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

Marco Ritelli, Chiara Dordoni, Marina Venturini, Nicola Chiarelli, Stefano Quinzani, Michele Traversa, Nicoletta Zoppi, Annalisa Vascellaro, Anita Wischmeijer, Emanuela Manfredini, Livia Garavelli, Piergiacomo Calzavara-Pinton, Marina Colombi

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article number58
JournalOrphanet Journal of Rare Diseases
Volume8
Issue number1
DOIs
Publication statusPublished - 2013

Fingerprint

Ehlers-Danlos Syndrome
Mutation
Joint Instability
Genes
Cicatrix
Nonsense Mediated mRNA Decay
Collagen Type V
Software Design
Haploinsufficiency
Skin
Connective Tissue Diseases
Genetic Testing
Connective Tissue
Wound Healing
Single Nucleotide Polymorphism
Blood Vessels

Keywords

  • Classic Ehlers-Danlos syndrome
  • COL1A1
  • COL5A1
  • COL5A2
  • Diagnostic flowchart
  • MLPA

ASJC Scopus subject areas

  • Medicine(all)
  • Genetics(clinical)
  • Pharmacology (medical)

Cite this

Clinical and molecular characterization of 40 patients with classic Ehlers-Danlos syndrome : Identification of 18 COL5A1 and 2 COL5A2 novel mutations. / Ritelli, Marco; Dordoni, Chiara; Venturini, Marina; Chiarelli, Nicola; Quinzani, Stefano; Traversa, Michele; Zoppi, Nicoletta; Vascellaro, Annalisa; Wischmeijer, Anita; Manfredini, Emanuela; Garavelli, Livia; Calzavara-Pinton, Piergiacomo; Colombi, Marina.

In: Orphanet Journal of Rare Diseases, Vol. 8, No. 1, 58, 2013.

Research output: Contribution to journalArticle

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 2013, 'Clinical and molecular characterization of 40 patients with classic Ehlers-Danlos syndrome: Identification of 18 COL5A1 and 2 COL5A2 novel mutations', Orphanet Journal of Rare Diseases, vol. 8, no. 1, 58. https://doi.org/10.1186/1750-1172-8-58
Ritelli, Marco ; Dordoni, Chiara ; Venturini, Marina ; Chiarelli, Nicola ; Quinzani, Stefano ; Traversa, Michele ; Zoppi, Nicoletta ; Vascellaro, Annalisa ; Wischmeijer, Anita ; Manfredini, Emanuela ; Garavelli, Livia ; Calzavara-Pinton, Piergiacomo ; Colombi, Marina. / Clinical and molecular characterization of 40 patients with classic Ehlers-Danlos syndrome : Identification of 18 COL5A1 and 2 COL5A2 novel mutations. In: Orphanet Journal of Rare Diseases. 2013 ; Vol. 8, No. 1.
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T1 - Clinical and molecular characterization of 40 patients with classic Ehlers-Danlos syndrome

T2 - Identification of 18 COL5A1 and 2 COL5A2 novel mutations

AU - Ritelli, Marco

AU - Dordoni, Chiara

AU - Venturini, Marina

AU - Chiarelli, Nicola

AU - Quinzani, Stefano

AU - Traversa, Michele

AU - Zoppi, Nicoletta

AU - Vascellaro, Annalisa

AU - Wischmeijer, Anita

AU - Manfredini, Emanuela

AU - Garavelli, Livia

AU - Calzavara-Pinton, Piergiacomo

AU - Colombi, Marina

PY - 2013

Y1 - 2013

N2 - 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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