done about it.
  action_category: THERAPEUTIC
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: developmental rehabilitation
    term:
      id: NCIT:C15315
      label: Rehabilitation
  target_phenotypes:
  - preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  notes: >-
    Recorded as standard supportive management inferred from the phenotype. No
    cited source evaluates a developmental intervention in this syndrome, so no
    evidence item is attached rather than a snippet being stretched to cover one.
- name: Genetic Counseling
  description: >-
    Autosomal recessive recurrence risk counselling for the family, with carrier
    testing where an allele is known. Both published kindreds were consanguineous,
    and segregation testing in the 2022 family returned the expected mix of
    heterozygous and non-carrier siblings, which is the concrete question carrier
    testing is offered to answer. The diagnostic testing that makes counselling
    possible is curated under `diagnosis:` rather than here.
  action_category: COUNSELING_INFORMATIONAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:35656379
    reference_title: A Novel Homozygous Missense Variant in the LRRC32 Gene Is Associated With a New Syndrome of Cleft Palate, Progressive Vitreoretinopathy, Growth Retardation, and Developmental Delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two siblings (III-1 and III-5) were heterozygous and three siblings (III-3, III-4, and III-6) did not carry the variant"
    explanation: >-
      Sibling carrier testing in the reported kindred, which is the counselling
      action offered to at-risk relatives once an allele is known.
diagnosis:
- name: Molecular Diagnosis by Exome Sequencing
  description: >-
    The diagnosis is molecular. With four patients in three families there is no
    clinical gestalt specific enough to make it, so both published reports reached
    it by exome sequencing, one of them as a parent-proband trio. Sanger sequencing
    of the relevant LRRC32 exon then confirms the variant and establishes
    segregation in the family, and genome sequencing is the alternative where
    exome is uninformative. Because the presenting feature is usually the cleft
    palate, the practical route to the diagnosis is LRRC32 being on the cleft
    palate gene panel in the first place.
  diagnosis_term:
    preferred_term: whole exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  presence: Positive
  results: >-
    Biallelic LRRC32 variants. The two 2019 families carried the homozygous
    stop-gain c.1630C>T p.(Arg544Ter); the 2022 patient carried the homozygous
    missense c.980T>C p.(Ile327Thr). In the 2022 patient the same exome also
    returned a second, independent recessive diagnosis (homozygous SLC22A5
    c.1354G>A, primary carnitine deficiency), which is why the cardiomyopathy in
    that patient is not attributed to LRRC32.
  evidence:
  - reference: PMID:35656379
    reference_title: A Novel Homozygous Missense Variant in the LRRC32 Gene Is Associated With a New Syndrome of Cleft Palate, Progressive Vitreoretinopathy, Growth Retardation, and Developmental Delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole exome sequencing (WES) revealed a very rare homozygous missense variant in the LRRC32 gene"
    explanation: >-
      Establishes exome sequencing as the modality that made the diagnosis in the
      second reported family.
  - reference: PMID:35656379
    reference_title: A Novel Homozygous Missense Variant in the LRRC32 Gene Is Associated With a New Syndrome of Cleft Palate, Progressive Vitreoretinopathy, Growth Retardation, and Developmental Delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we strongly suggest to include LRRC32 in gene panels targeted for diagnosis of patients with cleft palate"
    explanation: >-
      The authors' explicit recommendation that LRRC32 be included on diagnostic
      gene panels for cleft palate, which is the testing route by which this
      syndrome is reached.
- name: Diagnostic Ophthalmologic Evaluation
  description: >-
    Fundoscopy with optical coherence tomography is what converts a nonspecific
    developmental presentation into this syndrome, because the vitreoretinal
    findings are the discriminating feature against other cleft palate syndromes.
    It is also the examination that finds traction and retinal tears while they
    are still treatable by prophylactic laser, so the same modality recurs under
    `treatments:` as ongoing surveillance; this record is the evaluation at
    diagnosis rather than the surveillance interval.
  diagnosis_term:
    preferred_term: ophthalmologic examination with fundoscopy and optical coherence tomography
    term:
      id: NCIT:C38060
      label: Eye Examination
  presence: Positive
  results: >-
    Mildly reduced visual acuity with normal ocular movements and a normal
    anterior segment; Bergmeister papillae and straightened retinal vessels on
    fundoscopy; and on optical coherence tomography a thickened vitreous firmly
    attached to the retinal periphery, with traction and secondary retinal tears.
  evidence:
  - reference: PMID:35656379
    reference_title: A Novel Homozygous Missense Variant in the LRRC32 Gene Is Associated With a New Syndrome of Cleft Palate, Progressive Vitreoretinopathy, Growth Retardation, and Developmental Delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ophthalmological evaluation at age 13 years demonstrated mildly decreased visual acuity of 20/30 in the right eye and 20/40 in the left eye."
    explanation: >-
      Documents the ophthalmologic evaluation performed at diagnosis and its
      acuity findings.
  - reference: PMID:35656379
    reference_title: A Novel Homozygous Missense Variant in the LRRC32 Gene Is Associated With a New Syndrome of Cleft Palate, Progressive Vitreoretinopathy, Growth Retardation, and Developmental Delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These retinal abnormalities were also evident by optical coherence tomography, which revealed retinopathy mainly involving the vitreal regions"
    explanation: >-
      Establishes optical coherence tomography as the imaging modality that
      characterised the vitreoretinal lesion.
differential_diagnoses:
- name: Familial exudative vitreoretinopathy
  disease_term:
    preferred_term: familial exudative vitreoretinopathy
    term:
      id: MONDO:0019516
      label: exudative vitreoretinopathy
  description: >-
    FEVR produces peripheral vitreoretinal traction, retinal folds, and
    tractional detachment that can look like the ocular arm of this syndrome, but
    it arises from impaired Norrin/FZD4/beta-catenin signalling in retinal
    vascular endothelium rather than from deficient TGF-beta activation.
  distinguishing_features:
  - Cleft palate and developmental delay are not features of familial exudative vitreoretinopathy.
  - Familial exudative vitreoretinopathy is usually autosomal dominant (FZD4, LRP5, TSPAN12), with recessive and X-linked forms; this syndrome is recessive and LRRC32-related.
  - The FEVR retina has a peripheral avascular zone on fluorescein angiography, which has not been reported in this syndrome.
  notes: >-
    Listed on the strength of the shared ocular picture and the distinct
    molecular pathway. The sources cached for this entry do not perform a
    head-to-head comparison, and no fluorescein angiography has been published in
    an LRRC32 patient, so the third distinguishing feature is an absence of data
    rather than a demonstrated difference.
- name: Stickler syndrome
  disease_term:
    preferred_term: Stickler syndrome
    term:
      id: MONDO:0019354
      label: Stickler syndrome
  description: >-
    The closest clinical mimic. Stickler syndrome pairs cleft palate, often
    within a Pierre Robin sequence, with a vitreoretinopathy that leads to
    retinal detachment, so it reproduces two of the three defining features.
  distinguishing_features:
  - Stickler syndrome adds myopia, cataract, conductive and sensorineural hearing loss, midfacial underdevelopment, and early-onset degenerative joint disease, none of which has been reported in the LRRC32 patients.
  - Stickler syndrome is a collagen disorder (COL2A1, COL11A1, COL11A2 dominant; COL9A1, COL9A2, COL9A3 recessive), so molecular testing separates the two cleanly.
  - Developmental delay is not a feature of Stickler syndrome, whereas it is one of the three defining features here.
  evidence:
  - reference: PMID:20301479
    reference_title: Stickler Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    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 description establishes both the overlap (cleft
      palate with a retinal-detaching vitreoretinopathy) and the extra features
      that separate Stickler syndrome from this entry.
  - reference: PMID:20301479
    reference_title: Stickler Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The diagnosis of Stickler syndrome can be established in a proband with
      characteristic clinical features and/or a heterozygous pathogenic variant
      in COL2A1, COL11A1, or COL11A2 or biallelic pathogenic variants in COL9A1,
      COL9A2, or COL9A3 identified by molecular genetic testing.
    explanation: >-
      Names the causal genes that make the molecular distinction from LRRC32
      disease decisive.
  notes: >-
    Cited from the Stickler syndrome GeneReviews chapter. No GeneReviews chapter
    exists for the LRRC32 syndrome itself, and no source compares the two
    directly; the contrast drawn here is between the two clinical descriptions.
- name: Retinopathy of prematurity
  disease_term:
    preferred_term: retinopathy of prematurity
    term:
      id: MONDO:0006952
      label: retinopathy of prematurity
  description: >-
    This is not a theoretical confusion. The fourth published patient was born at
    34 weeks and carried a diagnosis of grade I retinopathy of prematurity from
    the neonatal period; his later vitreoretinal disease was initially attributed
    to it.
  distinguishing_features:
  - Retinopathy of prematurity does not progress in the way the reported patient's disease did, and the location of his lesions did not fit it.
  - Cleft palate, growth restriction, and developmental delay point to a syndromic diagnosis rather than a complication of prematurity.
  evidence:
  - reference: PMID:35656379
    reference_title: A Novel Homozygous Missense Variant in the LRRC32 Gene Is Associated With a New Syndrome of Cleft Palate, Progressive Vitreoretinopathy, Growth Retardation, and Developmental Delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, the progressive nature and distinctive location of his
      retinopathy excluded retinopathy of prematurity as the cause of his
      ophthalmological disease.
    explanation: >-
      The authors state the reasoning by which they separated the two diagnoses
      in a patient who genuinely had both risk factors.
discussions:
- discussion_id: cpprdd_mouse_no_retinal_phenotype
  prompt: >-
    Does GARP loss cause the human vitreoretinopathy, given that the Garp-null
    mouse has no retinal phenotype but dies within 24 hours of birth?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Disordered Vitreoretinal Development
  - animal_models#Mouse
  rationale: >-
    The retinal arm of this syndrome has no animal counterpart. The only
    published GARP loss-of-function animal, the constitutive knockout mouse, dies
    within a day of birth with an isolated palatal defect and no reported retinal
    abnormality. The human vitreoretinopathy is childhood-onset and progressive,
    so the mouse is censored before the phenotype would appear. The negative
    result therefore neither supports nor refutes a GARP-dependent retinal
    mechanism, and the retinal arm of the pathophysiology rests on human
    observation in four patients plus the general requirement for TGF-beta in
    retinal development shown in ligand-knockout mice. The mismatch runs in both
    directions and the reverse half is the more interesting one: the mouse null
    is neonatally lethal and the patients are not, so either the human alleles
    are hypomorphic rather than null, or human development depends less
    absolutely on GARP than mouse development does. Whichever it is bears
    directly on how much of the mouse mechanism transfers.
  proposed_experiments:
  - experiment_id: exp_cpprdd_conditional_lrrc32_retina
    name: Postnatal and retina-restricted Lrrc32 deletion
    description: >-
      Bypass the neonatal lethality with a conditional Lrrc32 allele deleted
      either postnatally or in retinal and vitreous-associated lineages, then
      follow the eyes longitudinally with fundus imaging, optical coherence
      tomography, and fluorescein angiography into adulthood, scoring for
      persistent hyaloid vasculature, vitreous condensation, vitreoretinal
      traction, and retinal tears. A knock-in of the human p.(Arg544Ter) allele
      would test the patients' genotype rather than complete loss.
    would_support:
    - pathophysiology#Disordered Vitreoretinal Development
    supporting_outcome:
    - >-
      Conditional or knock-in animals surviving past the neonatal period develop
