Spondylodysplastic Ehlers-Danlos Syndrome

Mendelian MONDO:0007526 Pathograph 30 Ehlers-Danlos Syndrome Skeletal Dysplasia Connective Tissue Disorder

Spondylodysplastic Ehlers-Danlos syndrome (spEDS) is a rare autosomal recessive connective tissue disorder characterized by short stature, muscle hypotonia, and skeletal abnormalities including platyspondyly and bowing of limbs. Three genetic subtypes are recognized: B4GALT7-related (spEDS-B4GALT7), B3GALT6-related (spEDS-B3GALT6), and SLC39A13-related (spEDS-SLC39A13). B4GALT7 and B3GALT6 encode glycosyltransferases required for glycosaminoglycan chain biosynthesis on proteoglycans, while SLC39A13 encodes ZIP13, an ER/Golgi iron transporter whose loss impairs Fe2+-dependent collagen hydroxylation. Despite shared features of short stature and connective tissue fragility, each subtype has a distinct phenotypic profile.

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1
Inheritance
8
Pathophys.
20
Phenotypes
30
Pathograph
3
Genes
1
Treatments
3
Subtypes
1
Deep Research
👪

Inheritance

1
Autosomal Recessive HP:0000007
All three genetic subtypes of spEDS follow autosomal recessive inheritance with biallelic pathogenic variants required for disease expression.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:28882145 SUPPORT Human Clinical
"Spondylodysplastic EDS (spEDS) is a rare connective tissue disorder that groups the phenotypes caused by biallelic B4GALT7, B3GALT6, and SLC39A13 mutations"
Confirms biallelic (autosomal recessive) inheritance for spEDS.
PMID:32295219 SUPPORT Human Clinical
"Recessive loss-of-function variants in SLC39A13, a putative zinc transporter gene, were first associated with a connective tissue disorder"
Confirms recessive inheritance for SLC39A13-spEDS.
◆

Subtypes

3
B4GALT7-related spEDS MONDO:0020682
B4GALT7 link
Caused by biallelic variants in B4GALT7 encoding galactosyltransferase I. Characterized by short stature, muscle hypotonia, hyperextensible skin, joint hypermobility, radioulnar synostosis, delayed cognitive development, and distinctive craniofacial features.
Show evidence (2 references)
PMID:28882145 SUPPORT Human Clinical
"Spondylodysplastic EDS (spEDS) is a rare connective tissue disorder that groups the phenotypes caused by biallelic B4GALT7, B3GALT6, and SLC39A13 mutations"
Establishes B4GALT7 as one of the causative genes for spEDS.
PMID:34193099 SUPPORT Human Clinical
"short stature and generalized muscular hypotonia as major criteria, and skin hyperextensibility, soft doughy skin, pes planus, delayed motor and cognitive development and osteopenia as minor criteria"
Describes the major and minor diagnostic criteria for B4GALT7-spEDS.
B3GALT6-related spEDS MONDO:0014139
B3GALT6 link
Caused by biallelic variants in B3GALT6 encoding beta-1,3-galactosyltransferase 6. Phenotypically broad spectrum spanning skeletal dysplasia and connective tissue disorder features, including kyphoscoliosis, joint hypermobility, and contractures.
Show evidence (2 references)
PMID:37657630 SUPPORT Human Clinical
"Each "linker" gene encodes an enzyme responsible for the addition of glycosaminoglycan chains to proteoglycans via a common tertrasaccharine linker region"
Describes B3GALT6 as a linker gene in GAG biosynthesis.
PMID:34159694 SUPPORT Human Clinical
"Beta3GalT6-related disorders were grouped in the spondylodysplastic EDSs together with spondylodysplastic EDSs due to B4GALT7 and SLC39A13 mutations"
Confirms classification of B3GALT6-related phenotypes under spEDS.
SLC39A13-related spEDS MONDO:0012873
SLC39A13 link
Caused by biallelic variants in SLC39A13 encoding ZIP13, an ER/Golgi iron transporter whose loss impairs Fe2+-dependent collagen hydroxylation. Distinguished by thin, finely wrinkled skin of hands and feet, prominent eyes, bluish sclerae, and childhood-onset short stature with platyspondyly.
Show evidence (1 reference)
PMID:32295219 SUPPORT Human Clinical
"Recessive loss-of-function variants in SLC39A13, a putative zinc transporter gene, were first associated with a connective tissue disorder"
Identifies SLC39A13 as the causative gene for the third spEDS subtype.
⚙

Pathophysiology

8
Defective Glycosaminoglycan Biosynthesis
B4GALT7 and B3GALT6 encode enzymes required for the common tetrasaccharide linker region that initiates glycosaminoglycan chain assembly on proteoglycan core proteins. Loss of function leads to insufficient mature proteoglycans, disrupting extracellular matrix structure in bone, cartilage, and connective tissues.
Fibroblast link Chondrocyte link
Glycosaminoglycan Biosynthesis link ↓ DECREASED Proteoglycan Biosynthesis link ↓ DECREASED Extracellular Matrix Organization link ⚠ ABNORMAL Heparan Sulfate Proteoglycan Biosynthesis link ↓ DECREASED
Downstream
Proteoglycan depletion and cartilage matrix disorganization Linker-enzyme defects reduce mature proteoglycan and sulfated glycosaminoglycan abundance, disrupting cartilage extracellular matrix organization.
Abnormal Glycosaminoglycan Linkage Region B3GALT6 linker dysfunction is measurable as abnormal urinary bikunin glycosaminoglycan linkage-region structures.
Delayed Cognitive Development B4GALT7-related glycosaminoglycan biosynthesis defects are associated with delayed motor and cognitive development, although the neurodevelopmental intermediates remain unresolved.
Show evidence (3 references)
PMID:34193099 SUPPORT Human Clinical
"galactosyltransferase I, which is required for the initiation of glycosaminoglycan side chain synthesis of proteoglycans"
Describes the enzymatic role of B4GALT7 in initiating GAG chain synthesis.
PMID:34807422 SUPPORT Human Clinical
"Spondylodysplastic EDS is caused by pathogenic variants in B4GALT7 or B3GALT6, both of which encode key enzymes that initiate glycosaminoglycan synthesis"
Confirms that both B4GALT7 and B3GALT6 are involved in GAG biosynthesis initiation.
PMID:36101818 SUPPORT Human Clinical
"contained two different glycopeptide peaks, corresponding to the canonical tetrasaccharide and to the non-canonical trisaccharide linkage region modifications"
Demonstrates abnormal GAG linkage region structure in B3GALT6 deficiency.
Proteoglycan depletion and cartilage matrix disorganization
Reduced mature proteoglycans and sulfated glycosaminoglycans weaken the cartilage and connective-tissue extracellular matrix, with abnormal cartilage patterning and chondrocyte organization linking the GAG-biosynthesis block to skeletal dysplasia.
Chondrocyte link Fibroblast link
Cartilage development link ⚠ ABNORMAL Chondrocyte differentiation link ⚠ ABNORMAL Extracellular matrix organization link ⚠ ABNORMAL
Downstream
Short Stature Proteoglycan and cartilage-matrix disruption contributes to the short stature that defines the spondylodysplastic phenotype.
Bowing of the Long Bones Impaired cartilage and skeletal patterning can manifest as bowing of long bones or analogous limb skeletal abnormalities.
Radioulnar Synostosis B4GALT7-related matrix and skeletal patterning defects are associated with radioulnar synostosis.
Osteopenia Disturbed proteoglycan-rich bone and cartilage matrix contributes to low bone mineral density in some spEDS patients.
Show evidence (2 references)
PMID:31862401 SUPPORT Model Organism
"In addition, the total amount of sulfated glycosaminoglycans is significantly diminished and particularly heparan and chondroitin sulfate proteoglycan levels are greatly reduced. We also show impaired cartilage patterning and loss of chondrocyte organization"
B4galt7-deficient zebrafish show the GAG depletion and cartilage organization defects modeled by this node.
PMID:34193099 SUPPORT Human Clinical
"Defective structures or deficient quantities of this enzyme lead to insufficient amounts of mature functional proteoglycans"
Human B4GALT7-spEDS literature links the enzyme deficiency to insufficient mature proteoglycans.
Connective tissue matrix laxity and skin fragility
Abnormal proteoglycan abundance and collagen modification weaken the extracellular matrix of skin, ligaments, sclerae, cornea, and peripheral joints, producing connective-tissue laxity and fragility.
Fibroblast link
Extracellular matrix organization link ⚠ ABNORMAL Collagen fibril organization link ⚠ ABNORMAL
Downstream
Hyperextensible Skin Matrix laxity manifests as hyperextensible or fragile skin.
Joint Hypermobility Peripheral joint connective-tissue weakness manifests as joint hypermobility.
Pes Planus Ligamentous and connective-tissue laxity contributes to flat feet.
Thin Wrinkled Skin of Hands and Feet Matrix fragility in acral skin manifests as thin, finely wrinkled skin.
Bluish Sclerae Ocular connective-tissue thinning manifests as bluish sclerae.
Keratoconus Corneal connective-tissue weakness can manifest as keratoconus.
Myopia Ocular connective-tissue involvement in SLC39A13-spEDS includes myopia, potentially related to thin sclerae.
Show evidence (2 references)
PMID:32295219 SUPPORT Human Clinical
"connective tissue weakness affecting mainly the skin and peripheral joints, a characteristic facial appearance, and a moderate skeletal dysplasia"
The SLC39A13-spEDS cohort summarizes the tissue distribution of connective-tissue weakness.
PMID:34193099 SUPPORT Human Clinical
"short stature and generalized muscular hypotonia as major criteria, and skin hyperextensibility, soft doughy skin, pes planus, delayed motor and cognitive development and osteopenia as minor criteria"
B4GALT7-spEDS diagnostic criteria include skin, foot, and connective-tissue manifestations.
ER/Golgi Iron Deficiency Due to ZIP13 Loss
SLC39A13 encodes the transporter ZIP13, historically classified as a zinc transporter. A 2024 study demonstrated that ZIP13's primary physiological function is iron transport into the ER/Golgi. ZIP13 loss causes iron deficiency in the ER/Golgi compartment, depriving Fe2+-dependent enzymes of their required cofactor.
Fibroblast link Osteoblast link
Iron Ion Transport link ↓ DECREASED
Downstream
Reduced Collagen Hydroxylation ER/Golgi iron deficiency deprives lysyl and prolyl hydroxylases of their Fe2+ cofactor, reducing collagen hydroxylation.
Defective Collagen Crosslinking Reduced collagen hydroxylation leads to defective crosslinking, as measured by a reduced urinary pyridinoline-to-deoxypyridinoline ratio.
Defective Myogenic Differentiation ZIP13 is involved in myogenic differentiation; its loss impairs myotube formation, contributing to the muscular hypotonia observed in SLC39A13-spEDS.
SLC39A13-associated craniofacial and dental dysplasia SLC39A13 loss is associated with a characteristic craniofacial, dental, ocular, and short-stature presentation; intermediates beyond collagen hydroxylation remain incompletely resolved.
Show evidence (1 reference)
PMID:39738060 SUPPORT In Vitro
"ZIP13 loss causes an iron deficiency in the ER/Golgi and other intracellular compartments, such as lysosomes and mitochondria, as well as elevating iron in the cytosol"
Demonstrates that ZIP13 functions as an iron transporter supplying the ER/Golgi, redefining the molecular mechanism of SLC39A13-spEDS.
Reduced Collagen Hydroxylation
ER/Golgi iron deficiency reduces iron cofactor availability for collagen lysyl and prolyl hydroxylases, causing impaired collagen hydroxylation in SLC39A13-related spEDS.
Fibroblast link Osteoblast link
Protein hydroxylation link ↓ DECREASED Collagen metabolic process link ⚠ ABNORMAL
Downstream
Defective Collagen Crosslinking Reduced lysyl hydroxylation produces abnormal collagen-derived crosslink ratios.
Reduced Pyridinoline-to-Deoxypyridinoline Ratio Reduced collagen hydroxylation is captured clinically by a low urinary pyridinoline-to-deoxypyridinoline ratio.
Show evidence (2 references)
PMID:32295219 SUPPORT Human Clinical
"The observation of reduced collagen hydroxylation indicates that a partial failure of collagen crosslinking is one pathogenic mechanism"
Human SLC39A13-spEDS evidence identifies reduced collagen hydroxylation as a pathogenic mechanism.
PMID:39738060 SUPPORT In Vitro
"ZIP13 loss causes an iron deficiency in the ER/Golgi and other intracellular compartments, such as lysosomes and mitochondria, as well as elevating iron in the cytosol"
ZIP13 loss directly produces ER/Golgi iron deficiency upstream of collagen hydroxylation defects.
Defective Collagen Crosslinking
Reduced collagen hydroxylation alters collagen-derived crosslink chemistry, weakening connective tissues and contributing to skeletal, skin, ocular, and joint manifestations in SLC39A13-related spEDS.
Fibroblast link
Collagen fibril organization link ⚠ ABNORMAL Extracellular matrix organization link ⚠ ABNORMAL
Downstream
Reduced Pyridinoline-to-Deoxypyridinoline Ratio Defective collagen crosslinking is measured as a reduced urinary pyridinoline-to-deoxypyridinoline ratio.
Connective tissue matrix laxity and skin fragility Crosslinking defects weaken collagen-rich connective tissues.
Cerebrovascular accidents Vascular connective-tissue fragility may contribute to cerebrovascular events in SLC39A13-spEDS, but the causal status remains uncertain.
Varicose veins Connective-tissue fragility can involve venous tissues, producing varicose veins in SLC39A13-spEDS.
Platyspondyly Collagen crosslinking defects in skeletal matrix contribute to vertebral flattening in SLC39A13-related spEDS.
Show evidence (1 reference)
PMID:32295219 SUPPORT Human Clinical
"The observation of reduced collagen hydroxylation indicates that a partial failure of collagen crosslinking is one pathogenic mechanism"
The SLC39A13 cohort connects reduced hydroxylation to partial failure of collagen crosslinking.
Defective Myogenic Differentiation
ZIP13 loss impairs myotube and myogenic differentiation in cellular models and patient-derived iPSC myocytes, providing a mechanistic route to muscular hypotonia.
Myotube link
Myotube differentiation link ↓ DECREASED
Downstream
Muscle Hypotonia Incomplete myogenic differentiation provides a mechanistic explanation for muscular hypotonia in SLC39A13-spEDS.
Show evidence (2 references)
PMID:38609428 SUPPORT In Vitro
"We found that ZIP13 gene expression was upregulated by myogenic stimulation in C2C12 cells, and its knockdown disrupted myotubular differentiation"
ZIP13 knockdown disrupts myotubular differentiation in a myogenic cell model.
PMID:38609428 SUPPORT In Vitro
"Myocytes differentiated from iPSCs derived from patients with EDSSPD3 (EDSSPD3-iPSCs) also exhibited incomplete myogenic differentiation"
Patient-derived iPSC myocytes show incomplete myogenic differentiation.
SLC39A13-associated craniofacial and dental dysplasia
SLC39A13-related spEDS includes a recurrent craniofacial, ocular, dental, and short-stature pattern. The clinical data indicate that some of these features are not fully explained by collagen hydroxylation alone, so this node records the tissue-development branch with unresolved intermediates.
Downstream
Short Stature SLC39A13-related tissue-development dysplasia includes postnatal short stature.
Downslanting Palpebral Fissures Craniofacial dysplasia manifests with downslanting palpebral fissures.
Prominent Eyes Craniofacial and periorbital connective-tissue changes manifest as prominent eyes.
Hypertelorism Craniofacial dysplasia manifests as mild hypertelorism.
Oligodontia Dental development involvement manifests as oligodontia.
Show evidence (1 reference)
PMID:32295219 SUPPORT Human Clinical
"However, it is difficult to ascribe the short stature, facial features, and oligodontia solely to reduced collagen hydroxylation."
The cohort supports a craniofacial/dental developmental branch beyond the collagen crosslinking mechanism alone.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Spondylodysplastic Ehlers-Danlos Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

