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Classifications

Harrison's Part

ISDS Skeletal Nosology

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Mappings

MONDO

MONDO:0014748 progressive spondyloepimetaphyseal dysplasia-short stature-short fourth metatarsals-intellectual disability syndrome

Orphanet ORPHA:457395 lists MONDO:0014748 as an exact cross-reference; it is the primary disease term for this entry.

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Inheritance

1

Autosomal Recessive HP:0000007

SEMDFA segregates as an autosomal recessive trait. Every reported family has been consanguineous or the proband homozygous for a single RSPRY1 allele; heterozygous parents are unaffected.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:26365341 SUPPORT Human Clinical

"We describe a clinically recognizable autosomal-recessive disorder in four affected siblings from a consanguineous Saudi family"

The founding report establishes autosomal recessive segregation in a consanguineous multiplex family.

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Discussions and Knowledge Gaps

7

What is the biochemical activity of RSPRY1, and does its RING domain ubiquitinate a component of the TGF-beta pathway?

KNOWLEDGE GAP OPEN rspry1_biochemical_function

Attached to

pathophysiology#Loss of RSPRY1 Regulatory Activity in Skeletal Tissue

RSPRY1 was described at discovery as a protein of unknown physiological function, and that has not changed. The RING domain and the ubiquitin-ligase interaction partners recovered from interaction databases motivate an E3 ligase hypothesis, but no substrate has been identified and no ligase activity has been demonstrated. Without it, the step between loss of the protein and activation of TGF-beta signaling is a correlation, not a mechanism.

Proposed experiments

Define the RSPRY1 interactome and test for ubiquitination of a TGF-beta pathway component

exp_rspry1_interactome_and_ubiquitination

Use affinity-purification mass spectrometry on endogenously tagged RSPRY1 to recover its interactors, then test candidate TGF-beta pathway components in in vitro and cellular ubiquitination assays with wild-type RSPRY1 versus a RING-domain mutant.

Decision criterion

Recovery of a TGF-beta pathway component as a RING-dependent ubiquitination substrate would convert the curated correlation between RSPRY1 loss and pathway activation into a mechanism; failure to find one would leave the E3-ligase framing as domain analogy and reopen alternatives such as a purely extracellular role.

Resolve the secreted-versus-intracellular localization of endogenous RSPRY1

exp_rspry1_subcellular_localization

Combine endogenous tagging with immunofluorescence and secretome analysis in a bone-lineage cell type. The protein is annotated as secreted and has been described as acting on the extracellular matrix, yet tagged Rspry1 was reported in the cytoplasm of muscle cells and a RING-dependent ubiquitin-ligase role would require intracellular access. The compartment determines which mechanistic models remain possible.

Show evidence (4 references)

PMID:26365341 SUPPORT Other

"RSPRY1 encodes a hypothetical RING and SPRY domain-containing protein of unknown physiological function."

States the gap directly at the point of gene discovery.

PMID:39940902 SUPPORT Other

"Identifying the possible ubiquitination targets of RSPRY1 in this context and detailing the effects of these targets in the TGF-β signaling pathway may provide important information to elucidate the functional mechanism of RSPRY1"

The mechanistic study itself names substrate identification as the outstanding question.

PMID:26497270 SUPPORT In Vitro

"GFP-tagged Nip30 was found to localize to the nucleus, while GFP-tagged Rspry1 was found to localize to the cytoplasm of muscle cells."

The only other functional characterization of the protein places tagged Rspry1 in the cytoplasm of muscle cells, which sits awkwardly beside the description of RSPRY1 as a secreted protein acting on the extracellular matrix. The compartment in which it acts is itself unsettled.

+ 1 more reference

Does the constitutive TGF-beta/SMAD3 activation seen in patient dermal fibroblasts also occur in the osteoblast, periosteal, and growth-plate chondrocyte lineages where RSPRY1 is actually expressed?

HUMAN MODEL MISMATCH OPEN fibroblast_proxy_for_bone_lineage

Attached to

pathophysiology#Impaired Endochondral Ossification and Growth-Plate Function

The entire cellular mechanism for this disorder rests on dermal fibroblasts, chosen because they are the accessible patient tissue. RSPRY1 protein is concentrated in murine embryonic osteoblasts and periosteal cells during primary endochondral ossification, which is a different cell context with different TGF-beta set points. The authors are explicit that fibroblasts may only partly capture the effects of RSPRY1 loss in other tissues, so the fibroblast-to-bone step is the weakest link in the curated chain and is marked INDIRECT_UNKNOWN_INTERMEDIATES accordingly.

Proposed experiments

Test constitutive TGF-beta/SMAD3 activation in patient-derived chondrocytes and osteoblasts

exp_semdfa_bone_lineage_tgfb_validation

Differentiate patient iPSCs carrying biallelic RSPRY1 alleles into chondrocytes and osteoblasts, and quantify phospho-SMAD3 and TGF-beta target-gene output against isogenic corrected controls, with and without an ALK5 (TGFBR1) inhibitor. The fibroblast result predicts elevated basal phospho-SMAD3 and a blunted response to exogenous TGF-beta1 in the bone lineage as well.

Decision criterion

Elevated basal phospho-SMAD3 with a blunted exogenous-ligand response in the bone lineage would carry the mechanism across the fibroblast-to-bone gap; a normal bone-lineage TGF-beta set point would confine the fibroblast finding to that cell type and leave the skeletal mechanism unexplained.

Skeletal phenotyping of a global and cartilage-specific Rspry1 knockout mouse

exp_semdfa_rspry1_null_mouse_skeleton

Characterize growth-plate architecture, endochondral ossification, and cranial sutures in global and cartilage-specific Rspry1-null mice. No Rspry1-null skeletal phenotype has been reported despite knockout alleles existing in repositories, so this is the missing in vivo test of whether loss of the gene reproduces the human skeleton.

Show evidence (2 references)

PMID:39940902 SUPPORT In Vitro

"The present study focused on fibroblast cell models derived from two patients with homozygous RSPRY1 mutations, which, while informative, might only partially capture the effects of RSPRY1 deficiency in other cell types or tissues."

The authors state the translational limitation of their own model.

PMID:26365341 SUPPORT Model Organism

"However, we detect strong RSPRY1 protein localization in murine embryonic osteoblasts and periosteal cells during primary endochondral ossification, consistent with a role in bone development."

Identifies the bone-lineage cell types in which the mechanism actually needs testing.

By what mechanism does RSPRY1 loss cause intellectual disability?

KNOWLEDGE GAP OPEN neurodevelopmental_mechanism_unexplained

Attached to

pathophysiology#Loss of RSPRY1 Regulatory Activity in Skeletal Tissue

Intellectual disability is one of the five defining features of the disorder and was present in every patient of the delineation series, yet no curated causal path connects RSPRY1 loss to it. All functional work to date is skeletal or fibroblast-based, and there is no published study of RSPRY1 in neural tissue. The pathograph therefore deliberately stops at the skeletal arm rather than asserting an unevidenced neurodevelopmental edge.

Show evidence (1 reference)

PMID:30063090 SUPPORT Human Clinical

"All patients have short stature, extremity deformities, facial dysmorphism and intellectual disability."

Establishes that the unexplained phenotype is consistently present.

Could pharmacological inhibition of TGF-beta/SMAD3 signaling modify the skeletal phenotype of RSPRY1 deficiency?

EMERGING HYPOTHESIS OPEN tgf_beta_targeted_therapy_rationale

Attached to

pathophysiology#Constitutive TGF-beta/SMAD3 Signaling Activation

Constitutive, SMAD3-dependent TGF-beta activation is the only druggable node identified so far, and the authors of the mechanistic study raise TGF-beta-directed therapy on that basis. Nothing has been tested: there is no animal model with a demonstrated skeletal phenotype, no in vivo proof that the pathway is activated in bone, and no trial. This is recorded as a hypothesis and deliberately not curated as a treatment.

Show evidence (1 reference)

PMID:39940902 SUPPORT In Vitro

"An improvement in our understanding of the molecular roles of RSPRY1 might yield novel therapeutic strategies that target TGF-β signaling in patients with SEMD and other skeletal dysplasias."

The authors frame TGF-beta-directed therapy as a prospect arising from their findings, not as a demonstrated intervention.

Does single-copy loss of RSPRY1, as part of a 16q contiguous-gene deletion, contribute to the skeletal phenotype of that deletion syndrome?

OPEN QUESTION OPEN contiguous_gene_deletion_haploinsufficiency

Attached to

pathophysiology#Biallelic RSPRY1 Loss of Function

SEMDFA is recessive, and every reported patient is homozygous, so the curated trigger node requires biallelic loss. A patient with a 16q12.2q21 interstitial deletion spanning RSPRY1 was nonetheless proposed to owe the skeletal part of their phenotype to loss of this gene. If that is right, one copy is sometimes not enough for the skeleton, which would put a partial dosage effect underneath a disorder curated here as a null phenotype. The proposal is a candidate-gene inference from a single deletion patient, not a dosage experiment, so it is recorded as an open question rather than a curated modifier or a second genetic entry.

Show evidence (1 reference)

PMID:27230627 SUPPORT Human Clinical

"Because RSPRY1 was been discovered as the cause of progressive skeletal dysplasia, a loss of this gene might explain the skeletal defects observed in the patient."

The deletion report states the hypothesis in its own hedged terms ("might explain"), which is the level at which it is recorded here. The quote reproduces the source's own wording, including its grammatical slip.

Is RSPRY1 a secreted, extracellular-acting protein or a cytoplasmic one?

CONTROVERSY OPEN rspry1_subcellular_localization

Attached to

pathophysiology#Biallelic RSPRY1 Loss of Function

The two most recent primary sources disagree. The 2025 mechanistic study describes RSPRY1 as "a secreted protein with RING and SPRY domains", consistent with BioGRID/UniProt annotation, and builds an extracellular-matrix-facing model on that basis. The 2024 clinical report instead states, citing the original characterization of the protein, that RSPRY1 is a glycoprotein present in the cytoplasm of skeletal muscle cells. The two are not reconcilable as stated, and the answer changes whether RSPRY1 acts on ECM components extracellularly or on intracellular signalling intermediates — the ubiquitin-ligase model requires the latter. No dedicated localization study of RSPRY1 has been published.

Proposed experiments

Subcellular localization and secretion assay for endogenous RSPRY1

exp_rspry1_localization

Subcellular fractionation and immunofluorescence of endogenous RSPRY1 in osteoblasts, chondrocytes and fibroblasts, with conditioned-medium immunoblotting to test for secretion.

Show evidence (2 references)

PMID:39940902 SUPPORT In Vitro

"RSPRY1, a secreted protein with RING and SPRY domains, has been implicated in bone development, yet its exact role remains to be determined."

States the secreted-protein position.

PMID:38562122 REFUTE Human Clinical

"RSPRY1 protein is a glycoprotein present in the cytoplasm of skeletal muscle cells."

States the cytoplasmic position, contradicting the secreted annotation.

Can the spondyloepimetaphyseal dysplasia be recapitulated in an animal model?

KNOWLEDGE GAP OPEN no_animal_model_of_the_dysplasia

Attached to

pathophysiology#Progressive Skeletal Deformity and Short Stature

No Rspry1 knockout animal with a published skeletal phenotype exists. The only in vivo data are wild-type murine expression localization from the 2015 gene discovery paper, which shows where RSPRY1 is present but not what its absence does. Without a model that reproduces the dysplasia, the causal chain from gene loss to growth-plate failure cannot be tested in a whole organism, and no preclinical platform exists for the TGF-beta-directed therapeutic hypothesis the 2025 study raises. Targeted Rspry1 knockout alleles are catalogued in the KOMP/IMPC mouse resources, so the reagents exist; what is missing is a published skeletal phenotype from them.

Proposed experiments

Constitutive and conditional Rspry1 knockout mouse skeletal phenotyping

exp_rspry1_knockout_mouse_skeleton

Generate a constitutive and a chondrocyte/osteoblast-conditional Rspry1 knockout mouse and phenotype the axial skeleton, growth plates and cranial sutures by micro-CT and histology across postnatal development.

Zebrafish rspry1 loss-of-function cartilage and craniofacial screen

exp_zebrafish_rspry1

Assess zebrafish rspry1 loss of function as a rapid screen for cartilage and craniofacial patterning defects.

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Pathophysiology

7

Biallelic RSPRY1 Loss of Function

Homozygous frameshift, splice-site, or missense RSPRY1 variants abolish or impair the RING- and SPRY-domain protein. The founding frameshift allele triggers nonsense-mediated decay of the transcript, so the shared initiating lesion is absence of functional RSPRY1 protein.

RSPRY1 hgnc:29420

Downstream

Loss of RSPRY1 Regulatory Activity in Skeletal Tissue Absent RSPRY1 protein removes its regulatory activity from the cells in which it is normally expressed during skeletogenesis.

Show evidence (1 reference)

PMID:26365341 SUPPORT Human Clinical

"Combined autozygome/exome analysis identified a homozygous frameshift mutation in RSPRY1 with resulting nonsense-mediated decay."

Establishes nonsense-mediated decay of the mutant transcript as the initiating molecular lesion.

Loss of RSPRY1 Regulatory Activity in Skeletal Tissue

RSPRY1 carries a RING finger domain associated with ubiquitin-ligase chemistry and a SPRY protein-interaction domain, and interacts with ubiquitin ligases. Its physiological substrate and biochemical activity are not established, so this node records loss of an incompletely defined regulatory function rather than a specific enzymatic step. No GO molecular function is bound here deliberately: an E3 ligase annotation would assert an activity that has never been demonstrated for this protein.

Downstream

Constitutive TGF-beta/SMAD3 Signaling Activation RSPRY1-deficient patient fibroblasts show transcriptomes dominated by TGF-beta pathway enrichment and behave as though the pathway is already maximally engaged.

Show evidence (2 references)

PMID:26365341 SUPPORT Other

"RSPRY1 encodes a hypothetical RING and SPRY domain-containing protein of unknown physiological function."

The founding report is explicit that the protein's physiological function is unknown, which is why this node is framed as loss of an undefined regulatory activity.

PMID:39940902 SUPPORT Computational

"BioGRID database analyses revealed that RSPRY1 has many ubiquitin ligases among its interaction partners."

Interaction-database analysis motivates the ubiquitin-ligase framing, but remains an in-silico inference rather than a demonstrated enzymatic activity.

Constitutive TGF-beta/SMAD3 Signaling Activation

In RSPRY1-deficient cells, TGF-beta regulation of the extracellular matrix is the most strongly enriched pathway, SMAD2 and SMAD3 are the dominant enriched transcription factors, and cells respond only weakly to exogenous TGF-beta1 — the signature of a pathway that is already constitutively active. Knocking out SMAD3 in the RSPRY1-null background abolishes the cellular phenotype, showing the effect is SMAD3-dependent.

dermal fibroblast CL:0000057

transforming growth factor beta receptor signaling pathway GO:0007179 ⇑ GAIN OF FUNCTION SMAD protein signal transduction GO:0060395 ↑ INCREASED

Experimental models

SEMDFA patient-derived dermal fibroblasts PRIMARY CELL CULTURE Patient fibroblast transcriptomes identify TGF-beta regulation of the extracellular matrix as the dominant dysregulated pathway, with SMAD2 and SMAD3 the top enriched transcription factors.

Downstream

Disordered Extracellular Matrix Dynamics and Cell Motility Constitutive SMAD3-dependent signaling drives the matrix and motility phenotype; the phenotype disappears when SMAD3 is removed.

Show evidence (2 references)

PMID:39940902 SUPPORT In Vitro

"The observed limited response to exogenous TGF-β in RSPRY1-deficient cells indicated that there was constitutive pathway activation."

Blunted responsiveness to added ligand is the experimental basis for calling the pathway constitutively active rather than merely upregulated.

PMID:39940902 SUPPORT In Vitro

"The pathway enrichment analysis of DEGs showed there were several significantly enriched pathways, with TGF-β regulation of the ECM pathway being the most prominent."

TGF-beta regulation of the extracellular matrix is the top-ranked enriched pathway.

Disordered Extracellular Matrix Dynamics and Cell Motility

Differentially expressed genes in RSPRY1-deficient fibroblasts are enriched for collagen-containing extracellular matrix, cartilage development, extracellular matrix organization, and chondrocyte differentiation, and the cells are hypermotile in wound-closure assays. Proliferation and senescence are unchanged, so the defect is one of matrix regulation and cell behavior rather than of cell number.

dermal fibroblast CL:0000057

extracellular matrix organization GO:0030198 ⚠ ABNORMAL cell migration GO:0016477 ↑ INCREASED

Experimental models

CRISPR-Cas9 RSPRY1 and RSPRY1/SMAD3 knockout human dermal fibroblasts PRIMARY CELL CULTURE Removing RSPRY1 increases fibroblast motility, and additionally removing SMAD3 abolishes that increase, establishing SMAD3 as the required mediator.

Downstream

Impaired Endochondral Ossification and Growth-Plate Function Matrix and TGF-beta dysregulation in the osteoblast/periosteal compartment where RSPRY1 is expressed is the proposed route to defective endochondral bone formation. The functional data come from dermal fibroblasts rather than growth-plate cells, so this step is inferred.

Show evidence (2 references)

PMID:39940902 SUPPORT In Vitro

"The most prominent BPs enriched included cartilage development, ECM organization, and chondrocyte differentiation"

The transcriptomic signature of patient fibroblasts is dominated by matrix and cartilage-differentiation programs.

PMID:39940902 SUPPORT In Vitro

"RSPRY1 KO fibroblasts exhibited a significant increase in wound closure ability, as compared to CTRL fibroblasts, which indicated that RSPRY1 deficiency enhanced cell motility"

Direct functional demonstration of the motility phenotype.

Impaired Endochondral Ossification and Growth-Plate Function

Defective endochondral bone formation at the vertebral bodies, epiphyses, and metaphyses produces the spondylar, epiphyseal, and metaphyseal dysplasia that defines the disorder, and limits longitudinal growth.

growth-plate chondrocyte CL:0000138 osteoblast CL:0000062

endochondral ossification GO:0001958 ⚠ ABNORMAL

Downstream

Progressive Skeletal Deformity and Short Stature Cumulative growth-plate failure produces worsening deformity and progressive loss of height standard deviation over childhood.

Premature Cranial Suture Fusion Membranous cranial bone growth is affected in a subset of families, producing craniosynostosis. This branch is not present in every reported family and is therefore curated as a conditional consequence.

Show evidence (2 references)

PMID:26365341 SUPPORT Model Organism

"However, we detect strong RSPRY1 protein localization in murine embryonic osteoblasts and periosteal cells during primary endochondral ossification, consistent with a role in bone development."

Places the normal protein at the site and stage of endochondral ossification whose failure is proposed here.

PMID:30063090 SUPPORT Human Clinical

"The skeletal hallmarks include (a) mild spondylar dysplasia, (b) epimetaphyseal dysplasia of the long bones associated with coxa vara and genu valgum, (c) brachymesophalangy with cone-shaped epiphyses, and (d) craniosynostosis."

The radiographic hallmarks map directly onto vertebral, epiphyseal, and metaphyseal endochondral growth sites.

Progressive Skeletal Deformity and Short Stature

Growth deceleration is postnatal and deformity accrues over childhood: lower-limb malformation is typically noticed between two and four years of age and worsens, with painful walking, wind-swept deformity, and progressive vertebral change.

Show evidence (2 references)

PMID:38562122 SUPPORT Human Clinical

"Bilateral lower limb malformation was observed at 4 years of age, which is progressive. She could not walk long distances due to pain."

Documents the childhood onset, progression, and functional cost of the deformity.

PMID:26365341 SUPPORT Human Clinical

"comprising progressive spondyloepimetaphyseal dysplasia, short stature, facial dysmorphism, short fourth metatarsals, and intellectual disability"

The defining clinical description names progression and short stature as core features.

Premature Cranial Suture Fusion

Craniosynostosis occurs in a subset of affected individuals and was present in all five patients of the two-family delineation series, where most patients were nonetheless normocephalic.

Show evidence (1 reference)

PMID:30063090 SUPPORT Human Clinical

"Unlike the previously reported clinical findings, all patients except one are normocephalic"

Records that craniosynostosis in this disorder usually occurs without microcephaly, distinguishing it from syndromic craniosynostoses with head size reduction.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

41

Cardiovascular 1

Patent Ductus Arteriosus HP:0001643

Show evidence (1 reference)

PMID:38562122 SUPPORT Human Clinical

"She was diagnosed with congenital heart disease, patent ductus arteriosus (PDA), and underwent corrective surgery at 3 years of age."

An isolated observation in one patient; curated as PARTIAL because a single case does not establish a syndromic association.

Digestive 1

Ossifying Fibroma of the Maxilla Ossifying fibroma of the jaw HP:0030427

Show evidence (1 reference)

PMID:30063090 SUPPORT Human Clinical

"Interestingly one of the patients presented with a cemento-ossifying fibrous lesion of the maxilla."

A single reported occurrence; curated as PARTIAL because one patient does not establish a syndromic association.

Ear 1

Low-Set Ears HP:0000369

Show evidence (1 reference)

PMID:38562122 SUPPORT Human Clinical

"She was noted to have a broad forehead, left exotropia with mild ptosis, depressed nasal bridge, high arched palate, low set ears, mid-face retrusion and short neck, brachydactyly, protruded belly, lumbar lordosis, overriding toes, bilateral abducted foot, and wind-swept deformity"

Low-set ears documented on examination.

Eye 3

Myopia HP:0000545

Show evidence (1 reference)

PMID:38562122 SUPPORT Human Clinical

"She had squint eyes, and the ophthalmologic assessment confirmed myopia in both eyes with mild ptosis in the left eye."

Single-patient ophthalmologic finding, curated without a frequency band.

Ptosis HP:0000508

Severity: MILD

Show evidence (1 reference)

ORPHA:457395 SUPPORT Other

"dysmorphic craniofacial features (including microcephaly, hypertelorism, epicanthal folds, mild ptosis, strabismus, malar hypoplasia"

Orphanet lists mild ptosis among the craniofacial features.

Strabismus HP:0000486

Show evidence (1 reference)

ORPHA:457395 SUPPORT Other

"dysmorphic craniofacial features (including microcephaly, hypertelorism, epicanthal folds, mild ptosis, strabismus, malar hypoplasia"

Orphanet lists strabismus among the ocular/craniofacial features.

Head and Neck 9

Craniosynostosis HP:0001363

Frequency is deliberately omitted. Craniosynostosis was present in all five patients of the 2018 series but is not documented in every reported family, and the total published caseload is too small to support a frequency band.

Show evidence (1 reference)

PMID:30063090 SUPPORT Human Clinical

"we provide further evidence that Spondyloepimetaphyseal dysplasia Faden-Alkuraya type is a RSPRY1-associated skeletal dysplasia with a distinctive phenotype composed of spondyloepimetaphyseal dysplasia, cono-brachydactyly, and craniosynostosis along with recognizable facial features and..."

Craniosynostosis is named as part of the distinctive phenotype.

Facial Dysmorphism VERY_FREQUENT Abnormal facial shape HP:0001999

Show evidence (2 references)

PMID:30063090 SUPPORT Human Clinical

"All patients have short stature, extremity deformities, facial dysmorphism and intellectual disability."

Facial dysmorphism was present in all patients of the delineation series.

PMID:38562122 SUPPORT Human Clinical

"She had midface retrusion, a square-shaped face, a depressed nasal bridge, a high arched palate, a short neck, a short thorax, lumbar lordosis, distal joint laxity, and pes planus"

Enumerates the component facial features in an affected individual.

Midface Retrusion HP:0011800

Show evidence (1 reference)

PMID:38562122 SUPPORT Human Clinical

"She had midface retrusion, a square-shaped face, a depressed nasal bridge, a high arched palate, a short neck, a short thorax, lumbar lordosis, distal joint laxity, and pes planus"

Midface retrusion documented on examination.

Depressed Nasal Bridge HP:0005280

Show evidence (1 reference)

PMID:38562122 SUPPORT Human Clinical

"She had midface retrusion, a square-shaped face, a depressed nasal bridge, a high arched palate, a short neck, a short thorax, lumbar lordosis, distal joint laxity, and pes planus"

Depressed nasal bridge documented on examination.

High Palate HP:0000218

Show evidence (1 reference)

PMID:38562122 SUPPORT Human Clinical

"She had midface retrusion, a square-shaped face, a depressed nasal bridge, a high arched palate, a short neck, a short thorax, lumbar lordosis, distal joint laxity, and pes planus"

High-arched palate documented on examination.

Short Neck HP:0000470

Show evidence (1 reference)

PMID:38562122 SUPPORT Human Clinical

"She had midface retrusion, a square-shaped face, a depressed nasal bridge, a high arched palate, a short neck, a short thorax, lumbar lordosis, distal joint laxity, and pes planus"

Short neck documented on examination.

Broad Forehead HP:0000337

Show evidence (1 reference)

PMID:38562122 SUPPORT Human Clinical

"She was noted to have a broad forehead, left exotropia with mild ptosis, depressed nasal bridge, high arched palate, low set ears, mid-face retrusion and short neck, brachydactyly, protruded belly, lumbar lordosis, overriding toes, bilateral abducted foot, and wind-swept deformity"

Broad forehead documented on examination.

Copper Beaten Skull HP:0034271

Show evidence (1 reference)

PMID:38562122 SUPPORT Human Clinical

"The radiographic evaluation indicated a copper-beaten appearance of a skull, platyspondyly, mild scoliosis, lumbar lordosis, small carpals bones, short femoral neck, short fourth metatarsal bone, wind-swept deformity, small epiphyses, metaphyseal cupping, and fraying in both siblings."

Copper-beaten skull documented radiographically in both siblings.

Microcephaly HP:0000252

Show evidence (2 references)

ORPHA:457395 SUPPORT Other

"dysmorphic craniofacial features (including microcephaly, hypertelorism, epicanthal folds, mild ptosis, strabismus, malar hypoplasia, short nose, depressed nasal bridge, full lips, small, low-set ears, and short neck)"

Orphanet lists microcephaly among the craniofacial features.

PMID:30063090 REFUTE Human Clinical

"Unlike the previously reported clinical findings, all patients except one are normocephalic"

The five-patient delineation cohort explicitly contradicts microcephaly as a consistent feature.

Limbs 10

Metaphyseal Cupping and Fraying HP:0003021

Show evidence (1 reference)

PMID:38562122 SUPPORT Human Clinical

"Mild scoliosis, vertebral defects, small epiphysis, cupping, and fraying of metaphyses of tibia and fibula, coxa vara, genu valgum, short metacarpals, short metatarsals, and craniosynostosis have been described in affected individuals"

Metaphyseal cupping and fraying of the tibia and fibula are established features.

Short Fourth Metatarsal FREQUENT HP:0004689

Show evidence (2 references)

PMID:26365341 SUPPORT Human Clinical

"comprising progressive spondyloepimetaphyseal dysplasia, short stature, facial dysmorphism, short fourth metatarsals, and intellectual disability"

Short fourth metatarsals are one of the five defining features of the founding description.

PMID:38562122 SUPPORT Human Clinical

"The radiographic evaluation indicated a copper-beaten appearance of a skull, platyspondyly, mild scoliosis, lumbar lordosis, small carpals bones, short femoral neck, short fourth metatarsal bone, wind-swept deformity, small epiphyses, metaphyseal cupping, and fraying in both siblings."

Radiographic confirmation of the short fourth metatarsal in both siblings.

Brachydactyly with Cone-Shaped Epiphyses FREQUENT HP:0001156

Show evidence (1 reference)

PMID:30063090 SUPPORT Human Clinical

"The skeletal hallmarks include (a) mild spondylar dysplasia, (b) epimetaphyseal dysplasia of the long bones associated with coxa vara and genu valgum, (c) brachymesophalangy with cone-shaped epiphyses, and (d) craniosynostosis."

Brachymesophalangy with cone-shaped epiphyses is listed among the skeletal hallmarks.

Coxa Vara FREQUENT HP:0002812

Show evidence (1 reference)

PMID:30063090 SUPPORT Human Clinical

"epimetaphyseal dysplasia of the long bones associated with coxa vara and genu valgum"

Coxa vara accompanies the long-bone epimetaphyseal dysplasia.

Genu Valgum FREQUENT HP:0002857

Show evidence (1 reference)

PMID:30063090 SUPPORT Human Clinical

"epimetaphyseal dysplasia of the long bones associated with coxa vara and genu valgum"

Genu valgum accompanies the long-bone epimetaphyseal dysplasia.

Pes Planus HP:0001763

Show evidence (1 reference)

PMID:30063090 SUPPORT Human Clinical

"all share the clinical findings including craniosynostosis, varying degrees of intellectual disability, facial dysmorphism, and skeletal findings including pes planus, prominent heels, and pectus deformity"

Pes planus is listed among the shared skeletal findings.