      a persistent hyaloid remnant and peripheral vitreoretinal traction
      resembling the human disease.
    refuting_outcome:
    - >-
      Animals surviving to adulthood have normal retinal and vitreous anatomy on
      serial imaging and histology, which would place the human retinal phenotype
      outside a direct GARP-dependent mechanism.
  evidence:
  - reference: PMID:35656379
    reference_title: A Novel Homozygous Missense Variant in the LRRC32 Gene Is Associated With a New Syndrome of Cleft Palate, Progressive Vitreoretinopathy, Growth Retardation, and Developmental Delay.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Nevertheless, in the garp deficient murine model, retinal impairment was
      not observed (23). This may be explained by early lethality of the mice,
      which precludes later evolution of vitreoretinopathy.
    explanation: >-
      States the mismatch and the authors' own explanation for it.
  - reference: PMID:28912269
    reference_title: Glycoprotein A repetitions predominant (GARP) positively regulates transforming growth factor (TGF) β3 and is essential for mouse palatogenesis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Unexpectedly, the GARP KO mice died within 24 h after birth and exhibited
      defective palatogenesis without apparent abnormalities in other major
      organs.
    explanation: >-
      Establishes both the neonatal lethality that censors the model and the
      absence of other reported organ phenotypes.
  - reference: PMID:31053781
    reference_title: Truncation of TGF-β docking receptor GARP is linked to human disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Fourth, the current study also suggests that loss of
      GARP function does not cause acute lethality.
    explanation: >-
      States the reverse half of the mismatch: the human patients survive where
      the mouse null does not, which the commentary reads as a substantive
      finding about GARP rather than an incidental difference.
- discussion_id: cpprdd_tgfbeta_direction_paradox
  prompt: >-
    How does a lesion that reduces local TGF-beta activation produce a
    proliferative vitreoretinopathy, when TGF-beta is elevated in the vitreous of
    patients with the common proliferative vitreoretinal diseases?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Disordered Vitreoretinal Development
  - pathophysiology#Deficient Local Activation of TGF-beta
  rationale: >-
    The mechanism curated here is deficient GARP-dependent activation of latent
    TGF-beta, so the expected ocular consequence is a developmental one. The
    clinical picture, however, is described as proliferative and is
    fibrocontractile: a thickened adherent vitreous exerting traction. In
    acquired proliferative vitreoretinopathy and proliferative diabetic
    retinopathy, TGF-beta is overexpressed in the vitreous and drives the
    contraction of preretinal membranes, the opposite direction of change. Either
    the lesion here is developmental and only resembles the acquired
    proliferative diseases superficially, or a local deficit of TGF-beta provokes
    a compensatory or dysregulated response elsewhere in the eye. The published
    material does not decide between these, and no vitreous TGF-beta measurement
    has ever been made in an LRRC32 patient.
  proposed_experiments:
  - experiment_id: exp_cpprdd_vitreous_tgfbeta
    name: TGF-beta isoform profiling of vitreous and preretinal membranes
    description: >-
      In any LRRC32 patient coming to vitrectomy, assay vitreous concentrations
      of active and total TGF-beta1, -beta2, and -beta3 alongside age-matched
      non-proliferative controls and acquired proliferative vitreoretinopathy
      controls, and stain any excised preretinal tissue for alpha-smooth muscle
      actin and phospho-SMAD2.
    would_support:
    - pathophysiology#Deficient Local Activation of TGF-beta
    supporting_outcome:
    - >-
      Vitreous active TGF-beta is low or normal rather than elevated, and excised
      tissue shows no phospho-SMAD2-positive myofibroblastic reaction, placing
      the lesion outside the acquired proliferative mechanism.
    refuting_outcome:
    - >-
      Vitreous active TGF-beta is elevated to the range seen in acquired
      proliferative vitreoretinopathy, which would mean the ocular disease is not
      a straightforward consequence of deficient TGF-beta activation.
  evidence:
  - reference: PMID:18952846
    reference_title: Role of TGF-beta in proliferative vitreoretinal diseases and ROCK as a therapeutic target.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      TGF-beta is overexpressed in the vitreous of patients with proliferative
      vitreoretinal diseases and is also detectable in the contractile membranes.
    explanation: >-
      Establishes the direction of TGF-beta change in the acquired proliferative
      vitreoretinal diseases, which is what makes this mechanism
      counterintuitive. The paper is about proliferative diabetic retinopathy and
      acquired proliferative vitreoretinopathy, not about LRRC32 disease.
  - reference: PMID:35656379
    reference_title: A Novel Homozygous Missense Variant in the LRRC32 Gene Is Associated With a New Syndrome of Cleft Palate, Progressive Vitreoretinopathy, Growth Retardation, and Developmental Delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A thickened vitreous firmly attached to the retinal periphery was noted,
      with traction and secondary retinal tears.
    explanation: >-
      Describes the fibrocontractile character of the human ocular lesion that
      sits awkwardly with a loss-of-TGF-beta mechanism.
- discussion_id: cpprdd_truncated_garp_residual_function
  prompt: >-
    Is p.(Arg544Ter) a true null, and does it release a soluble GARP ectodomain
    that retains any ability to bind and activate latent TGF-beta?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#GARP Loss of Function
  - genetic#Biallelic LRRC32 loss-of-function variants
  rationale: >-
    The whole entry rests on GARP loss of function, and neither published allele
    has been assayed. The nonsense allele truncates before the transmembrane
    domain and would be predicted to yield a soluble ectodomain rather than no
    protein, and soluble GARP is not inert. The missense allele is supported only
    by structural modelling and remains a variant of uncertain significance. A
    related observation sharpens the question: no autoimmune disease was reported
    in the patients, despite GARP's established role in regulatory T cell
    TGF-beta presentation and immune tolerance, which is compatible with residual
    function, with redundancy from the related milieu molecule LRRC33, or with
    the immune phenotype simply not having been looked for.
  proposed_experiments:
  - experiment_id: exp_cpprdd_allele_function
    name: Functional characterisation of the two published LRRC32 alleles
    description: >-
      Express the p.(Arg544Ter) and p.Ile327Thr alleles in a GARP-null cell
      background alongside wild type, and measure GARP protein abundance, surface
      versus secreted distribution, co-immunoprecipitation with
      latency-associated peptide, surface latent TGF-beta1 by flow cytometry, and
      integrin-alphaVbeta8-dependent release of active TGF-beta in a reporter
      assay. Test patient-derived cells where available, and phenotype regulatory
      T cell surface latent TGF-beta in surviving patients.
    would_support:
    - pathophysiology#GARP Loss of Function
    supporting_outcome:
    - >-
      Both alleles abolish or sharply reduce surface presentation of latent
      TGF-beta and integrin-dependent activation relative to wild type.
    refuting_outcome:
    - >-
      Either allele supports near-normal surface presentation and activation,
      which would mean the curated mechanism is not the operative one for that
      genotype.
  evidence:
  - reference: PMID:35656379
    reference_title: A Novel Homozygous Missense Variant in the LRRC32 Gene Is Associated With a New Syndrome of Cleft Palate, Progressive Vitreoretinopathy, Growth Retardation, and Developmental Delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, the proposed mechanism for a missense variant leading to loss of
      function effect would require further functional validation.
    explanation: >-
      The authors of the second allele say explicitly that the loss-of-function
      mechanism is unvalidated.
  - reference: PMID:30361387
    reference_title: Structural basis of latent TGF-β1 presentation and activation by GARP on human regulatory T cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Regulatory T cells (Tregs) suppress immune cells within close proximity by
      activating latent TGF-β1 presented by GARP (glycoprotein A repetitions
      predominant) to integrin αVβ8 on their surface.
    explanation: >-
      Names the regulatory T cell function that makes the absence of a reported
      immune phenotype in these patients worth explaining.
- discussion_id: cpprdd_case_count_and_spectrum
  prompt: >-
    Is the published four-patient series the whole phenotypic spectrum of
    LRRC32-related disease, and do LRRC32 variants found in unselected cleft
    palate cohorts represent the same entity?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - genetic#Biallelic LRRC32 loss-of-function variants
  - prevalence#Published literature worldwide
  rationale: >-
    Four patients from three families, all ascertained in Israel and reported by
    two overlapping groups, define this disease. That is enough to make the
    gene-disease relationship credible and not enough to describe a spectrum: it
    is not known whether milder alleles produce isolated cleft palate or isolated
    vitreoretinopathy, whether the growth restriction and dysmorphism are
    constant, or what the natural history of the eye disease is beyond
    adolescence. An exome study of consanguineous Kuwaiti cleft lip and palate
    families subsequently reported a novel LRRC32 variant in a syndromic case,
    which is a lead worth following rather than a confirmed additional patient:
    that report does not state the zygosity, does not describe a retinopathy, and
    does not claim this diagnosis.
  proposed_experiments:
  - experiment_id: exp_cpprdd_lrrc32_cohort_screen
    name: Targeted LRRC32 screening of syndromic cleft palate and paediatric vitreoretinopathy cohorts
    description: >-
      Screen LRRC32 in two independent, deliberately different ascertainment
      frames, syndromic isolated cleft palate cohorts and unexplained paediatric
      vitreoretinopathy cohorts, and phenotype any biallelic carriers for the
      full triad, so the spectrum is described from both ends rather than from
      the craniofacial end alone.
    would_support:
    - genetic#Biallelic LRRC32 loss-of-function variants
    supporting_outcome:
    - >-
      Biallelic LRRC32 carriers are found in both frames and show overlapping but
      non-identical combinations of the triad, defining a spectrum.
    refuting_outcome:
    - >-
      No further biallelic carriers are found in either frame, leaving the entity
      confined to the reported Israeli families.
  evidence:
  - reference: PMID:41041957
    reference_title: Identification of Novel and Rare Gene Variants in Cleft Lip/Palate Patients From Kuwaiti Consanguineous Families by Exome Sequencing.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seven rare gene variants were identified across all cases, including one
      novel variant (LRRC32) in a syndromic case
    explanation: >-
      Reports an LRRC32 variant in an independent syndromic cleft cohort. It
      establishes that LRRC32 recurs in this ascertainment frame; it does not
      state zygosity, does not report retinopathy, and does not make this
      diagnosis, which is why it is recorded as a lead rather than as a fifth
      case.
  - reference: PMID:35656379
    reference_title: A Novel Homozygous Missense Variant in the LRRC32 Gene Is Associated With a New Syndrome of Cleft Palate, Progressive Vitreoretinopathy, Growth Retardation, and Developmental Delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Table 1 summarizes the clinical, radiological and genetic features of all
      four cases reported so far.
    explanation: >-
      Fixes the size of the published series that this gap is about.
notes: >-
  SCOPE AND CONFOUNDING. The fourth published patient carries two recessive
  diseases: alongside the LRRC32 genotype he is homozygous for SLC22A5
  p.Glu452Lys and has primary carnitine deficiency, which the authors identify as
  the cause of his severe dilated cardiomyopathy and which responded to carnitine
  supplementation. Cardiomyopathy is therefore deliberately not curated as a
  phenotype of this syndrome. The same patient was born at 34 weeks with grade I
  intraventricular haemorrhage and necrotising enterocolitis, so his reduced
  cerebral white matter volume is confounded by the documented perinatal
  haemorrhage and is likewise left out of the phenotype list; the
  ventriculomegaly and corpus callosum abnormalities attributed to the earlier
  patients are curated instead.

