Progressive Spondyloepimetaphyseal Dysplasia-short Stature-short Fourth Metatarsals-intellectual Disability Syndrome

1. Disease Information

Overview. This is an ultra-rare autosomal recessive skeletal dysplasia syndrome first delineated by Faden, Alkuraya, and colleagues in 2015 in a large consanguineous Saudi Bedouin kindred. It is caused by biallelic loss-of-function or missense variants in RSPRY1 (Ring finger and SPRY domain containing 1, 16q13). The name used by Orphanet/GARD — "Progressive spondyloepimetaphyseal dysplasia–short stature–short fourth metatarsals–intellectual disability syndrome" — and the OMIM/clinical eponym "Spondyloepimetaphyseal Dysplasia, Faden-Alkuraya type" (SEMDFA) refer to the same entity. The original paper describes it as "a clinically recognizable autosomal-recessive disorder ... comprising progressive spondyloepimetaphyseal dysplasia, short stature, facial dysmorphism, short fourth metatarsals, and intellectual disability" (Faden et al. 2015, PMID: 26365341).

Key identifiers: - OMIM phenotype: #616723 — SPONDYLOEPIMETAPHYSEAL DYSPLASIA, FADEN-ALKURAYA TYPE (SEMDFA) (omim.org/entry/616723) - OMIM gene: 616585 — RSPRY1 (omim.org/entry/616585) - Orphanet: ORPHA:457395 (orpha.net/en/disease/detail/457395) - GARD: disease ID 17808 (rarediseases.info.nih.gov/diseases/17808) - Gene: RSPRY1, HGNC:29420, chromosome 16q13 - MONDO: an entry paired to the OMIM/Orphanet record should be sought/confirmed directly against a MONDO SPARQL/OLS lookup at curation time (not independently confirmed with a stable MONDO CURIE in this research pass — flag for verification before curating disease_term). - Synonyms:* "SEMDFA"; "Spondylo-epi-metaphyseal dysplasia Faden-Alkuraya type"; "RSPRY1-related spondyloepimetaphyseal dysplasia."

Provenance of information. Aggregated disease-level knowledge (OMIM, Orphanet, GARD, GeneCards) synthesizing individual case/family reports — this is not an EHR-derived or population-registry disease; all epidemiological and phenotypic knowledge derives from fewer than ~10 published probands across at least four unrelated families/kindreds (Saudi Bedouin, Peruvian, Turkish ×2, and Vietnamese/other Asian sisters).

2. Etiology

Disease causal factor: Purely monogenic/genetic — biallelic (homozygous or compound heterozygous) pathogenic variants in RSPRY1. No environmental, infectious, or multifactorial contribution has been described; GARD's generic boilerplate mentioning "environmental triggers" for genetic mutations does not reflect condition-specific literature and should not be curated as evidence-backed.

Genetic risk factors: - Consanguinity is the dominant risk factor reported across index families — the original description was in a large consanguineous Saudi Bedouin family with four affected siblings (Faden et al. 2015, PMID:26365341). - Reported causal variants to date: - Frameshift/1-bp duplication causing nonsense-mediated decay — original Saudi family (Faden et al. 2015) - Homozygous missense variant in a Peruvian simplex case, identified via "gene-centric matchmaking" (Faden et al. 2015) - Two additional distinct mutations reported in five individuals from two unrelated Turkish families (Simsek-Kiper et al. 2018, PMID:30063090) - c.1652G>A; p.(Cys551Tyr), a homozygous missense variant in the C3HC4 RING-finger domain (exon 15), reported in two sisters, "not present in gnomAD (v3.1.2)," in silico pathogenic (CADD phred 29.7, REVEL 0.967) (Zhu et al. 2024, PMID:38562122) - gnomAD constraint: RSPRY1 shows a pLI ≈1 and LOEUF ≈0.45, indicating strong intolerance to loss-of-function variation in the general population — consistent with a recessive, severe phenotype from biallelic loss (no specific carrier-frequency estimate is published; the gene is too rare/recently described for population carrier-screening panels).

Protective factors: None described in the literature — not applicable for this ultra-rare monogenic disorder.

Gene-environment interactions: None reported; disease penetrance and severity appear driven entirely by genotype (frameshift/null alleles vs. missense hypomorphic alleles may modulate severity, though this has not been formally established across the small case series).