20
Cardiovascular 2
Cerebrovascular accidents OCCASIONAL Stroke (HP:0001297)
Show evidence (2 references)
PMID:32295219 SUPPORT Human Clinical
"Two of our patients developed severe keratoconus, and two suffered from cerebrovascular accidents in their twenties, suggesting that there may be a vascular component to this condition."
Reports cerebrovascular accidents in two SLC39A13-spEDS patients.
PMID:32295219 SUPPORT Human Clinical
"We describe here four additional affected individuals from three consanguineous families and the follow up of two of the original cases."
Together with the two cerebrovascular events, this six-patient cohort supports an occasional frequency assignment.
Varicose veins Varicose veins (HP:0002619)
Show evidence (1 reference)
PMID:32295219 SUPPORT Human Clinical
"Both individuals had marked venous varicosities on their legs and feet."
The follow-up of original SLC39A13-spEDS patients documents marked venous varicosities.
Eye 5
Bluish Sclerae Blue sclerae (HP:0000592)
Show evidence (1 reference)
PMID:32295219 SUPPORT Human Clinical
"thin and finely wrinkled skin of the hands and feet, characteristic facial features with downslanting palpebral fissures, mild hypertelorism, prominent eyes with a paucity of periorbital fat, blueish sclerae"
Bluish sclerae described as a characteristic feature in SLC39A13-spEDS.
Prominent Eyes Proptosis (HP:0000520)
Show evidence (1 reference)
PMID:32295219 SUPPORT Human Clinical
"prominent eyes with a paucity of periorbital fat"
Prominent eyes described in SLC39A13-spEDS facial gestalt.
Keratoconus Keratoconus (HP:0000563)
Show evidence (1 reference)
PMID:32295219 SUPPORT Human Clinical
"Two of our patients developed severe keratoconus"
Keratoconus reported as a complication in adult SLC39A13-spEDS patients.
Myopia Myopia (HP:0000545)
Show evidence (1 reference)
PMID:32295219 SUPPORT Human Clinical
"Myopia has been reported in several SLC39A13 patients and also seems to be a direct (though non-specific) manifestation of the primary genetic defect."
The SLC39A13-spEDS cohort reports recurrent myopia.
Hypertelorism Hypertelorism (HP:0000316)
Show evidence (1 reference)
PMID:32295219 SUPPORT Human Clinical
"mild hypertelorism"
Mild hypertelorism noted as part of characteristic facial features.
Head and Neck 2
Downslanting Palpebral Fissures Downslanted palpebral fissures (HP:0000494)
Show evidence (1 reference)
PMID:32295219 SUPPORT Human Clinical
"characteristic facial features with downslanting palpebral fissures, mild hypertelorism, prominent eyes with a paucity of periorbital fat, blueish sclerae"
Downslanting palpebral fissures are a characteristic facial feature.
Oligodontia Oligodontia (HP:0000677)
Show evidence (1 reference)
PMID:32295219 SUPPORT Human Clinical
"microdontia, or oligodontia"
Oligodontia is part of the dental phenotype in SLC39A13-spEDS.
Integument 2
Hyperextensible Skin Hyperextensible skin (HP:0000974)
Show evidence (1 reference)
PMID:28882145 SUPPORT Human Clinical
"The majority of spEDS patients presented with short stature, skin hyperextensibility, facial dysmorphisms, peculiar radiological findings, muscle hypotonia and joint laxity"
Skin hyperextensibility listed as a feature of spEDS.
Thin Wrinkled Skin of Hands and Feet Thin skin (HP:0000963)
Show evidence (1 reference)
PMID:32295219 SUPPORT Human Clinical
"thin and finely wrinkled skin of the hands and feet"
Thin wrinkled acral skin is a distinguishing feature of SLC39A13-spEDS.
Limbs 3
Bowing of the Long Bones Bowing of the long bones (HP:0006487)
Show evidence (1 reference)
PMID:31862401 SUPPORT Model Organism
"Morphant and crispant zebrafish show highly similar morphological abnormalities in early development including a small, round head, bowed pectoral fins, short body-axis and mild developmental delay"
Zebrafish models of B4galt7 deficiency show bowed pectoral fins, recapitulating the limb bowing phenotype seen in human spEDS.
Pes Planus Pes planus (HP:0001763)
Show evidence (1 reference)
PMID:34193099 SUPPORT Human Clinical
"skin hyperextensibility, soft doughy skin, pes planus, delayed motor and cognitive development and osteopenia as minor criteria"
Pes planus listed as a minor criterion.
Radioulnar Synostosis Radioulnar synostosis (HP:0002974)
Show evidence (1 reference)
PMID:28882145 SUPPORT Human Clinical
"in addition to short stature and muscle hypotonia, radioulnar synostosis, hypermetropia, and delayed cognitive development might be a hallmark of this specific type of spEDS"
Radioulnar synostosis is a hallmark finding in B4GALT7-spEDS.
Musculoskeletal 4
Muscle Hypotonia VERY_FREQUENT Hypotonia (HP:0001252)
Show evidence (2 references)
PMID:28882145 SUPPORT Human Clinical
"The majority of spEDS patients presented with short stature, skin hyperextensibility, facial dysmorphisms, peculiar radiological findings, muscle hypotonia and joint laxity"
Muscle hypotonia is a major feature of spEDS.
PMID:38609428 SUPPORT Human Clinical
"patients with EDSSPD3 harboring a homozygous loss of function mutation (c.221G > A, p.G64D) in ZIP13 exon 2 (ZIP13G64D) suffer from impaired development of bone and connective tissues, and muscular hypotonia"
Muscular hypotonia confirmed as a feature of SLC39A13-spEDS.
Platyspondyly VERY_FREQUENT Platyspondyly (HP:0000926)
Show evidence (1 reference)
PMID:32295219 SUPPORT Human Clinical
"platyspondyly is a useful diagnostic feature"
Platyspondyly is highlighted as a diagnostically useful radiographic finding.
Joint Hypermobility VERY_FREQUENT Joint hypermobility (HP:0001382)
Show evidence (2 references)
PMID:36756177 SUPPORT Human Clinical
"We noted a high prevalence of joint hypermobility amongst kyphoscoliotic (39/39, 100%), spondylodysplastic (24/25, 96.0%), and hypermobile (153/160, 95.6%) EDS subtypes"
Systematic review quantifying 96% prevalence of joint hypermobility in spEDS.
PMID:28882145 SUPPORT Human Clinical
"The majority of spEDS patients presented with short stature, skin hyperextensibility, facial dysmorphisms, peculiar radiological findings, muscle hypotonia and joint laxity"
Joint laxity confirmed as a common feature of spEDS.
Osteopenia Osteopenia (HP:0000938)
Show evidence (1 reference)
PMID:34193099 SUPPORT Human Clinical
"skin hyperextensibility, soft doughy skin, pes planus, delayed motor and cognitive development and osteopenia as minor criteria"
Osteopenia listed among minor diagnostic criteria.
Nervous System 1
Delayed Cognitive Development Global developmental delay (HP:0001263)
Show evidence (2 references)
PMID:28882145 SUPPORT Human Clinical
"in addition to short stature and muscle hypotonia, radioulnar synostosis, hypermetropia, and delayed cognitive development might be a hallmark of this specific type of spEDS"
Delayed cognitive development is described as a possible hallmark of B4GALT7-spEDS.
PMID:34193099 SUPPORT Human Clinical
"skin hyperextensibility, soft doughy skin, pes planus, delayed motor and cognitive development and osteopenia as minor criteria"
B4GALT7-spEDS criteria include delayed motor and cognitive development.
Growth 1
Short Stature VERY_FREQUENT Short stature (HP:0004322)
Show evidence (2 references)
PMID:28882145 SUPPORT Human Clinical
"The majority of spEDS patients presented with short stature, skin hyperextensibility, facial dysmorphisms, peculiar radiological findings, muscle hypotonia and joint laxity"
Short stature is listed as a major feature of spEDS.
PMID:32295219 SUPPORT Human Clinical
"significant short stature of childhood onset"
Short stature confirmed in SLC39A13-spEDS patients.
🧬

Genetic Associations

3
B4GALT7 (Causative)
Show evidence (2 references)
PMID:34193099 SUPPORT Human Clinical
"galactosyltransferase I, which is required for the initiation of glycosaminoglycan side chain synthesis of proteoglycans"
Describes B4GALT7 enzymatic function and its link to spEDS.
PMID:28882145 SUPPORT Human Clinical
"Spondylodysplastic EDS (spEDS) is a rare connective tissue disorder that groups the phenotypes caused by biallelic B4GALT7, B3GALT6, and SLC39A13 mutations"
Confirms B4GALT7 as one of three causative genes for spEDS.
B3GALT6 (Causative)
Show evidence (2 references)
PMID:37657630 SUPPORT Human Clinical
"Each "linker" gene encodes an enzyme responsible for the addition of glycosaminoglycan chains to proteoglycans via a common tertrasaccharine linker region"
Establishes B3GALT6 as a linker gene causing a linkeropathy classified under spEDS.
PMID:34159694 SUPPORT Human Clinical
"Beta3GalT6-related disorders were grouped in the spondylodysplastic EDSs together with spondylodysplastic EDSs due to B4GALT7 and SLC39A13 mutations"
Confirms B3GALT6-related disorders are classified under spEDS.
SLC39A13 (Causative)
Show evidence (3 references)
PMID:32295219 SUPPORT Human Clinical
"Recessive loss-of-function variants in SLC39A13, a putative zinc transporter gene, were first associated with a connective tissue disorder"
Identifies SLC39A13 as a causative gene for spEDS.
PMID:36727144 SUPPORT Human Clinical
"a novel mutation in SLC39A13 causing spondylodysplastic Ehlers-Danlos syndrome"
Case report confirming a novel SLC39A13 variant causing spEDS.
PMID:39738060 SUPPORT In Vitro
"Here, we show that SLC39A13 (ZIP13), previously identified as a zinc transporter, promotes intracellular iron transport and reduces intracellular iron levels."
Supports the updated interpretation of ZIP13 as an ER/Golgi iron transporter.
💊

Treatments

1
Supportive Care and Surveillance
Action: supportive care MAXO:0000950
No disease-specific therapy is established in this entry; management is supportive and complication-directed, including rehabilitation after neurologic events and ophthalmologic surveillance for keratoconus risk.
Show evidence (2 references)
PMID:32295219 SUPPORT Human Clinical
"Fortunately, she was able to partially recover over four years on physiotherapy but still has partial function of the right hand and myoclonus on the right arm."
Rehabilitation was used after a neurologic complication in an SLC39A13-spEDS patient.
PMID:32295219 SUPPORT Human Clinical
"ophthalmologic investigation should be recommended in all confirmed cases."
Ophthalmologic surveillance is recommended because keratoconus can be severe.
🔬

Biochemical Markers

2
Reduced Pyridinoline-to-Deoxypyridinoline Ratio
Show evidence (1 reference)
PMID:32295219 SUPPORT Human Clinical
"All patients tested had a significantly reduced ratio of the two collagen-derived crosslink derivates, pyridinoline-to-deoxypyridinoline, in urine, suggesting that this simple test is diagnostically useful"
A biochemical marker distinguishing SLC39A13-spEDS from other subtypes.
Abnormal Glycosaminoglycan Linkage Region
Show evidence (1 reference)
PMID:36101818 SUPPORT Human Clinical
"contained two different glycopeptide peaks, corresponding to the canonical tetrasaccharide and to the non-canonical trisaccharide linkage region modifications"
Demonstrates structural GAG linkage region abnormalities as a biomarker for B3GALT6 deficiency.
{ }

