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Cited by 135Connective tissue disorders researchGenomics and Rare DiseasesDermatological and Skeletal Disorders

Clinical and molecular characterization of 40 patients with classic Ehlers-Danlos syndrome: Identification of 18 COL5A1 and 2 COL5A2 novel mutations

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Ritelli, Marco, Dordoni, Chiara, Venturini, Marina, Chiarelli, Nicola, Quinzani, Stefano, Traversa, Michele, Zoppi, Nicoletta, Vascellaro, Annalisa +5 more·2013·Orphanet Journal of Rare Diseases
DOI 10.1186/1750-1172-8-58PMC PMC3653713
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Abstract

Background: Classic Ehlers–Danlos syndrome (cEDS) is a rare autosomal dominant connective tissue disorder that is primarily characterized by skin hyperextensibility, abnormal wound healing/atrophic scars, and joint hypermobility. A recent study demonstrated that more than 90% of patients who satisfy all of these major criteria harbor a type V collagen (COLLV) defect. Methods: This cohort included 40 patients with cEDS who were clinically diagnosed according to the Villefranche nosology. The flowchart that was adopted for mutation detection consisted of sequencing the COL5A1 gene and, if no mutation was detected, COL5A2 analysis. In the negative patients the presence of large genomic rearrangements in COL5A1 was investigated using MLPA, and positive results were confirmed via SNP-array analysis. Results: We report the clinical and molecular characterization of 40 patients from 28 families, consisting of 14 pediatric patients and 26 adults. A family history of cEDS was present in 9 patients. The majority of the patients fulfilled all the major diagnostic criteria for cEDS; atrophic scars were absent in 2 females, skin hyperextensibility was not detected in a male and joint hypermobility was negative in 8 patients (20% of the entire cohort). Wide inter- and intra-familial phenotypic heterogeneity was observed. We identified causal mutations with a detection rate of approximately 93%. In 25/28 probands, COL5A1 or COL5A2 mutations were detected. Twenty-one mutations were in the COL5A1 gene, 18 of which were novel (2 recurrent). Of these, 16 mutations led to nonsense-mediated mRNA decay (NMD) and to COLLV haploinsufficiency and 5 mutations were structural. Two novel COL5A2 splice mutations were detected in patients with the most severe phenotypes. The known p. (Arg312Cys) mutation in the COL1A1 gene was identified in one patient with vascular-like cEDS. Conclusions: Our findings highlight that the three major criteria for cEDS are useful and sufficient for cEDS clinical diagnosis in the large majority of the patients. The borderline patients for whom these criteria fail can be diagnosed when minor signs of connective tissue diseases and family history are present and when genetic testing reveals a defect in COLLV. Our data also confirm that COL5A1 and COL5A2 are the major, if not the only, genes involved in cEDS.

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  • More than 90% of cEDS patients harbor a heterozygous mutation in one of the genes encoding type V collagen (COL5A1 and COL5A2).

    “Morethan 90% of cEDS patients harbor a heterozygous mutation in one of the genes encoding type V collagen ( COL5A1 and COL5A2 ) [Symoens et al., 2012; Ritelli et al., 2013; Zoppi et al., 2015]”

    From The 2017 international classification of the Ehlers–Danlos syndromes (2017) · cites this paper as Ritelli et al., 2013

  • The COL1A1 p.(Arg312Cys) mutation has subsequently been identified in two other individuals with EDS and complications of vascular fragility.

    “The p.(Arg312Cys) mutation has subsequently been identified in two other individuals with EDS and complications of vascular fragility [Ritelli et al., 2013;Gaines et al., 2015].”

    From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Ritelli et al., 2013

  • Patients with the COL1A1 p.(Arg312Cys) mutation are particularly at risk for vascular events.

    “Patients with the p.(Arg312Cys) mutation are particularly at risk for vascular events, highlighting the benefit of molecular confirmation in classical EDS patients for management purposes.”

    From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Ritelli et al., 2013

  • Classical EDS and vascular EDS are caused respectively by defects in collagen V and collagen III.

    “cEDS and vEDS are caused respectively by defects in collagen V and collagen III, whereas the molecular basis of hEDS is unknown.”

    From Cellular and Molecular Mechanisms in the Pathogenesis of Classical, Vascular, and Hypermobile Ehlers‒Danlos Syndromes (2019) · cites this paper as [41]

  • Rare COL5A1 variants and the majority of COL5A2 mutations affect collagen V structural integrity by exerting a dominant negative effect.

    “Collagen V haploinsufficiency is the most common molecular defect caused by COL5A1 null alleles, whereas rare COL5A1 variants and the majority of COL5A2 mutations reported so far affect collagen V structural integrity by exerting a dominant negative effect [40,41].”

    From Cellular and Molecular Mechanisms in the Pathogenesis of Classical, Vascular, and Hypermobile Ehlers‒Danlos Syndromes (2019) · cites this paper as [41]

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Authors
Ritelli, M., Dordoni, C., Venturini, M., Chiarelli, N., Quinzani, S., Traversa, M., Zoppi, N., Vascellaro, A., Wischmeijer, A., Manfredini, E., Garavelli, L., Calzavara-Pinton, P., & Colombi, M.
Affiliations
  • University of Brescia (IT)
  • Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia (IT)
  • IRCCS Azienda Ospedliero-Universitaria di Bologna Policlinico di Sant'Orsola (IT)
  • Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda (IT)
  • Santa Maria Nuova Hospital (IT)
Corresponding author
Colombi, Marina
ORCID
Venue
Orphanet Journal of Rare Diseases
Publisher
Springer Science and Business Media LLC
Published
2013-04-12
Volume
8
Issue
1
Pages
58-58
ISSN
1750-1172 (ISSN-L)
DOI
10.1186/1750-1172-8-58
PMC
PMC3653713
OpenAlex
W2065067440
Cited by
134
References
40
Citations by year
2026: 8 · 2025: 7 · 2024: 6 · 2023: 3 · 2022: 8 · 2021: 15 · 2020: 14 · 2019: 15 · 2018: 14 · 2017: 12 · 2016: 12 · 2015: 9 · 2014: 9 · 2013: 2
FWCI
7.08
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Orphanet Journal of Rare Diseases (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Institutional Research Information System (Università degli Studi di Brescia) (submittedVersion, other-oa)
Funders
Regione Lombardia
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Connective tissue disorders research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Dermatological and Skeletal Disorders
Keywords
type V collagen, novel mutations, nonsense-mediated mRNA decay, splicing mutation, phenotypic heterogeneity, connective tissue diseases, vascular Ehlers-Danlos syndrome
MeSH terms
Adolescent, Adult, Child, Collagen, Ehlers-Danlos Syndrome, Family, Female, Humans, Male, Mutation, Collagen Type V, Haploinsufficiency, Nonsense Mediated mRNA Decay

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