3. Phenotypes

Phenotype data are pooled from OMIM's clinical synopsis, Orphanet, GARD (~73 catalogued HPO-mapped findings), and the primary case reports.

Skeletal (core diagnostic features)

Craniofacial dysmorphism

Microcephaly (HP:0000252), hypertelorism (HP:0000316), epicanthal folds (HP:0000286), mild ptosis (HP:0000508), strabismus/exotropia (HP:0000486), malar hypoplasia/midface retrusion (HP:0000272), short nose with depressed nasal bridge (HP:0003196/HP:0000431), full lips (HP:0012471), small low-set ears (HP:0008551/HP:0000369), short neck (HP:0000470), broad forehead (HP:0000337).

Neurological / developmental

• Global developmental delay / intellectual disability, mild-to-moderate — HP:0001263 / HP:0001249. In one sister, Vineland social quotient 68 (mild ID).
• Severe expressive language delay — HP:0002465
• Generalized hypotonia — HP:0001290
• Gait disturbance — HP:0001288
• Generalized tonic-clonic seizures (reported in one sibling from age 5) — HP:0002069
• Brain MRI: asymmetry of cerebral hemispheres, mild thinning of corpus callosum — HP:0100543 / HP:0002079

Ocular

Myopia (both sisters, PMID:38562122) — HP:0000545; strabismus/exotropia; mild ptosis.

Cardiac (reported in a subset)

Mitral regurgitation (HP:0031650), patent ductus arteriosus (HP:0001643, surgically repaired at age 3 in one proband), patent foramen ovale (HP:0001655).

Onset, severity, progression: Onset is congenital/neonatal-to-infantile (symptoms typically evident by 4 weeks–23 months per GARD). The skeletal dysplasia is explicitly progressive — the defining adjective in the syndrome name — with vertebral and epimetaphyseal changes worsening over the first years of life, and lower-limb deformity progressing from ~age 2 in at least one reported case. Growth deficiency is severe (height in the −4 to −5 SD range by mid-childhood). Intellectual disability ranges mild-to-moderate. Frequency data across the ~9 published cases suggest craniofacial dysmorphism, short stature, and short 4th metatarsals as near-universal; craniosynostosis, seizures, and joint dislocation are reported in a minority and may represent phenotypic expansion rather than core features.

Quality-of-life impact: Not formally studied (no EQ-5D/SF-36/PROMIS data published); qualitatively, GARD notes substantial multidisciplinary burden (orthopedic, neurologic, developmental) and a diagnostic odyssey averaging >6 years.

4. Genetic/Molecular Information

Causal gene: RSPRY1 (Ring Finger and SPRY Domain Containing 1); HGNC:29420; OMIM *616585; chromosome 16q13.

Gene/protein structure: RSPRY1 encodes a 576-amino-acid protein containing: - A B30.2/SPRY domain (~residues 359–479), which mediates protein-protein interactions - A C3HC4-type RING-finger domain (~residues 526–565), characteristic of E3 ubiquitin ligases

The 2015 discovery paper describes RSPRY1 as "a hypothetical RING and SPRY domain-containing protein of unknown physiological function" at the time of publication (PMID:26365341).

Variants reported: | Family/Report | Variant | Type | Zygosity | |---|---|---|---| | Saudi Bedouin (index family, PMID:26365341) | 1-bp duplication (frameshift) | Nonsense-mediated decay (presumed null) | Homozygous | | Peruvian simplex case (PMID:26365341) | Missense | Likely pathogenic | Homozygous | | Turkish families ×2 (PMID:30063090) | Two additional distinct RSPRY1 variants | Not fully specified in available abstract | Reported in 5 individuals | | Two sisters, East/Southeast Asian (PMID:38562122) | c.1652G>A; p.(Cys551Tyr), exon 15, RING-finger domain | Missense, likely pathogenic (CADD 29.7, M-CAP 0.812, REVEL 0.967); absent from gnomAD v3.1.2 and an in-house 3,076-exome cohort | Homozygous |

Allele frequency: No RSPRY1 pathogenic variant is present in gnomAD, consistent with extreme rarity and strong purifying selection (gene-level pLI ≈1, LOEUF ≈0.45 per GeneCards/gnomAD constraint metrics).

Origin: All reported cases are germline, consistent with autosomal recessive Mendelian inheritance in consanguineous or otherwise genetically isolated families; no somatic or mosaic cases reported.

