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Archives of Dermatological Research

, Volume 311, Issue 4, pp 265–275 | Cite as

Understanding the basis of Ehlers–Danlos syndrome in the era of the next-generation sequencing

  • Francesca CortiniEmail author
  • Chiara Villa
  • Barbara Marinelli
  • Romina Combi
  • Angela Cecilia Pesatori
  • Alessandra Bassotti
Review
  • 240 Downloads

Abstract

Ehlers–Danlos syndrome (EDS) is a clinically and genetically heterogeneous group of heritable connective tissue disorders (HCTDs) defined by joint laxity, skin alterations, and joint hypermobility. The latest EDS classification recognized 13 subtypes in which the clinical and genetic phenotypes are often overlapping, making the diagnosis rather difficult and strengthening the importance of the molecular diagnostic confirmation. New genetic techniques such as next-generation sequencing (NGS) gave the opportunity to identify the genetic bases of unresolved EDS types and support clinical counseling. To date, the molecular defects have been identified in 19 genes, mainly in those encoding collagen, its modifying enzymes or other constituents of the extracellular matrix (ECM). In this review we summarize the contribution of NGS technologies to the current knowledge of the genetic background in different EDS subtypes.

Keywords

Ehlers–Danlos syndrome Heterogeneity Heritable connective tissue disorders 

Notes

Acknowledgements

Thanks to AISED for support and Dr. Bice Strumbo and Dr. Agostino Seresini for excellent technical assistance.