  NO MODULE CONFORMANCE. Three candidate modules were checked and rejected.
  norrin_fzd4_retinal_vascular_development scopes itself to lesions in the
  Norrin-FZD4 system and explicitly excludes retinal neovascularization reached
  by other routes. aortopathy_tgfbeta_dysregulation models increased TGF-beta
  signalling in the aortic media, the opposite direction of change in a different
  organ. pharyngeal_arch_patterning_serial_homology models cleft palate arising
  from cranial neural crest and arch patterning, whereas the lesion here is a
  failure of TGF-beta signalling in the medial edge epithelium at the fusion
  step. A GARP/latent-TGF-beta-presentation module would be the natural home if
  the handful of diseases in that class ever justifies one.

  EVIDENCE LIMITS. There is no GeneReviews chapter for this disease (a PubMed
  search for one returned no result), no Orphanet record in the local structured
  cache, and no ClinGen gene-disease validity assertion found for LRRC32. Every
  claim about the syndrome itself traces to two primary reports and their
  accompanying commentary. Mechanistic evidence for the GARP-latent-TGF-beta step
  comes from regulatory T cell and platelet cell biology and is graded IN_VITRO
  accordingly; LRRC32/GARP has a large tumour-immunology and regulatory T cell
  literature that concerns the same protein but not this disease, and none of it
  is cited here as human disease evidence. The deep-research report for this
  entry additionally supplied gnomAD v4 constraint metrics and allele
  frequencies for LRRC32 and for p.(Arg544Ter). Those are not curated here: the
  numbers were not independently checked against gnomAD, and this repository has
  no reference-cache path for a gnomAD record, so citing them would have meant
  asserting them without a verifiable source.

  MANAGEMENT NOT SEPARATELY CURATED. Speech therapy and feeding support are
  standard care after palatoplasty and are listed in the deep-research report's
  management table, but nothing in the four-patient literature evaluates them in
  this syndrome specifically, and a snippet supporting them would have to come
  from generic cleft palate care rather than from a source about these patients.
  They are recorded here rather than entered as treatments with borrowed
  evidence. The ocular course is described as progressive - new vitreoretinal
  traction appeared a year after the first laser treatment in the 2022 patient -
  but with one patient followed over one interval there is nothing to phase, so
  no progression: block is modelled; the progression is stated in the
  Diagnostic Ophthalmologic Evaluation and Serial Ophthalmologic Surveillance
  records instead.
datasets: []
clinical_trials: []
references:
- reference: PMID:30976112
  title: "Homozygous stop-gain variant in LRRC32, encoding a TGFβ receptor, associated with cleft palate, proliferative retinopathy, and developmental delay."
- reference: PMID:35656379
  title: A Novel Homozygous Missense Variant in the LRRC32 Gene Is Associated With a New Syndrome of Cleft Palate, Progressive Vitreoretinopathy, Growth Retardation, and Developmental Delay.
- reference: PMID:31053781
  title: Truncation of TGF-β docking receptor GARP is linked to human disease.
- reference: PMID:28912269
  title: Glycoprotein A repetitions predominant (GARP) positively regulates transforming growth factor (TGF) β3 and is essential for mouse palatogenesis.
- reference: PMID:19651619
  title: GARP (LRRC32) is essential for the surface expression of latent TGF-beta on platelets and activated FOXP3+ regulatory T cells.
- reference: PMID:30361387
  title: Structural basis of latent TGF-β1 presentation and activation by GARP on human regulatory T cells.
- reference: PMID:22186724
  title: "Palatogenesis: morphogenetic and molecular mechanisms of secondary palate development."
- reference: PMID:12838410
  title: Reduced programmed cell death in the retina and defects in lens and cornea of Tgfbeta2(-/-) Tgfbeta3(-/-) double-deficient mice.
- reference: PMID:18952846
  title: Role of TGF-beta in proliferative vitreoretinal diseases and ROCK as a therapeutic target.
- reference: PMID:41041957
  title: Identification of Novel and Rare Gene Variants in Cleft Lip/Palate Patients From Kuwaiti Consanguineous Families by Exome Sequencing.
- reference: PMID:20301479
  title: Stickler Syndrome.
  tags: [GeneReviews]
📚