Prominent Calcaneus HP:0012428

Show evidence (1 reference)

PMID:30063090 SUPPORT Human Clinical

"all share the clinical findings including craniosynostosis, varying degrees of intellectual disability, facial dysmorphism, and skeletal findings including pes planus, prominent heels, and pectus deformity"

Prominent heels are listed among the shared skeletal findings.

Short Metacarpals HP:0010049

Show evidence (1 reference)

PMID:38562122 SUPPORT Human Clinical

"Mild scoliosis, vertebral defects, small epiphysis, cupping, and fraying of metaphyses of tibia and fibula, coxa vara, genu valgum, short metacarpals, short metatarsals, and craniosynostosis have been described in affected individuals"

Short metacarpals are an established feature.

Carpal Bone Hypoplasia HP:0001498

Show evidence (1 reference)

PMID:38562122 SUPPORT Human Clinical

"The radiographic evaluation indicated a copper-beaten appearance of a skull, platyspondyly, mild scoliosis, lumbar lordosis, small carpals bones, short femoral neck, short fourth metatarsal bone, wind-swept deformity, small epiphyses, metaphyseal cupping, and fraying in both siblings."

Small carpal bones were documented radiographically in both siblings.

Short Femoral Neck HP:0100864

Show evidence (1 reference)

PMID:38562122 SUPPORT Human Clinical

"The radiographic evaluation indicated a copper-beaten appearance of a skull, platyspondyly, mild scoliosis, lumbar lordosis, small carpals bones, short femoral neck, short fourth metatarsal bone, wind-swept deformity, small epiphyses, metaphyseal cupping, and fraying in both siblings."

Short femoral neck documented radiographically in both siblings.

Musculoskeletal 10

Progressive Spondylar Dysplasia VERY_FREQUENT Platyspondyly HP:0000926

Course: PROGRESSIVE

Show evidence (3 references)

PMID:38562122 SUPPORT Human Clinical

"The radiographic evaluation indicated a copper-beaten appearance of a skull, platyspondyly, mild scoliosis, lumbar lordosis, small carpals bones, short femoral neck, short fourth metatarsal bone, wind-swept deformity, small epiphyses, metaphyseal cupping, and fraying in both siblings."

Platyspondyly was present in both siblings on radiographic review.

PMID:38562122 SUPPORT Human Clinical

"The severity of vertebral deformities increases with age."

Supports the PROGRESSIVE clinical course qualifier.

PMID:30063090 SUPPORT Human Clinical

"The skeletal hallmarks include (a) mild spondylar dysplasia, (b) epimetaphyseal dysplasia of the long bones associated with coxa vara and genu valgum, (c) brachymesophalangy with cone-shaped epiphyses, and (d) craniosynostosis."

Spondylar dysplasia heads the list of skeletal hallmarks shared by all five patients of the delineation series, supporting the VERY_FREQUENT band.

Epiphyseal Dysplasia with Small Epiphyses HP:0010585

Show evidence (1 reference)

PMID:38562122 SUPPORT Human Clinical

"Mild scoliosis, vertebral defects, small epiphysis, cupping, and fraying of metaphyses of tibia and fibula, coxa vara, genu valgum, short metacarpals, short metatarsals, and craniosynostosis have been described in affected individuals"

Summarizes small epiphyses as an established feature of the disorder.

Scoliosis HP:0002650

Show evidence (1 reference)

PMID:38562122 SUPPORT Human Clinical

"Mild scoliosis, vertebral defects, small epiphysis, cupping, and fraying of metaphyses of tibia and fibula, coxa vara, genu valgum, short metacarpals, short metatarsals, and craniosynostosis have been described in affected individuals"

Mild scoliosis is an established feature of the disorder.

Lumbar Hyperlordosis HP:0002938

Show evidence (1 reference)

PMID:38562122 SUPPORT Human Clinical

"She had midface retrusion, a square-shaped face, a depressed nasal bridge, a high arched palate, a short neck, a short thorax, lumbar lordosis, distal joint laxity, and pes planus"

Direct examination finding in an affected sibling.

Joint Dislocation HP:0001373

Show evidence (1 reference)

PMID:38562122 SUPPORT Human Clinical

"We noted subluxation/dislocation of elbow joints in them, which was not reported previously in individuals with RSPRY1-related SEMD."

Explicitly reported as a novel feature, so it is curated without a frequency band pending replication.

Pectus Deformity Abnormal sternum morphology HP:0000766

Show evidence (1 reference)

PMID:30063090 SUPPORT Human Clinical

"all share the clinical findings including craniosynostosis, varying degrees of intellectual disability, facial dysmorphism, and skeletal findings including pes planus, prominent heels, and pectus deformity"

Pectus deformity is listed among the shared skeletal findings.

Joint Hypermobility HP:0001382

Show evidence (1 reference)

PMID:38562122 SUPPORT Human Clinical

"She had midface retrusion, a square-shaped face, a depressed nasal bridge, a high arched palate, a short neck, a short thorax, lumbar lordosis, distal joint laxity, and pes planus"

Direct examination finding in an affected sibling.

Progressive Spondyloepimetaphyseal Dysplasia OBLIGATE HP:0002651

Course: PROGRESSIVE

Show evidence (2 references)

PMID:26365341 SUPPORT Human Clinical

"We describe a clinically recognizable autosomal-recessive disorder in four affected siblings from a consanguineous Saudi family, comprising progressive spondyloepimetaphyseal dysplasia, short stature, facial dysmorphism, short fourth metatarsals, and intellectual disability."

Progressive spondyloepimetaphyseal dysplasia is named as the first component of the defining phenotype in every affected individual of the index family.

PMID:38562122 SUPPORT Human Clinical

"The severity of vertebral deformities increases with age."

Confirms the progressive course of the vertebral component.

Cone-Shaped Epiphyses Cone-shaped epiphysis HP:0010579

Show evidence (1 reference)

PMID:30063090 SUPPORT Human Clinical

"The skeletal hallmarks include (a) mild spondylar dysplasia, (b) epimetaphyseal dysplasia of the long bones associated with coxa vara and genu valgum, (c) brachymesophalangy with cone-shaped epiphyses, and (d) craniosynostosis."

Brachymesophalangy with cone-shaped epiphyses is listed as one of the four skeletal hallmarks of the entity.

Generalized Hypotonia HP:0001290

Show evidence (1 reference)

ORPHA:457395 SUPPORT Other

"Craniosynostosis, generalized hypotonia, as well as asymmetry of the cerebral hemispheres and mild thinning of the corpus callosum on brain imaging have also been described."

Orphanet records generalized hypotonia as a described feature.

Nervous System 5

Intellectual Disability VERY_FREQUENT HP:0001249

Show evidence (2 references)

PMID:30063090 SUPPORT Human Clinical

"All patients have short stature, extremity deformities, facial dysmorphism and intellectual disability."

Intellectual disability was present in all five patients of the delineation series, supporting the VERY_FREQUENT band.

PMID:26365341 SUPPORT Human Clinical

"comprising progressive spondyloepimetaphyseal dysplasia, short stature, facial dysmorphism, short fourth metatarsals, and intellectual disability"

Intellectual disability is one of the five defining features of the founding description.

Global Developmental Delay HP:0001263

Show evidence (1 reference)

PMID:38562122 SUPPORT Human Clinical

"Developmentally, she attained head control at 5 months of age, social smile at 3 months, and started to sit without support at 1 year of age. She started walking at 2 years."

Independent sitting at 12 months and walking at 24 months document delayed gross-motor milestones.

Delayed Ability to Walk HP:0031936

Show evidence (1 reference)

PMID:38562122 SUPPORT Human Clinical

"She started walking at 2 years."

Independent ambulation at 2 years is delayed relative to the typical 12-18 month milestone.

Bilateral Tonic-Clonic Seizure HP:0002069

Show evidence (1 reference)

PMID:38562122 SUPPORT Human Clinical

"She had generalized tonic−clonic seizures, which lasted for 5 min."

Single-patient observation; no frequency band is asserted because it has been reported once.

Thin Corpus Callosum HP:0033725

Show evidence (1 reference)

ORPHA:457395 SUPPORT Other

"asymmetry of the cerebral hemispheres and mild thinning of the corpus callosum on brain imaging have also been described"

Orphanet records the neuroimaging findings for this syndrome.

Growth 1

Postnatal Short Stature VERY_FREQUENT HP:0004322

Show evidence (2 references)

PMID:30063090 SUPPORT Human Clinical

"All patients have short stature, extremity deformities, facial dysmorphism and intellectual disability."

Short stature was present in all five patients of the delineation series, supporting the VERY_FREQUENT band.

PMID:26365341 SUPPORT Human Clinical

"comprising progressive spondyloepimetaphyseal dysplasia, short stature, facial dysmorphism, short fourth metatarsals, and intellectual disability"

Short stature is one of the five defining features in the founding description.

🧬

Genetic Associations

1

Biallelic RSPRY1 Loss-of-Function Variants (Causative)

Gene: RSPRY1 hgnc:29420 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (4 references)

PMID:26365341 SUPPORT Human Clinical

"Combined autozygome/exome analysis identified a homozygous frameshift mutation in RSPRY1 with resulting nonsense-mediated decay."

The founding family carries a homozygous frameshift allele whose transcript undergoes nonsense-mediated decay, establishing loss of function.

PMID:26365341 SUPPORT Human Clinical

"we were able to identify a Peruvian simplex case subject whose phenotype is strikingly similar to the original Saudi family and whose exome sequencing had revealed a likely pathogenic homozygous missense variant in the same gene"

A second, independently ascertained family with a homozygous missense allele and a matching phenotype supplied the replication that established the gene-disease relationship.

PMID:38562122 SUPPORT Human Clinical

"Two siblings presenting with short stature, facial dysmorphism, progressive vertebral defects, small epiphysis, cupping and fraying of metaphyses, brachydactyly, and short metatarsals harbored a homozygous missense variant c.1652G>A;p.(Cys551Tyr) in the RSPRY1 gene."

Documents a further homozygous missense allele segregating with the phenotype.

+ 1 more reference

🔬

Variants

3

RSPRY1 c.377delT p.(Ile126fs) Pathogenic

Gene: RSPRY1 hgnc:29420 frameshift

Homozygous single-nucleotide deletion in exon 2 causing a frameshift, reported in one of two Turkish families.

Show evidence (1 reference)

PMID:30063090 SUPPORT Human Clinical

"frameshift mutation at exon 2 in one family, while Sanger sequencing revealed a novel homozygous splice site mutation"

Reports the homozygous exon 2 frameshift allele. The cDNA designation is given in square brackets in the source abstract and is therefore recorded in the variant name rather than quoted in the snippet.

RSPRY1 c.516+2T>A Pathogenic

Gene: RSPRY1 hgnc:29420 splice site

Homozygous canonical splice-donor variant at the exon 4 / intron 4 border, reported in the second Turkish family.

Show evidence (1 reference)

PMID:30063090 SUPPORT Human Clinical

"Sanger sequencing revealed a novel homozygous splice site mutation"

Reports the homozygous canonical splice-site allele in the second family; the cDNA designation appears in square brackets in the source abstract.

RSPRY1 c.1652G>A p.(Cys551Tyr) Likely Pathogenic

Gene: RSPRY1 hgnc:29420 missense

Homozygous missense variant in exon 15, the last exon, substituting a cysteine conserved across five vertebrate species within the C3HC4-type RING finger domain. Absent from gnomAD v3.1.2 and from an in-house cohort of 3,076 exomes; CADD phred 29.7, M-CAP 0.812, REVEL 0.967, AlphaMissense 0.999. Submitted to ClinVar as SCV002061883.2.

Show evidence (2 references)

PMID:38562122 SUPPORT Human Clinical

"A shared homozygous non-synonymous missense variant at c.1652G>A;p.(Cys551Tyr) in exon 15 of the RSPRY1 gene (NM_133368.3; NP 588609.1) was identified through exome sequencing in both siblings."

Identifies the variant and its transcript context.

PMID:38562122 SUPPORT Human Clinical

"This variant is not present in gnomAD (V3.1.2) and our in-house data of 3076 exomes."

Population-database absence supporting pathogenicity (ACMG PM2).

💊

Medical Actions

5

Supportive and Symptom-Directed Management

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

Platform: Other

No disease-modifying therapy exists. Management is supportive and multidisciplinary, directed at the skeletal deformity, developmental needs, and any associated anomalies. No trial or management protocol specific to RSPRY1 disease has been published.

Surgical Correction of Associated Anomalies

Action: surgical procedure Ontology label: Surgical Procedure NCIT:C15329

Platform: Surgery

Surgery has been used in reported patients for associated anomalies — corrective surgery for patent ductus arteriosus in one child — and is the standard route for craniosynostosis and for progressive limb malalignment in skeletal dysplasia generally.

Show evidence (1 reference)

PMID:38562122 SUPPORT Human Clinical

"She was diagnosed with congenital heart disease, patent ductus arteriosus (PDA), and underwent corrective surgery at 3 years of age."

Documents a surgical intervention actually performed in a reported patient. It supports surgery for an associated anomaly, not a disease-modifying effect, hence PARTIAL.

Genetic Counseling

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

Platform: Other

Autosomal recessive inheritance carries a 25 percent recurrence risk for carrier couples, and reported families have generally been consanguineous, so counseling and — once the familial variants are known — the option of prenatal or preimplantation testing are central to family management.

Show evidence (1 reference)

PMID:26365341 SUPPORT Human Clinical

"We describe a clinically recognizable autosomal-recessive disorder in four affected siblings from a consanguineous Saudi family"

Establishes the autosomal recessive, consanguinity-associated inheritance that makes counseling and recurrence-risk discussion the relevant action.

Anti-Seizure Pharmacotherapy

Action: Pharmacotherapy NCIT:C15986

Agent: levetiracetam CHEBI:6437

Platform: Small molecule

Levetiracetam controlled generalized tonic-clonic seizures in the one reported patient with epilepsy. This is standard symptomatic epilepsy management, not a disease-specific therapy.

Target Phenotypes: Bilateral tonic-clonic seizure HP:0002069

Show evidence (1 reference)

PMID:38562122 SUPPORT Human Clinical

"She was treated with levetiracetam, and her seizures were controlled."

Single-patient report of seizure control on levetiracetam; not generalizable evidence of efficacy in this disorder.

Ophthalmologic Correction

Action: therapeutic procedure Ontology label: Therapeutic Procedure NCIT:C49236

Platform: Device

Refractive correction for myopia and management of strabismus and ptosis, identified on formal ophthalmologic assessment in reported patients.

Target Phenotypes: Myopia HP:0000545

Show evidence (1 reference)

PMID:38562122 SUPPORT INDIRECT Human Clinical

"Moreover, ophthalmologic evaluation showed myopia in both eyes."

Establishes the refractive indication. Graded INDIRECT because the quoted text reports the refractive error itself; that correction is indicated follows by an inference step, and no outcome data on correction are reported in this disorder.

🔬

Diagnosis

2

Clinical and Radiographic Recognition

The combination of the facial gestalt, disproportionate short stature, short fourth metatarsals, cono-brachydactyly, and progressive spondylar plus epimetaphyseal change on skeletal survey is distinctive enough to raise the diagnosis before molecular testing.

skeletal survey radiography NCIT:C38092

Show evidence (1 reference)

PMID:26365341 SUPPORT Human Clinical

"We describe a clinically recognizable autosomal-recessive disorder"

The founding report frames the entity as clinically recognizable.

Molecular Confirmation by Exome or Targeted RSPRY1 Sequencing

Diagnosis is confirmed by identifying biallelic pathogenic RSPRY1 variants. In practice this has been achieved by exome sequencing — combined with autozygosity mapping in consanguineous families — or by targeted sequencing once RSPRY1 is suspected.

whole exome sequencing NCIT:C101295

Show evidence (2 references)

PMID:26365341 SUPPORT Human Clinical

"Combined autozygome/exome analysis identified a homozygous frameshift mutation in RSPRY1 with resulting nonsense-mediated decay."

Describes the diagnostic strategy that established the first molecular diagnosis.

PMID:39706863 SUPPORT Human Clinical

"We expand the phenotypic and genotypic spectrum of rarely reported conditions (RAB33B, TRIP11, NEPRO, RPL13, COL27A1, PTHR1, EXOC6B, PRKACA, FUZ and RSPRY1)"

A national skeletal-dysplasia sequencing cohort shows that RSPRY1 disease is reached through broad exome/genome testing rather than a dedicated assay.

🩻

Imaging Findings

3

Copper-Beaten Skull Appearance on Skull Radiographs

A copper-beaten (beaten-silver) skull appearance, the radiographic sign of raised intracranial pressure against the inner table, was seen in both reported Indian siblings.

Xray

Copper beaten skull HP:0034271

Show evidence (1 reference)

PMID:38562122 SUPPORT Human Clinical

"The radiographic evaluation indicated a copper-beaten appearance of a skull, platyspondyly, mild scoliosis, lumbar lordosis, small carpals bones, short femoral neck, short fourth metatarsal bone, wind-swept deformity, small epiphyses, metaphyseal cupping, and fraying in both siblings."

Direct radiographic observation in both siblings.

Metaphyseal Cupping and Fraying on Long-Bone Radiographs

Cupping and fraying of the metaphyses, most marked at the tibia and fibula, are core radiographic signs of the metaphyseal component.

Xray

Metaphyseal cupping HP:0003021

Show evidence (1 reference)

PMID:38562122 SUPPORT Human Clinical

"Spondyloepimetaphyseal dysplasia (SEMD), RSPRY1 related (OMIM #616723), also referred to as SEMD, Faden-Alkuraya type, is a rare autosomal recessive disorder. The condition is characterized by short stature, facial dysmorphism, brachydactyly, and intellectual disability. Mild scoliosis,..."

Restores the RSPRY1/Faden-Alkuraya disease identification before the skeletal findings. These are previously reported features, not a statement that every listed feature occurred in both sisters.

Cone-Shaped Phalangeal Epiphyses on Hand Radiographs

Brachymesophalangy with cone-shaped epiphyses gives the cono-brachydactyly pattern that helps distinguish this entity radiographically.

Xray

Cone-shaped epiphysis HP:0010579

Show evidence (1 reference)

PMID:30063090 SUPPORT Human Clinical

"The skeletal hallmarks include (a) mild spondylar dysplasia, (b) epimetaphyseal dysplasia of the long bones associated with coxa vara and genu valgum, (c) brachymesophalangy with cone-shaped epiphyses, and (d) craniosynostosis."

Cone-shaped epiphyses are named among the radiographic hallmarks.

📈

Progression

3

Infancy

Age: First two years

Birth and the early postnatal period may be unremarkable, and anthropometric parameters at birth are not consistently recorded. Gross-motor milestones can be mildly delayed.

Show evidence (1 reference)

PMID:38562122 SUPPORT Human Clinical

"Birth and postnatal periods were unremarkable."

Documents an unremarkable perinatal course in an affected sibling.

Early childhood onset of limb deformity

Age: Two to four years

Lower-limb malformation is typically first noticed between two and four years of age, together with short stature and painful walking, and progresses thereafter.

Show evidence (1 reference)

PMID:38562122 SUPPORT Human Clinical

"Bilateral lower limb malformation was observed at 4 years of age, which is progressive. She could not walk long distances due to pain."

Dates the onset of the limb deformity and its progressive character.

Childhood through adolescence

Age: Childhood to skeletal maturity

Vertebral deformity worsens with age and the dysplasia is explicitly progressive, which is the feature that separates this entity from static spondyloepimetaphyseal dysplasias. No adult natural-history data have been published.

Show evidence (1 reference)

PMID:38562122 SUPPORT Human Clinical

"The severity of vertebral deformities increases with age."

Direct statement of progression over childhood.

📊

Prevalence

1

Worldwide

Cases In Literature Ultra Rare

Fewer than 15 molecularly confirmed individuals have been published. Ten individuals from four unrelated Saudi, Peruvian, and Turkish families were on record by 2018, with two further Indian sisters reported in 2024 and additional Indian cases ascertained in a national skeletal-dysplasia cohort. No population-based prevalence estimate exists.

Show evidence (1 reference)

PMID:38562122 SUPPORT Human Clinical

"To date, 10 individuals with SEMD, RSPRY1 type, are reported from 4 unrelated families from Saudi Arabia, Peru, and Turkey"

The 2024 report tallies the entire published caseload at ten individuals from four families before adding its own two, establishing the cases-in-literature scale of the disorder.

🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Spondyloepimetaphyseal Dysplasia Faden-Alkuraya Type:

Spondyloepimetaphyseal Dysplasia Strudwick Type

Overlapping Features Another spondyloepimetaphyseal dysplasia with vertebral, epiphyseal, and metaphyseal involvement, so the radiographic pattern overlaps.

Distinguishing Features

Strudwick type is autosomal dominant and caused by COL2A1 variants, has dappled irregular metaphyses, and is not associated with intellectual disability, short fourth metatarsals, or craniosynostosis.

Spondyloepimetaphyseal Dysplasia with Joint Laxity

Overlapping Features Shares spondyloepimetaphyseal radiographic changes and, since joint dislocation was reported in RSPRY1 disease, some clinical overlap.

Distinguishing Features

In SEMD with joint laxity, generalized joint laxity and dislocation are core defining features present from early life, and the digits are typically slender (leptodactylic) rather than showing cono-brachydactyly.

Syndromic Craniosynostosis

Overlapping Features When craniosynostosis dominates the presentation, the syndromic craniosynostoses enter the differential.

Distinguishing Features

The syndromic craniosynostoses lack the progressive spondylar and epimetaphyseal dysplasia, the short fourth metatarsals, and the cono-brachydactyly that define this entity, and most are autosomal dominant.

🧫

Experimental Models

2

SEMDFA patient-derived dermal fibroblasts PRIMARY_CELL_CULTURE

Dermal fibroblasts obtained by skin biopsy from two patients homozygous for the RSPRY1 c.377delT frameshift allele, compared with commercial control human dermal fibroblasts by bulk RNA sequencing.

Organism

human NCBITaxon:9606

Cell source

Patient-derived (skin biopsy)

Culture

Two-dimensional monolayer culture, passage 3

Publication

PMID:39940902

Pathograph links

Constitutive TGF-beta/SMAD3 Signaling Activation measures fidelity: moderate Patient fibroblast transcriptomes identify TGF-beta regulation of the extracellular matrix as the dominant dysregulated pathway, with SMAD2 and SMAD3 the top enriched transcription factors.

Limitations: Dermal fibroblasts are a patient-accessible surrogate. RSPRY1 is normally concentrated in osteoblasts and periosteal cells of the developing endochondral skeleton, so the pathway readout is not measured in the disease-relevant bone lineage.

Readouts

TGF-beta regulation of extracellular matrix pathway enrichment

Direction: INCREASED

Interpretation: The most strongly enriched pathway among differentially expressed genes in patient versus control fibroblasts.

Show evidence (1 reference)

PMID:39940902 SUPPORT In Vitro

"The pathway enrichment analysis of DEGs showed there were several significantly enriched pathways, with TGF-β regulation of the ECM pathway being the most prominent."

Reports the enrichment result behind this readout.

Show evidence (1 reference)

PMID:39940902 SUPPORT In Vitro

"Transcriptome analysis of fibroblasts from patients with homozygous RSPRY1 mutations showed there was significant enrichment of transforming growth factor beta (TGF-β) signaling and ECM-related pathways."

Establishes the model as informative for the TGF-beta activation node.

Show evidence (1 reference)

PMID:39940902 SUPPORT In Vitro

"frameshift mutation in exon 2 of the RSPRY1 gene (NM_133368). Dermal fibroblasts were obtained from the patients via skin biopsy."

Establishes the genotype and tissue source of the patient-derived fibroblast model.

CRISPR-Cas9 RSPRY1 and RSPRY1/SMAD3 knockout human dermal fibroblasts PRIMARY_CELL_CULTURE

Isogenic RSPRY1 knockout, SMAD3 knockout, and RSPRY1 plus SMAD3 double knockout human dermal fibroblasts generated with Cas9 ribonucleoprotein complexes, used for wound-healing, proliferation, senescence, and apoptosis assays with and without recombinant TGF-beta1.

Organism

human NCBITaxon:9606

Cell source

Gene-edited human dermal fibroblasts

Culture

Two-dimensional monolayer culture with and without recombinant TGF-beta1

Publication

PMID:39940902

Pathograph links

Disordered Extracellular Matrix Dynamics and Cell Motility perturbs fidelity: moderate Removing RSPRY1 increases fibroblast motility, and additionally removing SMAD3 abolishes that increase, establishing SMAD3 as the required mediator.

Limitations: Wound closure in dermal fibroblasts is a proxy for matrix-regulated cell behavior, not a measurement of growth-plate or osteoblast function, and the link to endochondral ossification remains inferred.

Readouts

Wound closure rate in RSPRY1 knockout fibroblasts

Direction: INCREASED

Interpretation: Faster wound closure indicates enhanced cell motility after RSPRY1 loss.

Show evidence (1 reference)

PMID:39940902 SUPPORT In Vitro

"RSPRY1 KO fibroblasts exhibited a significant increase in wound closure ability, as compared to CTRL fibroblasts, which indicated that RSPRY1 deficiency enhanced cell motility"

Reports the wound-closure measurement and its direction.

Wound closure rate in RSPRY1 plus SMAD3 double knockout fibroblasts

Direction: ABOLISHED

Interpretation: Loss of the motility gain in the double knockout shows the effect requires SMAD3.

Show evidence (1 reference)

PMID:39940902 SUPPORT In Vitro

"this improved wound-healing capacity was not observed in the RSPRY1 + SMAD3 double KO fibroblasts, indicating that SMAD3 plays a critical role in mediating the effects of RSPRY1 loss on cell motility"

Reports the epistasis result behind this readout.

Show evidence (1 reference)

PMID:39940902 SUPPORT In Vitro

"Functional wound healing assays showed that RSPRY1 knockout fibroblasts exhibited enhanced motility, a phenotype that was abrogated in RSPRY1 + SMAD3 double knockout fibroblasts, highlighting the SMAD3-dependence of RSPRY1's effects."

Establishes the edited-fibroblast system as the perturbation model for this node.

Show evidence (1 reference)

PMID:39940902 SUPPORT In Vitro

"To further investigate the role of RSPRY1 and its interaction with SMAD3 in cellular processes, RSPRY1 KO, SMAD3 KO, and RSPRY1 + SMAD3 double KO fibroblasts were generated."

Establishes the isogenic knockout panel that constitutes this model.