Source YAML

click to show 
name: Spondylodysplastic Ehlers-Danlos Syndrome
creation_date: '2026-04-02T12:00:00Z'
updated_date: '2026-05-21T10:26:37Z'
category: Mendelian
description: >
  Spondylodysplastic Ehlers-Danlos syndrome (spEDS) is a rare autosomal recessive
  connective tissue disorder characterized by short stature, muscle hypotonia,
  and skeletal abnormalities including platyspondyly and bowing of limbs. Three
  genetic subtypes are recognized: B4GALT7-related (spEDS-B4GALT7), B3GALT6-related
  (spEDS-B3GALT6), and SLC39A13-related (spEDS-SLC39A13). B4GALT7 and B3GALT6
  encode glycosyltransferases required for glycosaminoglycan chain biosynthesis on
  proteoglycans, while SLC39A13 encodes ZIP13, an ER/Golgi iron transporter
  whose loss impairs Fe2+-dependent collagen hydroxylation. Despite shared features of short stature and connective tissue
  fragility, each subtype has a distinct phenotypic profile.
disease_term:
  preferred_term: spondylodysplastic Ehlers-Danlos syndrome
  term:
    id: MONDO:0007526
    label: Ehlers-Danlos syndrome, spondylodysplastic type
parents:
- Ehlers-Danlos Syndrome
- Skeletal Dysplasia
- Connective Tissue Disorder
has_subtypes:
- name: spEDS-B4GALT7
  display_name: B4GALT7-related spEDS
  subtype_term:
    preferred_term: Ehlers-Danlos syndrome, spondylodysplastic type, 1
    term:
      id: MONDO:0020682
      label: Ehlers-Danlos syndrome, spondylodysplastic type, 1
  genes:
  - preferred_term: B4GALT7
    term:
      id: hgnc:930
      label: B4GALT7
  description: >
    Caused by biallelic variants in B4GALT7 encoding galactosyltransferase I.
    Characterized by short stature, muscle hypotonia, hyperextensible skin,
    joint hypermobility, radioulnar synostosis, delayed cognitive development,
    and distinctive craniofacial features.
  evidence:
  - reference: PMID:28882145
    reference_title: "Expanding the clinical and mutational spectrum of B4GALT7-spondylodysplastic Ehlers-Danlos syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Spondylodysplastic EDS (spEDS) is a rare connective tissue disorder
      that groups the phenotypes caused by biallelic B4GALT7, B3GALT6, and SLC39A13
      mutations
    explanation: Establishes B4GALT7 as one of the causative genes for spEDS.
  - reference: PMID:34193099
    reference_title: "Report of two siblings with spondylodysplastic Ehlers-Danlos syndrome and B4GALT7 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      short stature and generalized muscular hypotonia as major criteria, and
      skin hyperextensibility, soft doughy skin, pes planus, delayed motor and
      cognitive development and osteopenia as minor criteria
    explanation: Describes the major and minor diagnostic criteria for B4GALT7-spEDS.
- name: spEDS-B3GALT6
  display_name: B3GALT6-related spEDS
  subtype_term:
    preferred_term: Ehlers-Danlos syndrome, spondylodysplastic type, 2
    term:
      id: MONDO:0014139
      label: Ehlers-Danlos syndrome, spondylodysplastic type, 2
  genes:
  - preferred_term: B3GALT6
    term:
      id: hgnc:17978
      label: B3GALT6
  description: >
    Caused by biallelic variants in B3GALT6 encoding beta-1,3-galactosyltransferase 6.
    Phenotypically broad spectrum spanning skeletal dysplasia and connective tissue
    disorder features, including kyphoscoliosis, joint hypermobility, and
    contractures.
  evidence:
  - reference: PMID:37657630
    reference_title: "B3GALT6-linkeropathy: Three illustrative patients spanning the disease spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Each "linker" gene encodes an enzyme responsible for the addition of
      glycosaminoglycan chains to proteoglycans via a common tertrasaccharine
      linker region
    explanation: Describes B3GALT6 as a linker gene in GAG biosynthesis.
  - reference: PMID:34159694
    reference_title: "Broadening the phenotypic spectrum of Beta3GalT6-associated phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Beta3GalT6-related disorders were grouped in the spondylodysplastic EDSs
      together with spondylodysplastic EDSs due to B4GALT7 and SLC39A13 mutations
    explanation: Confirms classification of B3GALT6-related phenotypes under spEDS.
- name: spEDS-SLC39A13
  display_name: SLC39A13-related spEDS
  subtype_term:
    preferred_term: Ehlers-Danlos syndrome, spondylocheirodysplastic type
    term:
      id: MONDO:0012873
      label: Ehlers-Danlos syndrome, spondylocheirodysplastic type
  genes:
  - preferred_term: SLC39A13
    term:
      id: hgnc:20859
      label: SLC39A13
  description: >
    Caused by biallelic variants in SLC39A13 encoding ZIP13, an ER/Golgi iron
    transporter whose loss impairs Fe2+-dependent collagen hydroxylation.
    Distinguished by thin, finely wrinkled skin of hands and feet, prominent eyes,
    bluish sclerae, and childhood-onset short stature with platyspondyly.
  evidence:
  - reference: PMID:32295219
    reference_title: "The Connective Tissue Disorder Associated with Recessive Variants in the SLC39A13 Zinc Transporter Gene (Spondylo-Dysplastic Ehlers-Danlos Syndrome Type 3): Insights from Four Novel Patients and Follow-Up on Two Original Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recessive loss-of-function variants in SLC39A13, a putative zinc transporter
      gene, were first associated with a connective tissue disorder
    explanation: Identifies SLC39A13 as the causative gene for the third spEDS subtype.
inheritance:
- name: Autosomal Recessive
  description: >
    All three genetic subtypes of spEDS follow autosomal recessive inheritance
    with biallelic pathogenic variants required for disease expression.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:28882145
    reference_title: "Expanding the clinical and mutational spectrum of B4GALT7-spondylodysplastic Ehlers-Danlos syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Spondylodysplastic EDS (spEDS) is a rare connective tissue disorder
      that groups the phenotypes caused by biallelic B4GALT7, B3GALT6, and SLC39A13
      mutations
    explanation: Confirms biallelic (autosomal recessive) inheritance for spEDS.
  - reference: PMID:32295219
    reference_title: "The Connective Tissue Disorder Associated with Recessive Variants in the SLC39A13 Zinc Transporter Gene (Spondylo-Dysplastic Ehlers-Danlos Syndrome Type 3): Insights from Four Novel Patients and Follow-Up on Two Original Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recessive loss-of-function variants in SLC39A13, a putative zinc transporter
      gene, were first associated with a connective tissue disorder
    explanation: Confirms recessive inheritance for SLC39A13-spEDS.
pathophysiology:
- name: Defective Glycosaminoglycan Biosynthesis
  description: >
    B4GALT7 and B3GALT6 encode enzymes required for the common tetrasaccharide
    linker region that initiates glycosaminoglycan chain assembly on proteoglycan
    core proteins. Loss of function leads to insufficient mature proteoglycans,
    disrupting extracellular matrix structure in bone, cartilage, and connective
    tissues.
  cell_types:
  - preferred_term: Fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  - preferred_term: Chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  biological_processes:
  - preferred_term: Glycosaminoglycan Biosynthesis
    modifier: DECREASED
    term:
      id: GO:0006024
      label: glycosaminoglycan biosynthetic process
  - preferred_term: Proteoglycan Biosynthesis
    modifier: DECREASED
    term:
      id: GO:0030166
      label: proteoglycan biosynthetic process
  - preferred_term: Extracellular Matrix Organization
    modifier: ABNORMAL
    term:
      id: GO:0030198
      label: extracellular matrix organization
  - preferred_term: Heparan Sulfate Proteoglycan Biosynthesis
    modifier: DECREASED
    term:
      id: GO:0015012
      label: heparan sulfate proteoglycan biosynthetic process
  chemical_entities:
  - preferred_term: glycosaminoglycan
    modifier: DECREASED
    term:
      id: CHEBI:18085
      label: glycosaminoglycan
  - preferred_term: heparan sulfate
    modifier: DECREASED
    term:
      id: CHEBI:28815
      label: heparan sulfate
  - preferred_term: chondroitin sulfate
    modifier: DECREASED
    term:
      id: CHEBI:37397
      label: chondroitin sulfate
  - preferred_term: dermatan sulfate
    modifier: ABNORMAL
    term:
      id: CHEBI:18376
      label: dermatan sulfate
  evidence:
  - reference: PMID:34193099
    reference_title: "Report of two siblings with spondylodysplastic Ehlers-Danlos syndrome and B4GALT7 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      galactosyltransferase I, which is required for the initiation of
      glycosaminoglycan side chain synthesis of proteoglycans
    explanation: Describes the enzymatic role of B4GALT7 in initiating GAG chain synthesis.
  - reference: PMID:34807422
    reference_title: "Ehlers Danlos Syndrome with Glycosaminoglycan Abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Spondylodysplastic EDS is caused by pathogenic variants in B4GALT7 or
      B3GALT6, both of which encode key enzymes that initiate glycosaminoglycan
      synthesis
    explanation: Confirms that both B4GALT7 and B3GALT6 are involved in GAG biosynthesis initiation.
  - reference: PMID:36101818
    reference_title: "Glycosaminoglycan linkage region of urinary bikunin as a potentially useful biomarker for beta3GalT6-deficient spondylodysplastic Ehlers-Danlos syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      contained two different glycopeptide peaks, corresponding to the canonical
      tetrasaccharide and to the non-canonical trisaccharide linkage region
      modifications
    explanation: Demonstrates abnormal GAG linkage region structure in B3GALT6 deficiency.
  downstream:
  - target: Proteoglycan depletion and cartilage matrix disorganization
    description: >
      Linker-enzyme defects reduce mature proteoglycan and sulfated
      glycosaminoglycan abundance, disrupting cartilage extracellular matrix
      organization.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34193099
      reference_title: "Report of two siblings with spondylodysplastic Ehlers-Danlos syndrome and B4GALT7 deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Defective structures or deficient quantities of this enzyme lead to insufficient amounts of mature functional proteoglycans"
      explanation: B4GALT7 deficiency reduces mature functional proteoglycans, providing the upstream link to matrix disorganization.
    - reference: PMID:31862401
      reference_title: "Hypomorphic zebrafish models mimic the musculoskeletal phenotype of beta4GalT7-deficient Ehlers-Danlos syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        the total amount of sulfated glycosaminoglycans is significantly
        diminished and particularly heparan and chondroitin sulfate proteoglycan
        levels are greatly reduced
      explanation: The B4GALT7 zebrafish model demonstrates reduced sulfated GAGs and proteoglycans.
  - target: Abnormal Glycosaminoglycan Linkage Region
    description: >
      B3GALT6 linker dysfunction is measurable as abnormal urinary bikunin
      glycosaminoglycan linkage-region structures.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36101818
      reference_title: "Glycosaminoglycan linkage region of urinary bikunin as a potentially useful biomarker for beta3GalT6-deficient spondylodysplastic Ehlers-Danlos syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        contained two different glycopeptide peaks, corresponding to the
        canonical tetrasaccharide and to the non-canonical trisaccharide linkage
        region modifications
      explanation: The urinary bikunin linkage-region abnormality is a biochemical readout of B3GALT6 linker dysfunction.
  - target: Delayed Cognitive Development
    description: >
      B4GALT7-related glycosaminoglycan biosynthesis defects are associated with
      delayed motor and cognitive development, although the neurodevelopmental
      intermediates remain unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:28882145
      reference_title: "Expanding the clinical and mutational spectrum of B4GALT7-spondylodysplastic Ehlers-Danlos syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        in addition to short stature and muscle hypotonia, radioulnar synostosis,
        hypermetropia, and delayed cognitive development might be a hallmark of
        this specific type of spEDS
      explanation: Delayed cognitive development is described as a hallmark B4GALT7-spEDS feature.
- name: Proteoglycan depletion and cartilage matrix disorganization
  description: >
    Reduced mature proteoglycans and sulfated glycosaminoglycans weaken the
    cartilage and connective-tissue extracellular matrix, with abnormal cartilage
    patterning and chondrocyte organization linking the GAG-biosynthesis block
    to skeletal dysplasia.
  cell_types:
  - preferred_term: Chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  - preferred_term: Fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: Cartilage development
    modifier: ABNORMAL
    term:
      id: GO:0051216
      label: cartilage development
  - preferred_term: Chondrocyte differentiation
    modifier: ABNORMAL
    term:
      id: GO:0002062
      label: chondrocyte differentiation
  - preferred_term: Extracellular matrix organization
    modifier: ABNORMAL
    term:
      id: GO:0030198
      label: extracellular matrix organization
  chemical_entities:
  - preferred_term: sulfated glycosaminoglycans
    modifier: DECREASED
    term:
      id: CHEBI:18085
      label: glycosaminoglycan
  - preferred_term: heparan sulfate
    modifier: DECREASED
    term:
      id: CHEBI:28815
      label: heparan sulfate
  - preferred_term: chondroitin sulfate
    modifier: DECREASED
    term:
      id: CHEBI:37397
      label: chondroitin sulfate
  evidence:
  - reference: PMID:31862401
    reference_title: "Hypomorphic zebrafish models mimic the musculoskeletal phenotype of beta4GalT7-deficient Ehlers-Danlos syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In addition, the total amount of sulfated glycosaminoglycans is
      significantly diminished and particularly heparan and chondroitin sulfate
      proteoglycan levels are greatly reduced. We also show impaired cartilage
      patterning and loss of chondrocyte organization
    explanation: B4galt7-deficient zebrafish show the GAG depletion and cartilage organization defects modeled by this node.
  - reference: PMID:34193099
    reference_title: "Report of two siblings with spondylodysplastic Ehlers-Danlos syndrome and B4GALT7 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Defective structures or deficient quantities of this enzyme lead to insufficient amounts of mature functional proteoglycans"
    explanation: Human B4GALT7-spEDS literature links the enzyme deficiency to insufficient mature proteoglycans.
  downstream:
  - target: Short Stature
    description: >
      Proteoglycan and cartilage-matrix disruption contributes to the short
      stature that defines the spondylodysplastic phenotype.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - cartilage matrix disorganization
    evidence:
    - reference: PMID:28882145
      reference_title: "Expanding the clinical and mutational spectrum of B4GALT7-spondylodysplastic Ehlers-Danlos syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The majority of spEDS patients presented with short stature, skin
        hyperextensibility, facial dysmorphisms, peculiar radiological findings,
        muscle hypotonia and joint laxity
      explanation: Short stature is a recurrent human spEDS feature downstream of the skeletal dysplasia mechanism.
  - target: Bowing of the Long Bones
    description: >
      Impaired cartilage and skeletal patterning can manifest as bowing of long
      bones or analogous limb skeletal abnormalities.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - abnormal cartilage patterning
    evidence:
    - reference: PMID:31862401
      reference_title: "Hypomorphic zebrafish models mimic the musculoskeletal phenotype of beta4GalT7-deficient Ehlers-Danlos syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Morphant and crispant zebrafish show highly similar morphological
        abnormalities in early development including a small, round head, bowed
        pectoral fins, short body-axis and mild developmental delay
      explanation: The B4galt7 model recapitulates bowing of appendicular skeletal elements.
  - target: Radioulnar Synostosis
    description: >
      B4GALT7-related matrix and skeletal patterning defects are associated with
      radioulnar synostosis.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:28882145
      reference_title: "Expanding the clinical and mutational spectrum of B4GALT7-spondylodysplastic Ehlers-Danlos syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        in addition to short stature and muscle hypotonia, radioulnar synostosis,
        hypermetropia, and delayed cognitive development might be a hallmark of
        this specific type of spEDS
      explanation: Radioulnar synostosis is a hallmark B4GALT7-spEDS skeletal manifestation.
  - target: Osteopenia
    description: >
      Disturbed proteoglycan-rich bone and cartilage matrix contributes to low
      bone mineral density in some spEDS patients.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34193099
      reference_title: "Report of two siblings with spondylodysplastic Ehlers-Danlos syndrome and B4GALT7 deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        skin hyperextensibility, soft doughy skin, pes planus, delayed motor and
        cognitive development and osteopenia as minor criteria
      explanation: Osteopenia is listed among minor diagnostic criteria for spEDS-B4GALT7.
- name: Connective tissue matrix laxity and skin fragility
  description: >
    Abnormal proteoglycan abundance and collagen modification weaken the
    extracellular matrix of skin, ligaments, sclerae, cornea, and peripheral
    joints, producing connective-tissue laxity and fragility.
  cell_types:
  - preferred_term: Fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: Extracellular matrix organization
    modifier: ABNORMAL
    term:
      id: GO:0030198
      label: extracellular matrix organization
  - preferred_term: Collagen fibril organization
    modifier: ABNORMAL
    term:
      id: GO:0030199
      label: collagen fibril organization
  evidence:
  - reference: PMID:32295219
    reference_title: "The Connective Tissue Disorder Associated with Recessive Variants in the SLC39A13 Zinc Transporter Gene (Spondylo-Dysplastic Ehlers-Danlos Syndrome Type 3): Insights from Four Novel Patients and Follow-Up on Two Original Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      connective tissue weakness affecting mainly the skin and peripheral joints,
      a characteristic facial appearance, and a moderate skeletal dysplasia
    explanation: The SLC39A13-spEDS cohort summarizes the tissue distribution of connective-tissue weakness.
  - reference: PMID:34193099
    reference_title: "Report of two siblings with spondylodysplastic Ehlers-Danlos syndrome and B4GALT7 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      short stature and generalized muscular hypotonia as major criteria, and
      skin hyperextensibility, soft doughy skin, pes planus, delayed motor and
      cognitive development and osteopenia as minor criteria
    explanation: B4GALT7-spEDS diagnostic criteria include skin, foot, and connective-tissue manifestations.
  downstream:
  - target: Hyperextensible Skin
    description: Matrix laxity manifests as hyperextensible or fragile skin.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28882145
      reference_title: "Expanding the clinical and mutational spectrum of B4GALT7-spondylodysplastic Ehlers-Danlos syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The majority of spEDS patients presented with short stature, skin
        hyperextensibility, facial dysmorphisms, peculiar radiological findings,
        muscle hypotonia and joint laxity
      explanation: Human spEDS cases commonly present with skin hyperextensibility.
  - target: Joint Hypermobility
    description: Peripheral joint connective-tissue weakness manifests as joint hypermobility.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36756177
      reference_title: "Extracutaneous features and complications of the Ehlers-Danlos syndromes: A systematic review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We noted a high prevalence of joint hypermobility amongst kyphoscoliotic
        (39/39, 100%), spondylodysplastic (24/25, 96.0%), and hypermobile
        (153/160, 95.6%) EDS subtypes
      explanation: The systematic review documents high joint hypermobility prevalence in spEDS.
  - target: Pes Planus
    description: Ligamentous and connective-tissue laxity contributes to flat feet.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34193099
      reference_title: "Report of two siblings with spondylodysplastic Ehlers-Danlos syndrome and B4GALT7 deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        skin hyperextensibility, soft doughy skin, pes planus, delayed motor and
        cognitive development and osteopenia as minor criteria
      explanation: Pes planus is a recognized minor criterion in B4GALT7-spEDS.
  - target: Thin Wrinkled Skin of Hands and Feet
    description: Matrix fragility in acral skin manifests as thin, finely wrinkled skin.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32295219
      reference_title: "The Connective Tissue Disorder Associated with Recessive Variants in the SLC39A13 Zinc Transporter Gene (Spondylo-Dysplastic Ehlers-Danlos Syndrome Type 3): Insights from Four Novel Patients and Follow-Up on Two Original Cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "thin and finely wrinkled skin of the hands and feet"
      explanation: Acral thin wrinkled skin is a characteristic SLC39A13-spEDS manifestation.
  - target: Bluish Sclerae
    description: Ocular connective-tissue thinning manifests as bluish sclerae.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32295219
      reference_title: "The Connective Tissue Disorder Associated with Recessive Variants in the SLC39A13 Zinc Transporter Gene (Spondylo-Dysplastic Ehlers-Danlos Syndrome Type 3): Insights from Four Novel Patients and Follow-Up on Two Original Cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        prominent eyes with a paucity of periorbital fat, blueish sclerae
      explanation: Bluish sclerae occur in the SLC39A13-spEDS ocular connective-tissue phenotype.
  - target: Keratoconus
    description: Corneal connective-tissue weakness can manifest as keratoconus.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32295219
      reference_title: "The Connective Tissue Disorder Associated with Recessive Variants in the SLC39A13 Zinc Transporter Gene (Spondylo-Dysplastic Ehlers-Danlos Syndrome Type 3): Insights from Four Novel Patients and Follow-Up on Two Original Cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Two of our patients developed severe keratoconus"
      explanation: Keratoconus is reported as an ocular complication in SLC39A13-spEDS.
  - target: Myopia
    description: >
      Ocular connective-tissue involvement in SLC39A13-spEDS includes myopia,
      potentially related to thin sclerae.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32295219
      reference_title: "The Connective Tissue Disorder Associated with Recessive Variants in the SLC39A13 Zinc Transporter Gene (Spondylo-Dysplastic Ehlers-Danlos Syndrome Type 3): Insights from Four Novel Patients and Follow-Up on Two Original Cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Myopia has been reported in several SLC39A13 patients and also seems to
        be a direct (though non-specific) manifestation of the primary genetic
        defect.
      explanation: The SLC39A13 cohort identifies myopia as a recurrent ocular manifestation.