Functional consequence: Loss-of-function (frameshift → NMD) and missense (hypomorphic/structurally destabilizing) alleles are both described, suggesting the phenotype arises from reduced or absent RSPRY1 activity rather than a specific gain-of-function or dominant-negative mechanism. The Cys551Tyr substitution is proposed to "perturb hydrophobic interactions, either in the core of the protein or on the surface" of the RING domain (PMID:38562122).

ClinGen status: As of this research, ClinGen has not yet published a gene-disease validity curation for RSPRY1 (confirmed via ClinGen KB, HGNC:29420) — an important curation caveat; the association currently rests on the primary literature (4 independent publications, ≥4 families) rather than a formal ClinGen classification.

Modifier genes / epigenetics / chromosomal abnormalities: None reported — this is a classical single-gene recessive disorder with no described modifier loci, epigenetic mechanism, or chromosomal rearrangement etiology.

5. Environmental Information

Not applicable/not described. No environmental toxin, lifestyle, or infectious trigger has been implicated in any published report; the disorder is fully genetically determined (autosomal recessive, biallelic RSPRY1).

6. Mechanism / Pathophysiology

Proposed causal chain (from primary literature):

1. Biallelic RSPRY1 loss-of-function or destabilizing missense variant → reduced/absent functional RSPRY1 protein (RING + SPRY domain protein, predicted E3 ubiquitin ligase activity; GO:0016567 protein ubiquitination, GO:0030163 protein catabolic process)
2. RSPRY1 shows "strong protein localization in murine embryonic osteoblasts and periosteal cells during primary endochondral ossification" (Faden et al. 2015), implicating a cell-autonomous role in osteoblast/periosteal biology during bone growth (CL:0000062 osteoblast; GO:0001958 endochondral ossification)
3. A 2025 mechanistic study (Unraveling the Role of RSPRY1 in TGF-β Pathway Dysregulation, PMID:39940902; PMC:11817781) used patient-derived fibroblast transcriptomics and CRISPR-Cas9 RSPRY1/SMAD3 knockout cell lines to show:
4. Significant enrichment of the "TGF-β regulation of the ECM pathway" (p = 1.12 × 10⁻²⁴), implicating SMAD3, COL1A1, WISP1 (CCN4), and RUNX2
5. RSPRY1 deficiency causes overactivation (not suppression) of TGF-β/SMAD signaling — RSPRY1 KO fibroblasts show constitutively enhanced wound-closure/motility, an effect abrogated in RSPRY1+SMAD3 double-knockout cells, establishing SMAD3-dependence
6. Exogenous TGF-β1 accelerated wound closure in control cells but had limited additional effect in RSPRY1-KO cells — consistent with a ceiling effect from constitutive pathway activation
7. The authors hypothesize RSPRY1 normally restrains TGF-β/SMAD signaling via ubiquitination of pathway components, and its loss removes this brake, driving dysregulated extracellular matrix (ECM) remodeling in growth-plate cartilage and bone
8. Downstream: dysregulated ECM dynamics at the growth plate/perichondrium → progressive epiphyseal/metaphyseal/vertebral dysplasia (the "spondyloepimetaphyseal" phenotype), disproportionate short stature, and characteristic acral findings (short 4th metatarsal, brachydactyly)
9. Craniofacial and neurodevelopmental features (microcephaly, ID, corpus callosum thinning) suggest RSPRY1 or its downstream TGF-β/ECM effects also influence neurocranial and CNS development, though the mechanistic link here is less well characterized than the skeletal arm.

Suggested GO terms: GO:0007179 (transforming growth factor beta receptor signaling pathway), GO:0030198 (extracellular matrix organization), GO:0001958 (endochondral ossification), GO:0016567 (protein ubiquitination), GO:0030282 (bone mineralization). Suggested CL terms: CL:0000062 (osteoblast), CL:0000138 (chondrocyte), CL:0000058 (chondroblast), CL:0000057 (fibroblast — used as the patient-derived disease-modeling cell type). Molecular pathway framing: This mechanism supports potential conforms_to linkage to a TGF-β/ECM-dysregulation pattern — note this is a distinct, RSPRY1-specific ubiquitination-mediated brake on TGF-β signaling, mechanistically related to but not identical to the canonical aortopathy_tgfbeta_dysregulation module's fibrillin/TGF-β receptor axis; a dismech curator should treat it as its own node rather than force-conforming it to that module without justification.

