Classical Ehlers-Danlos Syndrome (cEDS) is a Rare Autosomal Dominant Connective Tissue Disorder

Research continues on Classical Ehlers-Danlos Syndrome. This study has some analysis of this genetic disorder.

“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.”

Author: Marco RitelliChiara DordoniMarina  VenturiniNicola ChiarelliStefano QuinzaniMichele TraversaNicoletta ZoppiAnnalisa
VascellaroAnita WischmeijerEmanuela ManfrediniLivia GaravelliPiergiacomo  Calzavara-PintonMarina Colombi

Research is continuing to diagnosis this debilitating disorder.

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