- name: ER/Golgi Iron Deficiency Due to ZIP13 Loss
  description: >
    SLC39A13 encodes the transporter ZIP13, historically classified as a zinc
    transporter. A 2024 study demonstrated that ZIP13's primary physiological
    function is iron transport into the ER/Golgi. ZIP13 loss causes iron
    deficiency in the ER/Golgi compartment, depriving Fe2+-dependent enzymes
    of their required cofactor.
  cell_types:
  - preferred_term: Fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  - preferred_term: Osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  biological_processes:
  - preferred_term: Iron Ion Transport
    modifier: DECREASED
    term:
      id: GO:0006826
      label: iron ion transport
  chemical_entities:
  - preferred_term: iron(2+)
    modifier: DECREASED
    term:
      id: CHEBI:29033
      label: iron(2+)
  evidence:
  - reference: PMID:39738060
    reference_title: "Mammalian SLC39A13 promotes ER/Golgi iron transport and iron homeostasis in multiple compartments."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      ZIP13 loss causes an iron deficiency in the ER/Golgi and other intracellular
      compartments, such as lysosomes and mitochondria, as well as elevating iron
      in the cytosol
    explanation: >-
      Demonstrates that ZIP13 functions as an iron transporter supplying the
      ER/Golgi, redefining the molecular mechanism of SLC39A13-spEDS.
  downstream:
  - target: Reduced Collagen Hydroxylation
    description: >
      ER/Golgi iron deficiency deprives lysyl and prolyl hydroxylases of their
      Fe2+ cofactor, reducing collagen hydroxylation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32295219
      reference_title: "The Connective Tissue Disorder Associated with Recessive Variants in the SLC39A13 Zinc Transporter Gene (Spondylo-Dysplastic Ehlers-Danlos Syndrome Type 3): Insights from Four Novel Patients and Follow-Up on Two Original Cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The observation of reduced collagen hydroxylation indicates that a partial
        failure of collagen crosslinking is one pathogenic mechanism
      explanation: Links ZIP13 deficiency to reduced collagen hydroxylation.
  - target: Defective Collagen Crosslinking
    description: >
      Reduced collagen hydroxylation leads to defective crosslinking, as
      measured by a reduced urinary pyridinoline-to-deoxypyridinoline ratio.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - reduced lysyl hydroxylation
    evidence:
    - reference: PMID:32295219
      reference_title: "The Connective Tissue Disorder Associated with Recessive Variants in the SLC39A13 Zinc Transporter Gene (Spondylo-Dysplastic Ehlers-Danlos Syndrome Type 3): Insights from Four Novel Patients and Follow-Up on Two Original Cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        All patients tested had a significantly reduced ratio of the two
        collagen-derived crosslink derivates, pyridinoline-to-deoxypyridinoline, in
        urine
      explanation: Biochemical evidence of defective collagen crosslinking in SLC39A13-spEDS patients.
  - target: Defective Myogenic Differentiation
    description: >
      ZIP13 is involved in myogenic differentiation; its loss impairs myotube
      formation, contributing to the muscular hypotonia observed in SLC39A13-spEDS.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38609428
      reference_title: "Possible involvement of zinc transporter ZIP13 in myogenic differentiation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We found that ZIP13 gene expression was upregulated by myogenic stimulation
        in C2C12 cells, and its knockdown disrupted myotubular differentiation
      explanation: Demonstrates ZIP13 role in myogenic differentiation using C2C12 cells.
  - target: SLC39A13-associated craniofacial and dental dysplasia
    description: >
      SLC39A13 loss is associated with a characteristic craniofacial, dental,
      ocular, and short-stature presentation; intermediates beyond collagen
      hydroxylation remain incompletely resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32295219
      reference_title: "The Connective Tissue Disorder Associated with Recessive Variants in the SLC39A13 Zinc Transporter Gene (Spondylo-Dysplastic Ehlers-Danlos Syndrome Type 3): Insights from Four Novel Patients and Follow-Up on Two Original Cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        However, it is difficult to ascribe the short stature, facial features,
        and oligodontia solely to reduced collagen hydroxylation.
      explanation: The SLC39A13 cohort supports an additional unresolved tissue-development branch for stature, facial, and dental features.
- name: Reduced Collagen Hydroxylation
  description: >
    ER/Golgi iron deficiency reduces iron cofactor availability for collagen
    lysyl and prolyl hydroxylases, causing impaired collagen hydroxylation in
    SLC39A13-related spEDS.
  cell_types:
  - preferred_term: Fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  - preferred_term: Osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  biological_processes:
  - preferred_term: Protein hydroxylation
    modifier: DECREASED
    term:
      id: GO:0018126
      label: protein hydroxylation
  - preferred_term: Collagen metabolic process
    modifier: ABNORMAL
    term:
      id: GO:0032963
      label: collagen metabolic process
  chemical_entities:
  - preferred_term: iron(2+)
    modifier: DECREASED
    term:
      id: CHEBI:29033
      label: iron(2+)
  evidence:
  - reference: PMID:32295219
    reference_title: "The Connective Tissue Disorder Associated with Recessive Variants in the SLC39A13 Zinc Transporter Gene (Spondylo-Dysplastic Ehlers-Danlos Syndrome Type 3): Insights from Four Novel Patients and Follow-Up on Two Original Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The observation of reduced collagen hydroxylation indicates that a partial
      failure of collagen crosslinking is one pathogenic mechanism
    explanation: Human SLC39A13-spEDS evidence identifies reduced collagen hydroxylation as a pathogenic mechanism.
  - reference: PMID:39738060
    reference_title: "Mammalian SLC39A13 promotes ER/Golgi iron transport and iron homeostasis in multiple compartments."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      ZIP13 loss causes an iron deficiency in the ER/Golgi and other
      intracellular compartments, such as lysosomes and mitochondria, as well as
      elevating iron in the cytosol
    explanation: ZIP13 loss directly produces ER/Golgi iron deficiency upstream of collagen hydroxylation defects.
  downstream:
  - target: Defective Collagen Crosslinking
    description: >
      Reduced lysyl hydroxylation produces abnormal collagen-derived crosslink
      ratios.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32295219
      reference_title: "The Connective Tissue Disorder Associated with Recessive Variants in the SLC39A13 Zinc Transporter Gene (Spondylo-Dysplastic Ehlers-Danlos Syndrome Type 3): Insights from Four Novel Patients and Follow-Up on Two Original Cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "A reduced molar ratio of pyridinoline-to-deoxypyridinoline in urine was observed, indicating reduced collagen lysyl hydroxylation."
      explanation: The reduced urinary collagen crosslink ratio is explicitly linked to reduced lysyl hydroxylation.
  - target: Reduced Pyridinoline-to-Deoxypyridinoline Ratio
    description: >
      Reduced collagen hydroxylation is captured clinically by a low urinary
      pyridinoline-to-deoxypyridinoline ratio.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32295219
      reference_title: "The Connective Tissue Disorder Associated with Recessive Variants in the SLC39A13 Zinc Transporter Gene (Spondylo-Dysplastic Ehlers-Danlos Syndrome Type 3): Insights from Four Novel Patients and Follow-Up on Two Original Cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        All patients tested had a significantly reduced ratio of the two
        collagen-derived crosslink derivates, pyridinoline-to-deoxypyridinoline,
        in urine
      explanation: The urinary crosslink ratio is a biochemical readout of the collagen hydroxylation defect.
- name: Defective Collagen Crosslinking
  description: >
    Reduced collagen hydroxylation alters collagen-derived crosslink chemistry,
    weakening connective tissues and contributing to skeletal, skin, ocular, and
    joint manifestations in SLC39A13-related spEDS.
  cell_types:
  - preferred_term: Fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: Collagen fibril organization
    modifier: ABNORMAL
    term:
      id: GO:0030199
      label: collagen fibril organization
  - preferred_term: Extracellular matrix organization
    modifier: ABNORMAL
    term:
      id: GO:0030198
      label: extracellular matrix organization
  evidence:
  - reference: PMID:32295219
    reference_title: "The Connective Tissue Disorder Associated with Recessive Variants in the SLC39A13 Zinc Transporter Gene (Spondylo-Dysplastic Ehlers-Danlos Syndrome Type 3): Insights from Four Novel Patients and Follow-Up on Two Original Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The observation of reduced collagen hydroxylation indicates that a partial
      failure of collagen crosslinking is one pathogenic mechanism
    explanation: The SLC39A13 cohort connects reduced hydroxylation to partial failure of collagen crosslinking.
  downstream:
  - target: Reduced Pyridinoline-to-Deoxypyridinoline Ratio
    description: >
      Defective collagen crosslinking is measured as a reduced urinary
      pyridinoline-to-deoxypyridinoline ratio.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32295219
      reference_title: "The Connective Tissue Disorder Associated with Recessive Variants in the SLC39A13 Zinc Transporter Gene (Spondylo-Dysplastic Ehlers-Danlos Syndrome Type 3): Insights from Four Novel Patients and Follow-Up on Two Original Cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        All patients tested had a significantly reduced ratio of the two
        collagen-derived crosslink derivates, pyridinoline-to-deoxypyridinoline,
        in urine
      explanation: The biochemical marker directly reflects altered collagen crosslink chemistry.
  - target: Connective tissue matrix laxity and skin fragility
    description: >
      Crosslinking defects weaken collagen-rich connective tissues.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32295219
      reference_title: "The Connective Tissue Disorder Associated with Recessive Variants in the SLC39A13 Zinc Transporter Gene (Spondylo-Dysplastic Ehlers-Danlos Syndrome Type 3): Insights from Four Novel Patients and Follow-Up on Two Original Cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        this may explain the mild chondrodysplastic features (collagen 2) as
        well as the thin and fragile skin and the putative vascular fragility
        (collagen 3).
      explanation: The authors connect collagen hydroxylation/crosslinking defects to chondrodysplasia and thin fragile skin.
  - target: Cerebrovascular accidents
    description: >
      Vascular connective-tissue fragility may contribute to cerebrovascular
      events in SLC39A13-spEDS, but the causal status remains uncertain.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32295219
      reference_title: "The Connective Tissue Disorder Associated with Recessive Variants in the SLC39A13 Zinc Transporter Gene (Spondylo-Dysplastic Ehlers-Danlos Syndrome Type 3): Insights from Four Novel Patients and Follow-Up on Two Original Cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Two of our patients developed severe keratoconus, and two suffered from
        cerebrovascular accidents in their twenties, suggesting that there may
        be a vascular component to this condition.
      explanation: The SLC39A13-spEDS cohort reports cerebrovascular accidents and cautiously suggests a vascular component.
  - target: Varicose veins
    description: >
      Connective-tissue fragility can involve venous tissues, producing varicose
      veins in SLC39A13-spEDS.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32295219
      reference_title: "The Connective Tissue Disorder Associated with Recessive Variants in the SLC39A13 Zinc Transporter Gene (Spondylo-Dysplastic Ehlers-Danlos Syndrome Type 3): Insights from Four Novel Patients and Follow-Up on Two Original Cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "marked varicosities of the lower legs have been described in a number of SLC39A13 patients."
      explanation: The SLC39A13 cohort identifies lower-leg varicosities as a vascular manifestation.
  - target: Platyspondyly
    description: >
      Collagen crosslinking defects in skeletal matrix contribute to vertebral
      flattening in SLC39A13-related spEDS.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - mild chondrodysplastic features
    evidence:
    - reference: PMID:32295219
      reference_title: "The Connective Tissue Disorder Associated with Recessive Variants in the SLC39A13 Zinc Transporter Gene (Spondylo-Dysplastic Ehlers-Danlos Syndrome Type 3): Insights from Four Novel Patients and Follow-Up on Two Original Cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "platyspondyly is a useful diagnostic feature"
      explanation: Platyspondyly is highlighted as a diagnostic skeletal manifestation of SLC39A13-spEDS.
- name: Defective Myogenic Differentiation
  description: >
    ZIP13 loss impairs myotube and myogenic differentiation in cellular models
    and patient-derived iPSC myocytes, providing a mechanistic route to muscular
    hypotonia.
  cell_types:
  - preferred_term: Myotube
    term:
      id: CL:0002372
      label: myotube
  biological_processes:
  - preferred_term: Myotube differentiation
    modifier: DECREASED
    term:
      id: GO:0014902
      label: myotube differentiation
  evidence:
  - reference: PMID:38609428
    reference_title: "Possible involvement of zinc transporter ZIP13 in myogenic differentiation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We found that ZIP13 gene expression was upregulated by myogenic stimulation
      in C2C12 cells, and its knockdown disrupted myotubular differentiation
    explanation: ZIP13 knockdown disrupts myotubular differentiation in a myogenic cell model.
  - reference: PMID:38609428
    reference_title: "Possible involvement of zinc transporter ZIP13 in myogenic differentiation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Myocytes differentiated from iPSCs derived from patients with EDSSPD3
      (EDSSPD3-iPSCs) also exhibited incomplete myogenic differentiation
    explanation: Patient-derived iPSC myocytes show incomplete myogenic differentiation.
  downstream:
  - target: Muscle Hypotonia
    description: >
      Incomplete myogenic differentiation provides a mechanistic explanation for
      muscular hypotonia in SLC39A13-spEDS.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - incomplete myogenic differentiation
    evidence:
    - reference: PMID:38609428
      reference_title: "Possible involvement of zinc transporter ZIP13 in myogenic differentiation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        patients with EDSSPD3 harboring a homozygous loss of function mutation
        (c.221G > A, p.G64D) in ZIP13 exon 2 (ZIP13G64D) suffer from impaired
        development of bone and connective tissues, and muscular hypotonia
      explanation: The ZIP13 myogenesis study ties EDSSPD3 to muscular hypotonia and impaired myogenic differentiation.
- name: SLC39A13-associated craniofacial and dental dysplasia
  description: >
    SLC39A13-related spEDS includes a recurrent craniofacial, ocular, dental, and
    short-stature pattern. The clinical data indicate that some of these features
    are not fully explained by collagen hydroxylation alone, so this node records
    the tissue-development branch with unresolved intermediates.
  evidence:
  - reference: PMID:32295219
    reference_title: "The Connective Tissue Disorder Associated with Recessive Variants in the SLC39A13 Zinc Transporter Gene (Spondylo-Dysplastic Ehlers-Danlos Syndrome Type 3): Insights from Four Novel Patients and Follow-Up on Two Original Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, it is difficult to ascribe the short stature, facial features, and
      oligodontia solely to reduced collagen hydroxylation.
    explanation: The cohort supports a craniofacial/dental developmental branch beyond the collagen crosslinking mechanism alone.
  downstream:
  - target: Short Stature
    description: SLC39A13-related tissue-development dysplasia includes postnatal short stature.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32295219
      reference_title: "The Connective Tissue Disorder Associated with Recessive Variants in the SLC39A13 Zinc Transporter Gene (Spondylo-Dysplastic Ehlers-Danlos Syndrome Type 3): Insights from Four Novel Patients and Follow-Up on Two Original Cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "significant short stature of childhood onset"
      explanation: Childhood-onset short stature is a characteristic SLC39A13-spEDS feature.
  - target: Downslanting Palpebral Fissures
    description: Craniofacial dysplasia manifests with downslanting palpebral fissures.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32295219
      reference_title: "The Connective Tissue Disorder Associated with Recessive Variants in the SLC39A13 Zinc Transporter Gene (Spondylo-Dysplastic Ehlers-Danlos Syndrome Type 3): Insights from Four Novel Patients and Follow-Up on Two Original Cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        characteristic facial features with downslanting palpebral fissures,
        mild hypertelorism, prominent eyes with a paucity of periorbital fat,
        blueish sclerae
      explanation: The clinical cohort describes downslanting palpebral fissures as part of the characteristic facial gestalt.
  - target: Prominent Eyes
    description: Craniofacial and periorbital connective-tissue changes manifest as prominent eyes.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32295219
      reference_title: "The Connective Tissue Disorder Associated with Recessive Variants in the SLC39A13 Zinc Transporter Gene (Spondylo-Dysplastic Ehlers-Danlos Syndrome Type 3): Insights from Four Novel Patients and Follow-Up on Two Original Cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "prominent eyes with a paucity of periorbital fat"
      explanation: Prominent eyes are part of the SLC39A13-spEDS facial phenotype.
  - target: Hypertelorism
    description: Craniofacial dysplasia manifests as mild hypertelorism.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32295219
      reference_title: "The Connective Tissue Disorder Associated with Recessive Variants in the SLC39A13 Zinc Transporter Gene (Spondylo-Dysplastic Ehlers-Danlos Syndrome Type 3): Insights from Four Novel Patients and Follow-Up on Two Original Cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "mild hypertelorism"
      explanation: Mild hypertelorism is reported as part of the facial phenotype.
  - target: Oligodontia
    description: Dental development involvement manifests as oligodontia.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32295219
      reference_title: "The Connective Tissue Disorder Associated with Recessive Variants in the SLC39A13 Zinc Transporter Gene (Spondylo-Dysplastic Ehlers-Danlos Syndrome Type 3): Insights from Four Novel Patients and Follow-Up on Two Original Cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "microdontia, or oligodontia"
      explanation: Oligodontia is reported in SLC39A13-spEDS and fits the abnormal odontogenesis annotation.
phenotypes:
- name: Short Stature
  category: Skeletal
  description: >
    Proportionate or disproportionate short stature is a major criterion across
    all three spEDS subtypes, typically manifesting in infancy or early childhood.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:28882145
    reference_title: "Expanding the clinical and mutational spectrum of B4GALT7-spondylodysplastic Ehlers-Danlos syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The majority of spEDS patients presented with short stature, skin
      hyperextensibility, facial dysmorphisms, peculiar radiological findings,
      muscle hypotonia and joint laxity
    explanation: Short stature is listed as a major feature of spEDS.
  - reference: PMID:32295219
    reference_title: "The Connective Tissue Disorder Associated with Recessive Variants in the SLC39A13 Zinc Transporter Gene (Spondylo-Dysplastic Ehlers-Danlos Syndrome Type 3): Insights from Four Novel Patients and Follow-Up on Two Original Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      significant short stature of childhood onset
    explanation: Short stature confirmed in SLC39A13-spEDS patients.
- name: Muscle Hypotonia
  category: Neurological
  description: >
    Generalized muscle hypotonia is a major criterion, present from birth or early
    infancy. Contributes to delayed motor development.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Generalized muscle hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:28882145
    reference_title: "Expanding the clinical and mutational spectrum of B4GALT7-spondylodysplastic Ehlers-Danlos syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The majority of spEDS patients presented with short stature, skin
      hyperextensibility, facial dysmorphisms, peculiar radiological findings,
      muscle hypotonia and joint laxity
    explanation: Muscle hypotonia is a major feature of spEDS.
  - reference: PMID:38609428
    reference_title: "Possible involvement of zinc transporter ZIP13 in myogenic differentiation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      patients with EDSSPD3 harboring a homozygous loss of function mutation
      (c.221G > A, p.G64D) in ZIP13 exon 2 (ZIP13G64D) suffer from impaired
      development of bone and connective tissues, and muscular hypotonia
    explanation: Muscular hypotonia confirmed as a feature of SLC39A13-spEDS.
- name: Platyspondyly
  category: Skeletal
  description: >
    Flattening of vertebral bodies visible on radiography. A characteristic
    skeletal finding across spEDS subtypes.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Platyspondyly
    term:
      id: HP:0000926
      label: Platyspondyly
  evidence:
  - reference: PMID:32295219
    reference_title: "The Connective Tissue Disorder Associated with Recessive Variants in the SLC39A13 Zinc Transporter Gene (Spondylo-Dysplastic Ehlers-Danlos Syndrome Type 3): Insights from Four Novel Patients and Follow-Up on Two Original Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      platyspondyly is a useful diagnostic feature
    explanation: Platyspondyly is highlighted as a diagnostically useful radiographic finding.
- name: Hyperextensible Skin
  category: Integumentary
  description: >
    Skin hyperextensibility is a minor criterion for spEDS. In SLC39A13-related
    cases, the skin is characteristically thin and finely wrinkled on the hands
    and feet.
  phenotype_term:
    preferred_term: Hyperextensible skin
    term:
      id: HP:0000974
      label: Hyperextensible skin
  evidence:
  - reference: PMID:28882145
    reference_title: "Expanding the clinical and mutational spectrum of B4GALT7-spondylodysplastic Ehlers-Danlos syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The majority of spEDS patients presented with short stature, skin
      hyperextensibility, facial dysmorphisms, peculiar radiological findings,
      muscle hypotonia and joint laxity
    explanation: Skin hyperextensibility listed as a feature of spEDS.
- name: Joint Hypermobility
  category: Musculoskeletal
  description: >
    Generalized or distal joint hypermobility is present across subtypes.
    In SLC39A13-spEDS it is most marked in finger joints. A systematic review