7. Anatomical Structures Affected

Organ/system level: - Skeletal system (primary): axial skeleton (vertebral column — spondylo-), epiphyses and metaphyses of long bones (epimetaphyseal), skull (craniosynostosis, copper-beaten appearance), hands/feet (short 4th metatarsal, brachydactyly) - Craniofacial skeleton/soft tissue: midface, orbits, nose, ears - Nervous system: cerebral hemispheres (asymmetry), corpus callosum (thinning) — CNS structural involvement - Cardiovascular system: mitral valve, ductus arteriosus, foramen ovale (secondary/associated findings in a subset) - Ocular system: lens/refractive apparatus (myopia), extraocular muscles (strabismus, ptosis)

Tissue/cell level: Growth-plate cartilage (chondrocytes), periosteum and osteoblasts (per murine expression data), dermal fibroblasts (used as the patient-derived disease model in mechanistic studies).

Subcellular level: RSPRY1 is proposed as a secreted/extracellular-acting protein functioning via ubiquitin-mediated regulation — implicating the extracellular matrix compartment and secretory pathway (GO Cellular Component: GO:0005576 extracellular region) rather than a classical nuclear/cytoplasmic mechanism, though a defined subcellular localization study specific to RSPRY1 was not identified in this search.

Localization/laterality: Skeletal changes are typically bilateral/symmetric (e.g., bilateral short 4th metatarsals, symmetric epimetaphyseal changes); cerebral hemisphere asymmetry is itself a reported radiologic finding (not laterality of a symmetric process, but an intrinsic asymmetric brain finding).

Suggested UBERON terms: UBERON:0001474 (bone element), UBERON:0002228 (rib/vertebral column), UBERON:0002355 (metatarsal bone), UBERON:0000104 (life cycle stage-adjacent — not applicable), UBERON:0002316 (corpus callosum), UBERON:0002616 (odontoid — not applicable). Core: UBERON:0004357 (epiphysis), UBERON:0003064 (metaphysis), UBERON:0006558 (cartilaginous joint/growth plate).

8. Temporal Development

• Onset: Congenital-to-infantile; GARD states symptoms typically emerge "as a Newborn and as an Infant," within the first 4 weeks to 23 months of life.
• Onset pattern: Insidious/progressive rather than acute.
• Progression: Explicitly progressive — the skeletal dysplasia (vertebral, epiphyseal, metaphyseal changes) worsens through childhood; lower-limb deformity in one reported case progressed specifically from age 2 onward. No formal staging system exists (this is not a malignancy or a disease with a validated staging scheme).
• Disease course: Chronic, lifelong; no spontaneous remission described. Seizures, when present, began later in one case (age 5), suggesting some features may emerge progressively rather than being present from birth.
• Critical periods: Early childhood (infancy through the first several years) appears to be the period of most active skeletal deterioration based on the reported natural history, making this the presumptive window for orthopedic surveillance and any future intervention trials.

9. Inheritance and Population

Epidemiology: GARD estimates fewer than 1,000 people in the U.S. with this condition — consistent with an ultra-rare disorder; published literature comprises fewer than ~10 molecularly confirmed cases across 4+ unrelated families (Saudi Arabian Bedouin, Peruvian, two Turkish families, and an East/Southeast Asian sibling pair). No formal prevalence/incidence rate (cases per 100,000) has been published; this is a "cases in literature" epidemiological measure, not a population-based estimate.

Inheritance pattern: Autosomal recessive. GARD: "A child must inherit two copies of the mutated gene, one from each biological parent, to be affected by the disease," with the standard AR recurrence risk of 25% affected, 50% carrier, 25% unaffected per pregnancy for two carrier parents.

Penetrance: Presumed complete (all reported biallelic carriers are affected), though the very small case series limits confidence in this assessment.

Expressivity: Variable — severity of skeletal, neurodevelopmental (mild-vs-moderate ID), and additional features (craniosynostosis, seizures, joint dislocation, cardiac defects) differs between reported families and even between affected siblings, suggesting variable expressivity, possibly genotype-correlated (null vs. missense alleles) though this is not formally established.

Consanguinity: A major contributing factor — the founding family was a large consanguineous Saudi Bedouin kindred; consanguinity likely explains the homozygosity observed across most reported families and the extreme rarity of compound heterozygous presentations to date.