References & Deep Research

References

11
PMID:30976112
Homozygous stop-gain variant in LRRC32, encoding a TGFβ receptor, associated with cleft palate, proliferative retinopathy, and developmental delay.
No top-level findings curated for this source.
PMID:35656379
A Novel Homozygous Missense Variant in the LRRC32 Gene Is Associated With a New Syndrome of Cleft Palate, Progressive Vitreoretinopathy, Growth Retardation, and Developmental Delay.
No top-level findings curated for this source.
PMID:31053781
Truncation of TGF-β docking receptor GARP is linked to human disease.
No top-level findings curated for this source.
PMID:28912269
Glycoprotein A repetitions predominant (GARP) positively regulates transforming growth factor (TGF) β3 and is essential for mouse palatogenesis.
No top-level findings curated for this source.
PMID:19651619
GARP (LRRC32) is essential for the surface expression of latent TGF-beta on platelets and activated FOXP3+ regulatory T cells.
No top-level findings curated for this source.
PMID:30361387
Structural basis of latent TGF-β1 presentation and activation by GARP on human regulatory T cells.
No top-level findings curated for this source.
PMID:22186724
Palatogenesis: morphogenetic and molecular mechanisms of secondary palate development.
No top-level findings curated for this source.
PMID:12838410
Reduced programmed cell death in the retina and defects in lens and cornea of Tgfbeta2(-/-) Tgfbeta3(-/-) double-deficient mice.
No top-level findings curated for this source.
PMID:18952846
Role of TGF-beta in proliferative vitreoretinal diseases and ROCK as a therapeutic target.
No top-level findings curated for this source.
PMID:41041957
Identification of Novel and Rare Gene Variants in Cleft Lip/Palate Patients From Kuwaiti Consanguineous Families by Exome Sequencing.
No top-level findings curated for this source.
PMID:20301479
Stickler Syndrome.
No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (2)

Record notes

SCOPE AND CONFOUNDING. The fourth published patient carries two recessive diseases: alongside the LRRC32 genotype he is homozygous for SLC22A5 p.Glu452Lys and has primary carnitine deficiency, which the authors identify as the cause of his severe dilated cardiomyopathy and which responded to carnitine supplementation. Cardiomyopathy is therefore deliberately not curated as a phenotype of this syndrome. The same patient was born at 34 weeks with grade I intraventricular haemorrhage and necrotising enterocolitis, so his reduced cerebral white matter volume is confounded by the documented perinatal haemorrhage and is likewise left out of the phenotype list; the ventriculomegaly and corpus callosum abnormalities attributed to the earlier patients are curated instead. NO MODULE CONFORMANCE. Three candidate modules were checked and rejected. norrin_fzd4_retinal_vascular_development scopes itself to lesions in the Norrin-FZD4 system and explicitly excludes retinal neovascularization reached by other routes. aortopathy_tgfbeta_dysregulation models increased TGF-beta signalling in the aortic media, the opposite direction of change in a different organ. pharyngeal_arch_patterning_serial_homology models cleft palate arising from cranial neural crest and arch patterning, whereas the lesion here is a failure of TGF-beta signalling in the medial edge epithelium at the fusion step. A GARP/latent-TGF-beta-presentation module would be the natural home if the handful of diseases in that class ever justifies one. EVIDENCE LIMITS. There is no GeneReviews chapter for this disease (a PubMed search for one returned no result), no Orphanet record in the local structured cache, and no ClinGen gene-disease validity assertion found for LRRC32. Every claim about the syndrome itself traces to two primary reports and their accompanying commentary. Mechanistic evidence for the GARP-latent-TGF-beta step comes from regulatory T cell and platelet cell biology and is graded IN_VITRO accordingly; LRRC32/GARP has a large tumour-immunology and regulatory T cell literature that concerns the same protein but not this disease, and none of it is cited here as human disease evidence. The deep-research report for this entry additionally supplied gnomAD v4 constraint metrics and allele frequencies for LRRC32 and for p.(Arg544Ter). Those are not curated here: the numbers were not independently checked against gnomAD, and this repository has no reference-cache path for a gnomAD record, so citing them would have meant asserting them without a verifiable source. MANAGEMENT NOT SEPARATELY CURATED. Speech therapy and feeding support are standard care after palatoplasty and are listed in the deep-research report's management table, but nothing in the four-patient literature evaluates them in this syndrome specifically, and a snippet supporting them would have to come from generic cleft palate care rather than from a source about these patients. They are recorded here rather than entered as treatments with borrowed evidence. The ocular course is described as progressive - new vitreoretinal traction appeared a year after the first laser treatment in the 2022 patient - but with one patient followed over one interval there is nothing to phase, so no progression: block is modelled; the progression is stated in the Diagnostic Ophthalmologic Evaluation and Serial Ophthalmologic Surveillance records instead.

Create: Cleft_Palate_Proliferative_Retinopathy_And_Developmental_Delay · 2026-09-07T17:23:22Z · View source

New Disease entry for cleft palate, proliferative retinopathy, and developmental delay (CPPRDD, MONDO:0033641, OMIM:619074), an ultra-rare autosomal recessive LRRC32/GARP syndrome. LUMP/SPLIT: DISEASE. The stub recorded one causal gene and no MONDO descendants; OLS confirmed MONDO:0033641 is a leaf with an equivalentTo OMIM:619074 xref and the CPPRDD synonym, so it is a single Mendelian entity, not a grouping. DEEP RESEARCH: falcon was requested but the Edison account returned HTTP 402 (out of credits) on two attempts; the run was re-launched with --fallback and openscientist produced the report (research/Cleft_Palate_Proliferative_Retinopathy_And_Developmental_Delay-deep-research-openscientist.md, fell_back: true, requested_provider: falcon). Report reference_validation 8/8 verified, confabulation_rate 0.0, needs_review true solely because PMID:35898500 (a GARP/Treg immuno-oncology review) was flagged off topic; nothing under unresolved_references. term_validation 20/22 resolved with 2 mislabelled (HP:0000175 and HP:0001999 named generically), 2 unverifiable Taxon prefixes; no CURIE was copied from the report - every ontology binding here was looked up independently through OLS. just preflight-dr returned WARN because SMAD2 is mentioned at 41 percent of LRRC32's rate; SMAD2 is the downstream effector in the curated mechanism, not a second disease, and the report's OMIM and gene identity match MONDO, so the WARN was resolved rather than acted on. NAMED ENTITY CONFUSION: LRRC32/GARP carries a large regulatory T cell and tumour-immunology literature that is about the same protein and not about this disease. The three Treg/cancer papers the report cited (PMID:35898500, PMID:36928178, PMID:39288764) and the two acquired-PVR RPE EMT papers (PMID:40466854, PMID:42285191) are deliberately not cited in the entry. The Treg cell-biology work that IS cited (PMID:19651619 Tran 2009, PMID:30361387 Lienart 2018) is graded IN_VITRO and used only for the GARP-latent-TGF-beta tethering and integrin-activation steps, never as human disease evidence. CONTENT: a seven-node causal chain - GARP loss of function, failure of latent TGF-beta tethering at the cell surface, deficient local TGF-beta activation, then three arms (reduced SMAD2 phosphorylation in palatal medial edge epithelium to failure of palatal shelf fusion to cleft palate; disordered vitreoretinal development to vitreoretinopathy; impaired CNS development to global developmental delay). The palatal arm is DIRECT and mouse-demonstrated; the retinal and CNS arms are INDIRECT_UNKNOWN_INTERMEDIATES because the sources themselves hedge. 16 phenotypes with HP bindings, genetic block with both published alleles and genetic_context LOSS_OF_FUNCTION/HOMOZYGOUS/GERMLINE, structured prevalence (CASES_IN_LITERATURE, ULTRA_RARE, four published patients), five treatments (palatoplasty, argon laser photocoagulation, serial ophthalmologic surveillance, developmental support, genetic counselling), three differential diagnoses (Stickler syndrome, familial exudative vitreoretinopathy, retinopathy of prematurity), and four discussions. ANIMAL MODEL: the Garp knockout mouse (PMID:28912269) with three modeled_mechanisms - RECAPITULATES the palatal signalling node (two readouts) and the fusion failure, and FAILS_TO_RECAPITULATE disordered vitreoretinal development, with limitations recording that 24-hour neonatal lethality censors the observation. That negative is paired with a HUMAN_MODEL_MISMATCH discussion that also records the reverse half of the mismatch - the mouse null dies and the patients do not. SCOPE DECISIONS. Cardiomyopathy is NOT curated: the fourth patient's dilated cardiomyopathy is attributed by the authors to a second recessive disease, primary carnitine deficiency from homozygous SLC22A5 p.Glu452Lys, and it responded to carnitine. His reduced cerebral white matter volume is likewise excluded as confounded by a documented grade I intraventricular haemorrhage of prematurity. No conforms_to: norrin_fzd4_retinal_vascular_development scopes itself to Norrin-FZD4 lesions, aortopathy_tgfbeta_dysregulation models INCREASED aortic TGF-beta, and pharyngeal_arch_patterning_serial_homology models a neural-crest arch-patterning cleft rather than a medial-edge-epithelium fusion failure; all three rejections are recorded in notes. gnomAD constraint metrics supplied by the report are deliberately not curated - they were not independently checked and this repository has no reference-cache path for a gnomAD record. No GeneReviews chapter exists for this disease (PubMed search returned nothing); the Stickler syndrome GeneReviews chapter PMID:20301479 is cited for the differential only and is not tagged as this entry's GeneReviews baseline. No Orphanet record and no ClinGen validity assertion for LRRC32 were found in the local structured cache. VALIDATION: just validate passed (schema, terms, references); just validate-disorders (the batched --no-full-text sweep CI runs) passed with 70/70 snippets verified; check-duplicate-keys, check-entity-refs, check-causal-targets, check-qualifier-terms, check-enum-values all OK on the file; whole-KB check-folded-hyphens, check-snippet-length, check-title-snippets, check-snippet-grading, check-environmental-evidence and check-reference-titles all OK; normalize-cache, check-term-cache-integrity and check-cache-order clean. Weighted compliance 90.6 percent. Every references_cache file was produced by just fetch-reference; none was hand-written.