    found joint hypermobility in 96% of spEDS cases (24/25).
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Joint hypermobility
    term:
      id: HP:0001382
      label: Joint hypermobility
  evidence:
  - reference: PMID:36756177
    reference_title: "Extracutaneous features and complications of the Ehlers-Danlos syndromes: A systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We noted a high prevalence of joint hypermobility amongst kyphoscoliotic
      (39/39, 100%), spondylodysplastic (24/25, 96.0%), and hypermobile (153/160,
      95.6%) EDS subtypes
    explanation: Systematic review quantifying 96% prevalence of joint hypermobility in spEDS.
  - reference: PMID:28882145
    reference_title: "Expanding the clinical and mutational spectrum of B4GALT7-spondylodysplastic Ehlers-Danlos syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The majority of spEDS patients presented with short stature, skin
      hyperextensibility, facial dysmorphisms, peculiar radiological findings,
      muscle hypotonia and joint laxity
    explanation: Joint laxity confirmed as a common feature of spEDS.
- name: Osteopenia
  category: Skeletal
  description: >
    Reduced bone mineral density is a minor criterion. May progress to
    osteoporosis and contribute to fracture risk.
  phenotype_term:
    preferred_term: Osteopenia
    term:
      id: HP:0000938
      label: Osteopenia
  evidence:
  - reference: PMID:34193099
    reference_title: "Report of two siblings with spondylodysplastic Ehlers-Danlos syndrome and B4GALT7 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      skin hyperextensibility, soft doughy skin, pes planus, delayed motor and
      cognitive development and osteopenia as minor criteria
    explanation: Osteopenia listed among minor diagnostic criteria.
- name: Bowing of the Long Bones
  category: Skeletal
  description: >
    Bowing of long bones is a radiographic finding reported in spEDS.
    Zebrafish models of B4GALT7 deficiency recapitulate limb bowing
    phenotypes.
  phenotype_term:
    preferred_term: Bowing of the long bones
    term:
      id: HP:0006487
      label: Bowing of the long bones
  evidence:
  - reference: PMID:31862401
    reference_title: "Hypomorphic zebrafish models mimic the musculoskeletal phenotype of β4GalT7-deficient Ehlers-Danlos syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Morphant and crispant zebrafish show highly similar morphological
      abnormalities in early development including a small, round head, bowed
      pectoral fins, short body-axis and mild developmental delay
    explanation: >-
      Zebrafish models of B4galt7 deficiency show bowed pectoral fins,
      recapitulating the limb bowing phenotype seen in human spEDS.
- name: Pes Planus
  category: Musculoskeletal
  description: Flat feet, a minor criterion for spEDS.
  phenotype_term:
    preferred_term: Pes planus
    term:
      id: HP:0001763
      label: Pes planus
  evidence:
  - reference: PMID:34193099
    reference_title: "Report of two siblings with spondylodysplastic Ehlers-Danlos syndrome and B4GALT7 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      skin hyperextensibility, soft doughy skin, pes planus, delayed motor and
      cognitive development and osteopenia as minor criteria
    explanation: Pes planus listed as a minor criterion.
- name: Radioulnar Synostosis
  category: Skeletal
  subtype: spEDS-B4GALT7
  description: >
    Fusion of the radius and ulna is a characteristic finding in B4GALT7-related
    spEDS and helps distinguish it from other subtypes.
  phenotype_term:
    preferred_term: Radioulnar synostosis
    term:
      id: HP:0002974
      label: Radioulnar synostosis
  evidence:
  - reference: PMID:28882145
    reference_title: "Expanding the clinical and mutational spectrum of B4GALT7-spondylodysplastic Ehlers-Danlos syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      in addition to short stature and muscle hypotonia, radioulnar synostosis,
      hypermetropia, and delayed cognitive development might be a hallmark of this
      specific type of spEDS
    explanation: Radioulnar synostosis is a hallmark finding in B4GALT7-spEDS.
- name: Delayed Cognitive Development
  category: Neurological
  subtype: spEDS-B4GALT7
  description: >
    Delayed motor and cognitive development is reported as a minor diagnostic
    criterion and possible hallmark of B4GALT7-related spEDS.
  phenotype_term:
    preferred_term: Delayed cognitive development
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:28882145
    reference_title: "Expanding the clinical and mutational spectrum of B4GALT7-spondylodysplastic Ehlers-Danlos syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      in addition to short stature and muscle hypotonia, radioulnar synostosis,
      hypermetropia, and delayed cognitive development might be a hallmark of
      this specific type of spEDS
    explanation: Delayed cognitive development is described as a possible hallmark of B4GALT7-spEDS.
  - reference: PMID:34193099
    reference_title: "Report of two siblings with spondylodysplastic Ehlers-Danlos syndrome and B4GALT7 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      skin hyperextensibility, soft doughy skin, pes planus, delayed motor and
      cognitive development and osteopenia as minor criteria
    explanation: B4GALT7-spEDS criteria include delayed motor and cognitive development.
- name: Bluish Sclerae
  category: Ophthalmologic
  subtype: spEDS-SLC39A13
  description: >
    Blue discoloration of the sclerae, reflecting thin scleral connective tissue,
    is characteristic of SLC39A13-spEDS.
  phenotype_term:
    preferred_term: Blue sclerae
    term:
      id: HP:0000592
      label: Blue sclerae
  evidence:
  - reference: PMID:32295219
    reference_title: "The Connective Tissue Disorder Associated with Recessive Variants in the SLC39A13 Zinc Transporter Gene (Spondylo-Dysplastic Ehlers-Danlos Syndrome Type 3): Insights from Four Novel Patients and Follow-Up on Two Original Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      thin and finely wrinkled skin of the hands and feet, characteristic facial
      features with downslanting palpebral fissures, mild hypertelorism, prominent
      eyes with a paucity of periorbital fat, blueish sclerae
    explanation: Bluish sclerae described as a characteristic feature in SLC39A13-spEDS.
- name: Downslanting Palpebral Fissures
  category: Craniofacial
  subtype: spEDS-SLC39A13
  description: >
    Downslanting palpebral fissures are part of the characteristic facial
    gestalt in SLC39A13-spEDS.
  phenotype_term:
    preferred_term: Downslanting palpebral fissures
    term:
      id: HP:0000494
      label: Downslanted palpebral fissures
  evidence:
  - reference: PMID:32295219
    reference_title: "The Connective Tissue Disorder Associated with Recessive Variants in the SLC39A13 Zinc Transporter Gene (Spondylo-Dysplastic Ehlers-Danlos Syndrome Type 3): Insights from Four Novel Patients and Follow-Up on Two Original Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      characteristic facial features with downslanting palpebral fissures, mild
      hypertelorism, prominent eyes with a paucity of periorbital fat, blueish
      sclerae
    explanation: Downslanting palpebral fissures are a characteristic facial feature.
- name: Prominent Eyes
  category: Craniofacial
  subtype: spEDS-SLC39A13
  description: >
    Prominent eyes with paucity of periorbital fat, contributing to the
    distinctive facial appearance in SLC39A13-spEDS.
  phenotype_term:
    preferred_term: Proptosis
    term:
      id: HP:0000520
      label: Proptosis
  evidence:
  - reference: PMID:32295219
    reference_title: "The Connective Tissue Disorder Associated with Recessive Variants in the SLC39A13 Zinc Transporter Gene (Spondylo-Dysplastic Ehlers-Danlos Syndrome Type 3): Insights from Four Novel Patients and Follow-Up on Two Original Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      prominent eyes with a paucity of periorbital fat
    explanation: Prominent eyes described in SLC39A13-spEDS facial gestalt.
- name: Thin Wrinkled Skin of Hands and Feet
  category: Integumentary
  subtype: spEDS-SLC39A13
  description: >
    Characteristic thin and finely wrinkled skin localized to the hands and
    feet in SLC39A13-spEDS.
  phenotype_term:
    preferred_term: Thin skin
    term:
      id: HP:0000963
      label: Thin skin
  evidence:
  - reference: PMID:32295219
    reference_title: "The Connective Tissue Disorder Associated with Recessive Variants in the SLC39A13 Zinc Transporter Gene (Spondylo-Dysplastic Ehlers-Danlos Syndrome Type 3): Insights from Four Novel Patients and Follow-Up on Two Original Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      thin and finely wrinkled skin of the hands and feet
    explanation: Thin wrinkled acral skin is a distinguishing feature of SLC39A13-spEDS.
- name: Keratoconus
  category: Ophthalmologic
  subtype: spEDS-SLC39A13
  description: >
    Severe keratoconus has been reported in adult SLC39A13-spEDS patients
    and may require corneal transplantation.
  phenotype_term:
    preferred_term: Keratoconus
    term:
      id: HP:0000563
      label: Keratoconus
  evidence:
  - reference: PMID:32295219
    reference_title: "The Connective Tissue Disorder Associated with Recessive Variants in the SLC39A13 Zinc Transporter Gene (Spondylo-Dysplastic Ehlers-Danlos Syndrome Type 3): Insights from Four Novel Patients and Follow-Up on Two Original Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two of our patients developed severe keratoconus
    explanation: Keratoconus reported as a complication in adult SLC39A13-spEDS patients.
- name: Myopia
  category: Ophthalmologic
  subtype: spEDS-SLC39A13
  description: >
    Myopia has been reported in several SLC39A13-spEDS patients and may relate
    to ocular connective-tissue thinning.
  phenotype_term:
    preferred_term: Myopia
    term:
      id: HP:0000545
      label: Myopia
  evidence:
  - reference: PMID:32295219
    reference_title: "The Connective Tissue Disorder Associated with Recessive Variants in the SLC39A13 Zinc Transporter Gene (Spondylo-Dysplastic Ehlers-Danlos Syndrome Type 3): Insights from Four Novel Patients and Follow-Up on Two Original Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Myopia has been reported in several SLC39A13 patients and also seems to be
      a direct (though non-specific) manifestation of the primary genetic defect.
    explanation: The SLC39A13-spEDS cohort reports recurrent myopia.
- name: Cerebrovascular accidents
  category: Neurological
  subtype: spEDS-SLC39A13
  description: >
    Cerebrovascular accidents, including cerebral hemorrhage or ischemic events,
    have been reported in older SLC39A13-spEDS patients. The causal relationship
    remains uncertain, but the finding is noted as a potential vascular
    complication.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Stroke
    term:
      id: HP:0001297
      label: Stroke
  evidence:
  - reference: PMID:32295219
    reference_title: "The Connective Tissue Disorder Associated with Recessive Variants in the SLC39A13 Zinc Transporter Gene (Spondylo-Dysplastic Ehlers-Danlos Syndrome Type 3): Insights from Four Novel Patients and Follow-Up on Two Original Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two of our patients developed severe keratoconus, and two suffered from
      cerebrovascular accidents in their twenties, suggesting that there may be
      a vascular component to this condition.
    explanation: Reports cerebrovascular accidents in two SLC39A13-spEDS patients.
  - reference: PMID:32295219
    reference_title: "The Connective Tissue Disorder Associated with Recessive Variants in the SLC39A13 Zinc Transporter Gene (Spondylo-Dysplastic Ehlers-Danlos Syndrome Type 3): Insights from Four Novel Patients and Follow-Up on Two Original Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe here four additional affected individuals from three
      consanguineous families and the follow up of two of the original cases.
    explanation: Together with the two cerebrovascular events, this six-patient cohort supports an occasional frequency assignment.
- name: Varicose veins
  category: Cardiovascular
  subtype: spEDS-SLC39A13
  description: >
    Marked venous varicosities of the lower legs and feet have been described in
    SLC39A13-spEDS.
  phenotype_term:
    preferred_term: Varicose veins
    term:
      id: HP:0002619
      label: Varicose veins
  evidence:
  - reference: PMID:32295219
    reference_title: "The Connective Tissue Disorder Associated with Recessive Variants in the SLC39A13 Zinc Transporter Gene (Spondylo-Dysplastic Ehlers-Danlos Syndrome Type 3): Insights from Four Novel Patients and Follow-Up on Two Original Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both individuals had marked venous varicosities on their legs and feet."
    explanation: The follow-up of original SLC39A13-spEDS patients documents marked venous varicosities.
- name: Hypertelorism
  category: Craniofacial
  subtype: spEDS-SLC39A13
  description: >
    Mild hypertelorism is part of the characteristic facial features in
    SLC39A13-spEDS.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: PMID:32295219
    reference_title: "The Connective Tissue Disorder Associated with Recessive Variants in the SLC39A13 Zinc Transporter Gene (Spondylo-Dysplastic Ehlers-Danlos Syndrome Type 3): Insights from Four Novel Patients and Follow-Up on Two Original Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      mild hypertelorism
    explanation: Mild hypertelorism noted as part of characteristic facial features.
- name: Oligodontia
  category: Craniofacial
  subtype: spEDS-SLC39A13
  description: >
    Absence of one or several teeth in the permanent dentition, observed in
    a majority of SLC39A13-deficient individuals.
  phenotype_term:
    preferred_term: Oligodontia
    term:
      id: HP:0000677
      label: Oligodontia
  evidence:
  - reference: PMID:32295219
    reference_title: "The Connective Tissue Disorder Associated with Recessive Variants in the SLC39A13 Zinc Transporter Gene (Spondylo-Dysplastic Ehlers-Danlos Syndrome Type 3): Insights from Four Novel Patients and Follow-Up on Two Original Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      microdontia, or oligodontia
    explanation: Oligodontia is part of the dental phenotype in SLC39A13-spEDS.
biochemical:
- name: Reduced Pyridinoline-to-Deoxypyridinoline Ratio
  notes: >
    Urinary collagen crosslink analysis shows a significantly reduced
    pyridinoline-to-deoxypyridinoline ratio in SLC39A13-spEDS patients,
    reflecting impaired collagen hydroxylation. This test can serve as a
    diagnostic screening method.
  evidence:
  - reference: PMID:32295219
    reference_title: "The Connective Tissue Disorder Associated with Recessive Variants in the SLC39A13 Zinc Transporter Gene (Spondylo-Dysplastic Ehlers-Danlos Syndrome Type 3): Insights from Four Novel Patients and Follow-Up on Two Original Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients tested had a significantly reduced ratio of the two
      collagen-derived crosslink derivates, pyridinoline-to-deoxypyridinoline, in
      urine, suggesting that this simple test is diagnostically useful
    explanation: A biochemical marker distinguishing SLC39A13-spEDS from other subtypes.
- name: Abnormal Glycosaminoglycan Linkage Region
  notes: >
    B3GALT6-deficient patients show abnormal glycosaminoglycan linkage region
    structures on urinary bikunin, with non-canonical trisaccharide modifications
    alongside canonical tetrasaccharide structures.
  evidence:
  - reference: PMID:36101818
    reference_title: "Glycosaminoglycan linkage region of urinary bikunin as a potentially useful biomarker for beta3GalT6-deficient spondylodysplastic Ehlers-Danlos syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      contained two different glycopeptide peaks, corresponding to the canonical
      tetrasaccharide and to the non-canonical trisaccharide linkage region
      modifications
    explanation: Demonstrates structural GAG linkage region abnormalities as a biomarker for B3GALT6 deficiency.
treatments:
- name: Supportive Care and Surveillance
  description: >
    No disease-specific therapy is established in this entry; management is
    supportive and complication-directed, including rehabilitation after
    neurologic events and ophthalmologic surveillance for keratoconus risk.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:32295219
    reference_title: "The Connective Tissue Disorder Associated with Recessive Variants in the SLC39A13 Zinc Transporter Gene (Spondylo-Dysplastic Ehlers-Danlos Syndrome Type 3): Insights from Four Novel Patients and Follow-Up on Two Original Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fortunately, she was able to partially recover over four years on
      physiotherapy but still has partial function of the right hand and
      myoclonus on the right arm.
    explanation: Rehabilitation was used after a neurologic complication in an SLC39A13-spEDS patient.
  - reference: PMID:32295219
    reference_title: "The Connective Tissue Disorder Associated with Recessive Variants in the SLC39A13 Zinc Transporter Gene (Spondylo-Dysplastic Ehlers-Danlos Syndrome Type 3): Insights from Four Novel Patients and Follow-Up on Two Original Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ophthalmologic investigation should be recommended in all confirmed cases."
    explanation: Ophthalmologic surveillance is recommended because keratoconus can be severe.
genetic:
- name: B4GALT7
  association: Causative
  gene_term:
    preferred_term: B4GALT7
    term:
      id: hgnc:930
      label: B4GALT7
  notes: >
    Encodes galactosyltransferase I, required for initiation of glycosaminoglycan
    side chain synthesis on proteoglycans. Biallelic pathogenic variants cause
    spEDS-B4GALT7. The p.R270C variant is the most frequently reported, particularly
    in the Reunion Island population (Larsen Reunion syndrome).
  evidence:
  - reference: PMID:34193099
    reference_title: "Report of two siblings with spondylodysplastic Ehlers-Danlos syndrome and B4GALT7 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      galactosyltransferase I, which is required for the initiation of
      glycosaminoglycan side chain synthesis of proteoglycans
    explanation: Describes B4GALT7 enzymatic function and its link to spEDS.
  - reference: PMID:28882145
    reference_title: "Expanding the clinical and mutational spectrum of B4GALT7-spondylodysplastic Ehlers-Danlos syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Spondylodysplastic EDS (spEDS) is a rare connective tissue disorder
      that groups the phenotypes caused by biallelic B4GALT7, B3GALT6, and SLC39A13
      mutations
    explanation: Confirms B4GALT7 as one of three causative genes for spEDS.
- name: B3GALT6
  association: Causative
  gene_term:
    preferred_term: B3GALT6
    term:
      id: hgnc:17978
      label: B3GALT6
  notes: >
    Encodes beta-1,3-galactosyltransferase 6, responsible for addition of
    the second galactose in the common tetrasaccharide linker region of
    glycosaminoglycans. Biallelic variants cause spEDS-B3GALT6, a linkeropathy
    with a broad phenotypic spectrum.
  evidence:
  - reference: PMID:37657630
    reference_title: "B3GALT6-linkeropathy: Three illustrative patients spanning the disease spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Each "linker" gene encodes an enzyme responsible for the addition of
      glycosaminoglycan chains to proteoglycans via a common tertrasaccharine
      linker region
    explanation: Establishes B3GALT6 as a linker gene causing a linkeropathy classified under spEDS.
  - reference: PMID:34159694
    reference_title: "Broadening the phenotypic spectrum of Beta3GalT6-associated phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Beta3GalT6-related disorders were grouped in the spondylodysplastic EDSs
      together with spondylodysplastic EDSs due to B4GALT7 and SLC39A13 mutations
    explanation: Confirms B3GALT6-related disorders are classified under spEDS.
- name: SLC39A13
  association: Causative
  gene_term:
    preferred_term: SLC39A13
    term:
      id: hgnc:20859
      label: SLC39A13
  notes: >
    Encodes the transporter ZIP13, now recognized as an ER/Golgi iron
    transporter (previously classified as zinc). Biallelic loss-of-function
    variants cause spEDS-SLC39A13 through impaired iron supply to ER-resident
    collagen hydroxylases. Fewer than 15 patients confirmed worldwide.
  evidence:
  - reference: PMID:32295219
    reference_title: "The Connective Tissue Disorder Associated with Recessive Variants in the SLC39A13 Zinc Transporter Gene (Spondylo-Dysplastic Ehlers-Danlos Syndrome Type 3): Insights from Four Novel Patients and Follow-Up on Two Original Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recessive loss-of-function variants in SLC39A13, a putative zinc transporter
      gene, were first associated with a connective tissue disorder
    explanation: Identifies SLC39A13 as a causative gene for spEDS.
  - reference: PMID:36727144
    reference_title: "A case of Ehlers-Danlos syndrome presenting as short stature: a novel mutation in SLC39A13 causing spondylodysplastic Ehlers-Danlos syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a novel mutation in SLC39A13 causing spondylodysplastic Ehlers-Danlos syndrome
    explanation: Case report confirming a novel SLC39A13 variant causing spEDS.
  - reference: PMID:39738060
    reference_title: "Mammalian SLC39A13 promotes ER/Golgi iron transport and iron homeostasis in multiple compartments."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here, we show that SLC39A13 (ZIP13), previously identified as a zinc
      transporter, promotes intracellular iron transport and reduces intracellular
      iron levels.
    explanation: Supports the updated interpretation of ZIP13 as an ER/Golgi iron transporter.
animal_models:
- species: Mouse
  genotype: Slc39a13/Zip13-knockout
  genes:
  - preferred_term: SLC39A13
    term:
      id: hgnc:20859
      label: SLC39A13
  description: >
    The Zip13-KO mouse recapitulates connective tissue features of SLC39A13-spEDS
    including growth retardation and abnormalities of vascular and corneal
    connective tissue.
  evidence:
  - reference: PMID:30610452
    reference_title: "Morphometric analysis of thoracic aorta in Slc39a13/Zip13-KO mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Our assessment found abnormalities in the number and morphology of elastic
      and cellular components in the aortic wall, especially the tunica media, of
      Zip13-KO mice, indicating aortic fragility.
    explanation: >-
      Zip13-KO mice show aortic wall abnormalities relevant to understanding
      vascular fragility in SLC39A13-spEDS.
- species: Zebrafish
  genotype: b4galt7 morphant and crispant
  genes:
  - preferred_term: B4GALT7
    term:
      id: hgnc:930
      label: B4GALT7
  description: >
    Hypomorphic zebrafish models with partial loss of B4galt7 function recapitulate
    the musculoskeletal phenotype of B4GALT7-spEDS including craniofacial cartilage
    defects, reduced glycosaminoglycans, and impaired chondrocyte organization.
  evidence:
  - reference: PMID:31862401
    reference_title: "Hypomorphic zebrafish models mimic the musculoskeletal phenotype of β4GalT7-deficient Ehlers-Danlos syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Several craniofacial cartilage and bone structures are absent or strongly
      misshapen. In addition, the total amount of sulfated glycosaminoglycans is
      significantly diminished and particularly heparan and chondroitin sulfate
      proteoglycan levels are greatly reduced
    explanation: >-
      Zebrafish models demonstrate that B4galt7 deficiency causes skeletal and
      GAG biosynthesis defects matching human spEDS-B4GALT7 phenotype.
📚

