Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Archives of Dermatological Research
Published in: Archives of Dermatological Research 4/2019

01-05-2019 | Ehlers-Danlos Syndrome | Review

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

Authors: Francesca Cortini, Chiara Villa, Barbara Marinelli, Romina Combi, Angela Cecilia Pesatori, Alessandra Bassotti

Published in: Archives of Dermatological Research | Issue 4/2019

Login to get access

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.
Literature
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):148–161PubMedCrossRef
2.
Baldwin AK, Simpson A, Steer R et al (2013) Elastic fibres in health and disease. Expert Rev Mol Med 15:e8PubMedCrossRef
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):201–216PubMedPubMedCentralCrossRef
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 29:581–594PubMedCrossRef
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):31–37PubMedCrossRef
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 286:40255–40265PubMedPubMedCentralCrossRef
7.
Birk DE (2001) Type V collagen: heterotypic type I/V collagen interactions in the regulation of fibril assembly. Micron 32:223–237PubMedCrossRef
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):70–115PubMedCrossRef
9.
Byers PH, Murray ML (2014) Ehlers–Danlos syndrome: a showcase of conditions that lead to understanding matrix biology. Matrix Biol 33:10–15PubMedCrossRef
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):524–530PubMedCrossRef
11.
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):411–425PubMedCrossRef
13.
De Paepe A, Malfait F (2012) The Ehlers–Danlos syndrome, a disorder with many faces. Clin Genet 82(1):1–11PubMedCrossRef
14.
Eide DJ (2006) Zinc transporters and the cellular trafficking of zinc. Biochim Biophys Acta 1763:711–722PubMedCrossRef
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:39–45PubMedCrossRef
16.
Galat A (2003) Peptidylprolyl cis/trans isomerases (immunophilins): biological diversity-targets-functions. Curr Top Med Chem 3(12):1315–1347PubMedCrossRef
17.
18.
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):1341–1346CrossRef
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):1290–1305PubMedPubMedCentralCrossRef
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 30:456–461PubMedCrossRef
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):2353–2363PubMedCrossRef
23.
Hubmacher D, Tiedemann K, Reinhardt DP (2006) Fibrillins: from biogenesis of microfibrils to signaling functions. Curr Top Dev Biol 75:93–123PubMedCrossRef
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 217:1–13PubMedCrossRef
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):1005–1014PubMedPubMedCentralCrossRef
26.
Kielty CM, Sherratt MJ, Marson A, Baldock C (2005) Fibrillin microfibrils. Adv Protein Chem 70:405–436PubMedCrossRef
27.
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):2899–2903PubMedCrossRefPubMedCentral
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):387–395PubMedCrossRef
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):1233–1239PubMedCrossRef
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):935–945PubMedPubMedCentralCrossRef
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):8–26PubMedCrossRef
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):966–974PubMedCrossRef
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):3761–3772PubMedCrossRef
35.
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):927–934PubMedPubMedCentralCrossRef
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):25–39PubMedPubMedCentralCrossRef
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):673–680PubMedCrossRef
39.
Persikov AV, Ramshaw JAM, Brodsky B (2000) Collagen model peptides: sequence dependence of triple-helix stability. Biopolymers 55:436–450PubMedCrossRef
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):1411–1416PubMedPubMedCentralCrossRef
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):277–281PubMedPubMedCentralCrossRef
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):1342–1346PubMedCrossRefPubMedCentral
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 8:58PubMedPubMedCentralCrossRef
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):153PubMedPubMedCentralCrossRef
45.
Rozario T, DeSimone DW (2010) The extracellular matrix in development and morphogenesis: a dynamic view. Dev Biol 341(1):126–140PubMedCrossRef
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):1167–1175PubMedCrossRef
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):1757–1765PubMedPubMedCentralCrossRef
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):917–930PubMedPubMedCentralCrossRef
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):1949–1958PubMedCrossRef
50.
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):1485–1493PubMedCrossRef
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):882–891PubMedCrossRef
53.
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):53331–53337PubMedCrossRef
55.
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):2339–2352PubMedCrossRef
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):214–217PubMedPubMedCentralCrossRef
Metadata
Title
Understanding the basis of Ehlers–Danlos syndrome in the era of the next-generation sequencing
Authors
Francesca Cortini
Chiara Villa
Barbara Marinelli
Romina Combi
Angela Cecilia Pesatori
Alessandra Bassotti
Publication date
01-05-2019
Publisher
Springer Berlin Heidelberg
Published in
Archives of Dermatological Research / Issue 4/2019
Print ISSN: 0340-3696
Electronic ISSN: 1432-069X
DOI
https://doi.org/10.1007/s00403-019-01894-0

Other articles of this Issue 4/2019

Archives of Dermatological Research 4/2019 Go to the issue

Original Paper

Modulation of lipid fluidity likely contributes to the fructose/xylitol-induced acceleration of epidermal permeability barrier recovery

Original Paper

Association of GA genotype of SNP rs4680 in COMT gene with psoriasis

Concise Communication

Mast cells in hidradenitis suppurativa: a clinicopathological study

Review

The role of adipokines in systemic sclerosis: a missing link?

Original Paper

Malondialdehyde and advanced oxidation protein products are not increased in psoriasis: a controlled study

Original Paper

Malondialdehyde, lipoprotein-a, lipoprotein ratios, comprehensive lipid tetrad index and atherogenic index as surrogate markers for cardiovascular disease in patients with psoriasis: a case–control study