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

Marina Colombi⁴  Piergiacomo Calzavara-Pinton²  Livia Garavelli⁵  Emanuela Manfredini¹  Anita Wischmeijer³  Annalisa Vascellaro²  Nicoletta Zoppi⁴  Michele Traversa⁴  Stefano Quinzani⁴  Nicola Chiarelli⁴  Marina Venturini²  Chiara Dordoni⁴  Marco Ritelli⁴ 

[1] Dipartimento Materno Infantile, Ospedale Niguarda Ca’ Granda, Milan, Italy;Department of Dermatology, University Hospital Spedali Civili, Brescia, Italy;Department of Medical Genetics, Policlinico Sant’Orsola-Malpighi, University of Bologna, Bologna, Italy;Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy;Clinical Genetics Unit, Istituto di Ricovero e Cura a Carattere Scientifico, Arcispedale S. Maria Nuova, Reggio Emilia, Italy

关键词: Diagnostic flowchart;    MLPA;    COL1A1;    COL5A2;    COL5A1;    Classic Ehlers–Danlos syndrome;   

Others  :  864041
DOI  :  10.1186/1750-1172-8-58

 received in 2013-02-04, accepted in 2013-03-29,  发布年份 2013

【 摘 要 】

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.

【 授权许可】

   
2013 Ritelli et al.; licensee BioMed Central Ltd.

【 图 表 】

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