Funding

There is no funding source.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

References

  1. 1.
    Alazami AM, Patel N, Shamseldin HE et al (2015) Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families. Cell Rep 10(2):148–161Google Scholar
  2. 2.
    Baldwin AK, Simpson A, Steer R et al (2013) Elastic fibres in health and disease. Expert Rev Mol Med 15:e8Google Scholar
  3. 3.
    Baumann M, Giunta C, Krabichler B et al (2012) Mutations in FKBP14 cause a variant of Ehlers–Danlos syndrome with progressive kyphoscoliosis, myopathy, and hearing loss. Am J Hum Genet 90(2):201–216Google Scholar
  4. 4.
    Beighton P, De Paepe A, Danks D et al (1988) International nosology of heritable disorders of connective tissue, Berlin, 1986. Am J Med Genet 29:581–594Google Scholar
  5. 5.
    Beighton P, De Paepe A, Steinmann B et al (1998) Ehlers–Danlos syndromes: revised nosology, Villefranche, 1997. Ehlers–Danlos national foundation (USA) and Ehlers–Danlos support group (UK). Am J Med Genet 77(1):31–37Google Scholar
  6. 6.
    Bin BH, Fukada T, Hosaka T et al (2011) Biochemical characterization of human ZIP13 protein: a homodimerized zinc transporter involved in the spondylocheiro dysplastic Ehlers–Danlos syndrome. J Biol Chem 286:40255–40265Google Scholar
  7. 7.
    Birk DE (2001) Type V collagen: heterotypic type I/V collagen interactions in the regulation of fibril assembly. Micron 32:223–237Google Scholar
  8. 8.
    Brady AF, Demirdas S, Fournel-Gigleux S et al (2017) The Ehler–Danlos syndromes, rare types. Am J Med Genet C Semin Med Genet 175(1):70–115Google Scholar
  9. 9.
    Byers PH, Murray ML (2014) Ehlers–Danlos syndrome: a showcase of conditions that lead to understanding matrix biology. Matrix Biol 33:10–15Google Scholar
  10. 10.
    Colombi M, Dordoni C, Venturini M et al (2017) Delineation of Ehlers–Danlos syndrome phenotype due to the c.934C> T, p.(Arg312Cys) mutation in COL1A1: report on a three-generation family without cardiovascular events, and literature review. Am J Med Genet A 173(2):524–530Google Scholar
  11. 11.
    Danecek P, Anton A, Abecasis G et al (2011) The variant call format and VCF tools. Bioinformatics 27(15):2156–2158Google Scholar
  12. 12.
    Demirdas S, Dulfer E, Robert L et al (2017) Recognizing the tenascin-X deficient type of Ehlers–Danlos syndrome: a cross-sectional study in 17 patients. Clin Genet 91(3):411–425Google Scholar
  13. 13.
    De Paepe A, Malfait F (2012) The Ehlers–Danlos syndrome, a disorder with many faces. Clin Genet 82(1):1–11Google Scholar
  14. 14.
    Eide DJ (2006) Zinc transporters and the cellular trafficking of zinc. Biochim Biophys Acta 1763:711–722Google Scholar
  15. 15.
    Faiyaz-Ul-Haque M, Zaidi SHE, Al-Ali M et al (2004) A novel missense mutation in the galactosyltransferase-I (B4GALT7) gene in a family exhibiting facio skeletal anomalies and Ehlers–Danlos syndrome resembling the progeroid type. Am J Med Genet A 128A:39–45Google Scholar
  16. 16.
    Galat A (2003) Peptidylprolyl cis/trans isomerases (immunophilins): biological diversity-targets-functions. Curr Top Med Chem 3(12):1315–1347Google Scholar
  17. 17.
    García-García G, Baux D, Faugère V et al (2016) Assessment of the latest NGS enrichment capture methods in clinical context. Sci Rep 6:20948Google Scholar
  18. 18.
    Germain DP, Herrera-Guzman Y (2004) Vascular Ehlers–Danlos syndrome. Ann Genet 47:1–9Google Scholar
  19. 19.
    Giunta C, Chambaz C, Pedemonte M et al (1999) The arthrochalasia type of Ehlers–Danlos syndrome (EDS VIIA and VIIB): the diagnostic value of collagen fibril ultrastructure. Am J Med Genet A 146A(10):1341–1346Google Scholar
  20. 20.
    Giunta C, Elçioglu NH, Albrecht B et al (2008) Spondylocheiro dysplastic form of the Ehlers–Danlos syndrome—an autosomal-recessive entity caused by mutations in the zinc transporter gene SLC39A13. Am J Hum Genet 82(6):1290–1305Google Scholar
  21. 21.