OpenScientist ▸
Cleft Palate, Proliferative Retinopathy, and Developmental Delay (MONDO:0033641): A Comprehensive Disease Report
openscientist-autonomous 8 citations 2026-09-07T17:14:19.512609

Cleft Palate, Proliferative Retinopathy, and Developmental Delay (MONDO:0033641): A Comprehensive Disease Report

Summary

Cleft palate, proliferative retinopathy, and developmental delay (MONDO:0033641) is an ultra-rare autosomal-recessive Mendelian syndrome caused by biallelic loss-of-function variants in LRRC32 (encoding GARP, Glycoprotein A Repetitions Predominant; chromosome 11q13.5). To date, the disorder has been reported in only approximately four patients from consanguineous families, making it one of the least-characterized Mendelian conditions in the medical literature. The disease was first delineated by Harel and colleagues in 2019, who identified a homozygous stop-gain variant (LRRC32 c.1630C>T; p.(Arg544Ter)) segregating in two consanguineous families with the defining triad of developmental delay, cleft palate, and proliferative retinopathy. A second, independent family was reported in 2022 with a distinct homozygous missense variant, confirming the gene–disease association and expanding the phenotype to include severe pre- and postnatal growth retardation and dysmorphic features.

The mechanistic basis of the syndrome is loss of GARP function. GARP is a cell-surface docking receptor that binds and presents the latent form of transforming growth factor-beta (TGF-β) on the plasma membrane, where it is subsequently activated in an integrin-dependent manner (chiefly via αvβ8/αvβ6) to release mature, signaling-competent TGF-β. Loss of GARP therefore diminishes latent TGF-β presentation and activation, reducing downstream SMAD2/3 signaling. This mechanism has been directly demonstrated in the developing secondary palate: Garp/Lrrc32-null mice show reduced SMAD2 phosphorylation and failed apoptosis in the palatal medial edge epithelium (MEE), causing cleft palate and phenocopying Tgfb3-null mice. Because the TGF-β pathway is also essential for retinal and central nervous system development, the retinopathy and neurodevelopmental features are attributed — largely by inference — to the same signaling deficit operating in those tissues.

There is no targeted or disease-modifying therapy. Management is entirely supportive and multidisciplinary: surgical palatoplasty for the cleft palate, vitreoretinal surgery/ophthalmologic management for the proliferative retinopathy, and developmental/rehabilitative support for the neurodevelopmental delay, combined with genetic counseling (25% sibling recurrence risk in an autosomal-recessive pedigree). Because of the extreme rarity — no new cases have been described since 2022 — much of the clinical natural history, epidemiology, prognosis, and treatment response data remain undefined, and this report explicitly flags those gaps.

Key Findings

Finding 1 — LRRC32 (GARP) biallelic loss-of-function is the cause (autosomal recessive)

The syndrome is caused by biallelic (homozygous) loss-of-function variants in LRRC32, transmitted in an autosomal-recessive pattern. Harel et al. (2019) identified a homozygous stop-gain variant, LRRC32 c.1630C>T; p.(Arg544Ter), segregating in two consanguineous families comprising three affected individuals, all presenting with the triad of developmental delay, cleft palate, and proliferative retinopathy. The original report states directly: "We identified a homozygous stop-gain variant in LRRC32 (c.1630C>T; p.(Arg544Ter)) in two families with developmental delay, cleft palate, and proliferative retinopathy" (PMID: 30976112).

A second, independent line of evidence came from Hexner-Erlichman et al. (2022), who used whole-exome sequencing to identify a distinct homozygous missense variant — a substitution of a highly conserved isoleucine to threonine — in a fourth patient from another consanguineous family: "Whole exome sequencing (WES) revealed a very rare homozygous missense variant in the LRRC32 gene, which resulted in substitution of a highly conserved isoleucine to threonine" (PMID: 35656379). This second family, harboring a different variant type (missense vs. nonsense) yet producing an overlapping phenotype, provides allelic heterogeneity that reinforces the causal gene–disease relationship. Both families were consanguineous, consistent with a rare recessive disorder enriched in inbred pedigrees.

Evidence source types: human clinical (two independent reports); genetic (WES/segregation).

Finding 2 — Mechanism: GARP loss impairs latent TGF-β3 presentation/activation, reducing SMAD2 signaling and apoptosis in palatal medial edge epithelium

The molecular mechanism was established in a mouse model by Wu et al. (2017). Garp/Lrrc32-null mice die within 24 hours of birth with an isolated failure of secondary palate fusion. At embryonic day 14.5 (E14.5), the palatal medial edge epithelial (MEE) cells show decreased apoptosis and reduced SMAD2 phosphorylation: "we observed decreased apoptosis and SMAD2 phosphorylation in the medial edge epithelial cells of the palatal shelf of GARP KO embryos at embryonic day 14.5" (PMID: 28912269).

GARP and TGFβ3 co-localize in MEE cells, physically interact, and GARP is required for cell-surface display of membrane-associated latent TGFβ3: "GARP is indispensable for the surface expression of membrane-associated latent TGFβ3" (PMID: 28912269). Critically, the GARP-null palatal defect phenocopies the Tgfb3-null mouse: "the failure to develop the secondary palate and concurrent reduction of SMAD phosphorylation without other defects in GARP KO mice phenocopied TGFβ3 KO mice" (PMID: 28912269). This places GARP squarely upstream of TGF-β3/SMAD signaling in palatogenesis and provides the direct mechanistic explanation for the cleft-palate component of the human syndrome.

More broadly, GARP presents latent TGF-β1 on the surface of regulatory T cells and platelets, where activation requires integrin αvβ8 and release (or, per newer models, allosteric exposure) of mature TGF-β — a mechanism corroborated by multiple structural and immunological studies (see Evidence Base).

Evidence source types: model organism (mouse knockout); in vitro (co-localization, interaction, SMAD phosphorylation assays).

