TABLE 1.
Description of subtypes of EDS comparing 2017 nomenclature with the Villefranche and Berlin nosology
| Molecular biology of Ehlers-Danlos syndromes | |||||||
|---|---|---|---|---|---|---|---|
| Gene | Mutation(s) | Inheritance | Molecular biology | 2017 EDS nomenclature | Villefranche nosology | Berlin nosology | References |
| ADAMSTS2 | Homozygous nonsense mutations (p.(Gln225) and p.(Trp795*)), skipping in frame and out of frame of various exons, homozygous loss of function mutations (c.2927_2928delCT, p. (Pro976Argfs*42); c.669–670dupG, p. (Pro224Argfs*41); c.2751–2A>T) and compound heterozygous (p. (Met295Thrfs25*)) | AR | Enzymatic component of the ECM | Dermatosparaxis EDS (dEDS) | Dermatosparaxis type | Type VIIC | 3–5 |
| AEBP1 | Compound heterozygous (c,1470delC [p. Asn490_Met495delins(40)] and c,1743C>A [p.Cys581*]), homozygous (c,1320_1326del [p.Arg440Serfs*3]) homozygous splice site variant (c.1630J)1G>A), homozygous c,1925T>C p.(Leu642Pro) | AR | Regulates collagen fibrillogenesis | Classic-like EDS (clEDS) | N/A | N/A | 6,7 |
| B3GALT6 | Missense and frameshift mutations, in-frame deletions, start codon mutations, splice site mutations and in-frame duplication. Homozygous and compound heterozygous mutations. The following are the most commonly reported: p.(Pro67Leu), p. (Thr79Ala), p.(Arg232Cys), p.(Asp207His), p. (Phel86Leu), p.(Arg6Trp) p.(Glu265Asp), p. (Ser309Thr), p.(Glul74Alafs*266), p.(Metl?) | AR | Post-translational modification of proteins including proteogylcans | Spondylodysplastic EDS (spEDS) | EDS progeroid type | N/A | 8–13 |
| B4GALT7 | c.808C>T, p.(Arg270Cys); c,122T>C, p. (Leu41Pro); c.421C>T, p.(Argl41Trp); c.557C>A, p.(Alal86Asp); c.617T>G, p. (Leu206Pro); c.641G>A, p.(Cys214Tyr); c.277dup,p.(His93Profs*73); c.970T>A, p. (Cys324Ser) | AR | Post-translational modification of proteins including proteoglycans | Spondylodysplastic EDS (spEDS) | EDS progeroid type | N/A | 14–19 |
| C1R | Heterozygous missense and in-frame insertion/ deletion variants; p.Asp290Gly, p.Gly297Asp, p.Leu300Pro, p.Arg301Pro, p.Tyr302Cys, p. Ile306_Cys309delinsArgArg p.Cys309Trp, p. Cys309Trp, p.Cys338Arg, p.Cys358Phe, p. Trp364Cys, p.Cys371Trp, p. Arg401_Tyr405delinsHisValIle, p.Trp435Arg | AD | Complement immune system | Periodontal EDS (pEDS) | EDS periodontitis | Type VIII | 20 |
| CIS | Heterozygous missense and in-frame insertion/deletion variants p.Cys294Arg, p.Val316del | AD | Complement immune system | Periodontal EDS (pEDS) | EDS periodontitis | Type VIII | 20 |
| CHST14 | Loss of function, missense, frameshift and nonsense mutations p.(Pro281Leu), p. (Val49*), p.(Arg213Pro), p.(Tryr293Cys), p. (Arg29Gfs*113), p.(Lys69*), p. (Glnl 13Argfs*14), p.(Argl35Gly), p. (Leul37Gln), p.(Cysl52Leufs*10), p. (Phe209Ser), p.(Arg218Ser), p. (Gly228Leufs*13, p.(Glu262Lys), p. (Arg274Pro), p.(Met280Leu), p.(Cys289Ser), p.(Trp327Cfs*29), p.(Glu334Glyfs*107) | AR | Post-translational modification— conversion of sulfate to dermatan sulfate | Musculocontractural EDS (mcEDS) | N/A | N/A | 21–23 |
| C0L1A1 | c.934C>T, p.(Arg312Cys); c,1720C>T, p. (Arg574Cys); and c.3277C>T, p. (Argl093Cys) | AD | Structural ECM component | cEDS with vascular fragility, vEDS | Classical type, vascular type | Typel/II/IV | 24–26 |