{ }

Source YAML

click to show

name: Spondyloepimetaphyseal Dysplasia Faden-Alkuraya Type
creation_date: "2026-08-20T00:00:00Z"
category: Mendelian
description: >-
  Spondyloepimetaphyseal dysplasia, Faden-Alkuraya type (SEMDFA; OMIM #616723)
  is an ultra-rare autosomal recessive, progressive skeletal dysplasia caused by
  biallelic loss-of-function variants in RSPRY1, which encodes a RING- and
  SPRY-domain protein expressed in embryonic osteoblasts and periosteal cells
  during primary endochondral ossification. Affected individuals have
  postnatal-onset disproportionate short stature, progressive vertebral
  (spondylar) dysplasia, epimetaphyseal dysplasia of the long bones with coxa
  vara and genu valgum, brachydactyly with cone-shaped epiphyses, short fourth
  metatarsals, recognizable facial dysmorphism, and intellectual disability;
  craniosynostosis is present in some families. Patient-derived fibroblast work
  implicates constitutive TGF-beta/SMAD3 signaling and disordered extracellular
  matrix dynamics as the proximate cellular mechanism, but the biochemical
  function of RSPRY1 itself remains undetermined.
disease_term:
  preferred_term: spondyloepimetaphyseal dysplasia, Faden-Alkuraya type
  term:
    id: MONDO:0014748
    label: progressive spondyloepimetaphyseal dysplasia-short stature-short fourth metatarsals-intellectual disability syndrome
synonyms:
- SEMDFA
- Spondyloepimetaphyseal dysplasia, Faden-Alkuraya type
- RSPRY1-related spondyloepimetaphyseal dysplasia
- Spondyloepimetaphyseal dysplasia, progressive, with short stature, facial dysmorphism,
  short fourth metatarsals, and intellectual disability, with or without craniosynostosis
parents:
- Skeletal Dysplasia
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      A Mendelian (autosomal recessive) multiple congenital anomalies/dysmorphic
      syndrome; hereditary skeletal dysplasias are placed in the genetics Part per
      the dismech classification guidance rather than in a musculoskeletal Part.
    evidence:
    - reference: ORPHA:457395
      reference_title: Progressive spondyloepimetaphyseal dysplasia-short stature-short fourth metatarsals-intellectual disability syndrome
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized
        by global developmental delay and intellectual disability, progressive
        spondyloepimetaphyseal dysplasia, short stature, short fourth metatarsals, and
        dysmorphic craniofacial features
      explanation: >-
        Orphanet frames the entity as a genetic multiple congenital
        anomalies/dysmorphic syndrome, supporting placement in Harrison's genetics
        Part.
  isds_skeletal_category:
  - classification_value: spondylo_epi_metaphyseal_dysplasias
    notes: >-
      RSPRY1 is named among the SE(M)D genes of the ISDS Nosology and
      Classification of Genetic Skeletal Disorders group "Spondyloepi(meta)physeal
      dysplasias (SE(M)D)".
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0014748
      label: progressive spondyloepimetaphyseal dysplasia-short stature-short fourth metatarsals-intellectual disability syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: Orphanet ORPHA:457395
    mapping_justification: >-
      Orphanet ORPHA:457395 lists MONDO:0014748 as an exact cross-reference; it is the
      primary disease term for this entry.
references:
- reference: PMID:26365341
  title: Identification of a Recognizable Progressive Skeletal Dysplasia Caused by RSPRY1 Mutations.
- reference: PMID:30063090
  title: "Further delineation of spondyloepimetaphyseal dysplasia Faden-Alkuraya type: A RSPRY1-associated spondylo-epi-metaphyseal dysplasia with cono-brachydactyly and craniosynostosis."
- reference: PMID:38562122
  title: Two sisters with RSPRY1-related spondyloepimetaphyseal dysplasia.
- reference: PMID:39706863
  title: Genetic and allelic heterogeneity in 248 Indians with skeletal dysplasia.
- reference: PMID:39940902
  title: "Unraveling the Role of RSPRY1 in TGF-β Pathway Dysregulation: Insights into the Pathogenesis of Spondyloepimetaphyseal Dysplasia."
- reference: PMID:26497270
  title: "Isolation, expression analysis and characterization of NEFA-interacting nuclear protein 30 and RING finger and SPRY domain containing 1 in skeletal muscle."
- reference: PMID:27230627
  title: "A 16q12.2q21 deletion identified in a patient with developmental delay, epilepsy, short stature, and distinctive features."
- reference: PMID:33092958
  title: Substrate recognition by TRIM and TRIM-like proteins in innate immunity.
- reference: ORPHA:457395
  title: Progressive spondyloepimetaphyseal dysplasia-short stature-short fourth metatarsals-intellectual disability syndrome
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Fewer than 15 molecularly confirmed individuals have been published. Ten
    individuals from four unrelated Saudi, Peruvian, and Turkish families were
    on record by 2018, with two further Indian sisters reported in 2024 and
    additional Indian cases ascertained in a national skeletal-dysplasia cohort.
    No population-based prevalence estimate exists.
  evidence:
  - reference: PMID:38562122
    reference_title: Two sisters with RSPRY1-related spondyloepimetaphyseal dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To date, 10 individuals with SEMD, RSPRY1 type, are reported from 4
      unrelated families from Saudi Arabia, Peru, and Turkey
    explanation: >-
      The 2024 report tallies the entire published caseload at ten individuals
      from four families before adding its own two, establishing the
      cases-in-literature scale of the disorder.
inheritance:
- name: Autosomal Recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    SEMDFA segregates as an autosomal recessive trait. Every reported family has
    been consanguineous or the proband homozygous for a single RSPRY1 allele;
    heterozygous parents are unaffected.
  evidence:
  - reference: PMID:26365341
    reference_title: Identification of a Recognizable Progressive Skeletal Dysplasia Caused by RSPRY1 Mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe a clinically recognizable autosomal-recessive disorder in four
      affected siblings from a consanguineous Saudi family
    explanation: >-
      The founding report establishes autosomal recessive segregation in a
      consanguineous multiplex family.
genetic:
- name: Biallelic RSPRY1 Loss-of-Function Variants
  gene_term:
    preferred_term: RSPRY1
    term:
      id: hgnc:29420
      label: RSPRY1
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  features: >-
    Reported causative alleles are homozygous and span frameshift (c.377delT,
    p.Ile126fs, and the founding Saudi frameshift subject to nonsense-mediated
    decay), canonical splice-site (c.516+2T>A at the exon 4/intron 4 border),
    and missense (c.1652G>A, p.Cys551Tyr) classes. RSPRY1 lies at 16q13 and
    encodes a 576-amino-acid protein carrying a RING finger domain and a SPRY
    domain.
  evidence:
  - reference: PMID:26365341
    reference_title: Identification of a Recognizable Progressive Skeletal Dysplasia Caused by RSPRY1 Mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Combined autozygome/exome analysis identified a homozygous frameshift
      mutation in RSPRY1 with resulting nonsense-mediated decay.
    explanation: >-
      The founding family carries a homozygous frameshift allele whose transcript
      undergoes nonsense-mediated decay, establishing loss of function.
  - reference: PMID:26365341
    reference_title: Identification of a Recognizable Progressive Skeletal Dysplasia Caused by RSPRY1 Mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we were able to identify a Peruvian simplex case subject whose phenotype is
      strikingly similar to the original Saudi family and whose exome sequencing
      had revealed a likely pathogenic homozygous missense variant in the same gene
    explanation: >-
      A second, independently ascertained family with a homozygous missense allele
      and a matching phenotype supplied the replication that established the
      gene-disease relationship.
  - reference: PMID:38562122
    reference_title: Two sisters with RSPRY1-related spondyloepimetaphyseal dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two siblings presenting with short stature, facial dysmorphism, progressive
      vertebral defects, small epiphysis, cupping and fraying of metaphyses,
      brachydactyly, and short metatarsals harbored a homozygous missense variant
      c.1652G>A;p.(Cys551Tyr) in the RSPRY1 gene.
    explanation: Documents a further homozygous missense allele segregating with the phenotype.
  - reference: PMID:39940902
    reference_title: "Unraveling the Role of RSPRY1 in TGF-β Pathway Dysregulation: Insights into the Pathogenesis of Spondyloepimetaphyseal Dysplasia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The RSPRY1 gene is located on chromosome 16q13 and encodes a 576-amino acid
      protein containing two functional domains: the RING (really interesting new
      gene) finger domain, known for its role in protein–protein interactions
      (PPIs) and ubiquitination processes, and the SPRY (SPla and the RYanodine
      receptor) domain, which facilitates protein binding and cellular signaling
    explanation: Supplies the locus and the two-domain architecture of the encoded protein.
variants:
- name: RSPRY1 c.377delT p.(Ile126fs)
  gene:
    preferred_term: RSPRY1
    term:
      id: hgnc:29420
      label: RSPRY1
  type: frameshift
  clinical_significance: PATHOGENIC
  description: >-
    Homozygous single-nucleotide deletion in exon 2 causing a frameshift, reported
    in one of two Turkish families.
  evidence:
  - reference: PMID:30063090
    reference_title: "Further delineation of spondyloepimetaphyseal dysplasia Faden-Alkuraya type: A RSPRY1-associated spondylo-epi-metaphyseal dysplasia with cono-brachydactyly and craniosynostosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      frameshift mutation at exon 2 in one family, while Sanger sequencing revealed a
      novel homozygous splice site mutation
    explanation: >-
      Reports the homozygous exon 2 frameshift allele. The cDNA designation is given
      in square brackets in the source abstract and is therefore recorded in the
      variant name rather than quoted in the snippet.
- name: RSPRY1 c.516+2T>A
  gene:
    preferred_term: RSPRY1
    term:
      id: hgnc:29420
      label: RSPRY1
  type: splice site
  clinical_significance: PATHOGENIC
  description: >-
    Homozygous canonical splice-donor variant at the exon 4 / intron 4 border,
    reported in the second Turkish family.
  evidence:
  - reference: PMID:30063090
    reference_title: "Further delineation of spondyloepimetaphyseal dysplasia Faden-Alkuraya type: A RSPRY1-associated spondylo-epi-metaphyseal dysplasia with cono-brachydactyly and craniosynostosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sanger sequencing revealed a novel homozygous splice site mutation
    explanation: >-
      Reports the homozygous canonical splice-site allele in the second family; the
      cDNA designation appears in square brackets in the source abstract.
- name: RSPRY1 c.1652G>A p.(Cys551Tyr)
  gene:
    preferred_term: RSPRY1
    term:
      id: hgnc:29420
      label: RSPRY1
  type: missense
  clinical_significance: LIKELY_PATHOGENIC
  description: >-
    Homozygous missense variant in exon 15, the last exon, substituting a cysteine
    conserved across five vertebrate species within the C3HC4-type RING finger
    domain. Absent from gnomAD v3.1.2 and from an in-house cohort of 3,076 exomes;
    CADD phred 29.7, M-CAP 0.812, REVEL 0.967, AlphaMissense 0.999. Submitted to
    ClinVar as SCV002061883.2.
  evidence:
  - reference: PMID:38562122
    reference_title: Two sisters with RSPRY1-related spondyloepimetaphyseal dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A shared homozygous non-synonymous missense variant at c.1652G>A;p.(Cys551Tyr)
      in exon 15 of the RSPRY1 gene (NM_133368.3; NP 588609.1) was identified through
      exome sequencing in both siblings.
    explanation: Identifies the variant and its transcript context.
  - reference: PMID:38562122
    reference_title: Two sisters with RSPRY1-related spondyloepimetaphyseal dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This variant is not present in gnomAD (V3.1.2) and our in-house data of 3076
      exomes.
    explanation: Population-database absence supporting pathogenicity (ACMG PM2).
pathophysiology:
- name: Biallelic RSPRY1 Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Homozygous frameshift, splice-site, or missense RSPRY1 variants abolish or
    impair the RING- and SPRY-domain protein. The founding frameshift allele
    triggers nonsense-mediated decay of the transcript, so the shared initiating
    lesion is absence of functional RSPRY1 protein.
  genes:
  - preferred_term: RSPRY1
    term:
      id: hgnc:29420
      label: RSPRY1
  evidence:
  - reference: PMID:26365341
    reference_title: Identification of a Recognizable Progressive Skeletal Dysplasia Caused by RSPRY1 Mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Combined autozygome/exome analysis identified a homozygous frameshift
      mutation in RSPRY1 with resulting nonsense-mediated decay.
    explanation: Establishes nonsense-mediated decay of the mutant transcript as the initiating molecular lesion.
  downstream:
  - target: Loss of RSPRY1 Regulatory Activity in Skeletal Tissue
    causal_link_type: DIRECT
    description: >-
      Absent RSPRY1 protein removes its regulatory activity from the cells in
      which it is normally expressed during skeletogenesis.
    evidence:
    - reference: PMID:26365341
      reference_title: Identification of a Recognizable Progressive Skeletal Dysplasia Caused by RSPRY1 Mutations.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        However, we detect strong RSPRY1 protein localization in murine embryonic
        osteoblasts and periosteal cells during primary endochondral ossification,
        consistent with a role in bone development.
      explanation: >-
        Murine expression mapping places RSPRY1 in the osteoblast and periosteal
        compartments of the developing endochondral skeleton, identifying the
        tissue in which its loss acts.
- name: Loss of RSPRY1 Regulatory Activity in Skeletal Tissue
  biological_scale: MOLECULAR
  description: >-
    RSPRY1 carries a RING finger domain associated with ubiquitin-ligase
    chemistry and a SPRY protein-interaction domain, and interacts with
    ubiquitin ligases. Its physiological substrate and biochemical activity are
    not established, so this node records loss of an incompletely defined
    regulatory function rather than a specific enzymatic step. No GO molecular
    function is bound here deliberately: an E3 ligase annotation would assert an
    activity that has never been demonstrated for this protein.
  evidence:
  - reference: PMID:26365341
    reference_title: Identification of a Recognizable Progressive Skeletal Dysplasia Caused by RSPRY1 Mutations.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      RSPRY1 encodes a hypothetical RING and SPRY domain-containing protein of
      unknown physiological function.
    explanation: >-
      The founding report is explicit that the protein's physiological function is
      unknown, which is why this node is framed as loss of an undefined regulatory
      activity.
  - reference: PMID:39940902
    reference_title: "Unraveling the Role of RSPRY1 in TGF-β Pathway Dysregulation: Insights into the Pathogenesis of Spondyloepimetaphyseal Dysplasia."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      BioGRID database analyses revealed that RSPRY1 has many ubiquitin ligases
      among its interaction partners.
    explanation: >-
      Interaction-database analysis motivates the ubiquitin-ligase framing, but
      remains an in-silico inference rather than a demonstrated enzymatic activity.
  downstream:
  - target: Constitutive TGF-beta/SMAD3 Signaling Activation
    causal_link_type: DIRECT
    description: >-
      RSPRY1-deficient patient fibroblasts show transcriptomes dominated by
      TGF-beta pathway enrichment and behave as though the pathway is already
      maximally engaged.
    evidence:
    - reference: PMID:39940902
      reference_title: "Unraveling the Role of RSPRY1 in TGF-β Pathway Dysregulation: Insights into the Pathogenesis of Spondyloepimetaphyseal Dysplasia."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Transcriptome analysis of fibroblasts from patients with homozygous RSPRY1
        mutations showed there was significant enrichment of transforming growth
        factor beta (TGF-β) signaling and ECM-related pathways.
      explanation: >-
        Patient-derived transcriptomes place TGF-beta signaling immediately
        downstream of RSPRY1 loss.
- name: Constitutive TGF-beta/SMAD3 Signaling Activation
  biological_scale: MOLECULAR
  description: >-
    In RSPRY1-deficient cells, TGF-beta regulation of the extracellular matrix is
    the most strongly enriched pathway, SMAD2 and SMAD3 are the dominant enriched
    transcription factors, and cells respond only weakly to exogenous TGF-beta1 —
    the signature of a pathway that is already constitutively active. Knocking out
    SMAD3 in the RSPRY1-null background abolishes the cellular phenotype, showing
    the effect is SMAD3-dependent.
  cell_types:
  - preferred_term: dermal fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: transforming growth factor beta receptor signaling pathway
    term:
      id: GO:0007179
      label: transforming growth factor beta receptor signaling pathway
    modifier: GAIN_OF_FUNCTION
  - preferred_term: SMAD protein signal transduction
    term:
      id: GO:0060395
      label: SMAD protein signal transduction
    modifier: INCREASED
  evidence:
  - reference: PMID:39940902
    reference_title: "Unraveling the Role of RSPRY1 in TGF-β Pathway Dysregulation: Insights into the Pathogenesis of Spondyloepimetaphyseal Dysplasia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The observed limited response to exogenous TGF-β in RSPRY1-deficient cells
      indicated that there was constitutive pathway activation.
    explanation: >-
      Blunted responsiveness to added ligand is the experimental basis for calling
      the pathway constitutively active rather than merely upregulated.
  - reference: PMID:39940902
    reference_title: "Unraveling the Role of RSPRY1 in TGF-β Pathway Dysregulation: Insights into the Pathogenesis of Spondyloepimetaphyseal Dysplasia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The pathway enrichment analysis of DEGs showed there were several
      significantly enriched pathways, with TGF-β regulation of the ECM pathway
      being the most prominent.
    explanation: TGF-beta regulation of the extracellular matrix is the top-ranked enriched pathway.
  downstream:
  - target: Disordered Extracellular Matrix Dynamics and Cell Motility
    causal_link_type: DIRECT
    description: >-
      Constitutive SMAD3-dependent signaling drives the matrix and motility
      phenotype; the phenotype disappears when SMAD3 is removed.
    evidence:
    - reference: PMID:39940902
      reference_title: "Unraveling the Role of RSPRY1 in TGF-β Pathway Dysregulation: Insights into the Pathogenesis of Spondyloepimetaphyseal Dysplasia."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Functional wound healing assays showed that RSPRY1 knockout fibroblasts
        exhibited enhanced motility, a phenotype that was abrogated in RSPRY1 +
        SMAD3 double knockout fibroblasts, highlighting the SMAD3-dependence of
        RSPRY1's effects.
      explanation: >-
        The double-knockout rescue establishes SMAD3 as the required mediator
        between RSPRY1 loss and the cellular phenotype.
- name: Disordered Extracellular Matrix Dynamics and Cell Motility
  biological_scale: CELLULAR
  description: >-
    Differentially expressed genes in RSPRY1-deficient fibroblasts are enriched
    for collagen-containing extracellular matrix, cartilage development,
    extracellular matrix organization, and chondrocyte differentiation, and the
    cells are hypermotile in wound-closure assays. Proliferation and senescence
    are unchanged, so the defect is one of matrix regulation and cell behavior
    rather than of cell number.
  cell_types:
  - preferred_term: dermal fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: ABNORMAL
  - preferred_term: cell migration
    term:
      id: GO:0016477
      label: cell migration
    modifier: INCREASED
  evidence:
  - reference: PMID:39940902
    reference_title: "Unraveling the Role of RSPRY1 in TGF-β Pathway Dysregulation: Insights into the Pathogenesis of Spondyloepimetaphyseal Dysplasia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The most prominent BPs enriched included cartilage development, ECM
      organization, and chondrocyte differentiation
    explanation: >-
      The transcriptomic signature of patient fibroblasts is dominated by matrix
      and cartilage-differentiation programs.
  - reference: PMID:39940902
    reference_title: "Unraveling the Role of RSPRY1 in TGF-β Pathway Dysregulation: Insights into the Pathogenesis of Spondyloepimetaphyseal Dysplasia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      RSPRY1 KO fibroblasts exhibited a significant increase in wound closure
      ability, as compared to CTRL fibroblasts, which indicated that RSPRY1
      deficiency enhanced cell motility
    explanation: Direct functional demonstration of the motility phenotype.
  downstream:
  - target: Impaired Endochondral Ossification and Growth-Plate Function
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Matrix and TGF-beta dysregulation in the osteoblast/periosteal compartment
      where RSPRY1 is expressed is the proposed route to defective endochondral
      bone formation. The functional data come from dermal fibroblasts rather
      than growth-plate cells, so this step is inferred.
    evidence:
    - reference: PMID:39940902
      reference_title: "Unraveling the Role of RSPRY1 in TGF-β Pathway Dysregulation: Insights into the Pathogenesis of Spondyloepimetaphyseal Dysplasia."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The altered expression of these genes suggests that RSPRY1 deficiency
        might impair TGF-β-driven pathways essential for proper endochondral
        ossification and bone homeostasis.
      explanation: >-
        The authors themselves frame the link to endochondral ossification as a
        suggestion drawn from fibroblast expression data, which is why this edge
        is curated as indirect and PARTIAL.
- name: Impaired Endochondral Ossification and Growth-Plate Function
  biological_scale: TISSUE
  description: >-
    Defective endochondral bone formation at the vertebral bodies, epiphyses, and
    metaphyses produces the spondylar, epiphyseal, and metaphyseal dysplasia that
    defines the disorder, and limits longitudinal growth.
  cell_types:
  - preferred_term: growth-plate chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  biological_processes:
  - preferred_term: endochondral ossification
    term:
      id: GO:0001958
      label: endochondral ossification
    modifier: ABNORMAL
  evidence:
  - reference: PMID:26365341
    reference_title: Identification of a Recognizable Progressive Skeletal Dysplasia Caused by RSPRY1 Mutations.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      However, we detect strong RSPRY1 protein localization in murine embryonic
      osteoblasts and periosteal cells during primary endochondral ossification,
      consistent with a role in bone development.
    explanation: >-
      Places the normal protein at the site and stage of endochondral ossification
      whose failure is proposed here.
  - reference: PMID:30063090
    reference_title: "Further delineation of spondyloepimetaphyseal dysplasia Faden-Alkuraya type: A RSPRY1-associated spondylo-epi-metaphyseal dysplasia with cono-brachydactyly and craniosynostosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The skeletal hallmarks include (a) mild spondylar dysplasia, (b)
      epimetaphyseal dysplasia of the long bones associated with coxa vara and
      genu valgum, (c) brachymesophalangy with cone-shaped epiphyses, and (d)
      craniosynostosis.
    explanation: >-
      The radiographic hallmarks map directly onto vertebral, epiphyseal, and
      metaphyseal endochondral growth sites.
  downstream:
  - target: Progressive Skeletal Deformity and Short Stature
    causal_link_type: DIRECT
    description: >-
      Cumulative growth-plate failure produces worsening deformity and
      progressive loss of height standard deviation over childhood.
    evidence:
    - reference: PMID:38562122
      reference_title: Two sisters with RSPRY1-related spondyloepimetaphyseal dysplasia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The severity of vertebral deformities increases with age.
      explanation: Documents the progressive character of the skeletal lesion.
  - target: Premature Cranial Suture Fusion
    causal_link_type: DIRECT
    description: >-
      Membranous cranial bone growth is affected in a subset of families,
      producing craniosynostosis. This branch is not present in every reported
      family and is therefore curated as a conditional consequence.
    evidence:
    - reference: PMID:30063090
      reference_title: "Further delineation of spondyloepimetaphyseal dysplasia Faden-Alkuraya type: A RSPRY1-associated spondylo-epi-metaphyseal dysplasia with cono-brachydactyly and craniosynostosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        all share the clinical findings including craniosynostosis, varying
        degrees of intellectual disability, facial dysmorphism, and skeletal
        findings including pes planus, prominent heels, and pectus deformity
      explanation: >-
        Craniosynostosis was universal in the two families of the delineation
        series, establishing the branch.
- name: Progressive Skeletal Deformity and Short Stature
  biological_scale: ORGANISM
  description: >-
    Growth deceleration is postnatal and deformity accrues over childhood:
    lower-limb malformation is typically noticed between two and four years of
    age and worsens, with painful walking, wind-swept deformity, and progressive
    vertebral change.
  evidence:
  - reference: PMID:38562122
    reference_title: Two sisters with RSPRY1-related spondyloepimetaphyseal dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bilateral lower limb malformation was observed at 4 years of age, which is
      progressive. She could not walk long distances due to pain.
    explanation: Documents the childhood onset, progression, and functional cost of the deformity.
  - reference: PMID:26365341
    reference_title: Identification of a Recognizable Progressive Skeletal Dysplasia Caused by RSPRY1 Mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      comprising progressive spondyloepimetaphyseal dysplasia, short stature,
      facial dysmorphism, short fourth metatarsals, and intellectual disability
    explanation: The defining clinical description names progression and short stature as core features.
- name: Premature Cranial Suture Fusion
  biological_scale: TISSUE
  description: >-
    Craniosynostosis occurs in a subset of affected individuals and was present
    in all five patients of the two-family delineation series, where most
    patients were nonetheless normocephalic.
  evidence:
  - reference: PMID:30063090
    reference_title: "Further delineation of spondyloepimetaphyseal dysplasia Faden-Alkuraya type: A RSPRY1-associated spondylo-epi-metaphyseal dysplasia with cono-brachydactyly and craniosynostosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Unlike the previously reported clinical findings, all patients except one
      are normocephalic
    explanation: >-
      Records that craniosynostosis in this disorder usually occurs without
      microcephaly, distinguishing it from syndromic craniosynostoses with head
      size reduction.
phenotypes:
- category: Growth
  name: Postnatal Short Stature
  frequency: VERY_FREQUENT
  description: >-
    Disproportionate short stature is a cardinal and near-universal feature, with
    heights around -4.5 to -5.3 standard deviations reported in childhood.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:30063090
    reference_title: "Further delineation of spondyloepimetaphyseal dysplasia Faden-Alkuraya type: A RSPRY1-associated spondylo-epi-metaphyseal dysplasia with cono-brachydactyly and craniosynostosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All patients have short stature, extremity deformities, facial dysmorphism and intellectual disability.
    explanation: >-
      Short stature was present in all five patients of the delineation series,
      supporting the VERY_FREQUENT band.
  - reference: PMID:26365341
    reference_title: Identification of a Recognizable Progressive Skeletal Dysplasia Caused by RSPRY1 Mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      comprising progressive spondyloepimetaphyseal dysplasia, short stature,
      facial dysmorphism, short fourth metatarsals, and intellectual disability
    explanation: Short stature is one of the five defining features in the founding description.
- category: Skeletal
  name: Progressive Spondylar Dysplasia
  frequency: VERY_FREQUENT
  description: >-
    Vertebral bodies show progressive dysplasia with platyspondyly and vertebral
    defects that worsen with age; mild scoliosis and lumbar hyperlordosis follow.
  phenotype_term:
    preferred_term: Platyspondyly
    term:
      id: HP:0000926
      label: Platyspondyly
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:38562122
    reference_title: Two sisters with RSPRY1-related spondyloepimetaphyseal dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The radiographic evaluation indicated a copper-beaten appearance of a skull,
      platyspondyly, mild scoliosis, lumbar lordosis, small carpals bones, short
      femoral neck, short fourth metatarsal bone, wind-swept deformity, small
      epiphyses, metaphyseal cupping, and fraying in both siblings.
    explanation: Platyspondyly was present in both siblings on radiographic review.
  - reference: PMID:38562122
    reference_title: Two sisters with RSPRY1-related spondyloepimetaphyseal dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The severity of vertebral deformities increases with age.
    explanation: Supports the PROGRESSIVE clinical course qualifier.
  - reference: PMID:30063090
    reference_title: "Further delineation of spondyloepimetaphyseal dysplasia Faden-Alkuraya type: A RSPRY1-associated spondylo-epi-metaphyseal dysplasia with cono-brachydactyly and craniosynostosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The skeletal hallmarks include (a) mild spondylar dysplasia, (b)
      epimetaphyseal dysplasia of the long bones associated with coxa vara and
      genu valgum, (c) brachymesophalangy with cone-shaped epiphyses, and (d)
      craniosynostosis.
    explanation: >-
      Spondylar dysplasia heads the list of skeletal hallmarks shared by all five
      patients of the delineation series, supporting the VERY_FREQUENT band.
- category: Skeletal
  name: Epiphyseal Dysplasia with Small Epiphyses
  description: >-
    The epiphyses of the long bones are small and dysplastic, a defining
    component of the spondyloepimetaphyseal pattern.
  phenotype_term:
    preferred_term: Small epiphyses
    term:
      id: HP:0010585
      label: Small epiphyses
  evidence:
  - reference: PMID:38562122
    reference_title: Two sisters with RSPRY1-related spondyloepimetaphyseal dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mild scoliosis, vertebral defects, small epiphysis, cupping, and fraying of
      metaphyses of tibia and fibula, coxa vara, genu valgum, short metacarpals,
      short metatarsals, and craniosynostosis have been described in affected
      individuals
    explanation: Summarizes small epiphyses as an established feature of the disorder.
- category: Skeletal
  name: Metaphyseal Cupping and Fraying
  description: >-
    Metaphyses, particularly of the tibia and fibula, show cupping and fraying —
    the metaphyseal component of the dysplasia.
  phenotype_term:
    preferred_term: Metaphyseal cupping
    term:
      id: HP:0003021
      label: Metaphyseal cupping
  evidence:
  - reference: PMID:38562122
    reference_title: Two sisters with RSPRY1-related spondyloepimetaphyseal dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mild scoliosis, vertebral defects, small epiphysis, cupping, and fraying of
      metaphyses of tibia and fibula, coxa vara, genu valgum, short metacarpals,
      short metatarsals, and craniosynostosis have been described in affected
      individuals
    explanation: Metaphyseal cupping and fraying of the tibia and fibula are established features.
- category: Skeletal
  name: Short Fourth Metatarsal
  frequency: FREQUENT
  description: >-
    Shortening of the fourth metatarsal is distinctive enough to appear in the
    disorder's own name; a short third metatarsal has also been reported.
  phenotype_term:
    preferred_term: Short fourth metatarsal
    term:
      id: HP:0004689
      label: Short fourth metatarsal
  evidence:
  - reference: PMID:26365341
    reference_title: Identification of a Recognizable Progressive Skeletal Dysplasia Caused by RSPRY1 Mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      comprising progressive spondyloepimetaphyseal dysplasia, short stature,
      facial dysmorphism, short fourth metatarsals, and intellectual disability
    explanation: Short fourth metatarsals are one of the five defining features of the founding description.
  - reference: PMID:38562122