Finding 3 — LRRC32 is recessive-compatible in gnomAD; the recurrent pathogenic allele p.(Arg544Ter) is ultra-rare with no homozygotes

Population-genetic analysis of gnomAD is fully consistent with a rare recessive disease model. For LRRC32 (ENSG00000137507, GRCh38 chr11:76,657,524–76,670,747), gnomAD v4 reports pLI = 0.66 and an observed/expected loss-of-function ratio (oe_lof) = 0.33 (90% CI 0.17–0.70), with 5 observed vs. 15.0 expected LoF alleles (lof_z = 2.19). These values indicate that the gene tolerates heterozygous LoF variation (i.e., carriers are viable and present in the population), exactly as expected for a recessive disorder where only biallelic loss is pathogenic.

The recurrent disease allele c.1630C>T p.(Arg544Ter) (rs369867819) is ultra-rare, with an exome allele frequency ≈ 1.37 × 10⁻⁶ (2 heterozygous alleles observed) and no homozygotes in gnomAD. A missense change at the same codon, p.Arg544Gln, is also seen at very low frequency (AF ≈ 2.05 × 10⁻⁶). The absence of homozygotes in a reference database of >700,000 individuals is precisely what is expected for an ultra-rare, severe recessive condition and adds population-level support to the pathogenicity of the reported allele.

Evidence source types: computational/population-genetic (gnomAD v4 constraint metrics and allele frequencies).

Metric (gnomAD v4, LRRC32) Value Interpretation
pLI 0.66 Moderate LoF intolerance
oe_lof (90% CI) 0.33 (0.17–0.70) Some constraint; recessive-compatible
Observed / Expected LoF 5 / 15.0 Fewer LoF than expected
lof_z 2.19 Mild constraint
p.(Arg544Ter) exome AF ≈1.37 × 10⁻⁶ Ultra-rare
p.(Arg544Ter) homozygotes 0 Consistent with severe recessive disease

Finding 4 — Clinical triad and TGF-β developmental basis; neonatal lethality in the mouse null limits modeling

The defining clinical triad is cleft palate + proliferative retinopathy + developmental delay, congenital in onset, reported in two consanguineous families (three individuals; Harel et al. 2019). The unifying developmental explanation is the TGF-β pathway, which is essential for both palatogenesis and retinal development: "The transforming growth factor-beta (TGFβ) signaling pathway is essential for palatogenesis and retinal development" (PMID: 30976112).

A key limitation of the animal model is that complete Garp-null mice die within 24 hours of birth: "Garp-null mice have palate defects and die within 24 h after birth" (PMID: 30976112). This neonatal lethality means the mouse recapitulates the palatal defect but cannot model the postnatal ocular (proliferative retinopathy) or neurodevelopmental (developmental delay) features, which require postnatal survival to manifest and assess. The 2022 fourth patient additionally exhibited severe pre- and postnatal growth retardation and dysmorphic features, expanding the recognized phenotypic spectrum beyond the original triad.

Evidence source types: human clinical (phenotype); model organism (lethality/limitation).

Full Section-by-Section Report

1. Disease Information

Overview. MONDO:0033641 is an ultra-rare, congenital, autosomal-recessive multisystem syndrome defined by the co-occurrence of cleft palate, proliferative retinopathy, and developmental delay. It results from complete or near-complete loss of GARP (encoded by LRRC32), a chaperone/docking protein for latent TGF-β. The disorder was newly delineated as a Mendelian entity in 2019.

Key identifiers. - MONDO: MONDO:0033641 - Gene: LRRC32 (HGNC:4161), also known as GARP - OMIM: The molecular entity is captured through the LRRC32 gene entry (OMIM *137207); a discrete OMIM phenotype MIM number, if assigned, post-dates the original 2019 report. (Not definitively available.) - Orphanet / ICD-10 / ICD-11 / MeSH: No dedicated code was identified for this specific triad syndrome; component phenotypes map to generic terms (cleft palate ICD-10 Q35; congenital retinal disorders; unspecified developmental delay). (Not available as a unified code.)

Synonyms / alternative names. "LRRC32-related syndrome"; "GARP deficiency syndrome"; "cleft palate–proliferative retinopathy–developmental delay syndrome."

Data provenance. All information is derived from aggregated disease-level and case-report literature (two peer-reviewed clinical/genetic reports describing four patients) plus a mechanistic mouse study and public population databases — not from large EHR cohorts.

2. Etiology

Causal factors — genetic. The sole established cause is biallelic loss-of-function of LRRC32/GARP. Two variant classes are documented: a nonsense allele (p.Arg544Ter) and a missense allele (conserved Ile→Thr) (PMID: 30976112; PMID: 35656379).

Genetic risk factors. Consanguinity is the principal risk factor, as expected for an ultra-rare recessive disorder; both reported families were consanguineous. Carrier status (heterozygosity) confers no known phenotype.

Environmental risk factors / protective factors / gene–environment interactions. Not available / not applicable. No environmental contributors, protective alleles, dietary factors, or gene–environment interactions have been described for this monogenic disorder. Given the deterministic Mendelian etiology, environmental modifiers are unlikely to be primary drivers, though they cannot be excluded as modifiers of severity.

3. Phenotypes

Phenotype Type Suggested HPO Onset Frequency (of ~4 reported)
Cleft palate Physical malformation HP:0000175 Congenital Core triad feature
Proliferative retinopathy Clinical/ophthalmologic sign HP:0000556 (retinopathy) / HP:0008046 (abnormal retinal vasculature) Congenital/early Core triad feature
Developmental delay / intellectual disability Neurodevelopmental HP:0001263 (global developmental delay) Infancy Core triad feature
Severe pre-/postnatal growth retardation Growth abnormality HP:0001511 / HP:0008897 Prenatal onset 4th patient (2022)
Dysmorphic facial features Physical manifestation HP:0001999 Congenital 4th patient (2022)

Characteristics. Onset is congenital for the triad. Severity appears moderate to severe and the course is best described as stable/static (a congenital malformation syndrome rather than a progressive degeneration), although the proliferative retinopathy component carries risk of progression to vision loss without intervention. Frequency data are qualitative only, given the tiny patient count.

Quality-of-life impact. Not formally measured (no EQ-5D/SF-36/PROMIS data). By clinical inference, cleft palate impairs feeding and speech; proliferative retinopathy threatens vision; developmental delay affects cognition, communication, and independence — collectively implying substantial lifelong QoL burden. (Quantitative data not available.)

4. Genetic / Molecular Information

  • Causal gene: LRRC32 (GARP), HGNC:4161, located at 11q13.5 (GRCh38 chr11:76,657,524–76,670,747; ENSG00000137507).
  • Pathogenic variants:
  • c.1630C>T; p.(Arg544Ter) — nonsense/stop-gain; rs369867819; germline; homozygous in affected individuals; predicted loss of function (truncation). gnomAD exome AF ≈ 1.37 × 10⁻⁶, no homozygotes.
  • Homozygous missense, conserved Ile→Thr — germline; function-impairing; reported 2022.
  • Variant classification: Consistent with pathogenic/likely pathogenic per ACMG criteria (ultra-rare, homozygous in affected consanguineous families, segregation, LoF mechanism, functional support from mouse ortholog).
  • Somatic vs. germline: Germline (constitutional, inherited).
  • Functional consequence: Loss of function — reduced/absent GARP-mediated latent TGF-β presentation.
  • Modifier genes / epigenetics / chromosomal abnormalities: Not available. No modifier loci, methylation changes, or large-scale cytogenetic rearrangements have been implicated; the disorder is a single-gene point-mutation disorder.

5. Environmental Information

Not applicable. No environmental factors, lifestyle contributors, toxins, or infectious agents are associated with this monogenic recessive syndrome. (No CTD/TOXNET or exposure associations identified.)

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation):

  1. Biallelic LoF mutation in LRRC32 (nonsense p.Arg544Ter or function-impairing missense) → leads to loss/severe reduction of functional GARP protein. (Demonstrated: human genetics.)
  2. Loss of GARP → results in failure to display membrane-associated latent TGF-β (esp. TGF-β3 in palate; TGF-β1 in immune cells) on the cell surface. (Demonstrated in mouse MEE: GARP indispensable for surface latent TGFβ3.)
  3. Absent surface latent TGF-β → prevents integrin (αvβ8/αvβ6)-mediated activation and local presentation of mature TGF-β. (Demonstrated/mechanistically established.)
  4. Reduced local TGF-β activity → leads to decreased TGF-β receptor engagement and SMAD2/3 phosphorylation. (Demonstrated: reduced pSMAD2 in E14.5 palatal MEE.) 5a. Reduced SMAD2 signaling in palatal MEE → causes failed programmed cell death (apoptosis) of the medial edge epithelium → prevents palatal shelf fusion → cleft palate. (Demonstrated; phenocopies Tgfb3-null.) 5b. Reduced TGF-β/SMAD signaling in the developing retina → inferred to disrupt retinal vascular/neuroepithelial development → proliferative retinopathy. (Inferred, not directly demonstrated.) 5c. Reduced TGF-β/SMAD signaling in the developing CNS → inferred to impair neurodevelopment → developmental delay (± growth retardation/dysmorphism). (Inferred.)

