Table 1.
Overview of the EDS types, genes and proteins, and inheritance pattern (IP) as defined by the 2017 International EDS Classification with indication of the estimated prevalence, the associated pathophysiological mechanisms and available biochemical tests. AD: autosomal dominant, AR: autosomal recessive, NA: not available, ?: unknown.
| EDS Type | Gene | Protein | IP | Estimated Incidence/Reported Individuals | Pathophysiological Mechanism | Biochemical Testing |
|---|---|---|---|---|---|---|
| Defects in Collagen Structure and Collagen Processing | ||||||
| Classical (cEDS) |
COL5A1 COL5A2 (COL1A1 p.(Arg312Cys)) |
α1-chain of type V procollagen α2-chain of type V procollagen α1-chain of type I procollagen |
AD | 1:20,000 | Decreased type V collagen amounts affecting the initiation and assembly of heterotypic type I/V collagen fibrils Decreased type V collagen amounts affecting the initiation and assembly of heterotypic type I/V collagen fibrils Local destabilization of the type I collagen molecules and production of α1(I) dimers |
(Pro)collagen biochemistry |
| Vascular (vEDS) |
COL3A1 (COL1A1 p.(Arg312Cys), p.(Arg574Cys), p.(Arg1093Cys)) |
α1-chain of type III procollagen α1-chain of type I procollagen |
AD | 1:50,000–1:200,000 | Decreased type III collagen amounts affecting the initiation and assembly of heterotypic type I/III collagen fibrils Local destabilization of the type I collagen molecules and production of α1(I) dimers |
(Pro)collagen biochemistry (Pro)collagen biochemistry |
| Arthrochalasia (aEDS) |
COL1A1
COL1A2 |
α1-chain of type I procollagen α2-chain of type I procollagen |
AD | <60 reported individuals | (Partial or complete) deletion of exon 6 leading to partial processing of type I procollagen with retention of the N-propeptide of either the pro-α1(I)- or the pro-α2(I)-chain | (Pro)collagen biochemistry (Pro)collagen biochemistry |
| Dermatosparaxis (dEDS) |
ADAMTS2 | A Disintegrin And Metalloproteinase with Thrombospondin Motifs 2 (ADAMTS-2) | AR | 15 reported individuals (14 families) | Absent N-propeptide cleavage of both pro-α(I)-chains | Procollagen biochemistry |
| Cardiac-valvular (cvEDS) |
COL1A2 | α2-chain of type I procollagen | AR | 6 reported individuals (5 families) | Total absence of pro-α2(I)-chains leading to the formation of α1(I) homotrimers | (Pro)collagen biochemistry |
| Defects in Collagen Folding and Collagen Cross-Linking | ||||||
| Kyphoscoliotic (kEDS) |
PLOD1
FKBP14 |
Lysyl hydroxylase 1 (LH1) FK506 Binding Protein, 22 kDa (FKBP22) |
AR | <100 reported individuals <35 reported individuals |
Deficient post-translational hydroxylation of lysyl residues causing impaired crosslink formation in the collagen triple helix Deficiency of the molecular chaperone (possibly) leads to premature interaction and accumulation of collagen molecules in the endoplasmic reticulum |
(Pro)collagen biochemistry Urinary crosslink analysis: increased LP/HP ratio (between 2–9) |
| Defects in Extracellular Matrix Bridging Molecules | ||||||
| Classical-like (clEDS) |
TNXB | Tenascin X (TNX) | AR | <65 reported individuals | Interference with the normal organization and mechanical properties of collagen fibrils in the ECM | TNX serum levels |
| Myopathic (mEDS) |
COL12A1 | α1-chain of type XII procollagen | AD AR |
<20 reported individuals | Interference with the normal organization and mechanical properties of collagen fibrils in the ECM | NA |
| Defects in Intracellular Processes | ||||||
| Brittle cornea syndrome (BCS) |
ZNF469
PRDM5 |
Zinc Finger Protein 469 (ZNF469) PR/SET Domain 5 (PRDM5) |
AR | <55 reported individuals <35 reported individuals |
Disturbed ECM regulation, but exact pathophysiological mechanism remains unclear Disturbed ECM regulation, but exact pathophysiological mechanism remains unclear |
NA NA |
| Spondylodysplastic (spEDS) |
SLC39A13 | Zrt/Irt-Like Protein 13 (ZIP13) | AR | 13 reported individuals (7 families) | Generalized underhydroxylation of lysyl and prolyl residues of collagen and abnormal crosslinking of collagen in the ECM, but exact pathophysiological mechanism remains unclear | Urinary crosslink analysis: increased LP/HP ratio (around 1) |
| Defects in Glycosaminoglycan Biosynthesis | ||||||
| Musculocontractural (mcEDS) |
CHST14
DSE |
Dermatan 4-O-sulfotranferase-1 (D4ST1) Dermatan sulfate epimerase-1 (DS-epi1) |
AR | <70 reported individuals | Defective biosynthesis of dermatan sulfate (DS) resulting in depletion of DS | Urinary disaccharide analysis Urinary disaccharide analysis |
| Spondylodysplastic (spEDS) |
B4GALT7
B3GALT6 |
Galactosyltransferase I (b4GalT7) Galactosyltransferase II (b3GalT6) |
AR | <15 reported individuals <50 reported individuals |
Absence of the first galactose residue of the tetrasacharide linker region of proteoglycans Absence of the second galactose residue of the tetrasacharide linker region of proteoglycans |
Serum bikunin analysis Serum bikunin analysis |
| Defects in the Complement Pathway | ||||||
| Periodontal (pEDS) |
C1S
C1R |
Complement C1s (C1s) Complement C1r (C1r) |
AD | <150 reported individuals | Gain of function variants possibly leading to abnormal interactions with components of the ECM Gain of function variants possibly leading to abnormal interactions with components of the ECM |
NA |
| Molecularly Unresolved | ||||||
| Hypermobile (hEDS) |
? | unknown | ? | ? | ? | NA |
| Novel Type of EDS (Identified After the 2017 Classification) | ||||||
| Classical-like II (clEDS II) |
AEBP1 | Adipocyte enhancer-binding protein 1 (AEBP1) | AR | 9 reported individuals (9 families) | Interference with normal collagen fibril formation, but exact pathophysiological mechanism remains unclear | NA |