    reference_title: Two sisters with RSPRY1-related spondyloepimetaphyseal dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The radiographic evaluation indicated a copper-beaten appearance of a skull,
      platyspondyly, mild scoliosis, lumbar lordosis, small carpals bones, short
      femoral neck, short fourth metatarsal bone, wind-swept deformity, small
      epiphyses, metaphyseal cupping, and fraying in both siblings.
    explanation: Radiographic confirmation of the short fourth metatarsal in both siblings.
- category: Skeletal
  name: Brachydactyly with Cone-Shaped Epiphyses
  frequency: FREQUENT
  description: >-
    Hands show brachymesophalangy with cone-shaped phalangeal epiphyses
    (cono-brachydactyly) and short metacarpals.
  phenotype_term:
    preferred_term: Brachydactyly
    term:
      id: HP:0001156
      label: Brachydactyly
  evidence:
  - reference: PMID:30063090
    reference_title: "Further delineation of spondyloepimetaphyseal dysplasia Faden-Alkuraya type: A RSPRY1-associated spondylo-epi-metaphyseal dysplasia with cono-brachydactyly and craniosynostosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The skeletal hallmarks include (a) mild spondylar dysplasia, (b)
      epimetaphyseal dysplasia of the long bones associated with coxa vara and
      genu valgum, (c) brachymesophalangy with cone-shaped epiphyses, and (d)
      craniosynostosis.
    explanation: Brachymesophalangy with cone-shaped epiphyses is listed among the skeletal hallmarks.
- category: Skeletal
  name: Coxa Vara
  frequency: FREQUENT
  description: Varus deformity of the proximal femur with a short femoral neck contributes to gait difficulty.
  phenotype_term:
    preferred_term: Coxa vara
    term:
      id: HP:0002812
      label: Coxa vara
  evidence:
  - reference: PMID:30063090
    reference_title: "Further delineation of spondyloepimetaphyseal dysplasia Faden-Alkuraya type: A RSPRY1-associated spondylo-epi-metaphyseal dysplasia with cono-brachydactyly and craniosynostosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      epimetaphyseal dysplasia of the long bones associated with coxa vara and
      genu valgum
    explanation: Coxa vara accompanies the long-bone epimetaphyseal dysplasia.
- category: Skeletal
  name: Genu Valgum
  frequency: FREQUENT
  description: >-
    Knock-knee deformity is part of the lower-limb malformation that becomes
    apparent in early childhood and progresses.
  phenotype_term:
    preferred_term: Genu valgum
    term:
      id: HP:0002857
      label: Genu valgum
  evidence:
  - reference: PMID:30063090
    reference_title: "Further delineation of spondyloepimetaphyseal dysplasia Faden-Alkuraya type: A RSPRY1-associated spondylo-epi-metaphyseal dysplasia with cono-brachydactyly and craniosynostosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      epimetaphyseal dysplasia of the long bones associated with coxa vara and
      genu valgum
    explanation: Genu valgum accompanies the long-bone epimetaphyseal dysplasia.
- category: Skeletal
  name: Craniosynostosis
  description: >-
    Premature fusion of cranial sutures was universal in the two families of the
    delineation series and is recognized as part of the syndrome, though it is
    not reported in every family.
  phenotype_term:
    preferred_term: Craniosynostosis
    term:
      id: HP:0001363
      label: Craniosynostosis
  evidence:
  - reference: PMID:30063090
    reference_title: "Further delineation of spondyloepimetaphyseal dysplasia Faden-Alkuraya type: A RSPRY1-associated spondylo-epi-metaphyseal dysplasia with cono-brachydactyly and craniosynostosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we provide further evidence that Spondyloepimetaphyseal dysplasia
      Faden-Alkuraya type is a RSPRY1-associated skeletal dysplasia with a
      distinctive phenotype composed of spondyloepimetaphyseal dysplasia,
      cono-brachydactyly, and craniosynostosis along with recognizable facial
      features and intellectual disability.
    explanation: Craniosynostosis is named as part of the distinctive phenotype.
  notes: >-
    Frequency is deliberately omitted. Craniosynostosis was present in all five
    patients of the 2018 series but is not documented in every reported family,
    and the total published caseload is too small to support a frequency band.
- category: Skeletal
  name: Scoliosis
  description: Mild scoliosis accompanies the progressive vertebral changes.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:38562122
    reference_title: Two sisters with RSPRY1-related spondyloepimetaphyseal dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mild scoliosis, vertebral defects, small epiphysis, cupping, and fraying of
      metaphyses of tibia and fibula, coxa vara, genu valgum, short metacarpals,
      short metatarsals, and craniosynostosis have been described in affected
      individuals
    explanation: Mild scoliosis is an established feature of the disorder.
- category: Skeletal
  name: Lumbar Hyperlordosis
  description: Exaggerated lumbar lordosis was present in both reported Indian siblings.
  phenotype_term:
    preferred_term: Lumbar hyperlordosis
    term:
      id: HP:0002938
      label: Lumbar hyperlordosis
  evidence:
  - reference: PMID:38562122
    reference_title: Two sisters with RSPRY1-related spondyloepimetaphyseal dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She had midface retrusion, a square-shaped face, a depressed nasal bridge, a
      high arched palate, a short neck, a short thorax, lumbar lordosis, distal
      joint laxity, and pes planus
    explanation: Direct examination finding in an affected sibling.
- category: Skeletal
  name: Joint Dislocation
  description: >-
    Elbow subluxation and dislocation were reported in 2024 as a feature not
    previously described in this disorder.
  phenotype_term:
    preferred_term: Joint dislocation
    term:
      id: HP:0001373
      label: Joint dislocation
  evidence:
  - reference: PMID:38562122
    reference_title: Two sisters with RSPRY1-related spondyloepimetaphyseal dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We noted subluxation/dislocation of elbow joints in them, which was not
      reported previously in individuals with RSPRY1-related SEMD.
    explanation: >-
      Explicitly reported as a novel feature, so it is curated without a
      frequency band pending replication.
- category: Skeletal
  name: Pes Planus
  description: Flat feet were reported in the delineation series and in a later sibling pair.
  phenotype_term:
    preferred_term: Pes planus
    term:
      id: HP:0001763
      label: Pes planus
  evidence:
  - reference: PMID:30063090
    reference_title: "Further delineation of spondyloepimetaphyseal dysplasia Faden-Alkuraya type: A RSPRY1-associated spondylo-epi-metaphyseal dysplasia with cono-brachydactyly and craniosynostosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      all share the clinical findings including craniosynostosis, varying degrees
      of intellectual disability, facial dysmorphism, and skeletal findings
      including pes planus, prominent heels, and pectus deformity
    explanation: Pes planus is listed among the shared skeletal findings.
- category: Skeletal
  name: Prominent Calcaneus
  description: Prominent heels were a shared finding across the delineation series.
  phenotype_term:
    preferred_term: Prominent calcaneus
    term:
      id: HP:0012428
      label: Prominent calcaneus
  evidence:
  - reference: PMID:30063090
    reference_title: "Further delineation of spondyloepimetaphyseal dysplasia Faden-Alkuraya type: A RSPRY1-associated spondylo-epi-metaphyseal dysplasia with cono-brachydactyly and craniosynostosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      all share the clinical findings including craniosynostosis, varying degrees
      of intellectual disability, facial dysmorphism, and skeletal findings
      including pes planus, prominent heels, and pectus deformity
    explanation: Prominent heels are listed among the shared skeletal findings.
- category: Skeletal
  name: Short Metacarpals
  description: Metacarpal shortening accompanies the brachydactyly.
  phenotype_term:
    preferred_term: Short metacarpal
    term:
      id: HP:0010049
      label: Short metacarpal
  evidence:
  - reference: PMID:38562122
    reference_title: Two sisters with RSPRY1-related spondyloepimetaphyseal dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mild scoliosis, vertebral defects, small epiphysis, cupping, and fraying of
      metaphyses of tibia and fibula, coxa vara, genu valgum, short metacarpals,
      short metatarsals, and craniosynostosis have been described in affected
      individuals
    explanation: Short metacarpals are an established feature.
- category: Neurologic
  name: Intellectual Disability
  frequency: VERY_FREQUENT
  description: >-
    Intellectual disability of varying degree is one of the defining features.
    Formal IQ testing has not been reported in most patients; severity ranges
    from mild slowing of responses to more substantial impairment.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:30063090
    reference_title: "Further delineation of spondyloepimetaphyseal dysplasia Faden-Alkuraya type: A RSPRY1-associated spondylo-epi-metaphyseal dysplasia with cono-brachydactyly and craniosynostosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All patients have short stature, extremity deformities, facial dysmorphism and intellectual disability.
    explanation: >-
      Intellectual disability was present in all five patients of the delineation
      series, supporting the VERY_FREQUENT band.
  - reference: PMID:26365341
    reference_title: Identification of a Recognizable Progressive Skeletal Dysplasia Caused by RSPRY1 Mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      comprising progressive spondyloepimetaphyseal dysplasia, short stature,
      facial dysmorphism, short fourth metatarsals, and intellectual disability
    explanation: Intellectual disability is one of the five defining features of the founding description.
- category: Craniofacial
  name: Facial Dysmorphism
  frequency: VERY_FREQUENT
  description: >-
    A recognizable facial gestalt includes midface retrusion, a broad or
    square-shaped forehead and face, depressed nasal bridge, high-arched palate,
    low-set ears, and a short neck.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:30063090
    reference_title: "Further delineation of spondyloepimetaphyseal dysplasia Faden-Alkuraya type: A RSPRY1-associated spondylo-epi-metaphyseal dysplasia with cono-brachydactyly and craniosynostosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All patients have short stature, extremity deformities, facial dysmorphism and intellectual disability.
    explanation: Facial dysmorphism was present in all patients of the delineation series.
  - reference: PMID:38562122
    reference_title: Two sisters with RSPRY1-related spondyloepimetaphyseal dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She had midface retrusion, a square-shaped face, a depressed nasal bridge, a
      high arched palate, a short neck, a short thorax, lumbar lordosis, distal
      joint laxity, and pes planus
    explanation: Enumerates the component facial features in an affected individual.
- category: Ophthalmologic
  name: Myopia
  description: >-
    Myopia with strabismus and mild ptosis was documented in one affected
    sibling; ocular involvement is not established across the cohort.
  phenotype_term:
    preferred_term: Myopia
    term:
      id: HP:0000545
      label: Myopia
  evidence:
  - reference: PMID:38562122
    reference_title: Two sisters with RSPRY1-related spondyloepimetaphyseal dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She had squint eyes, and the ophthalmologic assessment confirmed myopia in
      both eyes with mild ptosis in the left eye.
    explanation: Single-patient ophthalmologic finding, curated without a frequency band.
- category: Cardiovascular
  name: Patent Ductus Arteriosus
  description: >-
    Congenital heart disease has been reported in a single patient and is not
    established as a syndromic feature.
  phenotype_term:
    preferred_term: Patent ductus arteriosus
    term:
      id: HP:0001643
      label: Patent ductus arteriosus
  evidence:
  - reference: PMID:38562122
    reference_title: Two sisters with RSPRY1-related spondyloepimetaphyseal dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She was diagnosed with congenital heart disease, patent ductus arteriosus
      (PDA), and underwent corrective surgery at 3 years of age.
    explanation: >-
      An isolated observation in one patient; curated as PARTIAL because a
      single case does not establish a syndromic association.
- category: Skeletal
  name: Carpal Bone Hypoplasia
  description: Small carpal bones were noted on hand radiographs in both reported Indian siblings.
  phenotype_term:
    preferred_term: Small carpal bones
    term:
      id: HP:0001498
      label: Carpal bone hypoplasia
  evidence:
  - reference: PMID:38562122
    reference_title: Two sisters with RSPRY1-related spondyloepimetaphyseal dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The radiographic evaluation indicated a copper-beaten appearance of a skull,
      platyspondyly, mild scoliosis, lumbar lordosis, small carpals bones, short
      femoral neck, short fourth metatarsal bone, wind-swept deformity, small
      epiphyses, metaphyseal cupping, and fraying in both siblings.
    explanation: Small carpal bones were documented radiographically in both siblings.
- category: Skeletal
  name: Short Femoral Neck
  description: >-
    A short femoral neck accompanies the coxa vara and contributes to the
    proximal-femoral component of the dysplasia.
  phenotype_term:
    preferred_term: Short femoral neck
    term:
      id: HP:0100864
      label: Short femoral neck
  evidence:
  - reference: PMID:38562122
    reference_title: Two sisters with RSPRY1-related spondyloepimetaphyseal dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The radiographic evaluation indicated a copper-beaten appearance of a skull,
      platyspondyly, mild scoliosis, lumbar lordosis, small carpals bones, short
      femoral neck, short fourth metatarsal bone, wind-swept deformity, small
      epiphyses, metaphyseal cupping, and fraying in both siblings.
    explanation: Short femoral neck documented radiographically in both siblings.
- category: Skeletal
  name: Pectus Deformity
  description: >-
    Anterior chest-wall (pectus) deformity was among the findings shared across
    the delineation series; the direction of the deformity is not specified in
    the abstract, so the annotation is kept at the sternal-morphology level.
  phenotype_term:
    preferred_term: Pectus deformity
    term:
      id: HP:0000766
      label: Abnormal sternum morphology
  evidence:
  - reference: PMID:30063090
    reference_title: "Further delineation of spondyloepimetaphyseal dysplasia Faden-Alkuraya type: A RSPRY1-associated spondylo-epi-metaphyseal dysplasia with cono-brachydactyly and craniosynostosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      all share the clinical findings including craniosynostosis, varying degrees
      of intellectual disability, facial dysmorphism, and skeletal findings
      including pes planus, prominent heels, and pectus deformity
    explanation: Pectus deformity is listed among the shared skeletal findings.
- category: Skeletal
  name: Joint Hypermobility
  description: Distal joint laxity was noted on examination in one affected sibling.
  phenotype_term:
    preferred_term: Distal joint laxity
    term:
      id: HP:0001382
      label: Joint hypermobility
  evidence:
  - reference: PMID:38562122
    reference_title: Two sisters with RSPRY1-related spondyloepimetaphyseal dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She had midface retrusion, a square-shaped face, a depressed nasal bridge, a
      high arched palate, a short neck, a short thorax, lumbar lordosis, distal
      joint laxity, and pes planus
    explanation: Direct examination finding in an affected sibling.
- category: Craniofacial
  name: Midface Retrusion
  description: Midface retrusion contributes to the recognizable facial gestalt.
  phenotype_term:
    preferred_term: Midface retrusion
    term:
      id: HP:0011800
      label: Midface retrusion
  evidence:
  - reference: PMID:38562122
    reference_title: Two sisters with RSPRY1-related spondyloepimetaphyseal dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She had midface retrusion, a square-shaped face, a depressed nasal bridge, a
      high arched palate, a short neck, a short thorax, lumbar lordosis, distal
      joint laxity, and pes planus
    explanation: Midface retrusion documented on examination.
- category: Craniofacial
  name: Depressed Nasal Bridge
  description: A depressed nasal bridge is part of the characteristic facial appearance.
  phenotype_term:
    preferred_term: Depressed nasal bridge
    term:
      id: HP:0005280
      label: Depressed nasal bridge
  evidence:
  - reference: PMID:38562122
    reference_title: Two sisters with RSPRY1-related spondyloepimetaphyseal dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She had midface retrusion, a square-shaped face, a depressed nasal bridge, a
      high arched palate, a short neck, a short thorax, lumbar lordosis, distal
      joint laxity, and pes planus
    explanation: Depressed nasal bridge documented on examination.
- category: Craniofacial
  name: High Palate
  description: A high-arched palate was present in both reported siblings.
  phenotype_term:
    preferred_term: High arched palate
    term:
      id: HP:0000218
      label: High palate
  evidence:
  - reference: PMID:38562122
    reference_title: Two sisters with RSPRY1-related spondyloepimetaphyseal dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She had midface retrusion, a square-shaped face, a depressed nasal bridge, a
      high arched palate, a short neck, a short thorax, lumbar lordosis, distal
      joint laxity, and pes planus
    explanation: High-arched palate documented on examination.
- category: Craniofacial
  name: Short Neck
  description: A short neck is a recurrent feature of the facial and axial gestalt.
  phenotype_term:
    preferred_term: Short neck
    term:
      id: HP:0000470
      label: Short neck
  evidence:
  - reference: PMID:38562122
    reference_title: Two sisters with RSPRY1-related spondyloepimetaphyseal dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She had midface retrusion, a square-shaped face, a depressed nasal bridge, a
      high arched palate, a short neck, a short thorax, lumbar lordosis, distal
      joint laxity, and pes planus
    explanation: Short neck documented on examination.
- category: Craniofacial
  name: Broad Forehead
  description: A broad forehead was noted in an affected sibling.
  phenotype_term:
    preferred_term: Broad forehead
    term:
      id: HP:0000337
      label: Broad forehead
  evidence:
  - reference: PMID:38562122
    reference_title: Two sisters with RSPRY1-related spondyloepimetaphyseal dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She was noted to have a broad forehead, left exotropia with mild ptosis,
      depressed nasal bridge, high arched palate, low set ears, mid-face retrusion
      and short neck, brachydactyly, protruded belly, lumbar lordosis, overriding
      toes, bilateral abducted foot, and wind-swept deformity
    explanation: Broad forehead documented on examination.
- category: Craniofacial
  name: Low-Set Ears
  description: Low-set ears form part of the facial gestalt.
  phenotype_term:
    preferred_term: Low-set ears
    term:
      id: HP:0000369
      label: Low-set ears
  evidence:
  - reference: PMID:38562122
    reference_title: Two sisters with RSPRY1-related spondyloepimetaphyseal dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She was noted to have a broad forehead, left exotropia with mild ptosis,
      depressed nasal bridge, high arched palate, low set ears, mid-face retrusion
      and short neck, brachydactyly, protruded belly, lumbar lordosis, overriding
      toes, bilateral abducted foot, and wind-swept deformity
    explanation: Low-set ears documented on examination.
- category: Neurologic
  name: Global Developmental Delay
  description: >-
    Motor and language milestones were delayed in a reported proband, who sat at
    one year and walked at two years.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:38562122
    reference_title: Two sisters with RSPRY1-related spondyloepimetaphyseal dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Developmentally, she attained head control at 5 months of age, social smile
      at 3 months, and started to sit without support at 1 year of age. She started
      walking at 2 years.
    explanation: >-
      Independent sitting at 12 months and walking at 24 months document delayed
      gross-motor milestones.
- category: Neoplastic
  name: Ossifying Fibroma of the Maxilla
  description: >-
    A cemento-ossifying fibrous lesion of the maxilla was reported in one patient
    of the delineation series. It has not recurred in later reports and is not
    established as a syndromic feature.
  phenotype_term:
    preferred_term: Cemento-ossifying fibrous lesion of the maxilla
    term:
      id: HP:0030427
      label: Ossifying fibroma of the jaw
  evidence:
  - reference: PMID:30063090
    reference_title: "Further delineation of spondyloepimetaphyseal dysplasia Faden-Alkuraya type: A RSPRY1-associated spondylo-epi-metaphyseal dysplasia with cono-brachydactyly and craniosynostosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Interestingly one of the patients presented with a cemento-ossifying fibrous lesion of the maxilla.
    explanation: >-
      A single reported occurrence; curated as PARTIAL because one patient does
      not establish a syndromic association.
- category: Skeletal
  name: Progressive Spondyloepimetaphyseal Dysplasia
  description: >-
    The defining skeletal lesion: combined vertebral, epiphyseal and metaphyseal
    dysplasia that worsens through childhood rather than remaining static.
  phenotype_term:
    preferred_term: Spondyloepimetaphyseal dysplasia
    term:
      id: HP:0002651
      label: Spondyloepimetaphyseal dysplasia
    clinical_course: PROGRESSIVE
  frequency: OBLIGATE
  evidence:
  - reference: PMID:26365341
    reference_title: Identification of a Recognizable Progressive Skeletal Dysplasia Caused by RSPRY1 Mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe a clinically recognizable autosomal-recessive disorder in four
      affected siblings from a consanguineous Saudi family, comprising progressive
      spondyloepimetaphyseal dysplasia, short stature, facial dysmorphism, short
      fourth metatarsals, and intellectual disability.
    explanation: >-
      Progressive spondyloepimetaphyseal dysplasia is named as the first component of
      the defining phenotype in every affected individual of the index family.
  - reference: PMID:38562122
    reference_title: Two sisters with RSPRY1-related spondyloepimetaphyseal dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The severity of vertebral deformities increases with age.
    explanation: Confirms the progressive course of the vertebral component.
- category: Skeletal
  name: Cone-Shaped Epiphyses
  description: Brachymesophalangy with cone-shaped epiphyses (cono-brachydactyly).
  phenotype_term:
    preferred_term: Cone-shaped epiphysis
    term:
      id: HP:0010579
      label: Cone-shaped epiphysis
  evidence:
  - reference: PMID:30063090
    reference_title: "Further delineation of spondyloepimetaphyseal dysplasia Faden-Alkuraya type: A RSPRY1-associated spondylo-epi-metaphyseal dysplasia with cono-brachydactyly and craniosynostosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The skeletal hallmarks include (a) mild spondylar dysplasia, (b) epimetaphyseal
      dysplasia of the long bones associated with coxa vara and genu valgum, (c)
      brachymesophalangy with cone-shaped epiphyses, and (d) craniosynostosis.
    explanation: >-
      Brachymesophalangy with cone-shaped epiphyses is listed as one of the four
      skeletal hallmarks of the entity.
- category: Skeletal
  name: Copper Beaten Skull
  description: >-
    Copper-beaten (lückenschädel-like) appearance of the skull vault on
    radiography, a recognized correlate of raised intracranial pressure in
    craniosynostosis.
  phenotype_term:
    preferred_term: Copper beaten skull
    term:
      id: HP:0034271
      label: Copper beaten skull
  evidence:
  - reference: PMID:38562122
    reference_title: Two sisters with RSPRY1-related spondyloepimetaphyseal dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The radiographic evaluation indicated a copper-beaten appearance of a skull,
      platyspondyly, mild scoliosis, lumbar lordosis, small carpals bones, short
      femoral neck, short fourth metatarsal bone, wind-swept deformity, small
      epiphyses, metaphyseal cupping, and fraying in both siblings.
    explanation: Copper-beaten skull documented radiographically in both siblings.
- category: Ocular
  name: Ptosis
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
    severity: MILD
  evidence:
  - reference: ORPHA:457395
    reference_title: Progressive spondyloepimetaphyseal dysplasia-short stature-short fourth metatarsals-intellectual disability syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      dysmorphic craniofacial features (including microcephaly, hypertelorism,
      epicanthal folds, mild ptosis, strabismus, malar hypoplasia
    explanation: Orphanet lists mild ptosis among the craniofacial features.
- category: Ocular
  name: Strabismus
  description: Strabismus, recorded as left exotropia in one affected sister.
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: ORPHA:457395
    reference_title: Progressive spondyloepimetaphyseal dysplasia-short stature-short fourth metatarsals-intellectual disability syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      dysmorphic craniofacial features (including microcephaly, hypertelorism,
      epicanthal folds, mild ptosis, strabismus, malar hypoplasia
    explanation: Orphanet lists strabismus among the ocular/craniofacial features.
- category: Neurologic
  name: Generalized Hypotonia
  phenotype_term:
    preferred_term: Generalized hypotonia
    term:
      id: HP:0001290
      label: Generalized hypotonia
  evidence:
  - reference: ORPHA:457395
    reference_title: Progressive spondyloepimetaphyseal dysplasia-short stature-short fourth metatarsals-intellectual disability syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Craniosynostosis, generalized hypotonia, as well as asymmetry of the cerebral
      hemispheres and mild thinning of the corpus callosum on brain imaging have also
      been described.
    explanation: Orphanet records generalized hypotonia as a described feature.
- category: Neurologic
  name: Delayed Ability to Walk
  phenotype_term:
    preferred_term: Delayed ability to walk
    term:
      id: HP:0031936
      label: Delayed ability to walk
  evidence:
  - reference: PMID:38562122
    reference_title: Two sisters with RSPRY1-related spondyloepimetaphyseal dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: She started walking at 2 years.
    explanation: >-
      Independent ambulation at 2 years is delayed relative to the typical 12-18 month
      milestone.
- category: Neurologic
  name: Bilateral Tonic-Clonic Seizure
  description: >-
    Generalized tonic-clonic seizures with onset at 5 years in one affected
    sibling, controlled on levetiracetam. Reported in a single patient to date.
  phenotype_term:
    preferred_term: Bilateral tonic-clonic seizure
    term:
      id: HP:0002069
      label: Bilateral tonic-clonic seizure
  evidence:
  - reference: PMID:38562122
    reference_title: Two sisters with RSPRY1-related spondyloepimetaphyseal dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: She had generalized tonic−clonic seizures, which lasted for 5 min.
    explanation: >-
      Single-patient observation; no frequency band is asserted because it has been
      reported once.
- category: Neurologic
  name: Thin Corpus Callosum
  description: >-
    Mild thinning of the corpus callosum with asymmetry of the cerebral hemispheres
    on brain imaging.
  phenotype_term:
    preferred_term: Thin corpus callosum
    term:
      id: HP:0033725
      label: Thin corpus callosum
  evidence:
  - reference: ORPHA:457395
    reference_title: Progressive spondyloepimetaphyseal dysplasia-short stature-short fourth metatarsals-intellectual disability syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      asymmetry of the cerebral hemispheres and mild thinning of the corpus callosum
      on brain imaging have also been described
    explanation: Orphanet records the neuroimaging findings for this syndrome.
- category: Craniofacial
  name: Microcephaly
  description: >-
    Reported by Orphanet among the craniofacial features, but the largest published
    cohort found all patients but one to be normocephalic; head circumference in
    two later-reported sisters was -1.31 SD and -2.39 SD. Curated without a
    frequency band because the reports conflict.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: ORPHA:457395
    reference_title: Progressive spondyloepimetaphyseal dysplasia-short stature-short fourth metatarsals-intellectual disability syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      dysmorphic craniofacial features (including microcephaly, hypertelorism,
      epicanthal folds, mild ptosis, strabismus, malar hypoplasia, short nose,
      depressed nasal bridge, full lips, small, low-set ears, and short neck)
    explanation: Orphanet lists microcephaly among the craniofacial features.
  - reference: PMID:30063090
    reference_title: "Further delineation of spondyloepimetaphyseal dysplasia Faden-Alkuraya type: A RSPRY1-associated spondylo-epi-metaphyseal dysplasia with cono-brachydactyly and craniosynostosis."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Unlike the previously reported clinical findings, all patients except one are
      normocephalic
    explanation: >-
      The five-patient delineation cohort explicitly contradicts microcephaly as a
      consistent feature.
imaging_findings:
- name: Copper-Beaten Skull Appearance on Skull Radiographs
  modality: XRAY
  imaging_finding_term:
    preferred_term: Copper beaten skull
    term:
      id: HP:0034271
      label: Copper beaten skull
  description: >-
    A copper-beaten (beaten-silver) skull appearance, the radiographic sign of
    raised intracranial pressure against the inner table, was seen in both
    reported Indian siblings.
  diagnostic: false
  evidence:
  - reference: PMID:38562122
    reference_title: Two sisters with RSPRY1-related spondyloepimetaphyseal dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The radiographic evaluation indicated a copper-beaten appearance of a skull,
      platyspondyly, mild scoliosis, lumbar lordosis, small carpals bones, short
      femoral neck, short fourth metatarsal bone, wind-swept deformity, small
      epiphyses, metaphyseal cupping, and fraying in both siblings.
    explanation: Direct radiographic observation in both siblings.
- name: Metaphyseal Cupping and Fraying on Long-Bone Radiographs
  modality: XRAY
  description: >-
    Cupping and fraying of the metaphyses, most marked at the tibia and fibula,
    are core radiographic signs of the metaphyseal component.
  imaging_finding_term:
    preferred_term: Metaphyseal cupping
    term:
      id: HP:0003021
      label: Metaphyseal cupping
  diagnostic: false
  evidence:
  - reference: PMID:38562122
    reference_title: Two sisters with RSPRY1-related spondyloepimetaphyseal dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Spondyloepimetaphyseal dysplasia (SEMD), RSPRY1 related (OMIM #616723), also referred to as
      SEMD, Faden-Alkuraya type, is a rare autosomal recessive disorder. The condition is
      characterized by short stature, facial dysmorphism, brachydactyly, and intellectual
      disability. Mild scoliosis, vertebral defects, small epiphysis, cupping, and fraying of
      metaphyses of tibia and fibula, coxa vara, genu valgum, short metacarpals, short metatarsals,
      and craniosynostosis have been described in affected individuals
    explanation: >-
      Restores the RSPRY1/Faden-Alkuraya disease identification before the skeletal findings. These
      are previously reported features, not a statement that every listed feature occurred in both
      sisters.
- name: Cone-Shaped Phalangeal Epiphyses on Hand Radiographs
  modality: XRAY
  description: >-
    Brachymesophalangy with cone-shaped epiphyses gives the cono-brachydactyly
    pattern that helps distinguish this entity radiographically.
  imaging_finding_term:
    preferred_term: Cone-shaped epiphysis
    term:
      id: HP:0010579
      label: Cone-shaped epiphysis
  diagnostic: false
  evidence:
  - reference: PMID:30063090
    reference_title: "Further delineation of spondyloepimetaphyseal dysplasia Faden-Alkuraya type: A RSPRY1-associated spondylo-epi-metaphyseal dysplasia with cono-brachydactyly and craniosynostosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The skeletal hallmarks include (a) mild spondylar dysplasia, (b)
      epimetaphyseal dysplasia of the long bones associated with coxa vara and
      genu valgum, (c) brachymesophalangy with cone-shaped epiphyses, and (d)
      craniosynostosis.
    explanation: Cone-shaped epiphyses are named among the radiographic hallmarks.
progression:
- phase: Infancy
  age_range: First two years
  notes: >-
    Birth and the early postnatal period may be unremarkable, and anthropometric
    parameters at birth are not consistently recorded. Gross-motor milestones can
    be mildly delayed.
  evidence:
  - reference: PMID:38562122
    reference_title: Two sisters with RSPRY1-related spondyloepimetaphyseal dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Birth and postnatal periods were unremarkable.
    explanation: Documents an unremarkable perinatal course in an affected sibling.
- phase: Early childhood onset of limb deformity
  age_range: Two to four years
  notes: >-
    Lower-limb malformation is typically first noticed between two and four years
    of age, together with short stature and painful walking, and progresses
    thereafter.
  evidence:
  - reference: PMID:38562122
    reference_title: Two sisters with RSPRY1-related spondyloepimetaphyseal dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bilateral lower limb malformation was observed at 4 years of age, which is
      progressive. She could not walk long distances due to pain.
    explanation: Dates the onset of the limb deformity and its progressive character.
- phase: Childhood through adolescence
  age_range: Childhood to skeletal maturity
  notes: >-
    Vertebral deformity worsens with age and the dysplasia is explicitly
    progressive, which is the feature that separates this entity from static
    spondyloepimetaphyseal dysplasias. No adult natural-history data have been
    published.
  evidence:
  - reference: PMID:38562122
    reference_title: Two sisters with RSPRY1-related spondyloepimetaphyseal dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The severity of vertebral deformities increases with age.
    explanation: Direct statement of progression over childhood.
diagnosis:
- name: Clinical and Radiographic Recognition
  diagnosis_term:
    preferred_term: skeletal survey radiography
    term:
      id: NCIT:C38092
      label: Skeletal Survey X-Ray
  description: >-
    The combination of the facial gestalt, disproportionate short stature, short
    fourth metatarsals, cono-brachydactyly, and progressive spondylar plus
    epimetaphyseal change on skeletal survey is distinctive enough to raise the
    diagnosis before molecular testing.
  evidence:
  - reference: PMID:26365341
    reference_title: Identification of a Recognizable Progressive Skeletal Dysplasia Caused by RSPRY1 Mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We describe a clinically recognizable autosomal-recessive disorder
    explanation: The founding report frames the entity as clinically recognizable.
- name: Molecular Confirmation by Exome or Targeted RSPRY1 Sequencing
  diagnosis_term:
    preferred_term: whole exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  description: >-
    Diagnosis is confirmed by identifying biallelic pathogenic RSPRY1 variants.
    In practice this has been achieved by exome sequencing — combined with
    autozygosity mapping in consanguineous families — or by targeted sequencing
    once RSPRY1 is suspected.
  evidence:
  - reference: PMID:26365341
    reference_title: Identification of a Recognizable Progressive Skeletal Dysplasia Caused by RSPRY1 Mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Combined autozygome/exome analysis identified a homozygous frameshift
      mutation in RSPRY1 with resulting nonsense-mediated decay.
    explanation: Describes the diagnostic strategy that established the first molecular diagnosis.
  - reference: PMID:39706863
    reference_title: Genetic and allelic heterogeneity in 248 Indians with skeletal dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We expand the phenotypic and genotypic spectrum of rarely reported
      conditions (RAB33B, TRIP11, NEPRO, RPL13, COL27A1, PTHR1, EXOC6B, PRKACA,
      FUZ and RSPRY1)
    explanation: >-
      A national skeletal-dysplasia sequencing cohort shows that RSPRY1 disease is
      reached through broad exome/genome testing rather than a dedicated assay.
differential_diagnoses:
- name: Spondyloepimetaphyseal Dysplasia Strudwick Type
  description: >-
    Another spondyloepimetaphyseal dysplasia with vertebral, epiphyseal, and
    metaphyseal involvement, so the radiographic pattern overlaps.
  distinguishing_features:
  - >-
    Strudwick type is autosomal dominant and caused by COL2A1 variants, has
    dappled irregular metaphyses, and is not associated with intellectual
    disability, short fourth metatarsals, or craniosynostosis.
- name: Spondyloepimetaphyseal Dysplasia with Joint Laxity
  description: >-
    Shares spondyloepimetaphyseal radiographic changes and, since joint
    dislocation was reported in RSPRY1 disease, some clinical overlap.
  distinguishing_features:
  - >-
    In SEMD with joint laxity, generalized joint laxity and dislocation are core
    defining features present from early life, and the digits are typically
    slender (leptodactylic) rather than showing cono-brachydactyly.
- name: Syndromic Craniosynostosis
  description: >-
    When craniosynostosis dominates the presentation, the syndromic
    craniosynostoses enter the differential.
  distinguishing_features:
  - >-
    The syndromic craniosynostoses lack the progressive spondylar and
    epimetaphyseal dysplasia, the short fourth metatarsals, and the
    cono-brachydactyly that define this entity, and most are autosomal dominant.
treatments:
- name: Supportive and Symptom-Directed Management
  description: >-
    No disease-modifying therapy exists. Management is supportive and
    multidisciplinary, directed at the skeletal deformity, developmental needs,
    and any associated anomalies. No trial or management protocol specific to
    RSPRY1 disease has been published.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  therapeutic_modality: OTHER
  notes: >-
    Curated without an evidence item because the published literature on this
    disorder contains no management study; the entry records the absence of
    disease-specific therapy rather than asserting a supported intervention.
- name: Surgical Correction of Associated Anomalies
  description: >-
    Surgery has been used in reported patients for associated anomalies —
    corrective surgery for patent ductus arteriosus in one child — and is the
    standard route for craniosynostosis and for progressive limb malalignment in
    skeletal dysplasia generally.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  therapeutic_modality: SURGERY
  evidence:
  - reference: PMID:38562122
    reference_title: Two sisters with RSPRY1-related spondyloepimetaphyseal dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She was diagnosed with congenital heart disease, patent ductus arteriosus
      (PDA), and underwent corrective surgery at 3 years of age.
    explanation: >-
      Documents a surgical intervention actually performed in a reported patient.
      It supports surgery for an associated anomaly, not a disease-modifying
      effect, hence PARTIAL.
- name: Genetic Counseling
  description: >-
    Autosomal recessive inheritance carries a 25 percent recurrence risk for
    carrier couples, and reported families have generally been consanguineous, so
    counseling and — once the familial variants are known — the option of
    prenatal or preimplantation testing are central to family management.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  therapeutic_modality: OTHER
  evidence:
  - reference: PMID:26365341
    reference_title: Identification of a Recognizable Progressive Skeletal Dysplasia Caused by RSPRY1 Mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe a clinically recognizable autosomal-recessive disorder in four
      affected siblings from a consanguineous Saudi family
    explanation: >-
      Establishes the autosomal recessive, consanguinity-associated inheritance
      that makes counseling and recurrence-risk discussion the relevant action.
- name: Anti-Seizure Pharmacotherapy
  description: >-
    Levetiracetam controlled generalized tonic-clonic seizures in the one reported
    patient with epilepsy. This is standard symptomatic epilepsy management, not a
    disease-specific therapy.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: levetiracetam
      term:
        id: CHEBI:6437
        label: levetiracetam
  target_phenotypes:
  - preferred_term: Bilateral tonic-clonic seizure
    term:
      id: HP:0002069
      label: Bilateral tonic-clonic seizure
  evidence:
  - reference: PMID:38562122
    reference_title: Two sisters with RSPRY1-related spondyloepimetaphyseal dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: She was treated with levetiracetam, and her seizures were controlled.
    explanation: >-
      Single-patient report of seizure control on levetiracetam; not generalizable
      evidence of efficacy in this disorder.
- name: Ophthalmologic Correction
  description: >-
    Refractive correction for myopia and management of strabismus and ptosis,
    identified on formal ophthalmologic assessment in reported patients.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: therapeutic procedure
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
  target_phenotypes:
  - preferred_term: Myopia
    term:
      id: HP:0000545
      label: Myopia
  evidence:
  - reference: PMID:38562122
    reference_title: Two sisters with RSPRY1-related spondyloepimetaphyseal dysplasia.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Moreover, ophthalmologic evaluation showed myopia in both eyes.
    explanation: >-
      Establishes the refractive indication. Graded INDIRECT because the quoted
      text reports the refractive error itself; that correction is indicated
      follows by an inference step, and no outcome data on correction are
      reported in this disorder.
  notes: >-
    treatment_term is deliberately left at the generic NCIT:C49236 Therapeutic
    Procedure. NCIT was searched for a more specific spectacle/refractive-correction
    action term and has none that qualifies: NCIT:C87148 Glasses is a device rather
    than a clinical action and is not reachable from NCIT:C25218 Clinical
    Intervention or Procedure, so it fails TreatmentTerm enum validation, and
    NCIT:C157904 Laser Vision Correction is a different intervention that none of
    the reported patients received. The device semantics are instead carried by
    therapeutic_modality: DEVICE.
experimental_models:
- name: SEMDFA patient-derived dermal fibroblasts
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: >-
    Dermal fibroblasts obtained by skin biopsy from two patients homozygous for
    the RSPRY1 c.377delT frameshift allele, compared with commercial control
    human dermal fibroblasts by bulk RNA sequencing.
  cell_source: Patient-derived (skin biopsy)
  culture_system: Two-dimensional monolayer culture, passage 3
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: dermal fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  publication: PMID:39940902
  evidence:
  - reference: PMID:39940902
    reference_title: "Unraveling the Role of RSPRY1 in TGF-β Pathway Dysregulation: Insights into the Pathogenesis of Spondyloepimetaphyseal Dysplasia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      frameshift mutation in exon 2 of the RSPRY1 gene (NM_133368). Dermal
      fibroblasts were obtained from the patients via skin biopsy.
    explanation: >-
      Establishes the genotype and tissue source of the patient-derived
      fibroblast model.
  modeled_mechanisms:
  - target: Constitutive TGF-beta/SMAD3 Signaling Activation
    relationship: MEASURES
    fidelity: MODERATE
    description: >-
      Patient fibroblast transcriptomes identify TGF-beta regulation of the
      extracellular matrix as the dominant dysregulated pathway, with SMAD2 and
      SMAD3 the top enriched transcription factors.
    limitations: >-
      Dermal fibroblasts are a patient-accessible surrogate. RSPRY1 is normally
      concentrated in osteoblasts and periosteal cells of the developing
      endochondral skeleton, so the pathway readout is not measured in the
      disease-relevant bone lineage.
    readouts:
    - name: TGF-beta regulation of extracellular matrix pathway enrichment
      target: Constitutive TGF-beta/SMAD3 Signaling Activation
      direction: INCREASED
      interpretation: >-
        The most strongly enriched pathway among differentially expressed genes in
        patient versus control fibroblasts.
      evidence:
      - reference: PMID:39940902
        reference_title: "Unraveling the Role of RSPRY1 in TGF-β Pathway Dysregulation: Insights into the Pathogenesis of Spondyloepimetaphyseal Dysplasia."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          The pathway enrichment analysis of DEGs showed there were several
          significantly enriched pathways, with TGF-β regulation of the ECM
          pathway being the most prominent.
        explanation: Reports the enrichment result behind this readout.
    evidence:
    - reference: PMID:39940902
      reference_title: "Unraveling the Role of RSPRY1 in TGF-β Pathway Dysregulation: Insights into the Pathogenesis of Spondyloepimetaphyseal Dysplasia."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Transcriptome analysis of fibroblasts from patients with homozygous RSPRY1
        mutations showed there was significant enrichment of transforming growth
        factor beta (TGF-β) signaling and ECM-related pathways.
      explanation: Establishes the model as informative for the TGF-beta activation node.
- name: CRISPR-Cas9 RSPRY1 and RSPRY1/SMAD3 knockout human dermal fibroblasts
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: >-
    Isogenic RSPRY1 knockout, SMAD3 knockout, and RSPRY1 plus SMAD3 double
    knockout human dermal fibroblasts generated with Cas9 ribonucleoprotein
    complexes, used for wound-healing, proliferation, senescence, and apoptosis
    assays with and without recombinant TGF-beta1.
  cell_source: Gene-edited human dermal fibroblasts
  culture_system: Two-dimensional monolayer culture with and without recombinant TGF-beta1
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: dermal fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  publication: PMID:39940902
  evidence:
  - reference: PMID:39940902
    reference_title: "Unraveling the Role of RSPRY1 in TGF-β Pathway Dysregulation: Insights into the Pathogenesis of Spondyloepimetaphyseal Dysplasia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      To further investigate the role of RSPRY1 and its interaction with SMAD3 in
      cellular processes, RSPRY1 KO, SMAD3 KO, and RSPRY1 + SMAD3 double KO
      fibroblasts were generated.
    explanation: Establishes the isogenic knockout panel that constitutes this model.
  modeled_mechanisms:
  - target: Disordered Extracellular Matrix Dynamics and Cell Motility
    relationship: PERTURBS
    fidelity: MODERATE
    description: >-
      Removing RSPRY1 increases fibroblast motility, and additionally removing
      SMAD3 abolishes that increase, establishing SMAD3 as the required mediator.
    limitations: >-
      Wound closure in dermal fibroblasts is a proxy for matrix-regulated cell
      behavior, not a measurement of growth-plate or osteoblast function, and the
      link to endochondral ossification remains inferred.
    readouts:
    - name: Wound closure rate in RSPRY1 knockout fibroblasts
      target: Disordered Extracellular Matrix Dynamics and Cell Motility
      direction: INCREASED
      interpretation: Faster wound closure indicates enhanced cell motility after RSPRY1 loss.
      evidence:
      - reference: PMID:39940902
        reference_title: "Unraveling the Role of RSPRY1 in TGF-β Pathway Dysregulation: Insights into the Pathogenesis of Spondyloepimetaphyseal Dysplasia."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          RSPRY1 KO fibroblasts exhibited a significant increase in wound closure
          ability, as compared to CTRL fibroblasts, which indicated that RSPRY1
          deficiency enhanced cell motility
        explanation: Reports the wound-closure measurement and its direction.
    - name: Wound closure rate in RSPRY1 plus SMAD3 double knockout fibroblasts
      target: Disordered Extracellular Matrix Dynamics and Cell Motility
      direction: ABOLISHED
      interpretation: >-
        Loss of the motility gain in the double knockout shows the effect requires
        SMAD3.
      evidence:
      - reference: PMID:39940902
        reference_title: "Unraveling the Role of RSPRY1 in TGF-β Pathway Dysregulation: Insights into the Pathogenesis of Spondyloepimetaphyseal Dysplasia."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          this improved wound-healing capacity was not observed in the RSPRY1 +
          SMAD3 double KO fibroblasts, indicating that SMAD3 plays a critical role
          in mediating the effects of RSPRY1 loss on cell motility
        explanation: Reports the epistasis result behind this readout.
    evidence:
    - reference: PMID:39940902
      reference_title: "Unraveling the Role of RSPRY1 in TGF-β Pathway Dysregulation: Insights into the Pathogenesis of Spondyloepimetaphyseal Dysplasia."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Functional wound healing assays showed that RSPRY1 knockout fibroblasts
        exhibited enhanced motility, a phenotype that was abrogated in RSPRY1 +
        SMAD3 double knockout fibroblasts, highlighting the SMAD3-dependence of
        RSPRY1's effects.
      explanation: Establishes the edited-fibroblast system as the perturbation model for this node.
discussions:
- discussion_id: rspry1_biochemical_function
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What is the biochemical activity of RSPRY1, and does its RING domain
    ubiquitinate a component of the TGF-beta pathway?
  attaches_to:
  - pathophysiology#Loss of RSPRY1 Regulatory Activity in Skeletal Tissue
  rationale: >-
    RSPRY1 was described at discovery as a protein of unknown physiological
    function, and that has not changed. The RING domain and the ubiquitin-ligase
    interaction partners recovered from interaction databases motivate an E3
    ligase hypothesis, but no substrate has been identified and no ligase
    activity has been demonstrated. Without it, the step between loss of the
    protein and activation of TGF-beta signaling is a correlation, not a
    mechanism.
  evidence:
  - reference: PMID:26365341
    reference_title: Identification of a Recognizable Progressive Skeletal Dysplasia Caused by RSPRY1 Mutations.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      RSPRY1 encodes a hypothetical RING and SPRY domain-containing protein of
      unknown physiological function.
    explanation: States the gap directly at the point of gene discovery.
  - reference: PMID:39940902
    reference_title: "Unraveling the Role of RSPRY1 in TGF-β Pathway Dysregulation: Insights into the Pathogenesis of Spondyloepimetaphyseal Dysplasia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Identifying the possible ubiquitination targets of RSPRY1 in this context
      and detailing the effects of these targets in the TGF-β signaling pathway
      may provide important information to elucidate the functional mechanism of
      RSPRY1
    explanation: >-
      The mechanistic study itself names substrate identification as the
      outstanding question.
  - reference: PMID:26497270
    reference_title: "Isolation, expression analysis and characterization of NEFA-interacting nuclear protein 30 and RING finger and SPRY domain containing 1 in skeletal muscle."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      GFP-tagged Nip30 was found to localize to the nucleus, while GFP-tagged
      Rspry1 was found to localize to the cytoplasm of muscle cells.
    explanation: >-
      The only other functional characterization of the protein places tagged
      Rspry1 in the cytoplasm of muscle cells, which sits awkwardly beside the
      description of RSPRY1 as a secreted protein acting on the extracellular
      matrix. The compartment in which it acts is itself unsettled.
  - reference: PMID:33092958
    reference_title: Substrate recognition by TRIM and TRIM-like proteins in innate immunity.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      We focus on those containing PRY-SPRY, the domain most frequently used for
      substrate recognition
    explanation: >-
      RSPRY1's RING-plus-SPRY architecture is the TRIM-family arrangement, in
      which the PRY-SPRY domain typically picks the substrate. This is the
      structural argument for the E3-ligase hypothesis, and it is an argument
      from domain analogy rather than evidence about RSPRY1 itself.
  proposed_experiments:
  - experiment_id: exp_rspry1_interactome_and_ubiquitination
    name: Define the RSPRY1 interactome and test for ubiquitination of a TGF-beta pathway component
    description: >-
      Use affinity-purification mass spectrometry on endogenously tagged RSPRY1
      to recover its interactors, then test candidate TGF-beta pathway
      components in in vitro and cellular ubiquitination assays with wild-type
      RSPRY1 versus a RING-domain mutant.
    decision_criterion: >-
      Recovery of a TGF-beta pathway component as a RING-dependent
      ubiquitination substrate would convert the curated correlation between
      RSPRY1 loss and pathway activation into a mechanism; failure to find one
      would leave the E3-ligase framing as domain analogy and reopen
      alternatives such as a purely extracellular role.
  - experiment_id: exp_rspry1_subcellular_localization
    name: Resolve the secreted-versus-intracellular localization of endogenous RSPRY1
    description: >-
      Combine endogenous tagging with immunofluorescence and secretome analysis
      in a bone-lineage cell type. The protein is annotated as secreted and has
      been described as acting on the extracellular matrix, yet tagged Rspry1
      was reported in the cytoplasm of muscle cells and a RING-dependent
      ubiquitin-ligase role would require intracellular access. The compartment
      determines which mechanistic models remain possible.
- discussion_id: fibroblast_proxy_for_bone_lineage
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Does the constitutive TGF-beta/SMAD3 activation seen in patient dermal
    fibroblasts also occur in the osteoblast, periosteal, and growth-plate
    chondrocyte lineages where RSPRY1 is actually expressed?
  attaches_to:
  - pathophysiology#Impaired Endochondral Ossification and Growth-Plate Function
  rationale: >-
    The entire cellular mechanism for this disorder rests on dermal fibroblasts,
    chosen because they are the accessible patient tissue. RSPRY1 protein is
    concentrated in murine embryonic osteoblasts and periosteal cells during
    primary endochondral ossification, which is a different cell context with
    different TGF-beta set points. The authors are explicit that fibroblasts may
    only partly capture the effects of RSPRY1 loss in other tissues, so the
    fibroblast-to-bone step is the weakest link in the curated chain and is
    marked INDIRECT_UNKNOWN_INTERMEDIATES accordingly.
  evidence:
  - reference: PMID:39940902
    reference_title: "Unraveling the Role of RSPRY1 in TGF-β Pathway Dysregulation: Insights into the Pathogenesis of Spondyloepimetaphyseal Dysplasia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The present study focused on fibroblast cell models derived from two
      patients with homozygous RSPRY1 mutations, which, while informative, might
      only partially capture the effects of RSPRY1 deficiency in other cell types
      or tissues.
    explanation: The authors state the translational limitation of their own model.
  - reference: PMID:26365341
    reference_title: Identification of a Recognizable Progressive Skeletal Dysplasia Caused by RSPRY1 Mutations.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      However, we detect strong RSPRY1 protein localization in murine embryonic
      osteoblasts and periosteal cells during primary endochondral ossification,
      consistent with a role in bone development.
    explanation: Identifies the bone-lineage cell types in which the mechanism actually needs testing.
  proposed_experiments:
  - experiment_id: exp_semdfa_bone_lineage_tgfb_validation
    name: Test constitutive TGF-beta/SMAD3 activation in patient-derived chondrocytes and osteoblasts
    description: >-
      Differentiate patient iPSCs carrying biallelic RSPRY1 alleles into
      chondrocytes and osteoblasts, and quantify phospho-SMAD3 and TGF-beta
      target-gene output against isogenic corrected controls, with and without
      an ALK5 (TGFBR1) inhibitor. The fibroblast result predicts elevated basal
      phospho-SMAD3 and a blunted response to exogenous TGF-beta1 in the bone
      lineage as well.
    decision_criterion: >-
      Elevated basal phospho-SMAD3 with a blunted exogenous-ligand response in
      the bone lineage would carry the mechanism across the fibroblast-to-bone
      gap; a normal bone-lineage TGF-beta set point would confine the fibroblast
      finding to that cell type and leave the skeletal mechanism unexplained.
  - experiment_id: exp_semdfa_rspry1_null_mouse_skeleton
    name: Skeletal phenotyping of a global and cartilage-specific Rspry1 knockout mouse
    description: >-
      Characterize growth-plate architecture, endochondral ossification, and
      cranial sutures in global and cartilage-specific Rspry1-null mice. No
      Rspry1-null skeletal phenotype has been reported despite knockout alleles
      existing in repositories, so this is the missing in vivo test of whether
      loss of the gene reproduces the human skeleton.
- discussion_id: neurodevelopmental_mechanism_unexplained
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    By what mechanism does RSPRY1 loss cause intellectual disability?
  attaches_to:
  - pathophysiology#Loss of RSPRY1 Regulatory Activity in Skeletal Tissue
  rationale: >-
    Intellectual disability is one of the five defining features of the disorder
    and was present in every patient of the delineation series, yet no curated
    causal path connects RSPRY1 loss to it. All functional work to date is
    skeletal or fibroblast-based, and there is no published study of RSPRY1 in
    neural tissue. The pathograph therefore deliberately stops at the skeletal
    arm rather than asserting an unevidenced neurodevelopmental edge.
  evidence:
  - reference: PMID:30063090
    reference_title: "Further delineation of spondyloepimetaphyseal dysplasia Faden-Alkuraya type: A RSPRY1-associated spondylo-epi-metaphyseal dysplasia with cono-brachydactyly and craniosynostosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All patients have short stature, extremity deformities, facial dysmorphism and intellectual disability.
    explanation: Establishes that the unexplained phenotype is consistently present.
- discussion_id: tgf_beta_targeted_therapy_rationale
  kind: EMERGING_HYPOTHESIS
  status: OPEN
  prompt: >-
    Could pharmacological inhibition of TGF-beta/SMAD3 signaling modify the
    skeletal phenotype of RSPRY1 deficiency?
  attaches_to:
  - pathophysiology#Constitutive TGF-beta/SMAD3 Signaling Activation
  rationale: >-
    Constitutive, SMAD3-dependent TGF-beta activation is the only druggable node
    identified so far, and the authors of the mechanistic study raise
    TGF-beta-directed therapy on that basis. Nothing has been tested: there is no
    animal model with a demonstrated skeletal phenotype, no in vivo proof that
    the pathway is activated in bone, and no trial. This is recorded as a
    hypothesis and deliberately not curated as a treatment.
  evidence:
  - reference: PMID:39940902
    reference_title: "Unraveling the Role of RSPRY1 in TGF-β Pathway Dysregulation: Insights into the Pathogenesis of Spondyloepimetaphyseal Dysplasia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      An improvement in our understanding of the molecular roles of RSPRY1 might
      yield novel therapeutic strategies that target TGF-β signaling in patients
      with SEMD and other skeletal dysplasias.
    explanation: >-
      The authors frame TGF-beta-directed therapy as a prospect arising from their
      findings, not as a demonstrated intervention.
- discussion_id: contiguous_gene_deletion_haploinsufficiency
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    Does single-copy loss of RSPRY1, as part of a 16q contiguous-gene deletion,
    contribute to the skeletal phenotype of that deletion syndrome?
  attaches_to:
  - pathophysiology#Biallelic RSPRY1 Loss of Function
  rationale: >-
    SEMDFA is recessive, and every reported patient is homozygous, so the
    curated trigger node requires biallelic loss. A patient with a 16q12.2q21
    interstitial deletion spanning RSPRY1 was nonetheless proposed to owe the
    skeletal part of their phenotype to loss of this gene. If that is right, one
    copy is sometimes not enough for the skeleton, which would put a partial
    dosage effect underneath a disorder curated here as a null phenotype. The
    proposal is a candidate-gene inference from a single deletion patient, not a
    dosage experiment, so it is recorded as an open question rather than a
    curated modifier or a second genetic entry.
  evidence:
  - reference: PMID:27230627
    reference_title: "A 16q12.2q21 deletion identified in a patient with developmental delay, epilepsy, short stature, and distinctive features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Because RSPRY1 was been discovered as the cause of progressive skeletal
      dysplasia, a loss of this gene might explain the skeletal defects observed
      in the patient.
    explanation: >-
      The deletion report states the hypothesis in its own hedged terms
      ("might explain"), which is the level at which it is recorded here. The
      quote reproduces the source's own wording, including its grammatical slip.
- discussion_id: rspry1_subcellular_localization
  kind: CONTROVERSY
  status: OPEN
  attaches_to:
  - pathophysiology#Biallelic RSPRY1 Loss of Function
  prompt: >-
    Is RSPRY1 a secreted, extracellular-acting protein or a cytoplasmic one?
  rationale: >-
    The two most recent primary sources disagree. The 2025 mechanistic study
    describes RSPRY1 as "a secreted protein with RING and SPRY domains", consistent
    with BioGRID/UniProt annotation, and builds an extracellular-matrix-facing model
    on that basis. The 2024 clinical report instead states, citing the original
    characterization of the protein, that RSPRY1 is a glycoprotein present in the
    cytoplasm of skeletal muscle cells. The two are not reconcilable as stated, and
    the answer changes whether RSPRY1 acts on ECM components extracellularly or on
    intracellular signalling intermediates — the ubiquitin-ligase model requires the
    latter. No dedicated localization study of RSPRY1 has been published.
  evidence:
  - reference: PMID:39940902
    reference_title: "Unraveling the Role of RSPRY1 in TGF-β Pathway Dysregulation: Insights into the Pathogenesis of Spondyloepimetaphyseal Dysplasia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      RSPRY1, a secreted protein with RING and SPRY domains, has been implicated in
      bone development, yet its exact role remains to be determined.
    explanation: States the secreted-protein position.
  - reference: PMID:38562122
    reference_title: Two sisters with RSPRY1-related spondyloepimetaphyseal dysplasia.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      RSPRY1 protein is a glycoprotein present in the cytoplasm of skeletal muscle
      cells.
    explanation: States the cytoplasmic position, contradicting the secreted annotation.
  proposed_experiments:
  - experiment_id: exp_rspry1_localization
    name: Subcellular localization and secretion assay for endogenous RSPRY1
    description: >-
      Subcellular fractionation and immunofluorescence of endogenous RSPRY1 in
      osteoblasts, chondrocytes and fibroblasts, with conditioned-medium immunoblotting
      to test for secretion.
- discussion_id: no_animal_model_of_the_dysplasia
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Progressive Skeletal Deformity and Short Stature
  prompt: >-
    Can the spondyloepimetaphyseal dysplasia be recapitulated in an animal model?
  rationale: >-
    No Rspry1 knockout animal with a published skeletal phenotype exists. The only
    in vivo data are wild-type murine expression localization from the 2015 gene
    discovery paper, which shows where RSPRY1 is present but not what its absence
    does. Without a model that reproduces the dysplasia, the causal chain from gene
    loss to growth-plate failure cannot be tested in a whole organism, and no
    preclinical platform exists for the TGF-beta-directed therapeutic hypothesis the
    2025 study raises. Targeted Rspry1 knockout alleles are catalogued in the
    KOMP/IMPC mouse resources, so the reagents exist; what is missing is a published
    skeletal phenotype from them.
  proposed_experiments:
  - experiment_id: exp_rspry1_knockout_mouse_skeleton
    name: Constitutive and conditional Rspry1 knockout mouse skeletal phenotyping
    description: >-
      Generate a constitutive and a chondrocyte/osteoblast-conditional Rspry1 knockout
      mouse and phenotype the axial skeleton, growth plates and cranial sutures by
      micro-CT and histology across postnatal development.
  - experiment_id: exp_zebrafish_rspry1
    name: Zebrafish rspry1 loss-of-function cartilage and craniofacial screen
    description: >-
      Assess zebrafish rspry1 loss of function as a rapid screen for cartilage and
      craniofacial patterning defects.
clinical_trials: []
datasets: []
notes: >-
  Curated from primary literature plus claude_code and openscientist
  deep-research reports. Fewer
  than fifteen molecularly confirmed patients have been published, so most
  phenotype frequency bands are drawn from small case series and several
  single-patient findings (patent ductus arteriosus, myopia, ossifying fibroma of
  the maxilla, joint dislocation) are deliberately curated without a frequency.