Founder effects: Not formally established, but the concentration of cases in specific consanguineous/isolated populations (Saudi Bedouin, and separately Turkish and Peruvian founder-type homozygous variants) is consistent with population-specific private alleles rather than a single recurrent founder mutation.

Carrier frequency: Not established/reported; RSPRY1 pathogenic variants are absent from gnomAD, precluding a population-based carrier-frequency estimate.

Population demographics: Reported cases span Middle Eastern (Saudi Arabian), South American (Peruvian), and Asian (Turkish, and separately an East/Southeast Asian sibling pair) ancestries — there is no evidence this is restricted to a single ethnic group, though ascertainment (via consanguineous-family exome sequencing) likely biases the reported cohort.

Sex ratio: No sex predilection reported; both male and female probands are represented across published families (autosomal recessive inheritance is expected to affect both sexes equally).

10. Diagnostics

Radiographic/skeletal survey: The primary diagnostic modality — findings include platyspondyly, mild scoliosis, lumbar lordosis, small carpal bones, short femoral neck, cone-shaped/small epiphyses with metaphyseal cupping and fraying, short metatarsals (particularly the 4th), copper-beaten skull appearance, and craniosynostosis on skull imaging.

Molecular genetic testing: - Confirmatory diagnosis requires molecular testing of RSPRY1 — via targeted single-gene sequencing, a skeletal dysplasia gene panel (e.g., "Spondylo-Epi-Metaphyseal dysplasias Comprehensive panel," listed in NCBI GTR), clinical exome sequencing (WES), or genome sequencing (WGS). WES was the diagnostic modality in essentially all published cases (combined autozygome/exome mapping in consanguineous families, or trio/singleton exome in simplex cases). - Chromosomal microarray/karyotype: Not causally relevant — this is a single-gene point-variant disorder, not a copy-number or chromosomal disorder; CMA/karyotype would be expected to be normal and are used only to exclude alternative diagnoses.

Brain MRI: Recommended given reported findings of cerebral hemisphere asymmetry and corpus callosum thinning.

Cardiac evaluation (echocardiography): Recommended given reported associations (PDA, PFO, mitral regurgitation) in a subset of patients.

Differential diagnosis: Other spondyloepimetaphyseal dysplasias should be excluded, including SEMD with joint laxity type 2 (OMIM #603546, B3GALT6), SEMD Missouri type, SEMD Kondo-Fu type, and Dyggve-Melchior-Clausen-spectrum disorders — distinguished from SEMDFA by the combination of short 4th metatarsals, characteristic craniofacial gestalt, and RSPRY1 molecular confirmation.

Diagnostic odyssey: GARD notes it can take "more than six years" on average to reach an accurate diagnosis, underscoring both the rarity and phenotypic overlap with other skeletal dysplasias, and the value of multidisciplinary evaluation at a specialized skeletal-dysplasia/genetics center.

Screening: No population newborn-screening or carrier-screening program exists for this condition given its extreme rarity; prenatal diagnosis would rely on targeted familial variant testing once a proband's RSPRY1 genotype is known, or on incidental prenatal ultrasound detection of skeletal disproportion followed by genetic confirmation.

11. Outcome/Prognosis

No formal survival, mortality, or life-expectancy data have been published — the literature to date does not report early mortality attributable to this condition, and the clinical picture (progressive skeletal dysplasia with developmental delay) is not inherently life-limiting based on available case reports, though longitudinal outcome data beyond childhood/adolescence are not available in the current literature.

Morbidity: Primary long-term morbidity relates to (1) progressive skeletal deformity — kyphoscoliosis, joint laxity/dislocation, and disproportionate short stature, which may require ongoing orthopedic management, and (2) neurodevelopmental impact — mild-to-moderate intellectual disability and expressive language delay affecting educational and functional independence, with seizures as an additional morbidity in a subset.

Quality of life: Not formally measured with validated instruments in this population; qualitatively substantial given multisystem involvement.

Prognostic factors: No validated prognostic biomarkers or severity predictors exist; genotype (null/frameshift vs. missense) is a plausible but unproven modifier of severity based on the pattern of variants reported.