Molecular pathways. Core pathway is TGF-β/SMAD2-3 signaling (KEGG hsa04350; Reactome "Signaling by TGF-beta Receptor Complex"). GARP (LRRC32) functions as the latent-TGF-β docking receptor upstream of receptor activation. Integrin αvβ8-mediated activation is the proximal activation step.

Cellular processes. Apoptosis of the palatal medial edge epithelium is the key demonstrated cellular event (GO:0006915 apoptotic process; specifically epithelial cell apoptosis during palate fusion). Loss of GARP → reduced MEE apoptosis → persistent midline epithelial seam → cleft.

Protein dysfunction. GARP is a leucine-rich-repeat transmembrane protein; the p.Arg544Ter truncation removes C-terminal/transmembrane-proximal sequence required for surface presentation, and the conserved Ile→Thr missense is predicted to impair folding/function — both yielding loss of function (failure to chaperone/present latent TGF-β).

Immune system involvement. GARP is the principal presenter of latent TGF-β1 on regulatory T cells and platelets; in cancer/immunology contexts it drives immunosuppression. In this developmental syndrome the immune role is secondary, but the same biochemistry (GARP:latent-TGF-β:integrin activation) underlies the disease. No overt immunodeficiency/autoimmunity has been reported in patients.

Suggested ontology terms. GO:0007179 (transforming growth factor beta receptor signaling pathway), GO:0006915 (apoptotic process), GO:0060021 (palate development), GO:0001654 (eye development). CL terms: epithelial cell CL:0000066 (palatal medial edge epithelium), retinal pigment epithelial cell CL:0002586, neuron CL:0000540. UBERON: secondary palate UBERON:0001716, retina UBERON:0000966, brain UBERON:0000955. CHEBI: TGF-β is a protein (not a small molecule), so no CHEBI term applies to the ligand itself.

7. Anatomical Structures Affected

  • Primary organs: secondary palate (UBERON:0001716), retina/eye (UBERON:0000966 retina; UBERON:0000970 eye), brain/CNS (UBERON:0000955).
  • Body systems: craniofacial/digestive-respiratory interface (palate), visual system, central nervous system; with growth (in the 2022 patient).
  • Tissue/cell level: palatal medial edge epithelium (epithelial tissue), retinal cells (including retinal pigment epithelium and vasculature), neural cells.
  • Subcellular: GARP is a plasma-membrane protein (GO:0005886 plasma membrane); the functional defect is at the cell surface (loss of surface latent-TGF-β complex).
  • Localization / lateralization: cleft palate is typically midline; retinopathy and developmental delay are bilateral. Specific laterality data are limited given the small cohort.

8. Temporal Development

  • Onset: congenital for the triad; growth retardation is prenatal-onset in the 2022 patient.
  • Onset pattern: developmental/structural (present at birth), not acute.
  • Progression: the malformation syndrome is largely static; however, proliferative retinopathy can progress to retinal detachment/vision loss without ophthalmologic intervention.
  • Disease duration: chronic, lifelong.
  • Critical periods: the palatal defect originates during secondary palate fusion (~E14.5 in mouse; ~weeks 8–12 of human gestation) — a window inaccessible to postnatal intervention. Postnatal critical windows exist for retinal intervention and early developmental/rehabilitative therapy.

9. Inheritance and Population

  • Inheritance: autosomal recessive (biallelic LRRC32 LoF); both families consanguineous.
  • Penetrance: appears complete in reported homozygotes (all biallelic individuals affected), though based on very few cases.
  • Expressivity: variable — the 2022 patient showed additional growth retardation/dysmorphism beyond the core triad.
  • Consanguinity: central to disease occurrence.
  • Carrier frequency: ultra-low; the recurrent p.(Arg544Ter) allele has gnomAD AF ≈ 1.37 × 10⁻⁶ with no homozygotes — consistent with a severe, ultra-rare recessive condition.
  • Founder effects / anticipation / mosaicism: No founder effect, genetic anticipation, or germline mosaicism has been documented. Anticipation is not expected (not a repeat-expansion disorder).
  • Epidemiology: prevalence and incidence are undefined — fewer than ~5 patients reported worldwide. Sex ratio, geographic distribution, and age distribution cannot be reliably estimated.

10. Diagnostics

  • Recommended approach: molecular genetic testing. Whole-exome sequencing (WES) was the diagnostic modality in both the original and second reports and is the highest-yield test; whole-genome sequencing (WGS) is a reasonable alternative. Targeted single-gene testing of LRRC32 is appropriate once the phenotype is recognized or a familial variant is known.
  • Variant interpretation: confirm biallelic status; classify per ACMG/AMP with ClinVar/segregation support.
  • Clinical/imaging workup: ophthalmologic examination and retinal imaging (to characterize the proliferative retinopathy), craniofacial/palate examination, and developmental assessment. Chromosomal microarray/karyotype are typically normal (point-mutation disorder) but may be performed to exclude structural mimics.
  • Differential diagnosis: other syndromic cleft-palate disorders (e.g., TGFB3-related, Van der Woude, Stickler syndrome — which also features cleft palate plus retinal detachment and is thus an important mimic), and other syndromic retinopathy/developmental-delay conditions. Molecular testing distinguishes them.
  • Screening: for at-risk consanguineous families with a known familial variant, carrier testing and cascade/prenatal testing are available. No population newborn screening exists.

11. Outcome / Prognosis

Formal survival, mortality, and quality-of-life outcome data are not available given the rarity. Inferences: the human disorder is compatible with postnatal survival (unlike the neonatal-lethal complete mouse null, human patients survive infancy — likely reflecting residual/hypomorphic function or species differences). Prognosis is shaped by the severity of the retinopathy (vision-threatening) and the degree of developmental delay (affecting long-term function), plus feeding/speech consequences of the cleft palate. Recovery of the structural defects is not spontaneous; surgical/rehabilitative intervention improves function. Prognostic biomarkers are not established.

12. Treatment

No targeted or disease-modifying therapy exists. Management is supportive and multidisciplinary:

Domain Intervention Suggested NCIT concept
Cleft palate Palatoplasty (surgical repair); feeding support; speech therapy Cleft palate repair; Speech therapy
Proliferative retinopathy Ophthalmologic surveillance; vitreoretinal surgery; consider anti-VEGF/laser per lesion type Vitrectomy; Laser therapy
Developmental delay Early developmental intervention; physical/occupational/speech therapy; special education Rehabilitation therapy
Family Genetic counseling (25% sibling recurrence) Genetic counseling

Pharmacotherapy / pharmacogenomics / gene therapy / cell therapy / RNA therapy / immunotherapy: None approved or in trials for this disorder specifically. No NCT-registered trials target MONDO:0033641. (Note: the broader GARP–TGF-β axis is an active oncology immunotherapy target — anti-GARP antibodies, CAR-T, bispecifics — but these aim to inhibit GARP and are unrelated to treating GARP-deficiency syndrome.)

Experimental outlook: As a monogenic LoF disorder, it is conceptually a candidate for future gene-replacement approaches, but the congenital/developmental timing of the palatal defect limits postnatal correction of already-formed malformations.

13. Prevention

  • Primary prevention: none at the population level. For known-carrier couples, preimplantation genetic testing (PGT) and prenatal diagnosis can prevent affected births.
  • Secondary prevention: cascade carrier testing in consanguineous families with a known variant; early ophthalmologic screening in an at-risk newborn to catch progressive retinopathy.
  • Tertiary prevention: timely palatoplasty, retinal intervention, and developmental therapy to prevent complications (malnutrition, aspiration, vision loss, functional decline).
  • Counseling: genetic counseling is central — autosomal-recessive 25% recurrence risk; discussion of consanguinity.
  • Immunization / public health / environmental interventions: not applicable.

14. Other Species / Natural Disease

  • Model species: Mus musculus (NCBI Taxon:10090) — Garp/Lrrc32 knockout. No naturally occurring animal disease (OMIA) is documented for this syndrome.
  • Orthologous gene: mouse Lrrc32/Garp; the gene and its TGF-β–presenting function are evolutionarily conserved.
  • Comparative pathology: the mouse null reproduces the cleft palate but is neonatal-lethal, so it does not model retinopathy or developmental delay. Zoonotic/cross-species transmission: not applicable (genetic disorder).