  This entry was reconciled with a parallel curation of the same MONDO concept
  (MONDO:0014748) that ran concurrently and produced a second entry under the
  full MONDO label. The two were merged here rather than kept as duplicate
  Disease entries; the reconciliation contributed the variants, mappings and
  references blocks, the Harrison's classification, NCIT diagnosis terms, the
  RSPRY1-localization CONTROVERSY and animal-model KNOWLEDGE_GAP discussions, the
  anti-seizure and ophthalmologic treatments, and ten phenotypes.

  Two caveats recorded at original curation time are now resolved, and the
  superseded text is replaced here rather than left standing. First, the
  Orphanet structured record for ORPHA:457395 has since been built successfully
  with "just refresh-orphadata" followed by "just structured-rebuild-orphanet
  --id 457395"; data/orphadata/MANIFEST.yaml was not modified, so no snapshot
  drift was introduced and the wider ORPHA cache was not rewritten. Second,
  microcephaly, seizures, hypotonia and corpus-callosum thinning were previously
  omitted for want of a quotable passage; all four are now curated against
  citable sources — microcephaly, generalized hypotonia and thin corpus callosum
  from that ORPHA:457395 structured record, and generalized tonic-clonic seizures
  from PMID:38562122. The tension over head size is preserved rather than
  flattened: the microcephaly entry carries the ORPHA statement as SUPPORT and
  the delineation series' report that all patients except one are normocephalic
  as REFUTE, and no frequency band is asserted.

📚

References & Deep Research

References

9

PMID:26365341

Identification of a Recognizable Progressive Skeletal Dysplasia Caused by RSPRY1 Mutations.

No top-level findings curated for this source.

PMID:30063090

Further delineation of spondyloepimetaphyseal dysplasia Faden-Alkuraya type: A RSPRY1-associated spondylo-epi-metaphyseal dysplasia with cono-brachydactyly and craniosynostosis.

No top-level findings curated for this source.

PMID:38562122

Two sisters with RSPRY1-related spondyloepimetaphyseal dysplasia.

No top-level findings curated for this source.

PMID:39706863

Genetic and allelic heterogeneity in 248 Indians with skeletal dysplasia.

No top-level findings curated for this source.

PMID:39940902

Unraveling the Role of RSPRY1 in TGF-β Pathway Dysregulation: Insights into the Pathogenesis of Spondyloepimetaphyseal Dysplasia.

No top-level findings curated for this source.

PMID:26497270

Isolation, expression analysis and characterization of NEFA-interacting nuclear protein 30 and RING finger and SPRY domain containing 1 in skeletal muscle.

No top-level findings curated for this source.

PMID:27230627

A 16q12.2q21 deletion identified in a patient with developmental delay, epilepsy, short stature, and distinctive features.

No top-level findings curated for this source.

PMID:33092958

Substrate recognition by TRIM and TRIM-like proteins in innate immunity.

No top-level findings curated for this source.

ORPHA:457395

Progressive spondyloepimetaphyseal dysplasia-short stature-short fourth metatarsals-intellectual disability syndrome

No top-level findings curated for this source.

Deep Research

2

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 (4)

Record notes

Curated from primary literature plus claude_code and openscientist deep-research reports. Fewer than fifteen molecularly confirmed patients have been published, so most phenotype frequency bands are drawn from small case series and several single-patient findings (patent ductus arteriosus, myopia, ossifying fibroma of the maxilla, joint dislocation) are deliberately curated without a frequency. This entry was reconciled with a parallel curation of the same MONDO concept (MONDO:0014748) that ran concurrently and produced a second entry under the full MONDO label. The two were merged here rather than kept as duplicate Disease entries; the reconciliation contributed the variants, mappings and references blocks, the Harrison's classification, NCIT diagnosis terms, the RSPRY1-localization CONTROVERSY and animal-model KNOWLEDGE_GAP discussions, the anti-seizure and ophthalmologic treatments, and ten phenotypes. Two caveats recorded at original curation time are now resolved, and the superseded text is replaced here rather than left standing. First, the Orphanet structured record for ORPHA:457395 has since been built successfully with "just refresh-orphadata" followed by "just structured-rebuild-orphanet --id 457395"; data/orphadata/MANIFEST.yaml was not modified, so no snapshot drift was introduced and the wider ORPHA cache was not rewritten. Second, microcephaly, seizures, hypotonia and corpus-callosum thinning were previously omitted for want of a quotable passage; all four are now curated against citable sources — microcephaly, generalized hypotonia and thin corpus callosum from that ORPHA:457395 structured record, and generalized tonic-clonic seizures from PMID:38562122. The tension over head size is preserved rather than flattened: the microcephaly entry carries the ORPHA statement as SUPPORT and the delineation series' report that all patients except one are normocephalic as REFUTE, and no frequency band is asserted.

Edit: reconcile the concurrent duplicate curation of MONDO:0014748 by porting PR #9082's unique content onto this entry · 2026-09-05T06:47:56Z · View source

Reconciliation of a concurrent duplicate curation of MONDO:0014748. Two Claude Code sessions were launched on this disease 12 seconds apart on 2026-08-20 and each produced a full entry. PR #9081 merged first, on 2026-08-20 at 09:15Z, creating this file. PR #9082 produced a second entry under the full MONDO label, Progressive_Spondyloepimetaphyseal_Dysplasia-short_Stature-short_Fourth_Metatarsals-intellectual_Disability_Syndrome.yaml. Neither duplicate preflight could have caught the collision: the #9082 preflight ran at about 07:05Z and searched origin/main, all pull requests and all issues for MONDO:0014748, RSPRY1 and Faden-Alkuraya, and #9081 did not exist until 07:58Z. Both the automated reviewer and the PR Shepherd independently confirmed the duplication and escalated it, since two Disease entries bound to one MONDO concept is invisible to CI - test_all_disorders_have_unique_names passes because the two name values differ, and there is no disease_term uniqueness test. The decision recorded by the repository owner was to keep this entry, under the shorter clinical Faden-Alkuraya name already merged and already referenced by history records, and to port the content unique to #9082 onto it rather than merge a second entry or discard the work. #9082 is closed. Ported onto this entry: a mappings block with the skos:exactMatch to MONDO:0014748 sourced to ORPHA:457395; a complete top-level references manifest covering all nine cited sources, including the three this entry already cited that the #9082 manifest did not know about (PMID:26497270, PMID:27230627, PMID:33092958); a variants section with the three curated RSPRY1 alleles c.377delT, c.516+2T>A and c.1652G>A p.(Cys551Tyr), the last carrying CADD, M-CAP, REVEL and AlphaMissense scores and a ClinVar SCV; a Harrison's classification with ORPHA-backed evidence, alongside the ISDS group this entry already carried; NCIT diagnosis terms on both diagnosis entries, NCIT:C38092 Skeletal Survey X-Ray and NCIT:C101295 Whole Exome Sequencing, chosen over the broader NCIT:C38101 because NCIT has a term for exactly that procedure; two treatments, anti-seizure pharmacotherapy with a CHEBI-bound levetiracetam agent and ophthalmologic correction; two discussions, a CONTROVERSY on whether RSPRY1 is secreted or cytoplasmic that carries paired SUPPORT and REFUTE evidence from PMID:39940902 and PMID:38562122, and a KNOWLEDGE_GAP on the absence of any animal model reproducing the dysplasia; and ten phenotypes. Deliberately not ported: the five #9082 discussions whose subject matter this entry already covered under different identifiers, the phenotypes whose HPO terms were already present or were less specific than this entry's (severe short stature against postnatal short stature, hyperlordosis against lumbar hyperlordosis), and the #9082 pathophysiology chain, which is a six-node restatement of the seven-node chain already here. The aim was to add what was missing, not to churn curation that was already sound. Two caveats in this entry's own notes were resolved rather than left standing, because the port contradicts them. The notes had recorded that an Orphanet structured record for ORPHA:457395 could not be built because the upstream bulk XML no longer matched the pinned checksum; it was in fact built during the #9082 session with just refresh-orphadata followed by just structured-rebuild-orphanet --id 457395, and data/orphadata/MANIFEST.yaml is unchanged, so there is no snapshot drift and the wider ORPHA cache was not rewritten. references_cache/ORPHA_457395.md is added by this change. The notes had also recorded that microcephaly, seizures, hypotonia and corpus-callosum thinning were omitted for want of a quotable passage; all four now have citable sources, three from the ORPHA structured record and the seizures from PMID:38562122. The head-size tension is preserved rather than flattened: the microcephaly phenotype carries the ORPHA statement as SUPPORT and the delineation series' normocephaly statement as REFUTE, with no frequency band asserted. The two deep-research reports from the #9082 session are added under research/ with their original query-derived filenames. They are the provenance for the ported variants and discussions. Both carry authentic provider frontmatter with linkml-reference-validator blocks (claude_code 6/6 references resolved, 2/2 quotes valid; openscientist 6/6 resolved, 10/11 quotes valid), and both passed the NEC preflight against MONDO:0014748 - claude_code PASS, openscientist WARN triggered only by SMAD3 mention counts, SMAD3 being the mechanistic partner rather than a rival disease entity. The #9082 history records were never merged to main, so nothing needed retargeting and no superseded_by block applies; this record is the surviving provenance for that work. Known gap worth its own issue, flagged by both the reviewer and the PR Shepherd: there is no test asserting one Disease entry per disease_term, which is why this duplication reached review rather than CI. Not addressed here, since this change is content reconciliation only. Validation: just validate passes for schema and terms; just count-verified-snippets reports 109/109 verified against cached references, up from the pre-port count. The full CI gate set was run - check_snippet_length, check_title_snippets, check_folded_hyphens, check_environmental_evidence, check_duplicate_yaml_keys over 4361 files, dismech-stubs check, term_cache_integrity, enum cache ordering and check-reference-cache-frontmatter all pass. Compliance is 92.8% global and 93.1% weighted. Cache additions are three rows: HP:0002651, HP:0034271 and NCIT:C38092. Curation was AI-assisted via claude-code; the model identifier is deliberately omitted from this record per the operating instructions for this session.

Fold in openscientist deep-research report (PR #9081) · 2026-08-20T08:03:22Z · View source

Follow-up EDIT folding in the openscientist deep-research report, which was still queued server-side when the CREATE record was written and landed afterwards (research/Spondyloepimetaphyseal_Dysplasia_Faden-Alkuraya_Type-deep-research-openscientist.md, 28 minutes, 5 autonomous iterations, 2 artifacts). Report validation as generated: 14/14 references resolved, 0 unresolved, 1/1 quoted claim valid; needs_review is true solely because 1 of 14 references (PMID:33989636, a TRIM7 B30.2 crystal-structure paper) was flagged as possibly off topic. That reference is not used here. NEC preflight on this report is WARN for the same benign reason as the claude_code one (SMAD3, the curated downstream effector, is the flagged rival gene); its OMIM check is a clean match, 616723 against the MONDO xref 616723. What was added, each independently verified against a freshly cached primary reference rather than taken from the report: 1. PMID:33092958 (TRIM/TRIM-like substrate recognition) added as PARTIAL/OTHER evidence to the rspry1_biochemical_function KNOWLEDGE_GAP. It supplies the structural argument for the E3-ligase hypothesis - PRY-SPRY is the domain most often used for substrate recognition in this family - and the explanation states plainly that this is domain analogy, not evidence about RSPRY1. 2. New OPEN_QUESTION discussion contiguous_gene_deletion_haploinsufficiency, citing PMID:27230627, a 16q12.2q21 interstitial-deletion patient whose authors proposed that loss of RSPRY1 might explain the skeletal defects. Recorded as an open question rather than as a genetic entry or modifier: SEMDFA is recessive and every reported patient is homozygous, so a single-copy contribution would be a dosage claim resting on one deletion patient's candidate-gene inference. The snippet reproduces the source's wording verbatim including its grammatical slip ("was been discovered"), and the explanation says so. This corrects an earlier judgement in the CREATE session, where PMID:27230627 was set aside as probably irrelevant on the strength of its title alone. 3. proposed_experiments added to two existing discussions - bone-lineage validation of the TGF-beta/SMAD3 mechanism in patient iPSC-derived chondrocytes/osteoblasts and skeletal phenotyping of an Rspry1-null mouse on the fibroblast_proxy_for_bone_lineage HUMAN_MODEL_MISMATCH; interactome/ubiquitination assays and endogenous-localization resolution on the rspry1_biochemical_function KNOWLEDGE_GAP. Each carries a decision_criterion stating what would and would not resolve the gap. Not taken from the report: its ClinVar variant table and gnomAD constraint metrics (pLI, LOEUF, o/e). Both are real and useful, but neither is quotable against a cached reference, so importing them would have put unverifiable numbers into the entry. Corroboration rather than new content: the report's own limitations section independently reaches all four gaps already curated in the CREATE commit - tiny evidence base, mechanism from a single fibroblast study, untested biochemical link, no animal model, no therapeutics. Validation: "just validate" passes (schema + terms + references); 88/88 snippets verified against cached references, up from 86.

Create: Spondyloepimetaphyseal Dysplasia Faden-Alkuraya Type (RSPRY1) · 2026-08-20T07:38:11Z · View source

New Mendelian entry for SEMDFA (MONDO:0014748, OMIM #616723, RSPRY1 / hgnc:29420), curated from primary literature plus a claude_code deep-research report. Deep-research providers: falcon was attempted first (the /curate default) and failed with HTTP 402 Payment Required from the Edison Scientific API, so no falcon report exists. claude_code was used instead and produced research/Spondyloepimetaphyseal_Dysplasia_Faden-Alkuraya_Type-deep-research-claude_code.md (14 web searches, 27 turns; its own reference-validation block reports 6/6 references resolved, 0 unresolved, 1/1 quoted claim valid, 6/6 on topic, needs_review not set). An openscientist run was submitted in parallel and was still queued server-side when this session finished; if it lands it can be folded in as a follow-up EDIT. NEC preflight: "just preflight-dr <report> MONDO:0014748" returns WARN, reviewed and judged benign. RSPRY1 dominates the report (53 mentions vs SMAD3 14); SMAD3 is the curated downstream effector of RSPRY1 loss, not a rival disease entity. The OMIM IDs the tool flagged as disagreeing with the MONDO xref (184250, 300106, 602271, 603546) all appear inside the report's differential-diagnosis section, and the report names OMIM #616723 as the disease's own identifier. GeneReviews: PubMed was searched for a GeneReviews chapter on RSPRY1 / SEMDFA; none exists, so no GeneReviews baseline applies. Content: a seven-node pathophysiology chain from biallelic RSPRY1 loss of function through constitutive TGF-beta/SMAD3 activation and disordered ECM dynamics to impaired endochondral ossification, progressive skeletal deformity, and a conditional craniosynostosis branch. The fibroblast-to-bone step is curated as INDIRECT_UNKNOWN_INTERMEDIATES because all functional data come from dermal fibroblasts. 31 phenotypes, 3 imaging findings, 3 progression phases, 2 diagnosis entries, 3 differential diagnoses, 3 treatments, 2 experimental models with modeled_mechanisms and readouts, and 4 discussions (2 KNOWLEDGE_GAP, 1 HUMAN_MODEL_MISMATCH, 1 EMERGING_HYPOTHESIS). Deliberate restraint: no GO molecular-function binding on the RSPRY1 node, because E3 ligase activity is inferred from domain architecture and interaction databases and has never been demonstrated. Frequency bands are given only where a snippet quantifies (5/5 or 2/2 patients); bands were withheld for small epiphyses, metaphyseal cupping, scoliosis, craniosynostosis, and every single-patient finding. Reported microcephaly, seizures, hypotonia, and corpus-callosum thinning were dropped because they could not be traced to a quotable passage in a cached primary reference, and the 2018 series states most patients were normocephalic. TGF-beta-directed therapy is recorded as an EMERGING_HYPOTHESIS discussion rather than as a treatment. An Orphanet structured record for ORPHA:457395 could not be built: the upstream Orphadata en_product1.xml no longer matches the sha256 pinned in data/orphadata/MANIFEST.yaml, and bumping that pin would rewrite the entire ORPHA cache. This is recorded in the entry notes as a separate maintenance task. Validation: "just validate" passes (schema + terms + references). "just count-verified-snippets" reports 85/85 verified against cached references. "just validate-disorders" (the batched CI-equivalent sweep, --no-full-text) passes. "just check-duplicate-keys" and "just check-title-snippets" pass. The stubs/ entry for MONDO:0014748 was deleted and "just check-stubs" passes.

Claude Code ▸

1. Disease Information

claude-haiku-4-5-20251001, claude-sonnet-5 14 citations 2026-08-20T07:23:03.002054

1. Disease Information

Overview: Spondyloepimetaphyseal dysplasia, Faden-Alkuraya type (SEMDFA) is a rare, autosomal recessive, progressive skeletal dysplasia first clinically delineated by Faden and colleagues and molecularly solved as caused by biallelic loss-of-function mutations in RSPRY1 (Ring finger and SPRY domain-containing protein 1). It is characterized by progressive vertebral (spondylo-), epiphyseal, and metaphyseal abnormalities, disproportionate short stature, a recognizable facial gestalt, short fourth (and sometimes third) metatarsals, brachydactyly with cone-shaped epiphyses, and variable intellectual disability, with craniosynostosis emerging as a recurrent — though not universal — additional feature in later reports (PMID:26365341; PMID:30063090).

Key identifiers: - OMIM: #616723 (phenotype, SEMDFA); 616585 (gene, RSPRY1) - MONDO: MONDO:0014748 - Orphanet: ORPHA:457395 - Gene (HGNC): RSPRY1, HGNC:29420, chromosome 16q13 - Inheritance:* Autosomal recessive

Synonyms: "SEMDFA"; "Spondyloepimetaphyseal dysplasia, RSPRY1-related"; "RSPRY1-related spondyloepimetaphyseal dysplasia"; occasionally described in early reports as a novel "progressive spondyloepimetaphyseal dysplasia" prior to gene identification.

Data provenance: All current knowledge derives from a small number of aggregated case-series publications (not large-cohort epidemiological or EHR-derived data). The literature comprises: (1) the original report of 4 affected siblings in a consanguineous Bedouin Saudi family plus a Peruvian simplex case identified via "matchmaking" (PMID:26365341); (2) a follow-up delineation of 5 additional patients from 2 unrelated families with craniosynostosis (PMID:30063090); (3) a 2024 report of two additional Turkish/other-origin sisters with joint dislocation as a novel feature (PMID from AJMG-A 2024, "Two sisters with RSPRY1-related spondyloepimetaphyseal dysplasia," PMC7616131/AJMG 63601); and (4) a 2025 functional/mechanistic study using patient-derived fibroblasts (PMID:39940902). Fewer than ~15 molecularly confirmed patients have been reported in total.

2. Etiology

Disease Causal Factor: SEMDFA is a monogenic disorder caused by biallelic (homozygous or compound heterozygous) loss-of-function variants in RSPRY1. There is no known environmental, infectious, or purely mechanistic (non-genetic) cause.

Genetic risk factors: - Homozygosity for pathogenic RSPRY1 variants, typically arising in the context of parental consanguinity (both the original Saudi Bedouin family and subsequent families were consanguineous or from populations with elevated consanguinity) (PMID:26365341). - Reported pathogenic alleles include: - c.377delT; p.(Ile126Argfs*) — homozygous frameshift in exon 2, predicted to trigger nonsense-mediated decay (originally reported as a 1-bp duplication/frameshift in the discovery family; re-described as c.377delT in later papers) (PMID:26365341; PMID:30063090; PMID:39940902) - A homozygous splice-site variant at the exon 4/intron 4 border (c.516+2T>A) (PMID:30063090) - A likely pathogenic homozygous missense variant identified in the Peruvian simplex case via GeneMatcher-style matchmaking (PMID:26365341) - c.1652G>A; p.(Cys551Tyr) — homozygous missense in exon 15, absent from gnomAD v3.1.2 and an in-house cohort of 3,076 exomes, with an AlphaMissense score of 0.999 and cross-species conservation of the affected cysteine (AJMG-A "Two sisters" report) - RSPRY1 has a gnomAD pLI of 1 and LOEUF of 0.45, consistent with strong intolerance to loss-of-function variation in the general population, supporting pathogenicity of truncating alleles. - No modifier genes have been reported.

Environmental risk factors: None identified; this is a purely Mendelian condition. Consanguinity increases the probability of biallelic inheritance but is a population/pedigree risk factor rather than a direct environmental cause.

Protective factors: None reported in the literature (no protective alleles or environmental protective factors described for this ultra-rare disorder).

Gene-environment interactions: None reported; no evidence of environmental modulation of phenotype severity.

Suggested ontology terms: MONDO:0014748 (disease); HGNC:29420 (gene); GENO term for autosomal recessive inheritance (GENO:0000388).

3. Phenotypes

Phenotype data are drawn from the combined case series (PMID:26365341, PMID:30063090, and the 2024 sisters report).

Craniofacial features (onset: congenital/early childhood; frequent-to-common across reported cases)

Microcephaly — HP:0000252
Broad/prominent forehead — HP:0000337
Hypertelorism — HP:0000316
Epicanthal folds — HP:0000286
Mild ptosis — HP:0000508
Strabismus / exotropia — HP:0000486
Malar hypoplasia / midface retrusion — HP:0000272 / HP:0011800
Depressed nasal bridge, short nose — HP:0005280 / HP:0003196
Full lips — HP:0012471
Low-set ears — HP:0000369
Short neck — HP:0000470
Square-shaped face reported in one proband

Skeletal — axial (progressive; worsens with age)

Platyspondyly — HP:0000926
Mild scoliosis / progressive kyphoscoliosis — HP:0002751
Lumbar lordosis — HP:0002938
Craniosynostosis — HP:0001363 (present in most but not all patients across the case series; "all patients except one were normocephalic" in the 2018 delineation cohort, indicating variable expressivity)
"Copper-beaten" skull appearance — HP:0002714

Skeletal — appendicular

Short stature, disproportionate — HP:0004322 / HP:0001510
Epiphyseal dysplasia with small/cone-shaped epiphyses — HP:0003046 / HP:0010580
Metaphyseal cupping and fraying — HP:0003026 / HP:0003026
Coxa vara — HP:0002812
Genu valgum — HP:0002857
Short 4th (and sometimes 3rd) metatarsal bone — HP:0010760
Brachydactyly / brachymesophalangy with cone-shaped epiphyses — HP:0001156
Small carpal bones — HP:0100926
Short femoral neck — HP:0100864
Pes planus — HP:0001763
Prominent heels — (no precise HP term; describe qualitatively)
Pectus deformity — HP:0000766
Joint laxity / dislocation (novel feature reported in 2024 sisters — elbow subluxation, metatarsal dislocation, "wind-swept" limb deformity) — HP:0001373 / HP:0001386
Cemento-ossifying fibrous lesion of the maxilla (reported once) — rare associated finding

Neurodevelopmental

Global developmental delay — HP:0001263
Intellectual disability, variable severity (mild to moderate) — HP:0001249
Generalized hypotonia — HP:0001290
Seizures (generalized tonic-clonic, reported in one patient) — HP:0002069
Brain imaging abnormalities: asymmetry of cerebral hemispheres, mild thinning of the corpus callosum — HP:0100542 / HP:0002079

Other

Congenital heart disease (patent ductus arteriosus reported in one proband) — HP:0001744 (PDA)

Onset: Congenital/prenatal-to-infantile recognition of facial and limb features; skeletal findings are explicitly progressive with age (worsening platyspondyly, epiphyseal/metaphyseal changes), which is a defining diagnostic feature distinguishing SEMDFA from static SEMDs.

Severity/frequency: Based on small case numbers, most craniofacial and skeletal features are reported in the majority of patients (qualitatively "frequent" to "common"), while craniosynostosis, seizures, congenital heart disease, and joint dislocation are reported in only a subset — precise percentage frequencies cannot be reliably computed from n<15 published cases; use qualitative HPO frequency terms (e.g., FREQUENT, OCCASIONAL) with caution and cite per-patient counts rather than population percentages.

Quality of life impact: Not formally studied (no EQ-5D/SF-36/QOL instrument data published); impacts are inferable from reported functional findings — short stature, joint instability, intellectual disability, and progressive spinal deformity would be expected to affect mobility, education, and independence, but this is not directly evidenced in the literature.

4. Genetic/Molecular Information

Causal gene: RSPRY1 (HGNC:29420; OMIM *616585), located at chromosome 16q13, encoding a 576-amino-acid protein.

Protein domains/function: RSPRY1 contains a RING-type (C3HC4) zinc finger domain and a SPRY/B30.2 domain, consistent with predicted E3 ubiquitin-protein ligase architecture, though at the time of its original description it was called "a hypothetical RING and SPRY domain-containing protein of unknown physiological function" (PMID:26365341). It has since been characterized as a secreted protein expressed strongly in osteoblasts and osteocytes during mid-to-late embryonic endochondral bone development (PMID:39940902).

Pathogenic variant types reported: | Variant | Type | Zygosity | Predicted consequence | Source | |---|---|---|---|---| | c.377delT; p.(Ile126fs*) | Frameshift, exon 2 | Homozygous | Nonsense-mediated decay / null allele | PMID:26365341; PMID:30063090; PMID:39940902 | | c.516+2T>A | Splice-site, intron 4 | Homozygous | Predicted aberrant splicing | PMID:30063090 | | Missense (Peruvian proband) | Missense | Homozygous | Likely pathogenic (unspecified residue) | PMID:26365341 | | c.1652G>A; p.(Cys551Tyr) | Missense, exon 15 | Homozygous | Likely pathogenic; AlphaMissense 0.999; absent from gnomAD v3.1.2 and 3,076 in-house exomes; affected Cys conserved across 5 vertebrate species | AJMG-A 2024 "Two sisters" |

Variant classification: ACMG/AMP framework applied in recent reports — missense c.1652G>A classified "likely pathogenic"; frameshift and splice variants are treated as loss-of-function/null alleles by nonsense-mediated decay.

Population frequency: RSPRY1 shows strong constraint in gnomAD (pLI = 1, LOEUF = 0.45), consistent with selection against loss-of-function variants in the general population — supportive of pathogenicity for truncating alleles but also indicating that population-level carrier frequency data for specific pathogenic alleles are not available (each reported variant is private/family-specific or found in only 1–2 unrelated families).

Somatic vs. germline: All reported variants are germline.

Functional consequences — molecular mechanism (2025 mechanistic study, PMID:39940902): - RNA-seq of patient-derived dermal fibroblasts (homozygous c.377delT) versus controls identified 456 downregulated and 545 upregulated genes (FDR p ≤ 0.001). - The most significantly enriched pathway was "TGF-β regulation of extracellular matrix" (p = 1.12 × 10⁻²⁴), with key genes including SMAD3, COL1A1, WISP1, and RUNX2. - CRISPR-Cas9 RSPRY1-knockout fibroblasts showed increased wound-healing motility that was SMAD3-dependent (abrogated in RSPRY1+SMAD3 double-knockout cells). - Exogenous TGF-β1 supplementation accelerated wound closure in control cells but had limited additional effect in RSPRY1-KO cells, suggesting endogenous TGF-β/SMAD3 signaling is already constitutively activated in RSPRY1-deficient cells. - Over 16% of differentially expressed genes were linked to SEMD-relevant phenotypes (mental retardation: 97 DEGs; microcephaly: 64 DEGs; dwarfism: 61 DEGs; short stature: 59 DEGs). - Conclusion: "RSPRY1 deficiency leads to overactivation of the TGF-β signaling pathway," disrupting extracellular-matrix dynamics required for endochondral ossification and skeletal homeostasis — providing the first mechanistic model linking RSPRY1 loss to the skeletal dysplasia phenotype.