12. Treatment

There is no disease-specific or FDA-approved therapy; GARD explicitly notes "only about 5% of rare diseases have FDA-approved treatments," and this condition has none. Management is entirely supportive/symptomatic and multidisciplinary:

Experimental/investigational: No registered clinical trials specific to RSPRY1-related SEMD were identified. The 2025 mechanistic finding of TGF-β/SMAD3 pathway overactivation raises a plausible future therapeutic hypothesis (e.g., TGF-β pathway modulation), analogous to strategies explored in other TGF-β-dysregulated skeletal/connective tissue disorders (e.g., losartan in Marfan-spectrum aortopathies), but this remains speculative and has not been tested in RSPRY1-deficient models or patients.

13. Prevention

No primary, secondary, or tertiary prevention strategy beyond genetic counseling and reproductive risk management is described. For known carrier couples (typically identified after an affected child or via consanguinity-related genetic counseling), options include prenatal diagnosis via targeted variant testing and preimplantation genetic testing (PGT-M), following standard AR-disorder counseling practice — no condition-specific guideline was identified in the literature reviewed. No immunization, screening program, or public-health intervention applies, given the disorder's monogenic, non-infectious, non-multifactorial etiology.

14. Other Species / Natural Disease

No naturally occurring RSPRY1-associated disease in non-human species (companion animals, livestock, wildlife) was identified in this search (no OMIA entry located). This appears to be a human-specific clinical description at present.

15. Model Organisms

Mouse (Mus musculus, NCBITaxon:10090): No RSPRY1 germline knockout mouse model with a published skeletal phenotype was identified in this search. However, the original discovery paper (Faden et al. 2015, PMID:26365341) reports RSPRY1 protein expression/localization studies in murine embryonic tissue, showing "strong RSPRY1 protein localization in murine embryonic osteoblasts and periosteal cells during primary endochondral ossification, consistent with a role in bone development" — this is an expression/localization study, not a functional knockout model, and does not itself demonstrate phenotype recapitulation.

Human patient-derived cellular models: The 2025 mechanistic study (PMID:39940902) generated CRISPR-Cas9 RSPRY1 knockout, SMAD3 knockout, and RSPRY1+SMAD3 double-knockout fibroblast lines from patient-derived dermal fibroblasts (>90% knockout efficiency), used to demonstrate constitutive TGF-β/SMAD3-dependent hypermotility (wound-healing assay) in the absence of RSPRY1. This is currently the only functional model system in the literature for this gene/disease and would be the appropriate experimental_models entry for a dismech curation (IN_VITRO evidence source; relationship RECAPITULATES with respect to the TGF-β/ECM dysregulation mechanism node, though NOT a whole-organism/skeletal-phenotype model).

Model limitations: No animal model recapitulating the skeletal dysplasia phenotype in vivo has yet been published, representing a clear knowledge gap for future curation (a KNOWLEDGE_GAP discussion node would be appropriate: mechanistic data exist only in 2D fibroblast culture, not in a skeletal-relevant cell type such as chondrocytes/osteoblasts in vivo, nor in an animal model demonstrating the actual dysplasia phenotype).

Summary Table of Key Primary Citations

Curation Caveats for dismech

1. MONDO ID was not definitively confirmed with a stable CURIE in this pass — verify via OAK/MONDO lookup before setting disease_term.
2. ClinGen has not yet curated RSPRY1 gene-disease validity — do not cite a ClinGen CGGV: record; the evidence base rests on 4 independent peer-reviewed publications instead.
3. GARD's "environmental triggers" boilerplate for the general concept of mutation causation is not disease-specific evidence and should not be curated as an environmental risk factor for this entry.
4. The Simsek-Kiper 2018 abstract could not be retrieved verbatim (PubMed blocked automated access) — before citing a specific quoted snippet from this paper in a kb/disorders evidence block, fetch and cache it properly via just fetch-reference PMID:30063090 and verify the exact wording against the cached abstract.
5. No animal model recapitulates the skeletal phenotype in vivo — only patient-fibroblast CRISPR KO models exist; curate experimental_models (not animal_models) for the mechanistic evidence.

Sources: - OMIM #616723 — SEMDFA - OMIM *616585 — RSPRY1 - Orphanet ORPHA:457395 - GARD Disease 17808 - MalaCards — SEMDFA - Faden et al. 2015, PMID:26365341 - Simsek-Kiper et al. 2018, PMID:30063090 - Zhu et al. 2024 (PMC7616131), PMID:38562122 - RSPRY1/TGF-β mechanistic study 2025, PMID:39940902 (PMC11817781) - ClinGen RSPRY1 (HGNC:29420) - GeneCards RSPRY1

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