Comprehensive molecular analysis demonstrates type V collagen mutations in over 90% of patients with classic EDS and allows to refine diagnostic criteria

Symoens, Sofie; Syx, Delfien; Malfait, Fransiska; Callewaert, Bert; De Backer, Julie; Vanakker, Olivier; Coucke, Paul; De Paepe, Anne

doi:10.1002/humu.22137

Cited by 165Connective tissue disorders researchDermatological and Skeletal DisordersGenomics and Rare Diseases

Comprehensive molecular analysis demonstrates type V collagen mutations in over 90% of patients with classic EDS and allows to refine diagnostic criteria

Symoens, Sofie, Syx, Delfien, Malfait, Fransiska, Callewaert, Bert, De Backer, Julie, Vanakker, Olivier, Coucke, Paul, De Paepe, Anne·2012·Human Mutation

DOI 10.1002/humu.22137

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Abstract

Type V collagen mutations are associated with classic Ehlers-Danlos Syndrome (EDS), but it is unknown for which proportion they account and to what extent other genes are involved. We analyzed COL5A1 and COL5A2 in 126 patients with a diagnosis or suspicion of classic EDS. In 93 patients, a type V collagen defect was found, of which 73 were COL5A1 mutations, 13 were COL5A2 mutations and seven were COL5A1 null-alleles with mutation unknown. The majority of the 73 COL5A1 mutations generated a COL5A1 null-allele, whereas one-third were structural mutations, scattered throughout COL5A1. All COL5A2 mutations were structural mutations. Reduced availability of type V collagen appeared to be the major disease-causing mechanism, besides other intra- and extracellular contributing factors. All type V collagen defects were identified within a group of 102 patients fulfilling all major clinical Villefranche criteria, that is, skin hyperextensibility, dystrophic scarring and joint hypermobility. No COL5A1/COL5A2 mutation was detected in 24 patients who displayed skin and joint hyperextensibility but lacked dystrophic scarring. Overall, over 90% of patients fulfilling all major Villefranche criteria for classic EDS were shown to harbor a type V collagen defect, which indicates that this is the major--if not only--cause of classic EDS.

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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 Symoens et al., 2012
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 [40]
Most cEDS patients harbor point mutations or chromosomal rearrangements in COL5A1 or COL5A2 genes encoding collagen V.
“Most patients harbor point mutations or chromosomal rearrangements in COL5A1 or COL5A2 genes encoding the collagen V [40,41].”
From Cellular and Molecular Mechanisms in the Pathogenesis of Classical, Vascular, and Hypermobile Ehlers‒Danlos Syndromes (2019) · cites this paper as [40]
Collagen V haploinsufficiency is the most common molecular defect caused by COL5A1 null alleles.
“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 [40]
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 [40]

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Authors: Symoens, S., Syx, D., Malfait, F., Callewaert, B., De Backer, J., Vanakker, O., Coucke, P., & De Paepe, A.
Affiliations: Ghent University Hospital (BE)
ORCID: Symoens, Sofie
Syx, Delfien
Malfait, Fransiska
Callewaert, Bert
Vanakker, Olivier
Coucke, Paul
Venue: Human Mutation
Publisher: Hindawi Limited
Published: 2012-07-05
Volume: 33
Issue: 10
Pages: 1485-1493
ISSN: 1059-7794 (ISSN-L)
DOI: 10.1002/humu.22137
OpenAlex: W2092877017
Cited by: 165
References: 41
Citations by year: 2026: 5 · 2025: 8 · 2024: 6 · 2023: 8 · 2022: 10 · 2021: 16 · 2020: 15 · 2019: 17 · 2018: 10 · 2017: 18 · 2016: 14 · 2015: 15 · 2014: 11 · 2013: 8 · 2012: 4
FWCI: 7.29
Type: journal article
Language: en
Open access: closed
Licence: doi.wiley.com/10.1002/tdm_license_1.1 (tdm, 1153 d)
Locations: Human Mutation (publishedVersion)
PubMed (publishedVersion)
Ghent University Academic Bibliography (Ghent University) (submittedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Connective tissue disorders research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Dermatological and Skeletal Disorders
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
Keywords: type V collagen, molecular diagnosis, skin hyperextensibility, joint hypermobility, structural mutations
MeSH terms: DNA Mutational Analysis, Ehlers-Danlos Syndrome, Humans, Mutation, Skin, Collagen Type V

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Comprehensive molecular analysis demonstrates type V collagen mutations in over 90% of patients with classic EDS and allows to refine diagnostic criteria

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