    Hernàndez A, Aguirre-Negrete MG, Gonzàlez-Flores S et al (1986) Ehlers–Danlos features with progeroid facies and mild mental retardation further delineation of the syndrome. Clin Genet 30:456–461Google Scholar
  22. 22.
    Hicks D, Farsani GT, Laval S, et (2014) Mutations in the collagen XII gene define a new form of extracellular matrix-related myopathy. Hum Mol Genet 23(9):2353–2363Google Scholar
  23. 23.
    Hubmacher D, Tiedemann K, Reinhardt DP (2006) Fibrillins: from biogenesis of microfibrils to signaling functions. Curr Top Dev Biol 75:93–123Google Scholar
  24. 24.
    Ikuta T, Sogawa H, Ariga T et al (1998) Structural analysis of mouse tenascin-X: evolutionary aspects of reduplication of FNIII repeats in the tenascin gene family. Gene 217:1–13Google Scholar
  25. 25.
    Kapferer-Seebacher I, Pepin M, Werner R et al (2016) Periodontal Ehlers–Danlos syndrome is caused by mutations in C1R and C1S, which encode subcomponents C1r and C1s of complement. Am J Hum Genet 99(5):1005–1014Google Scholar
  26. 26.
    Kielty CM, Sherratt MJ, Marson A, Baldock C (2005) Fibrillin microfibrils. Adv Protein Chem 70:405–436Google Scholar
  27. 27.
    Kielty CM (2006) Elastic fibres in health and disease. Expert Rev Mol Med 8:1–23Google Scholar
  28. 28.
    Krane SM, Pinnell SR, Erbe RW (1972) Lysyl-protocollagen hydroxylase deficiency in fibroblasts from siblings with hydroxylysine-deficient collagen. Proc Natl Acad Sci USA 69(10):2899–2903Google Scholar
  29. 29.
    Malfait F, Symoens S, De Backer J et al (2007) Three arginine to cysteine substitutions in the pro-alpha (I)-collagen chain cause Ehlers–Danlos syndrome with a propensity to arterial rupture in early adulthood. Hum Mutat 28(4):387–395Google Scholar
  30. 30.
    Malfait F, Syx D, Vlummens P et al (2010) Musculocontractural Ehlers–Danlos syndrome (former EDS type VIB) and adducted thumb clubfoot syndrome (ATCS) represent a single clinical entity caused by mutations in the dermatan-4-sulfotransferase 1 encoding CHST14 gene. Hum Mutat 31(11):1233–1239Google Scholar
  31. 31.
    Malfait F, Kariminejad A, Van Damme T et al (2013) Defective initiation of glycosaminoglycan synthesis due to B3GALT6 mutations causes a pleiotropic Ehlers–Danlos syndrome like connective tissue disorder. Am J Hum Genet 92(6):935–945Google Scholar
  32. 32.
    Malfait F, Francomano C, Byers P et al (2017) The 2017 international classification of the Ehlers–Danlos syndromes. Am J Med Genet C Semin Med Genet 175(1):8–26Google Scholar
  33. 33.
    Miyake N, Kosho T, Mizumoto S et al (2010) Loss-of-function mutations of CHST14 in a new type of Ehlers–Danlos syndrome. Hum Mutat 31(8):966–974Google Scholar
  34. 34.
    Muller T, Mizumoto S, Suresh I et al (2013) Loss of dermatan sulfate epimerase (DSE) function results in musculocontractural Ehlers–Danlos syndrome. Hum Mol Genet 22(18):3761–3772Google Scholar
  35. 35.
    Myllyharju J, Kivirikko KI (2001) Collagens and collagen-related diseases. Ann Med 33:7–21Google Scholar
  36. 36.
    Nakajima M, Mizumoto S, Miyake N et al (2013) Mutations in B3GALT6, which encodes a glycosaminoglycan linker region enzyme, cause a spectrum of skeletal and connective tissue disorders. Am J Hum Genet 92(6):927–934Google Scholar
  37. 37.
    Nitschke Y, Baujat G, Botschen U et al (2012) Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6. Am J Hum Genet 90(1):25–39Google Scholar
  38. 38.
    Pepin M, Schwarze U, Superti-Furga A, Byers PH (2000) Clinical and genetic features of Ehlers–Danlos syndrome type IV, the vascular type. N Engl J Med 342(10):673–680Google Scholar
  39. 39.
    Persikov AV, Ramshaw JAM, Brodsky B (2000) Collagen model peptides: sequence dependence of triple-helix stability. Biopolymers 55:436–450Google Scholar
  40. 40.
    Plancke A, Holder-Espinasse M, Rigau V et al (2009) Homozygosity for a null allele of COL3A1 results in recessive Ehlers–Danlos syndrome. Eur J Hum Genet 17(11):1411–1416Google Scholar