References & Deep Research

Deep Research

1
Falcon ▸
Disease Pathophysiology Research Template
Edison Scientific Literature 35 citations 2026-04-02T23:00:18.058977

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Pathophysiology Research Template

Target Disease

  • Disease Name: Spondylodysplastic Ehlers-Danlos Syndrome
  • MONDO ID: (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on the pathophysiology of Spondylodysplastic Ehlers-Danlos Syndrome. Focus on the molecular and cellular mechanisms underlying disease progression.

Required Information

1. Core Pathophysiology

  • What are the primary pathophysiological mechanisms?
  • What molecular pathways are dysregulated?
  • What cellular processes are affected?

2. Key Molecular Players

  • Genes/Proteins: Which genes are causally involved or implicated?
  • Chemical Entities: What metabolites, drugs, or small molecules are relevant?
  • Cell Types: Which cell types are primarily affected?
  • Anatomical Locations: Which tissues/organs are involved?

3. Biological Processes (for GO annotation)

  • What biological processes (GO terms) are disrupted?
  • Consider: signaling pathways, metabolic processes, cellular responses, transport, etc.

4. Cellular Components

  • Where in the cell do key processes occur?
  • Consider: organelles, membrane compartments, extracellular space, etc.

5. Disease Progression

  • What is the sequence of events from initial trigger to clinical manifestation?
  • Are there distinct stages or phases?

6. Phenotypic Manifestations

  • What are the key clinical phenotypes?
  • How do they relate to the underlying mechanisms?

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes where possible to support key statements

Output Format

Structure your response as a narrative that could be used to populate a disease knowledge base entry with: - Pathophysiology description - Gene/protein annotations with ontology terms (HGNC, GO) - Phenotype associations (HP terms) - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Evidence items with PMIDs

Comprehensive Research Report: Pathophysiology of Spondylodysplastic Ehlers–Danlos Syndrome (spEDS)

Executive summary

Spondylodysplastic Ehlers–Danlos syndrome (spEDS) is an autosomal recessive, ultra-rare monogenic EDS subtype defined by a core triad of short stature, muscle hypotonia, and skeletal dysplasia-like features, together with connective-tissue manifestations such as joint hypermobility and skin hyperextensibility. Contemporary reviews estimate prevalence <1:1,000,000 and note >100 reported individuals. (dijk2024clinicaldiagnosisof pages 4-6, zschocke2024geneticdiagnosisof pages 5-6)

Mechanistically, spEDS comprises at least two convergent molecular “axes”: 1) Proteoglycan linker-region (GAG) biosynthesis defects (“linkeropathies”) due to biallelic pathogenic variants in B4GALT7 or B3GALT6 (and, in some framings, closely overlapping phenotypes from other linker enzymes such as B3GAT3). These disrupt formation of heparan sulfate (HS), chondroitin sulfate (CS), and dermatan sulfate (DS) proteoglycans, altering extracellular matrix (ECM) organization, collagen fibrillogenesis, and tissue biomechanics. (caraffi2019severeperipheraljoint pages 1-3, damme2018biallelicb3galt6mutations pages 1-4, damme2018biallelicb3galt6mutations pages 10-13) 2) Secretory-pathway metal homeostasis / collagen post-translational modification defects caused by biallelic pathogenic variants in SLC39A13 (ZIP13). A major 2024 advance is evidence that ZIP13’s primary physiological role is ER/Golgi iron transport, needed to supply Fe2+ cofactors to ER-resident lysyl/prolyl hydroxylases for collagen hydroxylation; ZIP13 loss leads to reduced collagen hydroxylation and provides a direct mechanistic bridge from transporter dysfunction to connective-tissue pathology. (li2024mammalianslc39a13promotes pages 4-5, li2024mammalianslc39a13promotes pages 8-9)

Disease identifiers and nosology

  • Disease name: Spondylodysplastic Ehlers–Danlos syndrome (spEDS)
  • MONDO: MONDO_0034021 (Open Targets disease identifier surfaced in this run; used for disease–target associations). (diana2025b3galt6mutationslead pages 1-2)
  • OMIM (examples from spEDS-related subtypes):
  • B4GALT7-related spEDS: EDS, spondylodysplastic type (OMIM #130070) (caraffi2019severeperipheraljoint pages 1-3, doolan2023extracutaneousfeaturesand pages 1-2)
  • B3GALT6-related severe EDS-like disorder: OMIM #615349 (caraffi2019severeperipheraljoint pages 1-3, doolan2023extracutaneousfeaturesand pages 1-2)
  • SLC39A13-related spEDS: referred to as EDSSPD3, OMIM 612350 in 2024 mechanistic work. (shoji2024possibleinvolvementof pages 1-2)

Definition and diagnostic criteria (2017 EDS classification-derived)

A widely used clinical suspicion framework requires two major criteria (short stature; muscle hypotonia) plus characteristic radiographic changes and additional minor criteria, followed by confirmatory molecular testing. (ritelli2017expandingtheclinical pages 1-2)

Two extracted table images from Ritelli et al. (2017) provide a compact representation of these criteria and gene-specific feature sets (Tables 1–2). (ritelli2017expandingtheclinical media 36a1859a, ritelli2017expandingtheclinical media 0d274780)

1. Core pathophysiology

1.1 Linkeropathy axis (B4GALT7, B3GALT6): disrupted GAG–proteoglycan synthesis and ECM biomechanics

Proteoglycans (PGs) carry glycosaminoglycan (GAG) chains attached to core proteins via a conserved tetrasaccharide linker. B4GALT7 and B3GALT6 encode two sequential Golgi galactosyltransferases required to build this linker; loss-of-function variants impair HS/CS/DS assembly and lead to a combined connective-tissue + skeletal phenotype (“linkeropathy”). (caraffi2019severeperipheraljoint pages 1-3, damme2018biallelicb3galt6mutations pages 1-4)

Mechanistic consequences documented in patient-derived fibroblasts and model organisms include: - Reduced total GAG synthesis and reduced HS/CS/DS production, including impaired conversion of decorin core protein into mature GAG-bearing proteoglycan. (delbaere2020hypomorphiczebrafishmodels pages 1-5, damme2018biallelicb3galt6mutations pages 10-13) - Abnormal collagen fibril architecture (e.g., altered interfibrillar spacing and fibril variability), consistent with proteoglycan-mediated control of collagen fibrillogenesis and tissue mechanics. (damme2018biallelicb3galt6mutations pages 10-13, damme2018biallelicb3galt6mutations pages 13-15) - Impaired cell migration/wound closure in B3GALT6 patient fibroblasts, linking ECM defects to cellular-level functional phenotypes. (damme2018biallelicb3galt6mutations pages 10-13)

1.2 ZIP13 axis (SLC39A13): secretory-pathway iron handling, collagen hydroxylation, and cell fate programs

ZIP13 has historically been described as a zinc transporter, with spEDS linked to altered Zn2+ handling and downstream signaling (e.g., BMP/TGF-β-SMAD perturbation) and collagen modification defects. (malfait2020theehlers–danlossyndromes pages 11-12)

A key 2024 development is direct mechanistic evidence in mammalian systems: - ZIP13 loss “led to a decreased iron content in the ER/Golgi, resulting in the loss of iron cofactor for ER-resident lysine and proline hydroxylation enzymes,” and the “primary physiological function of ZIP13 is iron instead of zinc.” (li2024mammalianslc39a13promotes pages 8-9) - Experimentally, restoring iron to the secretory pathway improved collagen hydroxylation, supporting a causal chain: ZIP13 loss → ER/Golgi iron deficiency → reduced collagen hydroxylation → connective tissue fragility/dysplasia. (li2024mammalianslc39a13promotes pages 4-5, li2024mammalianslc39a13promotes pages 7-8)

In addition, 2024 iPSC/myoblast work provides cellular-mechanistic granularity: - A pathogenic ZIP13 variant (G64D) undergoes VCP-linked ubiquitin–proteasome degradation, producing functional ZIP13 deficiency. (shoji2024possibleinvolvementof pages 1-2) - ZIP13 is induced during myogenesis; knockdown disrupts myotube formation, and patient iPSC-derived myocytes show incomplete differentiation that is rescued by gene correction—supporting a plausible mechanism for hypotonia and muscle involvement. (shoji2024possibleinvolvementof pages 1-2)

2. Key molecular players

2.1 Genes/Proteins (HGNC symbols)

Core spEDS genes consistently cited in 2017–2024 clinical literature: - B4GALT7 (galactosyltransferase I; Golgi) (caraffi2019severeperipheraljoint pages 1-3, dijk2024clinicaldiagnosisof pages 4-6) - B3GALT6 (galactosyltransferase II; Golgi) (damme2018biallelicb3galt6mutations pages 1-4, damme2018biallelicb3galt6mutations pages 10-13) - SLC39A13 (ZIP13) (ER/Golgi metal transporter; iron transport strongly supported by 2024 data) (li2024mammalianslc39a13promotes pages 4-5, li2024mammalianslc39a13promotes pages 8-9)

Closely related “linkeropathy continuum” gene (overlap phenotypes sometimes grouped with spEDS-like presentations): - B3GAT3 (glucuronyltransferase; completes linker) (zschocke2024geneticdiagnosisof pages 5-6)

2.2 Chemical entities (ChEBI-style)

Evidence-supported relevant chemicals/ions and substrates: - Iron (Fe2+) as ER/Golgi cofactor supply determinant for collagen hydroxylation enzymes (li2024mammalianslc39a13promotes pages 8-9, li2024mammalianslc39a13promotes pages 4-5) - Zinc (Zn2+) historically implicated in ZIP13 biology and collagen processing hypotheses (malfait2020theehlers–danlossyndromes pages 11-12, zschocke2024geneticdiagnosisof pages 5-6) - Linker monosaccharides: xylose, galactose residues, glucuronic acid as part of the GAG linker assembly (damme2018biallelicb3galt6mutations pages 1-4, delbaere2020hypomorphiczebrafishmodels pages 1-5) - Experimental xyloside/fluorogenic substrates used to assay GAG priming (e.g., 4-MUX xyloside; Gal-Xyl(2P)-OMN), useful as mechanistic/assay anchors in research contexts (damme2018biallelicb3galt6mutations pages 10-13, damme2018biallelicb3galt6mutations pages 13-15)

2.3 Cell types (CL-style)

  • Fibroblasts: primary patient cells used for mechanistic evaluation of GAG synthesis and ECM defects (damme2018biallelicb3galt6mutations pages 10-13)
  • Chondrocytes (and cartilage lineage): implicated by zebrafish phenocopy studies showing loss of chondrocyte organization and cartilage patterning (delbaere2020hypomorphiczebrafishmodels pages 1-5)
  • Myoblasts/myocytes: ZIP13-dependent myogenic differentiation shown in C2C12 and patient iPSC-derived myocytes (shoji2024possibleinvolvementof pages 1-2)

2.4 Anatomical locations (UBERON-style)

Most consistently involved structures: - Skin/dermis and extracellular matrix (hyperextensible/doughy/translucent skin; collagen fibril disorganization) (damme2018biallelicb3galt6mutations pages 10-13, dijk2024clinicaldiagnosisof pages 4-6) - Bone and cartilage (skeletal dysplasia-like features; osteopenia/fractures; cartilage patterning defects in models) (zschocke2024geneticdiagnosisof pages 5-6, delbaere2020hypomorphiczebrafishmodels pages 1-5) - Spine/vertebrae (e.g., platyspondyly; cervical spine instability in some B3GALT6 cases) (agrawal2023acaseof pages 1-2, damme2018biallelicb3galt6mutations pages 1-4) - Eye (bluish sclera, megalocornea/myopia/keratoconus reported in SLC39A13 spEDS) (agrawal2023acaseof pages 1-1, agrawal2023acaseof pages 3-4) - Additional metal-homeostasis anatomy in Zip13 mouse models: liver, spleen macrophages, renal tubules with iron deposition patterns (mechanistic, not necessarily clinical hallmark). (li2024mammalianslc39a13promotes pages 8-9)

3. Dysregulated pathways and cellular processes

3.1 Dysregulated molecular pathways

  • GAG linker assembly / proteoglycan biosynthesis (Golgi): defective formation of the tetrasaccharide primer disrupts HS/CS/DS proteoglycans. (damme2018biallelicb3galt6mutations pages 1-4, caraffi2019severeperipheraljoint pages 1-3)
  • ECM assembly and collagen fibrillogenesis: proteoglycan abnormalities (notably decorin glycanation changes) associate with abnormal dermal collagen fibrils and altered biomechanical properties. (damme2018biallelicb3galt6mutations pages 13-15, damme2018biallelicb3galt6mutations pages 10-13)
  • Secretory-pathway iron transport → collagen hydroxylation: ZIP13-dependent iron supply to ER/Golgi supports iron-dependent lysyl/prolyl hydroxylases; depletion reduces collagen hydroxylation. (li2024mammalianslc39a13promotes pages 8-9, li2024mammalianslc39a13promotes pages 4-5)
  • Proteostasis and protein degradation: VCP-linked ubiquitin–proteasome degradation of pathogenic ZIP13 (G64D) (shoji2024possibleinvolvementof pages 1-2)
  • Myogenic differentiation programs: ZIP13 required for myotube differentiation and iPSC-derived myocyte maturation (shoji2024possibleinvolvementof pages 1-2)

3.2 Cellular components (GO-CC-style)

  • Golgi apparatus (linker glycosyltransferases B4GALT7/B3GALT6; GAG assembly) (damme2018biallelicb3galt6mutations pages 1-4, delbaere2020hypomorphiczebrafishmodels pages 1-5)
  • ER/Golgi secretory pathway (ZIP13 localization and iron transport; collagen hydroxylation enzymes) (li2024mammalianslc39a13promotes pages 4-5, li2024mammalianslc39a13promotes pages 8-9)
  • Extracellular matrix / collagen fibrils / elastic fibers (structural output of the dysregulated pathways) (damme2018biallelicb3galt6mutations pages 10-13)
  • Cell surface (HS distribution changes; cell–matrix signaling platform) (damme2018biallelicb3galt6mutations pages 10-13)
  • Mitochondria/lysosomes (secondary iron compartment changes after ZIP13 loss) (li2024mammalianslc39a13promotes pages 1-2)

4. Disease progression model (sequence of events)

A gene-to-phenotype causal chain consistent with available evidence: 1) Biallelic pathogenic variants in B4GALT7/B3GALT6 (linker enzymes) or SLC39A13 (ZIP13 transporter). (ritelli2017expandingtheclinical pages 1-2, dijk2024clinicaldiagnosisof pages 4-6) 2) Early cellular biochemical deficits: - Linkeropathies: impaired linker assembly → reduced/aberrant HS/CS/DS and proteoglycan glycanation → altered ECM assembly and cell migration. (damme2018biallelicb3galt6mutations pages 10-13, delbaere2020hypomorphiczebrafishmodels pages 1-5) - ZIP13: reduced ER/Golgi iron → reduced collagen hydroxylation; plus proteasomal degradation of pathogenic ZIP13 variants and myogenic differentiation defects. (li2024mammalianslc39a13promotes pages 8-9, shoji2024possibleinvolvementof pages 1-2) 3) Tissue-level ECM consequences: abnormal collagen fibril organization and connective-tissue biomechanics; impaired skeletal growth plate/cartilage organization in developmental contexts. (damme2018biallelicb3galt6mutations pages 13-15, delbaere2020hypomorphiczebrafishmodels pages 1-5) 4) Clinical manifestations become apparent in childhood: short stature and bowed limbs; hypotonia/motor delay; joint hypermobility and skin signs; potential complications (fractures, spine instability, rare vascular events). (dijk2024clinicaldiagnosisof pages 4-6, damme2018biallelicb3galt6mutations pages 1-4)

5. Phenotypic manifestations and mechanistic links (HPO-oriented)

Common phenotypes highlighted in recent diagnostic reviews: - Short stature and progressive growth delay (central diagnostic hallmarks; reflect impaired skeletal development/ECM in growth plate and bone). (zschocke2024geneticdiagnosisof pages 5-6, dijk2024clinicaldiagnosisof pages 4-6) - Muscle hypotonia (supported by ZIP13 myogenic differentiation defects; and general connective-tissue/musculoskeletal involvement). (shoji2024possibleinvolvementof pages 1-2, zschocke2024geneticdiagnosisof pages 5-6) - Limb bowing and skeletal dysplasia-like radiographic features (developmental cartilage/bone ECM defects; model phenocopies in B4galt7 zebrafish). (dijk2024clinicaldiagnosisof pages 4-6, delbaere2020hypomorphiczebrafishmodels pages 1-5) - Joint hypermobility (96% in one systematic review’s spEDS cases: 24/25) (doolan2023extracutaneousfeaturesand pages 1-2) - Skin hyperextensibility / doughy thin translucent skin (connective tissue ECM output of proteoglycan/collagen processing defects). (dijk2024clinicaldiagnosisof pages 4-6, damme2018biallelicb3galt6mutations pages 10-13)

Additional phenotypes reported (variable by gene): - Osteopenia / recurrent fractures and sometimes severe osteoporosis (GAG/ECM defects; reported in spEDS descriptions and B3GALT6 case series). (zschocke2024geneticdiagnosisof pages 5-6, damme2018biallelicb3galt6mutations pages 10-13) - Ocular findings such as bluish sclera, megalocornea, myopia/keratoconus (SLC39A13 subtype). (agrawal2023acaseof pages 1-1, agrawal2023acaseof pages 3-4) - Aortic dilation/aneurysm and other potentially life-threatening complications in some B3GALT6 cohorts (ECM integrity effects). (damme2018biallelicb3galt6mutations pages 1-4, damme2018biallelicb3galt6mutations pages 10-13)

6. Recent developments (prioritizing 2023–2024)

6.1 2024: ZIP13 is an ER/Golgi iron transporter linking metal homeostasis to collagen hydroxylation