Modifier genes: None identified.

Epigenetic information / chromosomal abnormalities: None reported for SEMDFA — this is a point-mutation/small-indel disorder, not associated with copy-number or chromosomal rearrangement etiology.

Suggested GO terms: - GO:0007179 (transforming growth factor beta receptor signaling pathway) — UPREGULATED/GAIN_OF_FUNCTION per the 2025 mechanistic data - GO:0030199 (collagen fibril organization) / GO:0030198 (extracellular matrix organization) - GO:0001503 (ossification) / GO:0060348 (bone development) - GO:0004842 (ubiquitin-protein transferase activity) — predicted RING E3 ligase activity (functionally unconfirmed)

5. Environmental Information

No environmental, lifestyle, or infectious contributing factors have been identified or are biologically plausible for this monogenic skeletal dysplasia. There is no ECTO-relevant exposure literature for SEMDFA.

6. Mechanism / Pathophysiology

Causal chain (as currently evidenced):

Trigger (molecular): Biallelic loss-of-function (or missense) variants in RSPRY1 → loss/reduction of functional RSPRY1 protein in osteoblasts/osteocytes and other cell types (fibroblasts used as a patient-accessible proxy tissue).
Molecular consequence: Loss of RSPRY1 (a putative RING/SPRY E3-ligase-like secreted regulatory protein) leads to dysregulated (overactivated) TGF-β/SMAD3 signaling, evidenced by transcriptomic enrichment of TGF-β–ECM pathway genes and by SMAD3-dependent hypermotility phenotypes in knockout fibroblasts (PMID:39940902).
Cellular consequence: Altered extracellular matrix gene expression (COL1A1, WISP1) and altered RUNX2 (a master osteoblast transcription factor) expression, implicating disrupted endochondral ossification and cell motility/matrix remodeling in growth-plate chondrocytes and osteoblasts.
Tissue-level consequence: Impaired/dysregulated growth-plate cartilage and metaphyseal bone formation → epiphyseal and metaphyseal dysplasia (cupping, fraying, cone-shaped epiphyses), vertebral body dysplasia (platyspondyly), and cranial suture abnormalities (craniosynostosis in a subset).
Organism-level consequence: Progressive short stature, skeletal deformity (scoliosis, coxa vara, genu valgum), craniofacial dysmorphism, and — via presumed CNS/neurodevelopmental involvement not yet mechanistically dissected — intellectual disability and hypotonia.

Upstream vs. downstream: RSPRY1 loss is the sole known upstream initiating lesion; TGF-β/SMAD3 pathway dysregulation is the best-characterized downstream molecular effector; skeletal dysplasia and craniosynostosis are the downstream tissue/organ phenotypes. The neurodevelopmental phenotype's mechanistic link to RSPRY1/TGF-β dysregulation has not been directly studied (a knowledge gap — RSPRY1's role in neural tissue is unexplored).

Cell types involved: Osteoblasts (CL:0000062), osteocytes (CL:0000138), growth-plate chondrocytes (CL:0000138/CL:1000320 chondrocyte of epiphyseal cartilage), dermal fibroblasts (CL:0000057, used as the experimental proxy cell type in the mechanistic study).

Biochemical/protein-level abnormality: Predicted E3-ubiquitin-ligase-like RSPRY1 loss is hypothesized to normally restrain/regulate TGF-β pathway components (e.g., via ubiquitination of a pathway member), though the direct substrate of RSPRY1's putative RING domain has not been identified — this remains an open mechanistic gap.

Molecular profiling data available: Bulk RNA-sequencing (transcriptomics) of patient fibroblasts vs. controls (PMID:39940902) is the only omics dataset published for this disease; no proteomics, metabolomics, lipidomics, single-cell, or spatial transcriptomics data exist to date.

Suggested GO/CL terms: GO:0007179 (TGFβR signaling), GO:0001501 (skeletal system development), GO:0060350 (endochondral bone morphogenesis), GO:0071711 (basement membrane organization), CL:0000062 (osteoblast), CL:0000138 (chondrocyte), CL:0000057 (fibroblast).

7. Anatomical Structures Affected

Organ/system level: - Skeletal system (primary): axial skeleton (vertebral column, skull/cranial sutures), appendicular skeleton (long bone epiphyses/metaphyses, carpals, metatarsals, phalanges) - Craniofacial skeleton: cranial sutures (craniosynostosis), facial bones (malar hypoplasia, nasal bridge) - Nervous system (secondary): brain (corpus callosum thinning, cerebral hemisphere asymmetry), reported in a subset - Cardiovascular system (secondary, isolated report): patent ductus arteriosus - Ocular system: strabismus, ptosis (extraocular muscles/lids)

Tissue/cell level: - Growth plate cartilage (epiphyseal/metaphyseal chondrocytes) - Bone (osteoblasts, osteocytes) - Cranial suture mesenchyme/osteogenic fronts - Dermal fibroblasts (studied ex vivo as disease model)

Subcellular level: Not directly studied; RSPRY1 is predicted to be secreted, implicating extracellular/ECM compartments (GO:0005576 extracellular region) rather than a specific organelle.

Localization/UBERON terms: - UBERON:0002481 (bone tissue), UBERON:0002050 (growth plate cartilage), UBERON:0001130 (vertebral column), UBERON:0003128 (cranial suture), UBERON:0002417 (skull), UBERON:0002423 (metatarsal bone)

Lateralization: Generally bilateral/symmetric skeletal involvement (as with most systemic skeletal dysplasias); no reports of unilateral or strongly asymmetric skeletal findings, though cerebral hemisphere asymmetry has been noted on brain imaging in one report.

8. Temporal Development

Onset: Congenital-to-infantile. Facial dysmorphism and short stature are typically recognized in early childhood; skeletal radiographic abnormalities (platyspondyly, metaphyseal changes) are present from early life but are explicitly described as progressive.
Onset pattern: Insidious/chronic — this is not an acute-onset condition.
Progression: Skeletal deformities (scoliosis, epiphyseal/metaphyseal changes) worsen with growth; the disorder is described in its founding publication as a "progressive spondyloepimetaphyseal dysplasia," distinguishing it from static/non-progressive SEMD entities.
Disease course pattern: Chronic, progressive, non-remitting; no spontaneous or treatment-induced remission has been described.
Disease duration: Lifelong; no natural history data on adult outcomes, life expectancy, or long-term progression beyond childhood/adolescence have been published (a significant literature gap, given the small number of reported patients and their young ages at publication).
Critical periods: Not formally defined, though early recognition (facial gestalt + short 4th metatarsal + progressive spine/epiphyseal changes) is emphasized in the 2015 and 2018 papers as the basis for clinical diagnosis prior to genetic confirmation.

9. Inheritance and Population

Inheritance pattern: Autosomal recessive (GENO:0000388), consistent across all reported families, several of which were consanguineous.
Penetrance: Appears complete among biallelic carriers in reported families (all homozygotes/compound heterozygotes were symptomatic), though with variable expressivity — e.g., craniosynostosis and seizures present in only a subset of patients ("all patients except one were normocephalic" in the 2018 cohort).
Expressivity: Variable — severity and specific feature combinations (craniosynostosis, joint dislocation, seizures, congenital heart disease) differ between and within families.
Genetic anticipation: Not applicable/not reported (not a repeat-expansion disorder).
Germline mosaicism: Not reported.
Founder effects: Not formally established, but the discovery family (consanguineous Bedouin Saudi) and subsequent Turkish (Simsek-Kiper et al., Hacettepe University) and Peruvian families suggest the condition has been identified across multiple, geographically/ethnically distinct populations rather than being confined to a single founder population; each reported family carries a distinct (private) pathogenic variant.
Consanguinity: Plays a central role — most reported families are consanguineous, consistent with autosomal recessive inheritance of a rare allele.
Carrier frequency: Not established in the general population (no population-based carrier screening data); RSPRY1's gnomAD constraint metrics (pLI=1, LOEUF=0.45) indicate the gene is intolerant of loss-of-function variation, but specific carrier frequencies for the known pathogenic alleles are not published.

Epidemiology: - Prevalence/Incidence: Not established — this is an ultra-rare disorder with fewer than ~15 molecularly confirmed cases published to date across 4 case reports/series (PMID:26365341 [5 cases: 4 sibs + 1 Peruvian]; PMID:30063090 [5 cases, 2 families]; 2024 AJMG-A report [2 sisters]; the 2025 mechanistic paper reused patient cells from the original cohort). No population prevalence estimate (e.g., Orphanet prevalence class) has been established; classify as prevalence_class: NOT_YET_DOCUMENTED or ULTRA_RARE and measure_type: CASES_IN_LITERATURE.

Population demographics: - Affected populations: Reported in families of Saudi Bedouin, Turkish, and Peruvian origin, indicating no single predominant ethnic association beyond the general enrichment of autosomal recessive disease in consanguineous populations. - Geographic distribution: Saudi Arabia (discovery family), Turkey (Hacettepe University cohort, 2018 delineation and 2025 mechanistic paper), Peru (simplex case), and additional unspecified origin in the 2024 sisters report. - Sex ratio: Both males and females affected across reported families (consistent with autosomal — not sex-linked — inheritance); no skew reported. - Age distribution: All reported patients are pediatric (ages from early childhood to adolescence at publication); no adult-onset diagnoses or long-term adult follow-up published.

10. Diagnostics

Clinical/radiographic tests (primary diagnostic modality given rarity): - Skeletal survey/radiography: Platyspondyly, "copper-beaten" skull appearance, metaphyseal cupping/fraying, cone-shaped epiphyses, coxa vara, genu valgum, short 4th metatarsal, small carpal bones — these radiographic findings, combined with the facial gestalt, form the basis of clinical suspicion prior to molecular confirmation (PMID:26365341; PMID:30063090). - Cranial imaging (CT/plain film): To assess craniosynostosis when present. - Brain MRI: Reported to show cerebral hemisphere asymmetry and mild corpus callosum thinning in a subset. - Echocardiography: Indicated given at least one reported case of PDA.

Genetic testing (definitive diagnosis): - Recommended approach: Given the rarity and lack of a commercial single-gene/panel-first pathway, diagnosis has been achieved via whole-exome sequencing (WES) in a consanguineous-family/autozygosity-mapping framework (homozygosity mapping combined with WES was the strategy in the discovery family) or targeted Sanger sequencing of RSPRY1 once a family's causal gene is suspected/confirmed. - Skeletal dysplasia gene panels: RSPRY1 is included in some commercial skeletal dysplasia and craniosynostosis gene panels (e.g., Invitae Skeletal Disorders Panel; Genomics England PanelApp "Rare syndromic craniosynostosis or isolated multisuture synostosis" panel). - Chromosomal microarray/karyotype: Not informative (RSPRY1 disease is due to point mutations/small indels, not CNVs); not part of the diagnostic algorithm beyond ruling out other differentials. - Family/matchmaking approaches: The original description of a second (Peruvian) family was made possible through gene-based matchmaking (e.g., GeneMatcher-style) connecting independently sequenced exomes sharing RSPRY1 variants — an important methodological note for this ultra-rare disease (PMID:26365341).

Differential diagnosis: Other spondyloepimetaphyseal dysplasias, notably: - SEMD, Strudwick type (COL2A1; OMIM #184250) - SEMD with joint laxity, type 2 (KIF22; OMIM #603546) — distinguished by leptodactylic (slender) rather than brachydactylic digits and joint laxity/dislocation as a core (not incidental) feature - SEMD, X-linked (OMIM #300106) - Axial spondylometaphyseal dysplasia (C21orf2; OMIM #602271) — distinguished by retinal dystrophy - Other craniosynostosis syndromes when craniosynostosis is prominent

Screening: No newborn screening, carrier screening panel, or population screening program exists for this ultra-rare disorder; genetic counseling for consanguineous families with an affected child is the primary "screening" relevant to recurrence risk (25% recurrence risk per pregnancy for carrier parents).

11. Outcome/Prognosis

Survival/mortality: No mortality has been reported in the published cohorts; there are no survival statistics, life-expectancy data, or disease-specific mortality figures available, reflecting both the rarity of the condition and the young age of reported patients.
Morbidity: Morbidity centers on progressive skeletal deformity (scoliosis, joint malalignment, short stature) and, in a subset, intellectual disability, seizures, and craniosynostosis-related complications (which, if untreated, can raise intracranial pressure).
Quality of life: Not formally measured; can be inferred to be affected by mobility limitations, orthopedic complications, and developmental delay, but no validated QOL instrument data exist.
Complications: Progressive scoliosis/kyphoscoliosis, coxa vara, joint dislocation/instability (elbow, metatarsal — newly reported feature), craniosynostosis-related complications, and in a subset, seizures and congenital heart disease.
Recovery potential: This is a progressive, non-reversible skeletal dysplasia; there is no described mechanism of spontaneous improvement. Orthopedic and craniofacial surgical interventions (where performed, e.g., craniosynostosis correction) address complications rather than the underlying disease process.
Prognostic factors: No formal prognostic biomarkers or predictors of disease severity have been identified; genotype-phenotype correlation is limited by small case numbers (e.g., it is not yet clear whether frameshift/null alleles produce more severe phenotypes than the missense alleles reported).

12. Treatment

There is no disease-specific or targeted pharmacotherapy for SEMDFA; management is supportive and multidisciplinary, following general skeletal dysplasia care principles (inferred from the disorder's classification as a skeletal dysplasia, though the literature reviewed does not describe a dedicated management protocol specific to RSPRY1-SEMDFA):

Orthopedic surgical management: Correction of scoliosis, coxa vara, genu valgum, and joint instability/dislocation as clinically indicated (NCIT:C15329 Surgical Procedure; NCIT:C16186 Orthopedic Surgical Procedure).
Craniofacial surgery: Craniosynostosis correction where present (NCIT:C15329).
Cardiac management: Standard care for congenital heart disease (e.g., PDA closure) when present.
Neurodevelopmental support: Early intervention, special education, physical/occupational/speech therapy for developmental delay and intellectual disability (NCIT:C15302 Physical Therapy; NCIT:C121351 Occupational Therapy; NCIT:C159273 Speech Therapy).
Seizure management: Standard antiepileptic pharmacotherapy where seizures occur (NCIT:C15986 Pharmacotherapy).
Genetic counseling: Recommended for families, particularly given the autosomal recessive inheritance and consanguinity association (NCIT:C15240 Genetic Counseling).

Emerging/experimental therapeutic rationale: The 2025 mechanistic study (PMID:39940902) identifying SMAD3-dependent TGF-β pathway overactivation as a downstream consequence of RSPRY1 loss suggests that TGF-β pathway-targeted therapies (e.g., TGF-β/SMAD3 inhibitors, by analogy to their investigational use in other connective tissue/skeletal disorders such as Marfan syndrome) represent a plausible, but entirely untested, future therapeutic direction. The authors explicitly frame their findings as identifying "potential therapeutic targets within TGF-β signaling for treating skeletal dysplasias," but no clinical trials, drug candidates, or NCT-registered studies exist for SEMDFA specifically.

Experimental treatments in clinical trials: None identified (no ClinicalTrials.gov entries specific to RSPRY1-SEMDFA were found).

13. Prevention

Primary prevention: Not applicable in the traditional sense (this is a genetic, not preventable, disorder); the closest analog is reproductive genetic counseling for consanguineous couples or known carrier couples, including discussion of prenatal testing (chorionic villus sampling/amniocentesis for RSPRY1 variant testing once a familial variant is known) and preimplantation genetic testing (PGT) as options.
Secondary prevention: Early clinical recognition (facial gestalt, short 4th metatarsal, skeletal survey) to enable early genetic confirmation and initiation of surveillance (e.g., serial spine imaging for scoliosis progression, cranial imaging surveillance for craniosynostosis) — this constitutes early detection rather than disease prevention.
Tertiary prevention: Proactive orthopedic/craniofacial surveillance and timely surgical intervention to prevent secondary complications (e.g., preventing neurological compromise from untreated craniosynostosis or progressive scoliosis).
Genetic counseling: Central to family planning for at-risk (carrier) couples, given the 25% recurrence risk for autosomal recessive inheritance.
Population/public health interventions: None specific (not applicable to this ultra-rare monogenic disorder); no vaccine, environmental, or public-health-level intervention is relevant.

14. Other Species / Natural Disease

Taxonomy: RSPRY1 orthologs exist across vertebrates (NCBI Taxon comparisons implied by cross-species conservation analysis of the p.Cys551Tyr residue across 5 vertebrate species in the 2024 AJMG-A report), but no naturally occurring RSPRY1-related skeletal dysplasia has been reported in any non-human species (no OMIA entry identified in this research pass).
Orthologous gene: Mouse ortholog Rspry1 (MGI:1914860); human RSPRY1 (NCBI Gene, HGNC:29420).
Comparative biology/veterinary relevance: Not established; no veterinary case reports or naturally occurring animal disease models were found in this research.
Zoonotic potential: Not applicable (non-infectious, monogenic disorder).

15. Model Organisms

Mouse models: Targeted knockout alleles of Rspry1 exist in mouse repositories — Rspry1^tm1Lex^ (MGI:5007310) and Rspry1^tm1(KOMP)Wtsi^ (MGI:4419609) — generated as part of large-scale knockout mouse programs (Lexicon/KOMP), and the gene has an active International Mouse Phenotyping Consortium (IMPC) entry (MGI:1914860). However, detailed published phenotyping data specifically characterizing skeletal, craniofacial, or neurodevelopmental phenotypes recapitulating human SEMDFA in these mouse lines were not identified in this research pass — this represents a notable gap: no peer-reviewed report of an Rspry1-knockout mouse skeletal phenotype was found, despite the alleles existing in repositories. (This should be flagged as a HUMAN_MODEL_MISMATCH/KNOWLEDGE_GAP-type consideration if used for curation: allele exists, but recapitulation status is unconfirmed pending IMPC phenotyping data review.)
Cellular/in vitro models: The best-characterized "model system" for this disease is patient-derived dermal fibroblasts, used in the 2025 study (PMID:39940902) alongside CRISPR-Cas9-generated isogenic RSPRY1-knockout and RSPRY1+SMAD3 double-knockout fibroblast lines (>90% knockout efficiency), which recapitulated key molecular features (TGF-β/ECM pathway dysregulation, SMAD3-dependent hypermotility) and served as the functional validation system for the TGF-β mechanistic hypothesis.
Model characteristics/limitations: Fibroblasts are a patient-accessible surrogate cell type, not the primary disease-relevant cell type (osteoblasts/chondrocytes); the study explicitly notes RSPRY1 is normally concentrated in osteoblasts and osteocytes during embryonic skeletal development, so fibroblast-based findings, while mechanistically informative (TGF-β/SMAD3 activation), have translational-fidelity limitations for the skeletal phenotype and have not yet been confirmed in bone-lineage cells or an animal model — an appropriate candidate for a HUMAN_MODEL_MISMATCH discussion in curation.
Applications: The fibroblast/CRISPR-KO system enables study of RSPRY1's role in TGF-β/SMAD3 signaling and cell motility/ECM regulation, and could support future drug-repurposing or TGF-β-pathway-inhibitor screening relevant to skeletal dysplasia mechanisms.
Resources: MGI (MGI:1914860), IMPC (mousephenotype.org gene page for Rspry1), Taconic Biosciences (Rspry1 knockout mouse research model listing).

Summary of Key Primary Citations

PMID	Citation	Contribution
26365341	Faden M et al., Am J Hum Genet 2015;97(4):608-615	Original description; WES + autozygome mapping identifies RSPRY1 frameshift in 4-sib Saudi family + Peruvian matchmaking case
30063090	Simsek-Kiper PÖ et al., Am J Med Genet A 2018;176(9):2009-2016	Further delineation in 5 patients/2 families; establishes craniosynostosis, cono-brachydactyly as recurrent features; new frameshift (c.377delT) and splice (c.516+2T>A) variants
(AJMG-A 2024, "Two sisters with RSPRY1-related SEMD," Singh et al.)	Am J Med Genet A 2024	Two additional sisters; novel p.(Cys551Tyr) missense variant; joint dislocation described as a novel clinical feature
39940902	Int J Mol Sci 2025;26(3):1134	Mechanistic study: patient fibroblast transcriptomics + CRISPR knockout demonstrate RSPRY1 loss drives SMAD3-dependent TGF-β pathway overactivation

Data gaps for curation to flag explicitly: No established population prevalence; no adult natural-history/long-term outcome data; no confirmed in vivo (mouse) skeletal phenotype recapitulation despite existing knockout alleles; no disease-specific treatment trials; genotype-phenotype correlation (frameshift/null vs. missense) not yet established given small case numbers.

Sources: - Entry - #616723 - SPONDYLOEPIMETAPHYSEAL DYSPLASIA, FADEN-ALKURAYA TYPE; SEMDFA - OMIM - Entry - *616585 - RING FINGER- AND SPRY DOMAIN-CONTAINING PROTEIN 1; RSPRY1 - OMIM - Identification of a Recognizable Progressive Skeletal Dysplasia Caused by RSPRY1 Mutations - PMC (PMID:26365341) - Further delineation of spondyloepimetaphyseal dysplasia Faden-Alkuraya type - PubMed (PMID:30063090) - Two sisters with RSPRY1-related spondyloepimetaphyseal dysplasia - PMC - Unraveling the Role of RSPRY1 in TGF-β Pathway Dysregulation - PMC (PMID:39940902) - Spondyloepimetaphyseal Dysplasia, Faden-Alkuraya Type - MalaCards - RSPRY1 gene - GeneCards - RSPRY1 ring finger and SPRY domain containing 1 - NIH Genetic Testing Registry (GTR) - Gene: RSPRY1 - Genomics England PanelApp (Rare syndromic craniosynostosis panel) - RSPRY1 curation results - ClinGen - Rspry1 MGI Mouse Gene Detail - MGI:1914860 - Rspry1 - IMPC - Rspry1 Targeted Allele Detail - MGI:5007310

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Spondyloepimetaphyseal Dysplasia, Faden-Alkuraya Type (SEMDFA): A Comprehensive Disease Characteristics Report

openscientist-autonomous 10 citations 2026-08-20T07:46:45.615889

Spondyloepimetaphyseal Dysplasia, Faden-Alkuraya Type (SEMDFA): A Comprehensive Disease Characteristics Report

Disease: Spondyloepimetaphyseal Dysplasia, Faden-Alkuraya Type (SEMDFA) MONDO ID: MONDO:0014748 | OMIM: #616723 | Orphanet: ORPHA:457395 Causal Gene: RSPRY1 (Ring Finger and SPRY Domain Containing 1), 16q13 Category: Mendelian (autosomal recessive)

Summary

Spondyloepimetaphyseal dysplasia, Faden-Alkuraya type (SEMDFA) is an ultra-rare, autosomal-recessive skeletal dysplasia first delineated in 2015 and caused by biallelic loss-of-function variants in RSPRY1, a gene on chromosome 16q13 encoding a 576-amino-acid secreted protein that contains an N-terminal RING (Really Interesting New Gene) domain and a C-terminal B30.2/SPRY (PRY-SPRY) domain. The disease is defined clinically by a recognizable constellation of progressive spondyloepimetaphyseal dysplasia, disproportionate short stature, facial dysmorphism, short (fourth) metatarsals and cono-brachydactyly, craniosynostosis, and variable intellectual disability. Consanguinity is the principal risk factor, and all reported families to date derive from consanguineous or founder backgrounds (Saudi Arabian, Turkish, Peruvian, Indian).

Mechanistically, the most important recent advance is the demonstration that RSPRY1 deficiency causes constitutive, SMAD3-dependent activation of TGF-β signaling with dysregulated extracellular-matrix (ECM) dynamics. Transcriptomic profiling of patient fibroblasts showed significant enrichment of TGF-β and ECM pathways; RSPRY1-knockout fibroblasts exhibited enhanced motility that was abolished by concurrent SMAD3 knockout, and RSPRY1-deficient cells responded poorly to exogenous TGF-β — the signature of a pathway already maximally (constitutively) activated. This places SEMDFA within the broader family of TGF-β–dysregulated skeletal dysplasias and nominates TGF-β/SMAD3 inhibition as a rational, though still entirely experimental, therapeutic hypothesis.

RSPRY1 is one of the more constrained genes in the human genome (gnomAD pLI ≈ 1.0; LOEUF 0.45; missense Z = 4.05), consistent with strong purifying selection against both loss-of-function and missense variation, and with the severe developmental phenotype produced by complete loss of function. The variant spectrum spans frameshift, nonsense, canonical splice-site, and missense alleles, plus large 16q contiguous-gene deletions that encompass RSPRY1 and produce overlapping skeletal features. There is currently no disease-specific therapy; management is supportive (orthopedic correction of coxa vara/genu valgum, developmental support, monitoring for craniosynostosis) and prevention relies on genetic counseling with carrier and prenatal/preimplantation testing in at-risk families.

Key Findings

Finding 1 — SEMDFA is an autosomal-recessive dysplasia caused by biallelic loss-of-function RSPRY1 variants

SEMDFA was established as a distinct, recognizable Mendelian entity by Faden and colleagues in 2015 using combined autozygome/exome analysis. In a consanguineous Saudi family with four affected siblings, they identified a homozygous frameshift mutation in RSPRY1 resulting in nonsense-mediated mRNA decay (NMD) — i.e., a true null allele — and confirmed the locus in an independent simplex Peruvian case carrying a homozygous missense variant. The original report noted: "Combined autozygome/exome analysis identified a homozygous frameshift mutation in RSPRY1 with resulting nonsense-mediated decay" (PMID: 26365341).

The recessive loss-of-function mechanism has been reproduced across multiple independent families and variant classes:

Study	Family origin	Variant(s)	Type	Patients
Faden et al. 2015 (PMID: 26365341)	Saudi (consanguineous)	Homozygous frameshift → NMD	Frameshift/null	4 siblings
Faden et al. 2015	Peruvian (simplex)	Homozygous missense	Missense	1
Simsek-Kiper et al. 2018 (PMID: 30063090)	Two families	c.377delT p.Ile126fs*; c.516+2T>A (splice)	Frameshift; splice	5
Singh et al. 2024 (PMID: 38562122)	Two sisters	c.1652G>A p.(Cys551Tyr)	Missense	2

Simsek-Kiper et al. reported: "Whole exome sequencing revealed a novel homozygous [c.377delT] [p.Ile126fs*] frameshift mutation at exon 2 in one family, while Sanger sequencing revealed a novel homozygous splice site mutation [c.516+2T>A] at exon 4/intron 4 border of RSPRY1 in the other family" (PMID: 30063090). The convergence of frameshift, nonsense, splice, and missense variants — all homozygous, all in consanguineous or founder settings — firmly supports a loss-of-function, autosomal-recessive disease model. OMIM assigns the disease number #616723; RSPRY1 (HGNC:29420; NCBI Gene 89970) maps to chromosome 16q13.

Finding 2 — Core clinical phenotype: progressive spondyloepimetaphyseal dysplasia with short stature, facial dysmorphism, cono-brachydactyly, and intellectual disability

The phenotype is remarkably consistent across all reported cohorts. The original description defined the syndrome as "comprising progressive spondyloepimetaphyseal dysplasia, short stature, facial dysmorphism, short fourth metatarsals, and intellectual disability" (PMID: 26365341).

Simsek-Kiper et al. (n = 5) provided the most detailed radiographic delineation, defining the skeletal hallmarks as: "(a) mild spondylar dysplasia, (b) epimetaphyseal dysplasia of the long bones associated with coxa vara and genu valgum, (c) brachymesophalangy with cone-shaped epiphyses, and (d) craniosynostosis" (PMID: 30063090). They additionally documented pes planus, prominent heels, pectus deformity, and — notably — a cemento-ossifying fibrous lesion of the maxilla in one patient.

Singh et al. (2024) further expanded the spectrum, reporting joint dislocation as a novel clinical feature: "We observed joint dislocation as a novel clinical feature of this condition" (PMID: 38562122), alongside vertebral defects, small epiphyses, and metaphyseal cupping/fraying.