  41. 41.
    Punetha J, Kesari A, Hoffman EP et al (2016) Novel Col12A1 variant expands the clinical picture of congenital myopathies with extracellular matrix defects. Muscle Nerve 55(2):277–281Google Scholar
  42. 42.
    Quentin E, Gladen A, Rodèn L, Kresse H (1990) A genetic defect in the biosynthesis of dermatan sulfate proteoglycan: galactosyltransferase I deficiency in fibroblasts from patient with a progeroid syndrome. Proc Natl Acad Sci USA 87(4):1342–1346Google Scholar
  43. 43.
    Ritelli M, Dordoni C, Venturini M et al (2013) Clinical and molecular characterization of 40 patients with classic Ehlers–Danlos syndrome: identification of 18 COL5A1 and 2 COL5A2 novel mutations. Orphanet J Rare Dis 8:58Google Scholar
  44. 44.
    Ritelli M, Dordoni C, Cinquina V et al (2017) Expanding the clinical and mutational spectrum of B4GALT7-spondylodysplastic Ehlers–Danlos syndrome. Orphanet J Rare Dis 12(1):153Google Scholar
  45. 45.
    Rozario T, DeSimone DW (2010) The extracellular matrix in development and morphogenesis: a dynamic view. Dev Biol 341(1):126–140Google Scholar
  46. 46.
    Schalkwijk J, Zweers MC, Steijlen PM et al (2001) A recessive form of the Ehlers–Danlos syndrome caused by tenascin-X deficiency. N Engl J Med 345(16):1167–1175Google Scholar
  47. 47.
    Schwarze U, Atkinson M, Hoffman GG et al (2000) Null alleles of the COL5A1 gene of type V collagen are a cause of the classical forms of Ehlers–Danlos syndrome (types I and II). Am J Hum Genet 66(6):1757–1765Google Scholar
  48. 48.
    Schwarze U, Hata R, McKusick VA et al (2004) Rare autosomal recessive cardiac valvular form of Ehlers–Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway. Am J Hum Genet 74(5):917–930Google Scholar
  49. 49.
    Shimizu K, Okamoto N, Miyake N et al (2011) Delineation of dermatan 4-Osulfotransferase1 deficient Ehlers–Danlos syndrome: observation of two additional patients and comprehensive review of 20 reported patients. Am J Med Genet A 155A(8):1949–1958Google Scholar
  50. 50.
    Shoulders MD, Raines RT (2009) Collagen structure and stability. Annu Rev Biochem 78:929–958Google Scholar
  51. 51.
    Symoens S, Syx D, Malfait F et al (2012) Comprehensive molecular analysis demonstrates type V collagen mutations in over 90% of patients with classic EDS and allows to refine diagnostic criteria. Hum Mutat 33(10):1485–1493Google Scholar
  52. 52.
    Van Damme T, Colige A, Syx D et al (2016) Expanding the clinical and mutational spectrum of the Ehlers–Danlos syndrome, dermatosparaxis type. Genet Med 18(9):882–891Google Scholar
  53. 53.
    Wagenseil JE, Mecham RP (2012) Elastin in large artery stiffness and hypertension. J Cardiovasc Transl Res 5(3):264–273Google Scholar
  54. 54.
    Wenstrup RJ, Florer JB, Brunskill EW et al (2004) Type V collagen controls the initiation of collagen fibril assembly. J Biol Chem 279(51):53331–53337Google Scholar
  55. 55.
    Yang Y, Muzny DM, Reid JG et al (2013) Clinical whole-exome sequencing for the diagnosis of mendelian disorders. N Engl J Med 369(16):1502–1511Google Scholar
  56. 56.
    Zou Y, Zwolanek D, Izu Y et al (2014) Recessive and dominant mutations in COL12A1 cause a novel EDS/myopathy overlap syndromein humans and mice. Hum Mol Genet 23(9):2339–2352Google Scholar
  57. 57.
    Zweers MC, Bristow J, Steijlen PM et al (2003) Haploinsufficiency of TNXB is associated with hypermobility type of Ehlers–Danlos syndrome. Am J Hum Genet 73(1):214–217Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Clinical Sciences and Community HealthUniversity of Milan, IRCCS Ca’ Granda FoundationMilanItaly
  2. 2.Department of Medicine Preventive ServicesUOC Occupational Medicine, IRCCS Ca’ Granda FoundationMilanItaly
  3. 3.School of Medicine and SurgeryUniversity of Milano-BicoccaMonzaItaly
  4. 4.Regional Center of Ehlers-Danlos SyndromeIRCCS Ca’ Granda FoundationMilanItaly

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