| C0L1A1 | Splice site mutations that lead deletions of exon 6 (intron 5–2A>G/T; intron 5-lG>A/C/ T; exon 6-lG>A/C) | AD | Structural ECM component | Arthrochalasia EDS (aEDS) | Athroscorasia type | Type VIIA/B | 27–29 |
| C0L1A2 | c.213dupC,p.(Arg99*) homozygous, six splice site mutations (two homozygous (c.3105+ 2T>C and c.3601G>T)) and two compound heterozygous (c.70+717A>G; c.1404+1G>A and c.540+5G>A; c,1404G>C) | AR | Structural ECM component | Cardiac-valvular (cvEDS) | N/A | N/A | 30–33 |
| Splice site mutations that lead deletions of exon 6 | 34 | ||||||
| C0L1A2 | (intron 5–2A>G; intron 5-lG>A/C; exon 6-lG>A; intron 6+lG>A/T/C; intron 6+2T>C/G) | AD | Structural ECM component | Arthrochalasia EDS (aEDS) | Athroscorasia type | Type VIIA/B | 29,35–39 |
| C0L3A1 | p.(Gly637Ser) | AD | Structural ECM component | Hypermobile EDS (hEDS)? One Family | Hypermobility type (EDS-HT) | Type III | 40 |
| C0L3A1 | Glycine substitutions, splice-site insertions/ deletions, in-frame insertions/deletions, haploinsufficiency, nonglycine missense variants in the triple helix, nonglycine missense variants and in-frame insertions/ deletions, in the N- or C-terminal | AD | Structural ECM component | Vascular EDS (vEDS) | Vascular type | Type IV | 41,42 |
| C0L5A1 | Mutations leading to nonsense mediated mRNA decay, haploinsufficiency and structural mutations | AD | Structural ECM component | Classical EDS (cEDS) | Classical type | Type I/II | 26,43 |
| COL5A2 | Structural mutations and splice site mutations | AD | Structural ECM component | Classical EDS (cEDS) | Classical type | Type I/II | 26,43 |
| C0L12A1 | Heterozygous missense mutations that are autosomal dominant (c.7167 T>C, p. (Ile2334Thr), C.C5893T, p.(Argl965Cys), 8329G>C, p.(Gly2777Arg), C.G8357A, p. (Gly2786Asp)) and a homozygous frameshift mutation that is autosomal recessive (c.8006 +1 G>A, p.(2567Asp>Phefs*2) | AR or AD | ECM component | Myopathic EDS (mEDS) | N/A | N/A | 44–46 |
| DSE | Homozygous loss of function, missense mutations (p.(Arg267Gly), p.(Ser268Leu)) | AR | Biosynthesis of dermatan sulfate | Musculocontractural EDS (mcEDS) | N/A | N/A | 23,47 |
| FKPB14 | Duplication (c.362dup, p.(Glul22Argfs*7), homozygous deletion (c,197+5_197+ 8delGTAA), compound heterozygous mutations | AR or compound heterozygosity | ER folding/transport of collagen | Kyphoscoliotic EDS (kEDS) | Kyphoscoliosis type | Type VI, Type VIA | 48–51 |
| LZTS1 | p.(His211Gln) | AD | Tumor suppressor | Hypermobile EDS (hEDS)? One Family | Hypermobility type (EDS-HT) | Type III | 52 |
| PRDM5 | c. 1517_1527dell 1, p.(Val506Glufs*5); c.974delG, p.(Cys325Leufs*2); c.711_714delTGTT, p.(Val238Alafs*35); c,1768C>T, p.(Arg590*); c.320A>G, p. (Tyrl07Cys); c,17T>G, p.(ValôGly); C.93+ 1G>A | AR | Collagen synthesis | Brittle cornea syndrome (BCS) | N/A | N/A | 53–55 |
| PL0D1 | p.Ile454IlefsX2, p.Ala667Thr, and p.His706Arg, homozygous for exons 10–16 duplication, p. Ile454IlefsX2, homozygous for p.Arg319X | AR | ER folding/transport of collagen | Kyphoscoliotic EDS (kEDS) | Kyphoscoliosis type | Type VI, Type VIA | 56–64 |
| SLC39A13 | Homozygous 9-bp in-frame deletion in exon 4 | AR | Zinc transporter | Spondylodysplastic EDS (spEDS) | EDS progeroid type | N/A | 65–67 |
| ZNF469 | 5294delA, 9527delG, Cys 3339Tyr, Glul392Ter | AR | Collagen synthesis | Brittle cornea syndrome (BCS) | N/A | N/A | 68–73 |
Note: Gene mutation, inheritance pattern, molecular biology, nomenclature, and references are listed.