15. Model Organisms

  • Model type / system: mammalian — mouse Garp/Lrrc32 knockout (constitutive null). In vitro/ex vivo palatal shelf cultures and MEE cell assays supplement the model.
  • Genetic models available: constitutive knockout demonstrated; conditional/tissue-specific alleles would be needed to bypass neonatal lethality (see follow-up).
  • Phenotype recapitulation: Good for the palatal phenotype — the KO shows isolated secondary palate fusion failure with reduced MEE apoptosis and pSMAD2, phenocopying Tgfb3-null mice. Poor for ocular/neurodevelopmental phenotypes — death within 24 h of birth precludes their assessment.
  • Applications: dissecting GARP → latent-TGF-β3 → SMAD2 → MEE-apoptosis axis in palatogenesis; testing whether TGF-β pathway restoration rescues palate fusion.
  • Resources: MGI (mouse), IMPC/KOMP for allele availability.

Mechanistic Model / Interpretation

   Biallelic LoF in LRRC32 (p.Arg544Ter  /  conserved Ile→Thr missense)
                │
                ▼
     Loss / severe reduction of functional GARP protein
                │
                ▼
      Failure to present membrane-bound LATENT TGF-β on the cell surface
      (TGF-β3 in palatal epithelium; TGF-β1 in immune cells)
                │
                ▼
No integrin-αvβ8–mediated activation → ↓ mature TGF-β locally
                │
                ▼
 ↓ TGF-β receptor engagement → ↓ SMAD2/3 phosphorylation
                │
┌───────────────────────┼─────────────────────────────┐
▼ (DEMONSTRATED)        ▼ (INFERRED)                   ▼ (INFERRED)
  ↓ apoptosis of palatal   disrupted retinal          impaired CNS
  medial edge epithelium   vascular/neuroepithelial   development
│                  development                        │
▼                        ▼                            ▼
   CLEFT PALATE          PROLIFERATIVE RETINOPATHY     DEVELOPMENTAL DELAY
 (phenocopies Tgfb3-null)                          (± growth retardation,
                                     dysmorphism — 2022 pt)

The upstream, demonstrated portion of this chain (mutation → loss of GARP → loss of surface latent TGF-β3 → ↓SMAD2 → ↓MEE apoptosis → cleft palate) rests on direct experimental evidence in the mouse. The downstream retinal and neurodevelopmental branches are inferred from (a) the established requirement of TGF-β signaling for retinal and CNS development and (b) the co-segregation of these features with the biallelic LRRC32 genotype in humans. The consistency of a single, well-understood signaling deficit across all three affected tissues makes the unified GARP–TGF-β model parsimonious and compelling, while honestly flagging that the ocular and neural mechanisms have not been directly proven in this disease.

Evidence Base

PMID Title (abbrev.) Evidence type Role in this report
30976112 Homozygous stop-gain variant in LRRC32... cleft palate, proliferative retinopathy, developmental delay (Harel et al. 2019) Human clinical/genetic Foundational — establishes gene–disease link, triad, TGF-β rationale, mouse lethality
35656379 A Novel Homozygous Missense Variant in LRRC32 (Hexner-Erlichman et al. 2022) Human clinical/genetic Confirmatory — 2nd family, allelic heterogeneity, phenotype expansion
28912269 GARP positively regulates TGFβ3 and is essential for mouse palatogenesis (Wu et al. 2017) Model organism/in vitro Mechanistic core — GARP→latent-TGFβ3→SMAD2→MEE apoptosis; phenocopies Tgfb3-null
gnomAD v4 LRRC32 constraint & allele frequencies Computational/population Recessive-compatible constraint; ultra-rare allele, no homozygotes

Supporting context (GARP–TGF-β axis biology). Multiple recent structural and immunological studies corroborate that GARP presents latent TGF-β on the cell surface and that activation is integrin-dependent — e.g., cryo-EM/allostery work showing αvβ8-mediated activation of L-TGF-β1/GARP (PMID: 39288764), and reviews/therapeutic studies confirming GARP (LRRC32) as the docking receptor presenting latent TGF-β on Tregs and platelets (PMID: 35898500; PMID: 36928178). These strengthen the biochemical plausibility of the disease mechanism, although they address immuno-oncology rather than the developmental syndrome directly.

Challenges / caveats to the model. Newer "dynamic allostery" data suggest mature TGF-β may signal without physical release from the latent complex (PMID: 39288764); this refines but does not overturn the conclusion that GARP loss impairs TGF-β activation. The extensive PVR (proliferative vitreoretinopathy) literature involving TGF-β-driven RPE epithelial–mesenchymal transition (PMID: 42285191; PMID: 40466854) concerns acquired adult retinopathy and is mechanistically distinct from the congenital retinopathy in this syndrome — a reminder that "proliferative retinopathy" here should not be conflated with adult PVR.

Limitations and Knowledge Gaps

  1. Extreme rarity (~4 patients). All clinical inferences rest on a handful of individuals from consanguineous families; prevalence, incidence, sex ratio, penetrance, expressivity, and natural history are essentially undefined.
  2. Ocular and neurodevelopmental mechanisms are inferred, not demonstrated. The mouse null's neonatal lethality prevents modeling of retinopathy and developmental delay; no tissue-specific evidence links GARP loss to these features directly.
  3. No confirmed OMIM phenotype / Orphanet / ICD unified code was identified for the triad syndrome, complicating standardized annotation.
  4. No treatment evidence base. Management is extrapolated from component-condition standards; no outcome, response-rate, or QoL data specific to this syndrome exist.
  5. Genotype–phenotype correlation is unresolved. Whether the missense (2022) vs. nonsense (2019) alleles produce systematically different severity (e.g., the added growth retardation) cannot be determined from two families.
  6. Human residual function unexplained. Why humans survive infancy while complete mouse nulls die within 24 h is unknown (hypomorphic alleles? species differences in GARP dependence?).

Proposed Follow-up Experiments / Actions

  1. Conditional/tissue-specific mouse models (e.g., retina- and CNS-specific Lrrc32 knockouts, or hypomorphic/knock-in alleles mimicking the human p.Arg544Ter and Ile→Thr variants) to bypass neonatal lethality and directly test the retinal and neurodevelopmental branches of the causal chain.
  2. Functional validation of the missense allele — express the conserved Ile→Thr variant in cells and assay surface presentation of latent TGF-β and SMAD2 activation to confirm loss-of-function and quantify residual activity relative to the nonsense allele.
  3. Patient registry / GeneMatcher outreach to identify additional families, enabling genotype–phenotype correlation, penetrance/expressivity estimates, and natural-history documentation.
  4. iPSC-derived retinal organoids and cortical organoids from patient cells (or CRISPR-engineered LRRC32 nulls) to model the human-specific ocular and neural phenotypes in vitro and probe TGF-β/SMAD signaling deficits.
  5. Formal variant curation in ClinVar/ClinGen and assignment/confirmation of OMIM and Orphanet identifiers to standardize the disease entry.
  6. Ophthalmologic natural-history study in any identified patients to define the trajectory of the proliferative retinopathy and optimal intervention windows.

Report compiled from a five-iteration autonomous investigation. Evidence sources are distinguished as human clinical (PMID 30976112, 35656379), model organism/in vitro (PMID 28912269), and computational/population-genetic (gnomAD v4). Findings F001–F004 are recorded in the knowledge state with verified abstract quotations.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 8
Resolved 8
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 8
On topic 3
Off topic 1

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

  • PMID:35898500 (3 mentions) - GARP as a Therapeutic Target for the Modulation of Regulatory T Cells in Cancer and Autoimmunity.
  • shared terms: garp

Weighed against this report's own most characteristic terms: palate, retinopathy, garp, developmental, lrrc32, cleft, tgf, delay, mouse, syndrome, loss, genetic, proliferative, disease, patient, retinal, phenotype, disorder, clinical, familie.

All extracted references resolved successfully. Resolving is not the same as being relevant, though - see the references listed above as possibly off topic.

Term Validation

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

Outcome Count
Terms checked 22
Resolved 20
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 2
Terms whose name was checked 10
Terms named correctly 5
Terms named as a different term 2
Terms whose name is worth a second look 3

Terms the report names something else

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

  • HP:0000175 (1 mention) - the report calls it "Physical malformation"; HP calls it Cleft palate
  • HP:0001999 (1 mention) - the report calls it "Physical manifestation"; HP calls it Abnormal facial shape

Terms whose name is worth a second look

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

  • GO:0060021 (1 mention) - the report calls it "palate development"; GO calls it roof of mouth development, and lists "palatum development" among its other names
  • UBERON:0001716 (2 mentions) - the report calls it "palate", "Primary organs: secondary palate"; UBERON calls it secondary palate
  • UBERON:0000955 (2 mentions) - the report calls it "brain/CNS"; UBERON calls it brain

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • HGNC:4161 - called "LRRC32", "Gene:* LRRC32"
  • UBERON:0001716 - called "palate", "Primary organs: secondary palate"

Prefixes with no resolver

Terms 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: Taxon.