A major mechanistic advance is mammalian evidence that ZIP13’s primary physiological function is iron trafficking to the secretory pathway, and that ZIP13 loss reduces ER/Golgi iron and collagen hydroxylation (a direct molecular path to ECM defects). (li2024mammalianslc39a13promotes pages 8-9, li2024mammalianslc39a13promotes pages 4-5) - Publication: Nature Communications, Dec 2024. DOI/URL: https://doi.org/10.1038/s41467-024-55149-2 (li2024mammalianslc39a13promotes pages 4-5) - Key quoted statements: - “the primary physiological function of ZIP13 is iron instead of zinc” (li2024mammalianslc39a13promotes pages 8-9) - ZIP13 loss “led to a decreased iron content in the ER/Golgi, resulting in the loss of iron cofactor for ER-resident lysine and proline hydroxylation enzymes.” (li2024mammalianslc39a13promotes pages 8-9)

6.2 2024: Patient iPSC-based mechanistic modeling of ZIP13-related spEDS features

  • Publication: Scientific Reports, Apr 2024. DOI/URL: https://doi.org/10.1038/s41598-024-56912-7 (shoji2024possibleinvolvementof pages 1-2)
  • Key advances include iPSC-derived myocyte phenotypes, gene-editing rescue, and the mechanism of pathogenic ZIP13 protein degradation via VCP-linked ubiquitin–proteasome pathways. (shoji2024possibleinvolvementof pages 1-2)

6.3 2024: Expert diagnostic syntheses for monogenic EDS

Two 2024 expert reviews provide updated disease framing: - Clinical diagnosis of monogenic EDS (Nov 2024) includes prevalence estimate <1:1,000,000 and key diagnostic features. DOI/URL: https://doi.org/10.1515/medgen-2024-2060 (dijk2024clinicaldiagnosisof pages 4-6) - Genetic diagnosis of EDS (Nov 2024) describes spEDS features, autosomal recessive inheritance, and notes >100 individuals reported, while emphasizing core etiologic mechanisms (GAG linker enzymes and a zinc transporter phenotype). DOI/URL: https://doi.org/10.1515/medgen-2024-2061 (zschocke2024geneticdiagnosisof pages 5-6)

6.4 2023: Systematic review evidence on extracutaneous features/complications

A 2023 systematic review (n=839 EDS cases) reported joint hypermobility prevalence in spEDS of 96.0% (24/25). DOI/URL: https://doi.org/10.3389/fmed.2023.1053466 (doolan2023extracutaneousfeaturesand pages 1-2)

7. Current applications and real-world implementations

7.1 Diagnostics

  • Gene panel testing with massively parallel sequencing is described as the gold standard for confirming monogenic EDS types in contemporary expert reviews. (zschocke2024geneticdiagnosisof pages 5-6)
  • For spEDS, clinical suspicion is guided by major/minor criteria and gene-specific features; molecular confirmation is required for definitive diagnosis. (ritelli2017expandingtheclinical pages 1-2)
  • Case literature explicitly notes diagnosis via next-generation sequencing and emphasizes that short stature differentiates spEDS from other EDS types. (agrawal2023acaseof pages 3-4)

7.2 Management and surveillance (supportive care)

Directly stated management elements from a genetically confirmed SLC39A13 case report include: - Multidisciplinary follow-up with regular screening of developmental milestones, vision, and growth, and “Regular surveillance of vision and growth is required,” including ophthalmologic surveillance. (agrawal2023acaseof pages 3-4) - Vascular fragility is described as not a consistent feature in spEDS relative to other EDS types, but rare severe events have been reported, supporting clinical vigilance. (agrawal2023acaseof pages 3-4)

7.3 Ongoing clinical research / trials

A clinicaltrials.gov-style search using spEDS terms and core genes did not identify spEDS-specific interventional trials in this run (no relevant trials returned). (clinical trials search executed; no relevant trials in state)

8. Evidence-linked ontology annotations (for knowledge base ingestion)

8.1 Biological processes (GO-style phrases; mechanistically supported)

  • glycosaminoglycan biosynthetic process; proteoglycan metabolic process; heparan sulfate biosynthesis; chondroitin/dermatan sulfate biosynthesis (damme2018biallelicb3galt6mutations pages 1-4, delbaere2020hypomorphiczebrafishmodels pages 1-5)
  • extracellular matrix organization; collagen fibril organization/collagen fibrillogenesis (damme2018biallelicb3galt6mutations pages 10-13, damme2018biallelicb3galt6mutations pages 13-15)
  • cell migration / wound healing (fibroblast scratch closure deficits) (damme2018biallelicb3galt6mutations pages 10-13)
  • intracellular iron ion homeostasis; ER/Golgi iron transport (li2024mammalianslc39a13promotes pages 8-9, li2024mammalianslc39a13promotes pages 1-2)
  • collagen hydroxylation / collagen post-translational modification (lysyl/prolyl hydroxylases) (li2024mammalianslc39a13promotes pages 8-9, li2024mammalianslc39a13promotes pages 4-5)
  • myogenic differentiation (shoji2024possibleinvolvementof pages 1-2)

8.2 Cellular components (GO-CC-style phrases)

  • Golgi apparatus (linker glycosyltransferases; GAG synthesis) (damme2018biallelicb3galt6mutations pages 1-4, delbaere2020hypomorphiczebrafishmodels pages 1-5)
  • ER/Golgi secretory pathway (ZIP13 localization and iron transport) (li2024mammalianslc39a13promotes pages 4-5, li2024mammalianslc39a13promotes pages 8-9)
  • extracellular matrix; collagen fibril; elastic fiber; cell surface proteoglycans (damme2018biallelicb3galt6mutations pages 10-13)

8.3 Cell types (CL-style)

  • fibroblast (patient fibroblast biochemical/structural assays) (damme2018biallelicb3galt6mutations pages 10-13)
  • chondrocyte lineage (cartilage patterning and organization changes in models) (delbaere2020hypomorphiczebrafishmodels pages 1-5)
  • myoblast / skeletal muscle cell (ZIP13-dependent differentiation) (shoji2024possibleinvolvementof pages 1-2)

8.4 Anatomical entities (UBERON-style)

  • skin/dermis; extracellular matrix (dijk2024clinicaldiagnosisof pages 4-6, damme2018biallelicb3galt6mutations pages 10-13)
  • bone; cartilage; vertebral column/cervical spine; long bone metaphyses (damme2018biallelicb3galt6mutations pages 10-13, delbaere2020hypomorphiczebrafishmodels pages 1-5)
  • eye (sclera/cornea-related phenotypes) (agrawal2023acaseof pages 1-1, agrawal2023acaseof pages 3-4)
  • aorta (thoracic aorta aneurysm/dilation in some B3GALT6 cases) (damme2018biallelicb3galt6mutations pages 10-13)

8.5 Chemical entities (ChEBI-style)

  • iron(II) / iron (Fe2+); zinc(II) / zinc (Zn2+) (li2024mammalianslc39a13promotes pages 8-9, malfait2020theehlers–danlossyndromes pages 11-12)
  • glycosaminoglycans (heparan sulfate; chondroitin sulfate; dermatan sulfate) (damme2018biallelicb3galt6mutations pages 1-4, damme2018biallelicb3galt6mutations pages 10-13)

Consolidated gene–mechanism–phenotype table

Gene (HGNC symbol) Protein/function Inheritance Key molecular mechanism Key affected pathways/bioprocesses (GO-style phrases) Primary affected cell types/tissues Representative phenotypes (HPO-style phrases) Key recent evidence (2023-2024) with DOI/URL Key foundational evidence with DOI/URL Notes/biomarkers/therapeutic implications
B4GALT7 β4GalT7 / galactosyltransferase I; Golgi glycosyltransferase adding the first galactose to xylose in the proteoglycan tetrasaccharide linker Autosomal recessive Defective linker-region assembly impairs initiation of HS/CS/DS GAG chains; reduced sulfated GAGs and incomplete decorin proteoglycan maturation disrupt ECM organization, cartilage patterning, and musculoskeletal development (delbaere2020hypomorphiczebrafishmodels pages 1-5, caraffi2019severeperipheraljoint pages 1-3) glycosaminoglycan biosynthetic process; proteoglycan metabolic process; extracellular matrix organization; collagen fibril organization; skeletal system development; cartilage development (delbaere2020hypomorphiczebrafishmodels pages 1-5, caraffi2019severeperipheraljoint pages 1-3) Fibroblasts/dermis; chondrocytes/cartilage; bone; muscle/connective tissue (delbaere2020hypomorphiczebrafishmodels pages 1-5, caraffi2019severeperipheraljoint pages 1-3, dijk2024clinicaldiagnosisof pages 4-6) Short stature; muscle hypotonia; bowing of limbs; joint hypermobility; skin hyperextensibility; doughy/thin translucent skin; skeletal dysplasia-like presentation (dijk2024clinicaldiagnosisof pages 4-6, doolan2023extracutaneousfeaturesand pages 1-2) Dijk et al. 2024, Clinical diagnosis of the monogenic EDS DOI: 10.1515/medgen-2024-2060 URL: https://doi.org/10.1515/medgen-2024-2060 (dijk2024clinicaldiagnosisof pages 4-6); Zschocke et al. 2024, Genetic diagnosis of the EDS DOI: 10.1515/medgen-2024-2061 URL: https://doi.org/10.1515/medgen-2024-2061 (zschocke2024geneticdiagnosisof pages 5-6) Delbaere et al. 2020, Hypomorphic zebrafish models mimic the musculoskeletal phenotype of β4galt7-deficient EDS DOI: 10.1016/j.matbio.2019.12.002 URL: https://doi.org/10.1016/j.matbio.2019.12.002 (delbaere2020hypomorphiczebrafishmodels pages 1-5); Ritelli et al. 2017 DOI: 10.1186/s13023-017-0704-3 URL: https://doi.org/10.1186/s13023-017-0704-3 (ritelli2017expandingtheclinical pages 1-2) Diagnostic clue: linkeropathy/spEDS phenotype with major criteria short stature + hypotonia; molecular confirmation by sequencing is required. No disease-specific therapy identified; management is supportive and surveillance-based (ritelli2017expandingtheclinical pages 1-2, dijk2024clinicaldiagnosisof pages 4-6)
B3GALT6 β3GalT6 / galactosyltransferase II; Golgi glycosyltransferase adding the second galactose in the linker region Autosomal recessive Loss of galactosyltransferase activity causes strongly reduced GAG priming and ~70–80% lower total GAG production in patient fibroblasts, markedly reduced decorin glycanation, reduced cell-surface HS, delayed wound closure/cell migration, abnormal collagen fibril spacing/diameter, fragmented elastic fibers, and compromised tissue biomechanics; partial compensation can occur via B3GAT3/GlcAT-I forming an alternative trisaccharide linker (damme2018biallelicb3galt6mutations pages 13-15, damme2018biallelicb3galt6mutations pages 10-13, diana2025b3galt6mutationslead pages 1-2, diana2025b3galt6mutationslead pages 12-14) glycosaminoglycan biosynthetic process; heparan sulfate proteoglycan biosynthetic process; chondroitin sulfate/dermatan sulfate biosynthetic process; collagen fibril organization; extracellular matrix organization; wound healing/cell migration; connective tissue development (damme2018biallelicb3galt6mutations pages 13-15, damme2018biallelicb3galt6mutations pages 10-13, diana2025b3galt6mutationslead pages 1-2, diana2025b3galt6mutationslead pages 12-14) Dermal fibroblasts; skin ECM; tendon/ligament/connective tissue; bone and cartilage (damme2018biallelicb3galt6mutations pages 13-15, damme2018biallelicb3galt6mutations pages 10-13, dijk2024clinicaldiagnosisof pages 4-6) Short stature; muscle hypotonia; severe distal/peripheral joint laxity; osteopenia/recurrent fractures; cervical spine instability; respiratory insufficiency; possible aortic dilatation/aneurysm; skin hyperextensibility/doughy skin (damme2018biallelicb3galt6mutations pages 1-4, caraffi2019severeperipheraljoint pages 1-3, dijk2024clinicaldiagnosisof pages 4-6) Shoji et al. 2024 is gene-specific to SLC39A13, not B3GALT6; for B3GALT6 recent mechanistic context is summarized in 2024 diagnostic reviews: Dijk et al. 2024 DOI: 10.1515/medgen-2024-2060 URL: https://doi.org/10.1515/medgen-2024-2060 (dijk2024clinicaldiagnosisof pages 4-6); Zschocke et al. 2024 DOI: 10.1515/medgen-2024-2061 URL: https://doi.org/10.1515/medgen-2024-2061 (zschocke2024geneticdiagnosisof pages 5-6) Van Damme et al. 2018, Biallelic B3GALT6 mutations cause spondylodysplastic EDS DOI: 10.1093/hmg/ddy234 URL: https://doi.org/10.1093/hmg/ddy234 (damme2018biallelicb3galt6mutations pages 13-15, damme2018biallelicb3galt6mutations pages 1-4, damme2018biallelicb3galt6mutations pages 10-13); Caraffi et al. 2019 DOI: 10.3390/genes10100799 URL: https://doi.org/10.3390/genes10100799 (caraffi2019severeperipheraljoint pages 1-3) Potential biomarker concepts: abnormal decorin glycanation, reduced HS staining, altered collagen fibril ultrastructure. Therapeutic implication remains supportive; 2025 mechanistic work suggests collagen XII glycosylation/biomechanics as translational readouts, but not yet clinical standard (damme2018biallelicb3galt6mutations pages 10-13, diana2025b3galt6mutationslead pages 1-2, diana2025b3galt6mutationslead pages 12-14)
SLC39A13 ZIP13 / solute carrier family 39 member 13; ER/Golgi-localized metal transporter historically linked to zinc homeostasis, now strongly supported as a secretory-pathway iron transporter Autosomal recessive ZIP13 deficiency causes ER/Golgi iron deficiency, depriving lysyl/prolyl hydroxylases of Fe2+ and producing reduced collagen hydroxylation/under-crosslinking; older models also implicated altered Zn2+ homeostasis, ER stress, and BMP/TGF-β-SMAD dysregulation. The recurrent pathogenic p.G64D protein undergoes VCP-linked ubiquitin-proteasome degradation, producing functional ZIP13 deficiency. ZIP13 loss additionally impairs myogenic differentiation in C2C12 and patient-iPSC-derived myocytes, reversible by gene correction (li2024mammalianslc39a13promotes pages 4-5, li2024mammalianslc39a13promotes pages 3-4, li2024mammalianslc39a13promotes pages 8-9, li2024mammalianslc39a13promotes pages 7-8, malfait2020theehlers–danlossyndromes pages 11-12, shoji2024possibleinvolvementof pages 1-2) intracellular iron ion homeostasis; ER/Golgi metal ion transport; collagen metabolic process; collagen hydroxylation/cross-linking; extracellular matrix organization; BMP signaling/TGF-β signaling; myoblast differentiation; skeletal muscle regeneration (li2024mammalianslc39a13promotes pages 4-5, li2024mammalianslc39a13promotes pages 8-9, malfait2020theehlers–danlossyndromes pages 11-12, shoji2024possibleinvolvementof pages 1-2) Fibroblasts; ER/Golgi secretory pathway; myoblasts/myocytes; skeletal muscle; skin; bone/connective tissue (li2024mammalianslc39a13promotes pages 4-5, li2024mammalianslc39a13promotes pages 7-8, shoji2024possibleinvolvementof pages 1-2) Short stature; muscle hypotonia; delayed motor development; hypermobile joints; hyperextensible skin; finely wrinkled palms; protuberant eyes/bluish sclera; platyspondyly and other radiologic changes; occasional white-matter abnormalities reported in case literature (agrawal2023acaseof pages 1-1, agrawal2023acaseof pages 3-4, agrawal2023acaseof pages 1-2, dijk2024clinicaldiagnosisof pages 4-6) Li et al. 2024, Mammalian SLC39A13 promotes ER/Golgi iron transport and iron homeostasis in multiple compartments DOI: 10.1038/s41467-024-55149-2 URL: https://doi.org/10.1038/s41467-024-55149-2 (li2024mammalianslc39a13promotes pages 4-5, li2024mammalianslc39a13promotes pages 3-4, li2024mammalianslc39a13promotes pages 8-9, li2024mammalianslc39a13promotes pages 7-8); Shoji et al. 2024, Possible involvement of zinc transporter ZIP13 in myogenic differentiation DOI: 10.1038/s41598-024-56912-7 URL: https://doi.org/10.1038/s41598-024-56912-7 (shoji2024possibleinvolvementof pages 1-2); Agrawal et al. 2023 DOI: 10.1093/omcr/omac107 URL: https://doi.org/10.1093/omcr/omac107 (agrawal2023acaseof pages 1-1, agrawal2023acaseof pages 3-4) Foundational mechanism summarized in Malfait et al. 2020, The Ehlers–Danlos syndromes DOI: 10.1038/s41572-020-0194-9 URL: https://doi.org/10.1038/s41572-020-0194-9 (malfait2020theehlers–danlossyndromes pages 11-12); original disease association PMIDs cited in Open Targets evidence include 18513683 and 18985159 (diana2025b3galt6mutationslead pages 1-2) Strongest emerging translational implication in this run: secretory-pathway iron restoration rescued collagen hydroxylation in experimental systems, suggesting metal-compartment homeostasis as a tractable mechanistic axis; no registered interventional trials identified here (li2024mammalianslc39a13promotes pages 4-5, li2024mammalianslc39a13promotes pages 7-8)
B3GAT3 (related linkeropathy; not classically listed in 2017 spEDS but included in 2024 genetic diagnosis review as causing a highly similar phenotype) GlcAT-I / glucuronyltransferase adding glucuronic acid to complete the linker tetrasaccharide Autosomal recessive Deficiency disrupts final linker assembly step; clinically overlaps the spEDS/linkeropathy continuum. In B3GALT6-deficient systems, GlcAT-I can partially compensate by generating an alternative trisaccharide linker, highlighting pathway-level convergence (diana2025b3galt6mutationslead pages 12-14, zschocke2024geneticdiagnosisof pages 5-6) glycosaminoglycan biosynthetic process; proteoglycan metabolic process; extracellular matrix organization; skeletal system development (diana2025b3galt6mutationslead pages 12-14, zschocke2024geneticdiagnosisof pages 5-6) Fibroblasts/connective tissue; cartilage; bone; cardiovascular tissues in broader linkeropathy literature (zschocke2024geneticdiagnosisof pages 5-6) Skeletal dysplasia, short stature, joint hypermobility/contractures, variable skin/connective tissue findings; considered part of a linkeropathy continuum bridging EDS and skeletal dysplasias (zschocke2024geneticdiagnosisof pages 5-6) Zschocke et al. 2024 DOI: 10.1515/medgen-2024-2061 URL: https://doi.org/10.1515/medgen-2024-2061 (zschocke2024geneticdiagnosisof pages 5-6); Dijk et al. 2024 DOI: 10.1515/medgen-2024-2060 URL: https://doi.org/10.1515/medgen-2024-2060 (dijk2024clinicaldiagnosisof pages 4-6) Ritelli et al. 2019, Further Defining the Phenotypic Spectrum of B3GAT3 Mutations and Literature Review on Linkeropathy Syndromes DOI: 10.3390/genes10090631 URL: https://doi.org/10.3390/genes10090631 (paper-search result summarized in run); pathway context in Van Damme et al. 2018 DOI: 10.1093/hmg/ddy234 URL: https://doi.org/10.1093/hmg/ddy234 (diana2025b3galt6mutationslead pages 12-14) Best represented as a related linkeropathy / phenotypic continuum note in a knowledge base, rather than a core 2017 spEDS gene, unless adopting the broader 2024 framing (zschocke2024geneticdiagnosisof pages 5-6)

Table: This table summarizes the gene-specific molecular mechanisms, affected pathways, tissues, phenotypes, and evidence base for spondylodysplastic Ehlers-Danlos syndrome. It is designed for knowledge-base use and highlights both recent 2023–2024 findings and foundational studies.

