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Ehlers-Danlos Syndrome, Genetic Testing

Ehlers-Danlos syndrome (EDS) is a group of rare genetic connective tissue disorders characterized by symptoms affecting the skin, joints, and blood vessels. Connective tissues support the body's skin, organs, blood vessels, and other structures.

Ehlers-Danlos syndrome genetic testing is included in Diagnostiki Athinon Monogenic Diseases Genetic Testing along with approximetaly 100 other inherited diseases, including cystic fibrosis (71 mutations) and hereditary breast cancer (genes BRCA1 415 mutations & BRCA2 419 mutations).

There are several subtypes of Ehlers-Danlos syndrome, each with its own features. Still, the commonality among them is a defect in collagen, a key component of connective tissue. Collagen provides strength and elasticity to various tissues in the body.  Up to 13 clinical types of the disease are known to be caused by alterations in 19 genes.

The major types of Ehlers-Danlos syndrome include:

  • Classical EDS (cEDS): Characterized by joint hypermobility, skin that is smooth, soft, and hyperelastic (stretchy), and a tendency to form scars easily.
  • Hypermobility EDS (hEDS): Primarily characterized by joint hypermobility and musculoskeletal pain. Skin involvement is usually less pronounced than in other subtypes.
  • Vascular EDS (vEDS): Involves the risk of serious complications, including arterial and organ rupture. People with vEDS may have thin, translucent skin and easy bruising.
  • Kyphoscoliotic EDS (kEDS): Characterized by severe muscle hypotonia at birth, progressive scoliosis, and joint hypermobility.
  • Arthrochalasia EDS (aEDS): Involves severe joint hypermobility and congenital hip dislocation.
  • Dermatosparaxis EDS (dEDS): Characterized by extremely fragile soft and doughy skin, with severe bruising.
  • Brittle Cornea Syndrome (BCS): Features thinning of the cornea and a tendency for the cornea to rupture.
  • Progeroid EDS: Like other more common forms of EDS, patients with the progeroid variant present features including joint laxity, skin hyperextensibility, and poor wound healing. In contrast, the patients with the progeroid variant have additional features, including congenital joint dislocations and short stature.

The hypermobile type (hEDS) is the most common SED, but the genetic basis is still unknown. The classic Ehlers-Danlos syndrome (cEDS), which has an incidence of one person per 10.000 to 20.000 people, is the second most common type of EDS.

Diagnosis of Ehlers-Danlos syndrome involves a thorough clinical evaluation and family history assessment and may include genetic testing to identify specific mutations associated with the condition.

Management of Ehlers-Danlos syndrome focuses on addressing symptoms and preventing complications. This may include physical therapy, pain management, joint protection strategies, and, in some cases, surgical interventions.

The severity and specific symptoms can vary widely between individuals with Ehlers-Danlos syndrome, even within the same subtype. Treatment plans are often tailored to the individual's unique condition presentation.

The genes involved in the various types of Ehlers-Danlos syndrome (EDS) encode fibrillar collagen, proteoglycans, and their processing enzymes. Pathogenic variants in the COL5A1 and COL5A2 genes produce the type V gene defects found in approximately half of the patients with classic EDS (cEDS); in a minority of cases, the affected gene is COL1A1. For these three genes, EDS is inherited in an autosomal dominant manner, i.e., a single copy of a pathogenic variant is sufficient for the pathology to develop. Most of the identified causal variants lead to COL5A1 haploinsufficiency due to a non-functional COL5A1 allele, which decreases the availability of type V collagen in the extracellular matrix (ECM). This test analyzes the c.934C>T (p.Arg312Cys) variant in the COL1A1 gene, whose presence markedly increases the risk of vascular rupture while producing the cEDS phenotype.

The COL5A1 gene encodes for an alpha chain of the V-type fibrillar collagen molecule, which is a structural component of the ECM that, in connective tissue, confers resistance to traction. This type of collagen is involved in many biological processes, such as the development of blood vessels, skin, and tendons, the organization of the ECM, and wound healing, among others.

In vascular-type EDS (vEDS), the affected gene is COL3A1; in this case, as in cEDS, the mode of inheritance is autosomal dominant. In individuals with the presence of a pathogenic variant in COL3A1, there is a risk of arterial rupture, perforation of the colon, uterine rupture in the third trimester of pregnancy in women, carotid-cavernous fistula, and pneumothorax. Progeroid-type EDS is associated with alterations in proteoglycans caused by mutations in the B4GALT7 or B3GALT6 genes, which encode key enzymes that initiate glycosaminoglycan synthesis. The B4GALT7 gene encodes for the enzyme galactosyltransferase-I, which catalyzes the addition of galactose to proteoglycans. The characteristics associated with patients with progeroid-type EDS are short stature, developmental anomalies of the forearm and elbow bones, limb bowing, and the classic features of Ehlers-Danlos syndrome.

FKBP14 is a gene recently linked to EDS and produces some characteristic symptoms such as congenital hearing impairment, follicular hyperkeratosis, muscle atrophy, and bladder diverts (hernias in the bladder mucosa). This test analyzes the c.362dup variant (p.Glu122fs), which is more frequent in Europe and causes EDS in homozygosis, i.e., it follows an autosomal recessive mode of inheritance.

The c.808C>T (p.Arg270Cys) polymorphism is located in the B4GALT7 gene and is described as a pathogenic variant of progeroid-type EDS. It has been shown to reduce the degree of sulfation of heparin sulfate, a proteoglycan that modulates several biological processes related to wound repair.

Finally, this test analyzes variants in the ADAMTS2 gene (related to EDS Dermatosparaxis; autosomal recessive mode of inheritance) and C1S (related to EDS periodontal; autosomal dominant mode of inheritance).

In total, genetic testing of Ehlers-Danlos Syndrome analyzes the 3 most frequent pathogenic mutations of COL1A1 gene plus the 2 most frequent pathogenic mutations of COL1A2 gene plus the 27 most frequent pathogenic mutations of COL3A1 gene plus the 3 most frequent pathogenic mutations of COL5A1 gene plus the 1 most frequent pathogenic mutation of FKBP14 gene plus the 2 most frequent pathogenic mutations of B4GALT7 gene plus the 2 most frequent pathogenic mutations of C1S gene.

With the technique used for genetic testing, only the gene's specific mutations, which are the most important and frequent in the literature, are analyzed. However, it should be noted that there are likely other gene or chromosomal mutations in the gene to be tested, which cannot be identified with this method. Different analysis techniques can be used for these cases, such as, e.g., next-generation sequencing (NGS).

Additional information
Results Time4 - 5 Weeks
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