Suggested HPO-annotated phenotype profile:

Phenotype	HPO term	Onset / character	Frequency
Progressive spondyloepimetaphyseal dysplasia	HP:0002762 (SEMD spectrum)	Congenital→childhood, progressive	Universal
Short stature (often disproportionate)	HP:0004322	Childhood, progressive	Universal
Facial dysmorphism	HP:0001999	Congenital	Universal
Intellectual disability (variable)	HP:0001249	Childhood	Most (variable)
Short (fourth) metatarsals	HP:0004689	Childhood	Common
Brachydactyly / brachymesophalangy	HP:0001156 / HP:0005831	Childhood	Common
Cone-shaped epiphyses	HP:0010579	Childhood	Common
Craniosynostosis	HP:0001363	Congenital/early	Reported cohort
Coxa vara	HP:0002812	Progressive	Common
Genu valgum	HP:0002857	Childhood	Common
Mild spondylar/vertebral dysplasia	HP:0000925	Progressive	Common
Metaphyseal cupping/fraying	HP:0003023 / HP:0003021	Childhood	Reported (Singh 2024)
Pectus / pes planus	HP:0000766 / HP:0001763	Childhood	Reported
Joint dislocation	HP:0001373	Childhood	Novel (Singh 2024)

Severity is best characterized as moderate-to-severe and progressive for the skeletal component, with variable intellectual disability. Cumulative published patients number ~11 across 5 families, so robust per-phenotype frequency percentages are not available; the features above are qualitatively consistent ("core") versus variable/expanding.

Finding 3 — RSPRY1 deficiency dysregulates TGF-β/SMAD3 signaling and ECM dynamics (the molecular mechanism)

The pivotal mechanistic study is Imren et al. 2025 (Int J Mol Sci), which performed transcriptomic analysis of fibroblasts from patients with homozygous RSPRY1 mutations. They reported: "Transcriptome analysis of fibroblasts from patients with homozygous RSPRY1 mutations showed there was significant enrichment of transforming growth factor beta (TGF-β) signaling and ECM-related pathways" (PMID: 39940902).

Two functional experiments establish the causal, SMAD3-dependent nature of the mechanism:

Epistasis / motility rescue: "RSPRY1 knockout fibroblasts exhibited enhanced motility, a phenotype that was abrogated in RSPRY1 + SMAD3 double knockout fibroblasts, highlighting the SMAD3-dependence of RSPRY1's effects" (PMID: 39940902). The rescue of the cellular phenotype by removing SMAD3 places SMAD3 genetically downstream of RSPRY1 loss.
Constitutive activation: "The observed limited response to exogenous TGF-β in RSPRY1-deficient cells indicated that there was constitutive pathway activation" (PMID: 39940902). A blunted response to added ligand is the hallmark of a pathway already operating near its ceiling.

Together these define the disease as one of de-repressed / constitutive TGF-β–SMAD3 signaling, consistent with the well-established role of TGF-β superfamily signaling in chondrocyte proliferation/differentiation and endochondral ossification, and consistent with the observed epimetaphyseal (growth-plate) pathology.

Suggested GO / pathway terms: GO:0007179 (transforming growth factor beta receptor signaling pathway); GO:0060395 (SMAD protein signal transduction); GO:0030198 (extracellular matrix organization); GO:0001958 (endochondral ossification); GO:0002062 (chondrocyte differentiation); Reactome R-HSA-170834 (Signaling by TGF-β Receptor Complex).

Finding 4 — Genomic context (16q12.2–q21), contiguous-gene deletions, and skeletal-muscle expression

RSPRY1 lies within the 16q12.2–q21 region. Yamamoto et al. (2016) described a patient with a 16q12.2q21 interstitial deletion encompassing RSPRY1 who presented with developmental delay, epilepsy, short stature, and distinctive features, and proposed: "Because RSPRY1 was been discovered as the cause of progressive skeletal dysplasia, a loss of this gene might explain the skeletal defects observed in the patient" (PMID: 27230627). This supports a contribution of RSPRY1 to the skeletal component of larger copy-number syndromes, while the full recessive disease requires biallelic loss.

At the expression level, Waddell et al. (2016) showed that Rspry1 is expressed in skeletal muscle and is transcriptionally regulated during muscle wasting: "Nip30 and Rspry1 were transcriptionally induced in response to neurogenic muscle wasting in mice and were also found to be expressed endogenously at the RNA and protein level in C2C12 mouse muscle cells" (PMID: 26497270). These two genes share a regulatory region with a conserved MyoD1-bound E-box enhancer.

The tissue relevance to bone is anchored by the original report's immunolocalization data: "we detect strong RSPRY1 protein localization in murine embryonic osteoblasts and periosteal cells during primary endochondral ossification, consistent with a role in bone development" (PMID: 26365341).

Finally, Jacob et al. (2025), a cohort of 248 Indians with skeletal dysplasia (73.6% diagnostic yield; 60% autosomal recessive; 35% consanguinity), expanded the genotype/phenotype spectrum, listing RSPRY1 among rarely reported conditions confirmed in their cohort: "We expand the phenotypic and genotypic spectrum of rarely reported conditions (RAB33B, TRIP11, NEPRO, RPL13, COL27A1, PTHR1, EXOC6B, PRKACA, FUZ and RSPRY1)" (PMID: 39706863).

Finding 5 — Authoritative identifiers and RSPRY1 protein annotation

Cross-referenced ontology identifiers: MONDO:0014748 ("progressive spondyloepimetaphyseal dysplasia-short stature-short fourth metatarsals-intellectual disability syndrome"); OMIM #616723; Orphanet ORPHA:457395; GARD 0017808; UMLS C5568882; MedGen 1800305. Common synonyms: SEMDFA; "spondyloepimetaphyseal dysplasia, Faden-Alkuraya type"; "RSPRY1-associated SEMD with cono-brachydactyly and craniosynostosis."

The RSPRY1 protein corresponds to UniProt Q96DX4 (RSPRY_HUMAN), is 576 amino acids long, is annotated with a Secreted subcellular localization, and contains a B30.2/SPRY domain (≈ residues 300–483) and an N-terminal RING domain. The original report described it as "a hypothetical RING and SPRY domain-containing protein of unknown physiological function" (PMID: 26365341). The RING + PRY/SPRY architecture is shared with the TRIM (tripartite-motif) family of E3 ubiquitin ligases and substrate-recognition proteins, in which PRY-SPRY is the domain "most frequently used for substrate recognition" (PMID: 33092958) — a plausible structural basis for RSPRY1 acting as a ubiquitin-ligase/adaptor that normally restrains TGF-β signaling.

Finding 6 — Expanded pathogenic variant spectrum from ClinVar

ClinVar (reference transcript NM_133368.3) contains ~244 RSPRY1 variant records, of which ~31 are classified pathogenic/likely pathogenic. Beyond the published case-report alleles, curated pathogenic/likely-pathogenic small variants include:

Variant (cDNA)	Protein	Class	Classification
c.109del	p.Ala37fs	Frameshift	Pathogenic
c.358G>T	p.Glu120Ter	Nonsense	Pathogenic
c.1422T>A	p.Cys474Ter	Nonsense	Pathogenic
c.1279dup	p.Thr427fs	Frameshift	Pathogenic
c.121G>T	p.Gly41Cys	Missense	Pathogenic/LP
c.901+3_901+15del / c.901_901+15del	—	Splice-region	Conflicting/uncertain
c.1652G>A	p.(Cys551Tyr)	Missense	Pathogenic (Singh 2024)

The published missense allele was confirmed clinically: "harbored a homozygous missense variant c.1652G>A;p.(Cys551Tyr) in the RSPRY1 gene" (PMID: 38562122). Many additional pathogenic ClinVar entries are large 16q contiguous-gene copy-number gains/losses (e.g., 16q13-21 deletions) spanning RSPRY1. Nearly all point variants are germline and homozygous; no somatic disease association is reported.

Finding 7 — RSPRY1 is highly constrained in the general population

gnomAD constraint metrics (GRCh38; Ensembl ENSG00000159579) indicate strong purifying selection:

Metric	Value	Interpretation
pLI	0.9995	Extremely LoF-intolerant
Observed/expected LoF (o/e)	0.315 (90% CI 0.226–0.446)	~68% depletion of LoF
LOEUF	0.446	High constraint
LoF Z	4.97	Strong LoF depletion
Missense Z	4.05	Significant missense depletion
Synonymous Z	0.95	Neutral (as expected)

The strong depletion of both LoF and missense variation is consistent with a gene whose complete biallelic loss produces a severe developmental disorder, supports the pathogenicity of the reported missense alleles, and explains the near-absence of biallelic LoF in the general population. Heterozygous carriers are clinically unaffected (recessive disease); the constraint reflects gene essentiality/selection at the population level.

Mechanistic Model / Interpretation

The findings assemble into a coherent causal chain from genotype to skeletal phenotype:

  Biallelic LoF in RSPRY1 (frameshift / nonsense / splice / missense; or 16q CNV)
│
▼
  Loss of functional RSPRY1 protein (RING + B30.2/SPRY; annotated Secreted;
  expressed in embryonic osteoblasts, periosteal cells, growth-plate region)
│
▼
  De-repression of TGF-β signaling  ──►  Constitutive, SMAD3-dependent
  pathway activation (blunted response to exogenous TGF-β)
│
▼
  Dysregulated ECM organization + enhanced fibroblast motility
  (rescued by SMAD3 knockout → SMAD3 is downstream effector)
│
▼
  Disturbed endochondral ossification & growth-plate biology
│
▼
  Spondylo- (vertebral) + epi- + metaphyseal dysplasia, coxa vara/genu valgum,
  cono-brachydactyly, short metatarsals, craniosynostosis, short stature
  (+ variable intellectual disability, joint dislocation)

Upstream vs downstream: The upstream trigger is loss of RSPRY1 function. The proximate downstream event is constitutive TGF-β/SMAD3 activation; SMAD3 sits genetically downstream (its removal rescues the RSPRY1-null cellular phenotype). ECM dysregulation and abnormal cell motility are further downstream cellular readouts, and disturbed endochondral ossification is the tissue-level consequence that yields the clinical skeletal dysplasia.

Cell types and structures involved: osteoblasts (CL:0000062), chondrocytes (CL:0000138), preosteoblasts (CL:0007010), periosteal/perichondrial cells, and fibroblasts (CL:0000057) — the last being the experimental system in which the mechanism was established. Anatomically the disease targets the growth plate / metaphysis and epiphysis of long bones (UBERON:0006588 epiphyseal plate; UBERON:0004421 metaphysis; UBERON:0006755 epiphysis), the vertebral column (UBERON:0001130), the cranial sutures (UBERON:0007842) via craniosynostosis, and the hands/feet (short metatarsals, brachydactyly). Subcellular compartments implicated include the extracellular/secreted space (GO:0005576; GO:0031012 extracellular matrix) and, given the RING/SPRY architecture, potentially the ubiquitin–proteasome machinery (GO:0004842 ubiquitin-protein transferase activity) — the latter unconfirmed for RSPRY1.

Why the RING/SPRY architecture matters: RSPRY1 shares its domain layout with TRIM-family E3 ubiquitin ligases, in which the PRY-SPRY (B30.2) domain is the principal substrate-recognition module (PMID: 33092958). A parsimonious hypothesis — not yet directly demonstrated for RSPRY1 — is that RSPRY1 normally ubiquitinates or otherwise restrains a component of the TGF-β/SMAD3 cascade; its loss removes that brake, producing constitutive signaling. Note that the UniProt "Secreted" annotation sits in apparent tension with a classic intracellular E3-ligase role; resolving this is a key open question.

Section-by-Section Disease Characteristics

1. Disease Information

SEMDFA is an ultra-rare autosomal-recessive skeletal dysplasia characterized by progressive spondyloepimetaphyseal dysplasia, short stature, facial dysmorphism, cono-brachydactyly/short metatarsals, craniosynostosis, and variable intellectual disability. It was first delineated in 2015 in a consanguineous Saudi family and named after the lead investigators Faden and Alkuraya. Identifiers: MONDO:0014748; OMIM #616723; ORPHA:457395; GARD 0017808; UMLS C5568882; MedGen 1800305. ICD-10 maps only to the non-specific Q77.8 (osteochondrodysplasia); no specific MeSH term exists (indexed under "Osteochondrodysplasias"). Synonyms: SEMDFA; spondyloepimetaphyseal dysplasia, Faden-Alkuraya type; "RSPRY1-associated SEMD with cono-brachydactyly and craniosynostosis." Information is derived from individual patient case reports (~11 patients aggregated from 5 families), not from population-level EHR or registry resources.

2. Etiology

Primary cause: biallelic loss-of-function variants in RSPRY1 (purely genetic; Mendelian recessive). Genetic risk factors: homozygous/compound-heterozygous LoF RSPRY1 alleles; the gene is highly constrained (pLI ≈ 1.0). Environmental risk factors: none identified; the dominant non-genetic contributor to risk is consanguinity (family structure), which increases homozygosity for founder alleles. Protective factors / gene-environment interactions: none established; not applicable to a fully penetrant recessive Mendelian disorder.

3. Phenotypes

See Finding 2 table for the full HPO-annotated phenotype list, onset, and severity. Phenotype types span physical/skeletal manifestations (dysplasia, brachydactyly, coxa vara, genu valgum, craniosynostosis), clinical signs (short stature, dysmorphism, joint dislocation), and neurodevelopmental features (intellectual disability). Onset is congenital-to-childhood with a progressive skeletal course. Quality-of-life impact is driven by short stature, orthopedic deformity/mobility limitation, and developmental/cognitive impairment; formal QoL instrument data (EQ-5D, SF-36, PROMIS) are not available for this ultra-rare disease.

4. Genetic/Molecular Information

Causal gene: RSPRY1 (HGNC:29420; NCBI Gene 89970; Ensembl ENSG00000159579; 16q13; reference transcript NM_133368.3). Variant classes: frameshift, nonsense, canonical splice-site, missense, and large 16q CNVs (Findings 1, 4, 6). Functional consequence: loss of function (NMD for truncating alleles; splice disruption; SPRY-domain missense likely disrupts substrate binding/folding). Population frequency: pathogenic alleles are extremely rare/private to consanguineous families; the gene is strongly depleted of LoF/missense variation in gnomAD (Finding 7). Origin: germline, biallelic. Modifier genes / epigenetics: none established; no methylation/histone data. Chromosomal abnormalities: contiguous-gene 16q12.2–q21 deletions represent the main structural abnormality involving the locus (Finding 4).

5. Environmental Information

Not applicable as a cause. No toxic, infectious, lifestyle, or occupational agents are implicated. Consanguinity is a population/social risk factor for homozygosity, not an environmental disease cause.

6. Mechanism / Pathophysiology

Constitutive, SMAD3-dependent TGF-β pathway activation with ECM dysregulation, downstream of RSPRY1 loss, disturbing endochondral ossification (Finding 3; Mechanistic Model above). Molecular profiling to date is transcriptomic (patient fibroblasts, bulk RNA-seq) plus functional CRISPR-knockout fibroblast models. Proteomic, metabolomic, single-cell, and spatial data are not yet available. No enzyme deficiency, immune dysregulation, or metabolic derangement is reported. Tissue damage is developmental (abnormal growth-plate/epimetaphyseal ossification) rather than degenerative or inflammatory. Suggested terms: GO:0007179, GO:0060395, GO:0030198, GO:0001958; Reactome R-HSA-170834.

7. Anatomical Structures Affected

Organ/system: skeletal system (primary) — vertebrae, long-bone epiphyses/metaphyses, cranium (sutures), hands/feet; nervous system (intellectual disability); connective tissue/ECM; joints (dislocation). Cells: osteoblasts (CL:0000062), chondrocytes (CL:0000138), fibroblasts (CL:0000057), periosteal cells. UBERON: epiphyseal plate (UBERON:0006588), metaphysis (UBERON:0004421), epiphysis (UBERON:0006755), vertebral column (UBERON:0001130), cranial suture (UBERON:0007842). Subcellular: extracellular space/ECM (GO:0005576, GO:0031012), consistent with the secreted annotation. Lateralization: generalized, bilateral, symmetric.

8. Temporal Development

Congenital-to-early-childhood onset; chronic, insidious pattern. The skeletal disease is explicitly progressive (spondylar changes, coxa vara, deformities worsen during growth), whereas neurocognitive impairment is static/developmental. Lifelong disorder; no spontaneous remission; no genetic anticipation (recessive, non-repeat-expansion). The critical window for orthopedic intervention corresponds to growth-plate–active childhood/adolescence.

9. Inheritance and Population

Inheritance: autosomal recessive — "a clinically recognizable autosomal-recessive disorder in four affected siblings from a consanguineous Saudi family" (PMID: 26365341). Penetrance: effectively complete for biallelic LoF. Expressivity: variable (intellectual-disability degree; head circumference — microcephaly in the original family vs normocephaly in the 2018 cohort; craniosynostosis). Epidemiology: ultra-rare; prevalence/incidence unknown (~11 published patients; Orphanet <1/1,000,000). Founder/consanguinity: central — all families consanguineous; homozygosity via autozygosity; reported in Saudi, Turkish, Peruvian, and Indian families. Carrier frequency: unknown, expected very low. Sex ratio: no sex bias (autosomal recessive). Recurrence risk: 25% per pregnancy for two carrier parents.

10. Diagnostics

Diagnosis rests on a characteristic skeletal survey (mild spondylar dysplasia; epimetaphyseal dysplasia with coxa vara/genu valgum; cone-shaped epiphyses/brachymesophalangy; metaphyseal cupping/fraying; short metatarsals; craniosynostosis) combined with molecular confirmation of biallelic RSPRY1 variants. Genetic testing: whole-exome sequencing was the diagnostic modality in all discovery reports; WGS and skeletal-dysplasia gene panels including RSPRY1 are alternatives; single-gene Sanger sequencing confirms/segregates. Autozygosity mapping is powerful in consanguineous families; GeneMatcher-style matchmaking was pivotal — "Using a gene-centric 'matchmaking' system, we were able to identify a Peruvian simplex case subject" (PMID: 26365341). Chromosomal microarray detects large 16q contiguous-gene deletions that sequencing panels may miss (PMID: 27230627). Karyotype/FISH/mtDNA/repeat-expansion testing are not relevant. No specific biochemical biomarker or newborn-screening test exists. Differential diagnoses include other spondyloepimetaphyseal/spondylometaphyseal dysplasias, Dyggve-Melchior-Clausen dysplasia, and cone-shaped-epiphysis syndromes; RSPRY1 genotyping is discriminating.

11. Outcome / Prognosis

No reports indicate reduced life expectancy; the disorder is a chronic, non-lethal skeletal dysplasia compatible with survival to adulthood. Morbidity is dominated by short stature, progressive orthopedic deformity (coxa vara, genu valgum, joint dislocation) and mobility limitation, plus variable cognitive disability; craniosynostosis may require neurosurgical attention. Skeletal changes are structural and not reversible. Prognostic factors are inferred (deformity severity, degree of intellectual disability); no validated prognostic biomarkers exist.

12. Treatment

There is no disease-specific or disease-modifying therapy. Management is supportive and multidisciplinary: orthopedic surgical correction of coxa vara/genu valgum and joint dislocations (NCIT: orthopedic surgical procedure), craniosynostosis repair where indicated, physical/occupational therapy and rehabilitation, and developmental/educational support for intellectual disability. Mechanistically, the constitutive SMAD3-dependent TGF-β activation nominates TGF-β/SMAD3 pathway inhibition as a candidate therapeutic hypothesis (PMID: 39940902) — entirely experimental (candidate agents such as ALK5/SMAD3 inhibitors or losartan-type TGF-β modulation used in other connective-tissue disorders), with no preclinical or clinical validation in SEMDFA and no registered trials. No pharmacogenomic considerations are established.

13. Prevention

Primary prevention is via genetic counseling in consanguineous/at-risk families, carrier testing, and reproductive options including prenatal diagnosis and preimplantation genetic testing (PGT-M) once the familial RSPRY1 variant is known. Cascade testing identifies at-risk relatives. Secondary/tertiary prevention focuses on early orthopedic and developmental intervention to limit complications. No population-based screening, immunization, or environmental interventions apply.

14. Other Species / Natural Disease

No naturally occurring SEMDFA-equivalent disease is documented in companion animals or wildlife (no OMIA entry identified). Orthologous genes exist across vertebrates (mouse Rspry1; NCBI Taxon Homo sapiens 9606, Mus musculus 10090); the gene is expressed in mouse skeletal muscle and C2C12 cells (PMID: 26497270), and murine embryonic bone was used to localize the protein (PMID: 26365341). No zoonotic or cross-species transmission relevance (Mendelian, non-infectious).

15. Model Organisms

No dedicated in vivo Rspry1 knockout disease model has been reported. Available systems are cellular/in vitro: patient-derived dermal fibroblasts with homozygous RSPRY1 mutations and engineered RSPRY1-knockout (± SMAD3 double-knockout) fibroblasts used to establish the TGF-β/SMAD3 mechanism (PMID: 39940902), plus mouse C2C12 muscle cells for expression studies (PMID: 26497270). Recommended future models: an Rspry1 knockout/knock-in mouse (IMPC/KOMP), zebrafish rspry1 CRISPR knockdown for skeletal phenotyping, and patient-derived iPSC → osteoblast/chondrocyte or organoid systems. Phenotype recapitulation is unknown — a major research gap.

Evidence Base

PMID	Title (abbrev.)	Contribution	Evidence type
26365341	Identification of a Recognizable Progressive Skeletal Dysplasia Caused by RSPRY1 Mutations	Founding report: gene discovery, NMD LoF mechanism, core phenotype, osteoblast localization	Human clinical + in vitro
30063090	Further delineation of SEMDFA…	Radiographic hallmarks; new frameshift + splice alleles; craniosynostosis/cono-brachydactyly	Human clinical
38562122	Two sisters with RSPRY1-related SEMD	Homozygous missense c.1652G>A p.(Cys551Tyr); novel joint dislocation	Human clinical
39940902	Unraveling the Role of RSPRY1 in TGF-β Pathway Dysregulation	Core mechanism: constitutive SMAD3-dependent TGF-β activation; ECM dysregulation	In vitro / patient cells
27230627	A 16q12.2q21 deletion…	Contiguous-gene deletion including RSPRY1 explains skeletal defects	Human clinical
26497270	NIP30 and RSPRY1 in skeletal muscle	Rspry1 muscle expression/regulation; MyoD1 E-box enhancer	Model organism / in vitro
39706863	Genetic and allelic heterogeneity in 248 Indians with skeletal dysplasia	Expands RSPRY1 genotype/phenotype spectrum in a large cohort	Human clinical
33092958	Substrate recognition by TRIM/TRIM-like proteins	Contextualizes PRY-SPRY as a substrate-recognition module (structural analogy)	Review

Supporting TRIM/SPRY-family literature (PMID: 36675197, 33989636, 40593126, 38780244, 37139802) establishes the general biochemistry of RING + PRY/SPRY proteins as E3 ubiquitin ligases/substrate adaptors, providing an analogy-based (not SEMDFA-specific) framework for RSPRY1 function. An endometriosis Mendelian-randomization study (PMID: 39978332) lists RSPRY1 as a candidate eQTL target in an unrelated disease context and is not directly relevant to SEMDFA pathogenesis.

Supported hypotheses: biallelic LoF RSPRY1 causation; autosomal-recessive inheritance with consanguinity; the progressive SEMD + short stature + facial dysmorphism + intellectual disability ± craniosynostosis phenotype; RSPRY1 action in bone-forming cells during endochondral ossification; constitutive SMAD3-dependent TGF-β/ECM dysregulation as the molecular mechanism.

Refuted / not supported: dominant inheritance, environmental/infectious causation, and gain-of-function mechanisms are not supported. Universal microcephaly (suggested by the original family) was refuted by the 2018 cohort, in which most patients were normocephalic (PMID: 30063090).

Limitations and Knowledge Gaps

Very small evidence base. ~11 patients across 5 consanguineous families underpin the entire clinical picture; per-phenotype frequencies, prognosis, and natural history are not quantifiable with confidence, and there are no epidemiologic, registry, or QoL data.
Mechanism from a single functional study in fibroblasts. The TGF-β/SMAD3 model rests primarily on one report using patient fibroblasts and knockout cell lines (PMID: 39940902); it has not been validated in chondrocytes/osteoblasts or in vivo, the cell types most relevant to the skeletal phenotype.
Molecular link untested. The direct biochemical connection between RSPRY1 (RING/SPRY, secreted) and TGF-β/SMAD3 restraint — e.g., a specific ubiquitination substrate — is inferred by analogy to TRIM proteins, not demonstrated for RSPRY1.
Discordant localization annotations. UniProt annotates RSPRY1 as "Secreted," yet a RING/SPRY E3-ligase function and the intracellular constitutive TGF-β phenotype imply intracellular activity; this apparent discrepancy is unresolved.
No animal model of the disease. No Rspry1-null mouse skeletal phenotype has been reported, limiting causal in-vivo confirmation and preclinical therapy testing.
No therapeutics. TGF-β inhibition is a hypothesis only; efficacy and safety in SEMDFA are untested and no trials are registered.
Epidemiology absent. No prevalence/incidence estimates, carrier frequencies, or geographic-variant maps beyond consanguineous founder observations.

Proposed Follow-up Experiments / Actions

Generate an Rspry1 mouse model (global and cartilage-specific conditional knockout, e.g., Col2a1-Cre) and characterize growth-plate architecture, endochondral ossification, and craniofacial sutures to test skeletal recapitulation.
Validate the TGF-β/SMAD3 mechanism in disease-relevant cells — patient-derived iPSC chondrocytes/osteoblasts and growth-plate organoids — with phospho-SMAD3 quantification and rescue by SMAD3 knockdown or ALK5 (TGFβR1) inhibitors (e.g., SB-431542, galunisertib).
Define the RSPRY1 interactome and substrate(s). Use affinity purification–mass spectrometry and ubiquitination assays to test whether the RING/SPRY domain targets a TGF-β pathway component for ubiquitination, bridging the structural annotation (Finding 5) and functional mechanism (Finding 3).
Resolve subcellular localization with endogenous tagging/immunofluorescence and secretome analysis to reconcile the "secreted" annotation with an intracellular E3-ligase function.
Preclinical therapeutic proof-of-concept: test TGF-β/SMAD3 pathway inhibitors in the mouse model and in patient chondrocyte organoids for correction of ECM and differentiation defects.
Establish an international patient registry to collect standardized skeletal, developmental, and pediatric HRQoL outcomes and to define natural history, penetrance, and expressivity.
Systematic variant curation with functional assays (minigene splicing for splice variants; NMD/expression assays for truncating alleles; overexpression rescue for missense) to reclassify VUS and the conflicting splice-region ClinVar entries.
Carrier-frequency and founder-haplotype studies in consanguineous populations (Saudi, Turkish, Indian, Peruvian) to inform targeted carrier screening and counseling.

Report compiled from an autonomous multi-iteration literature and database investigation (7 confirmed findings; 15 papers reviewed). Evidence types are distinguished as human clinical, in vitro/patient-cell, model organism, and computational throughout.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	14
Resolved	14
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	1
Quoted claims found in source	1
Quoted claims not found in source	0
References weighed for topical relevance	14
On topic	7
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:33989636 (1 mention) - Crystal structure and mutational analysis of the human TRIM7 B30.2 domain provide insights into the molecular basis of its binding to glycogenin-1.
shared terms: mechanism, protein

Weighed against this report's own most characteristic terms: rspry1, disease, skeletal, dysplasia, gene, patient, tgf, craniosynostosis, cell, phenotype, type, progressive, consanguineous, disability, familie, variant, biallelic, developmental, mechanism, protein.

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

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Classifications

Mappings

Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Variants

Medical Actions

Diagnosis

Imaging Findings

Progression

Prevalence

Differential Diagnoses

Experimental Models

Source YAML

References & Deep Research

References

Deep Research

1. Disease Information

2. Etiology

3. Phenotypes

Craniofacial features (onset: congenital/early childhood; frequent-to-common across reported cases)

Skeletal — axial (progressive; worsens with age)

Skeletal — appendicular

Neurodevelopmental

Other

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Summary of Key Primary Citations

Reference Validation

Spondyloepimetaphyseal Dysplasia, Faden-Alkuraya Type (SEMDFA): A Comprehensive Disease Characteristics Report

Summary

Key Findings

Finding 1 — SEMDFA is an autosomal-recessive dysplasia caused by biallelic loss-of-function RSPRY1 variants

Finding 2 — Core clinical phenotype: progressive spondyloepimetaphyseal dysplasia with short stature, facial dysmorphism, cono-brachydactyly, and intellectual disability

Finding 3 — RSPRY1 deficiency dysregulates TGF-β/SMAD3 signaling and ECM dynamics (the molecular mechanism)

Finding 4 — Genomic context (16q12.2–q21), contiguous-gene deletions, and skeletal-muscle expression

Finding 5 — Authoritative identifiers and RSPRY1 protein annotation

Finding 6 — Expanded pathogenic variant spectrum from ClinVar

Finding 7 — RSPRY1 is highly constrained in the general population

Mechanistic Model / Interpretation

Section-by-Section Disease Characteristics

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Artifacts

Reference Validation

References that may not be about this subject