Statistics and data points (recent sources)

  • Prevalence estimate: spEDS prevalence <1:1,000,000 (2024 review). (dijk2024clinicaldiagnosisof pages 4-6)
  • Reported individuals: spEDS reported in >100 individuals (2024 review). (zschocke2024geneticdiagnosisof pages 5-6)
  • Joint hypermobility frequency: 96.0% (24/25) among spEDS cases in a 2023 systematic review. (doolan2023extracutaneousfeaturesand pages 1-2)
  • SLC39A13 molecular case count: as of a 2023 case report, 13 individuals with molecularly diagnosed SLC39A13-related spEDS had been reported prior to that case. (agrawal2023acaseof pages 1-1)

Limitations of this evidence set

  • Several mechanistic claims in EDS biology are supported by high-authority reviews but are not accompanied by explicit PMIDs in the retrieved excerpts; where PMIDs were visible in OpenTargets evidence (e.g., 18513683, 18985159 for SLC39A13), full primary texts were not retrieved in this run. (diana2025b3galt6mutationslead pages 1-2)
  • The 2023 systematic review contains additional spEDS phenotype frequencies in a table, but the retrieved text segment did not preserve labeled phenotype-to-percentage mapping; only the clearly labeled 24/25 hypermobility statistic could be used confidently. (doolan2023extracutaneousfeaturesand pages 1-2, doolan2023extracutaneousfeaturesand pages 4-4)

Key references (with publication dates and URLs)

  • van Dijk FS et al. Clinical diagnosis of the monogenic Ehlers-Danlos syndromes. Medizinische Genetik. Nov 2024. https://doi.org/10.1515/medgen-2024-2060 (dijk2024clinicaldiagnosisof pages 4-6)
  • Zschocke J et al. Genetic diagnosis of the Ehlers-Danlos syndromes. Medizinische Genetik. Nov 2024. https://doi.org/10.1515/medgen-2024-2061 (zschocke2024geneticdiagnosisof pages 5-6)
  • Li H et al. Mammalian SLC39A13 promotes ER/Golgi iron transport and iron homeostasis in multiple compartments. Nature Communications. Dec 2024. https://doi.org/10.1038/s41467-024-55149-2 (li2024mammalianslc39a13promotes pages 4-5)
  • Shoji M et al. Possible involvement of zinc transporter ZIP13 in myogenic differentiation. Scientific Reports. Apr 2024. https://doi.org/10.1038/s41598-024-56912-7 (shoji2024possibleinvolvementof pages 1-2)
  • Doolan BJ et al. Extracutaneous features and complications of the Ehlers-Danlos syndromes: A systematic review. Frontiers in Medicine. Jan 2023. https://doi.org/10.3389/fmed.2023.1053466 (doolan2023extracutaneousfeaturesand pages 1-2)
  • Agrawal P et al. A case of Ehlers–Danlos syndrome presenting as short stature: a novel mutation in SLC39A13 causing spEDS. Oxford Medical Case Reports. Jan 2023. https://doi.org/10.1093/omcr/omac107 (agrawal2023acaseof pages 1-1)

References

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  2. (zschocke2024geneticdiagnosisof pages 5-6): Johannes Zschocke, Serwet Demirdas, and Fleur S. van Dijk. Genetic diagnosis of the ehlers-danlos syndromes. Medizinische Genetik, 36:235-245, Nov 2024. URL: https://doi.org/10.1515/medgen-2024-2061, doi:10.1515/medgen-2024-2061. This article has 4 citations.

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  4. (damme2018biallelicb3galt6mutations pages 1-4): Tim Van Damme, Xiaomeng Pang, Brecht Guillemyn, Sandrine Gulberti, Delfien Syx, Riet De Rycke, Olivier Kaye, Christine E M de Die-Smulders, Rolph Pfundt, Ariana Kariminejad, Sheela Nampoothiri, Geneviève Pierquin, Saskia Bulk, Austin A Larson, Kathryn C Chatfield, Marleen Simon, Anne Legrand, Marion Gerard, Sofie Symoens, Sylvie Fournel-Gigleux, and Fransiska Malfait. Biallelic b3galt6 mutations cause spondylodysplastic ehlers‐danlos syndrome. Human Molecular Genetics, 27:3475–3487, Jun 2018. URL: https://doi.org/10.1093/hmg/ddy234, doi:10.1093/hmg/ddy234. This article has 54 citations and is from a domain leading peer-reviewed journal.

  5. (damme2018biallelicb3galt6mutations pages 10-13): Tim Van Damme, Xiaomeng Pang, Brecht Guillemyn, Sandrine Gulberti, Delfien Syx, Riet De Rycke, Olivier Kaye, Christine E M de Die-Smulders, Rolph Pfundt, Ariana Kariminejad, Sheela Nampoothiri, Geneviève Pierquin, Saskia Bulk, Austin A Larson, Kathryn C Chatfield, Marleen Simon, Anne Legrand, Marion Gerard, Sofie Symoens, Sylvie Fournel-Gigleux, and Fransiska Malfait. Biallelic b3galt6 mutations cause spondylodysplastic ehlers‐danlos syndrome. Human Molecular Genetics, 27:3475–3487, Jun 2018. URL: https://doi.org/10.1093/hmg/ddy234, doi:10.1093/hmg/ddy234. This article has 54 citations and is from a domain leading peer-reviewed journal.

  6. (li2024mammalianslc39a13promotes pages 4-5): Huihui Li, Yanmei Cui, Yule Hu, Mengran Zhao, Kuanyu Li, Xiaoyun Pang, Fei Sun, and Bing Zhou. Mammalian slc39a13 promotes er/golgi iron transport and iron homeostasis in multiple compartments. Nature Communications, Dec 2024. URL: https://doi.org/10.1038/s41467-024-55149-2, doi:10.1038/s41467-024-55149-2. This article has 20 citations and is from a highest quality peer-reviewed journal.

  7. (li2024mammalianslc39a13promotes pages 8-9): Huihui Li, Yanmei Cui, Yule Hu, Mengran Zhao, Kuanyu Li, Xiaoyun Pang, Fei Sun, and Bing Zhou. Mammalian slc39a13 promotes er/golgi iron transport and iron homeostasis in multiple compartments. Nature Communications, Dec 2024. URL: https://doi.org/10.1038/s41467-024-55149-2, doi:10.1038/s41467-024-55149-2. This article has 20 citations and is from a highest quality peer-reviewed journal.

  8. (diana2025b3galt6mutationslead pages 1-2): Roméo Milan Diana, Benjamin Jolivet, Jean-Baptiste Vincourt, Sébastien Hergalant, Grégory Francius, Yasaman Karami, Hamed Khakzad, Rebekka Wild, Marie Bourgeais, Anne Robert, Alison Wurtz, Guillermo Barreto, Nick Ramalanjaona, Déborah Helle, Rachel Onifarasoaniaina, Sophie Front, Chrystel Lopin-Bon, Delfien Syx, Fransiska Malfait, Sylvie Fournel-Gigleux, Sandrine Gulberti, and Catherine Bui. B3galt6 mutations lead to compromised connective tissue biomechanics in ehlers-danlos syndrome. JCI Insight, Aug 2025. URL: https://doi.org/10.1172/jci.insight.179474, doi:10.1172/jci.insight.179474. This article has 1 citations and is from a domain leading peer-reviewed journal.

  9. (doolan2023extracutaneousfeaturesand pages 1-2): Brent J. Doolan, Mark E. Lavallee, Ingrid Hausser, Jane R. Schubart, F. Michael Pope, Suranjith L. Seneviratne, Ingrid M. Winship, and Nigel P. Burrows. Extracutaneous features and complications of the ehlers-danlos syndromes: a systematic review. Frontiers in Medicine, Jan 2023. URL: https://doi.org/10.3389/fmed.2023.1053466, doi:10.3389/fmed.2023.1053466. This article has 27 citations.

  10. (shoji2024possibleinvolvementof pages 1-2): Masaki Shoji, Takuto Ohashi, Saki Nagase, Haato Yuri, Kenta Ichihashi, Teruhisa Takagishi, Yuji Nagata, Yuki Nomura, Ayako Fukunaka, Sae Kenjou, Hatsuna Miyake, Takafumi Hara, Emi Yoshigai, Yoshio Fujitani, Hidetoshi Sakurai, Heloísa G. dos Santos, Toshiyuki Fukada, and Takashi Kuzuhara. Possible involvement of zinc transporter zip13 in myogenic differentiation. Scientific Reports, Apr 2024. URL: https://doi.org/10.1038/s41598-024-56912-7, doi:10.1038/s41598-024-56912-7. This article has 4 citations and is from a peer-reviewed journal.

  11. (ritelli2017expandingtheclinical pages 1-2): Marco Ritelli, Chiara Dordoni, Valeria Cinquina, Marina Venturini, Piergiacomo Calzavara-Pinton, and Marina Colombi. Expanding the clinical and mutational spectrum of b4galt7-spondylodysplastic ehlers-danlos syndrome. Orphanet Journal of Rare Diseases, Sep 2017. URL: https://doi.org/10.1186/s13023-017-0704-3, doi:10.1186/s13023-017-0704-3. This article has 50 citations and is from a peer-reviewed journal.

  12. (ritelli2017expandingtheclinical media 36a1859a): Marco Ritelli, Chiara Dordoni, Valeria Cinquina, Marina Venturini, Piergiacomo Calzavara-Pinton, and Marina Colombi. Expanding the clinical and mutational spectrum of b4galt7-spondylodysplastic ehlers-danlos syndrome. Orphanet Journal of Rare Diseases, Sep 2017. URL: https://doi.org/10.1186/s13023-017-0704-3, doi:10.1186/s13023-017-0704-3. This article has 50 citations and is from a peer-reviewed journal.

  13. (ritelli2017expandingtheclinical media 0d274780): Marco Ritelli, Chiara Dordoni, Valeria Cinquina, Marina Venturini, Piergiacomo Calzavara-Pinton, and Marina Colombi. Expanding the clinical and mutational spectrum of b4galt7-spondylodysplastic ehlers-danlos syndrome. Orphanet Journal of Rare Diseases, Sep 2017. URL: https://doi.org/10.1186/s13023-017-0704-3, doi:10.1186/s13023-017-0704-3. This article has 50 citations and is from a peer-reviewed journal.

  14. (delbaere2020hypomorphiczebrafishmodels pages 1-5): Sarah Delbaere, Tim Van Damme, Delfien Syx, Sofie Symoens, Paul Coucke, Andy Willaert, and Fransiska Malfait. Hypomorphic zebrafish models mimic the musculoskeletal phenotype of β4galt7-deficient ehlers-danlos syndrome. Matrix Biology, 89:59-75, Jul 2020. URL: https://doi.org/10.1016/j.matbio.2019.12.002, doi:10.1016/j.matbio.2019.12.002. This article has 32 citations and is from a domain leading peer-reviewed journal.

  15. (damme2018biallelicb3galt6mutations pages 13-15): Tim Van Damme, Xiaomeng Pang, Brecht Guillemyn, Sandrine Gulberti, Delfien Syx, Riet De Rycke, Olivier Kaye, Christine E M de Die-Smulders, Rolph Pfundt, Ariana Kariminejad, Sheela Nampoothiri, Geneviève Pierquin, Saskia Bulk, Austin A Larson, Kathryn C Chatfield, Marleen Simon, Anne Legrand, Marion Gerard, Sofie Symoens, Sylvie Fournel-Gigleux, and Fransiska Malfait. Biallelic b3galt6 mutations cause spondylodysplastic ehlers‐danlos syndrome. Human Molecular Genetics, 27:3475–3487, Jun 2018. URL: https://doi.org/10.1093/hmg/ddy234, doi:10.1093/hmg/ddy234. This article has 54 citations and is from a domain leading peer-reviewed journal.

  16. (malfait2020theehlers–danlossyndromes pages 11-12): Fransiska Malfait, Marco Castori, Clair A. Francomano, Cecilia Giunta, Tomoki Kosho, and Peter H. Byers. The ehlers–danlos syndromes. Nature Reviews Disease Primers, 6:1-25, Jul 2020. URL: https://doi.org/10.1038/s41572-020-0194-9, doi:10.1038/s41572-020-0194-9. This article has 372 citations.

  17. (li2024mammalianslc39a13promotes pages 7-8): Huihui Li, Yanmei Cui, Yule Hu, Mengran Zhao, Kuanyu Li, Xiaoyun Pang, Fei Sun, and Bing Zhou. Mammalian slc39a13 promotes er/golgi iron transport and iron homeostasis in multiple compartments. Nature Communications, Dec 2024. URL: https://doi.org/10.1038/s41467-024-55149-2, doi:10.1038/s41467-024-55149-2. This article has 20 citations and is from a highest quality peer-reviewed journal.

  18. (agrawal2023acaseof pages 1-2): Poorvi Agrawal, Harpreet Kaur, Alpana Kondekar, and Surbhi Rathi. A case of ehlers–danlos syndrome presenting as short stature: a novel mutation in slc39a13 causing spondylodysplastic ehlers–danlos syndrome. Oxford Medical Case Reports, Jan 2023. URL: https://doi.org/10.1093/omcr/omac107, doi:10.1093/omcr/omac107. This article has 7 citations and is from a peer-reviewed journal.

  19. (agrawal2023acaseof pages 1-1): Poorvi Agrawal, Harpreet Kaur, Alpana Kondekar, and Surbhi Rathi. A case of ehlers–danlos syndrome presenting as short stature: a novel mutation in slc39a13 causing spondylodysplastic ehlers–danlos syndrome. Oxford Medical Case Reports, Jan 2023. URL: https://doi.org/10.1093/omcr/omac107, doi:10.1093/omcr/omac107. This article has 7 citations and is from a peer-reviewed journal.

  20. (agrawal2023acaseof pages 3-4): Poorvi Agrawal, Harpreet Kaur, Alpana Kondekar, and Surbhi Rathi. A case of ehlers–danlos syndrome presenting as short stature: a novel mutation in slc39a13 causing spondylodysplastic ehlers–danlos syndrome. Oxford Medical Case Reports, Jan 2023. URL: https://doi.org/10.1093/omcr/omac107, doi:10.1093/omcr/omac107. This article has 7 citations and is from a peer-reviewed journal.

  21. (li2024mammalianslc39a13promotes pages 1-2): Huihui Li, Yanmei Cui, Yule Hu, Mengran Zhao, Kuanyu Li, Xiaoyun Pang, Fei Sun, and Bing Zhou. Mammalian slc39a13 promotes er/golgi iron transport and iron homeostasis in multiple compartments. Nature Communications, Dec 2024. URL: https://doi.org/10.1038/s41467-024-55149-2, doi:10.1038/s41467-024-55149-2. This article has 20 citations and is from a highest quality peer-reviewed journal.

  22. (diana2025b3galt6mutationslead pages 12-14): Roméo Milan Diana, Benjamin Jolivet, Jean-Baptiste Vincourt, Sébastien Hergalant, Grégory Francius, Yasaman Karami, Hamed Khakzad, Rebekka Wild, Marie Bourgeais, Anne Robert, Alison Wurtz, Guillermo Barreto, Nick Ramalanjaona, Déborah Helle, Rachel Onifarasoaniaina, Sophie Front, Chrystel Lopin-Bon, Delfien Syx, Fransiska Malfait, Sylvie Fournel-Gigleux, Sandrine Gulberti, and Catherine Bui. B3galt6 mutations lead to compromised connective tissue biomechanics in ehlers-danlos syndrome. JCI Insight, Aug 2025. URL: https://doi.org/10.1172/jci.insight.179474, doi:10.1172/jci.insight.179474. This article has 1 citations and is from a domain leading peer-reviewed journal.

  23. (li2024mammalianslc39a13promotes pages 3-4): Huihui Li, Yanmei Cui, Yule Hu, Mengran Zhao, Kuanyu Li, Xiaoyun Pang, Fei Sun, and Bing Zhou. Mammalian slc39a13 promotes er/golgi iron transport and iron homeostasis in multiple compartments. Nature Communications, Dec 2024. URL: https://doi.org/10.1038/s41467-024-55149-2, doi:10.1038/s41467-024-55149-2. This article has 20 citations and is from a highest quality peer-reviewed journal.

  24. (doolan2023extracutaneousfeaturesand pages 4-4): Brent J. Doolan, Mark E. Lavallee, Ingrid Hausser, Jane R. Schubart, F. Michael Pope, Suranjith L. Seneviratne, Ingrid M. Winship, and Nigel P. Burrows. Extracutaneous features and complications of the ehlers-danlos syndromes: a systematic review. Frontiers in Medicine, Jan 2023. URL: https://doi.org/10.3389/fmed.2023.1053466, doi:10.3389/fmed.2023.1053466. This article has 27 citations.