Ehlers-Danlos Syndromes (EDS) Panel

Ehlers-Danlos syndrome (EDS) is a clinically and genetically heterogeneous group of heritable connective tissue disorders. These disorders are multisystemic and variable in nature; however they mainly affect the skin, joints, ligaments, blood vessels, and internal organs (Byers and Murray. 2012. PubMed ID: 23154631). There are several distinct subtypes of EDS that reflect separate etiologies rather than variable expressions of one disorder (Byers and Murray. 2012. PubMed ID: 23154631). The major features common among the more prevalent types of EDS include joint hypermobility, skin extensibility, abnormal scarring, and tissue friability (Byers and Murray. 2012. PubMed ID: 23154631). The clinical features of the rare forms of EDS may also include joint contractures, generalized hypotonia, scoliosis, blue sclera, or hearing loss (Brady et al. 2017. PubMed ID: 28306225). The signs and symptoms of EDS may become apparent during childhood. However, the age of diagnosis may vary depending upon the form and severity.

Combined, the prevalence of EDS is estimated to be ~1 in 5,000 individuals worldwide (Vanakker et al. 2015. PubMed ID: 26002060). However, it is difficult to determine the exact prevalence of EDS as those with mild clinical features may be undiagnosed. The hypermobile, classic, and vascular forms of EDS are the most common. The hypermobile type may affect as many as ~1 in 5,000 to 20,000 individuals (Levy and Levy. 1993. PubMed ID: 20301456). The classic type occurs in ~1 in 20,000 to 40,000 individuals (Malfait et al. 1993. PubMed ID: 20301422). The vascular form is estimated to affect ~1 in 50,000-1 in 200,000 individuals (Byers et al. 2017. PubMed ID: 28306228). The other forms of EDS are rare and only have a few cases or affected families described in literature (Brady et al. 2017. PubMed ID: 28306225).

The advantages of genetic testing include providing a prognosis for patients, personalized treatment and management plans, and allowing for reproductive planning (Sobey. 2015. PubMed ID: 24994860). There are numerous differential diagnoses for EDS, including, but not limited to, Loeys-Dietz syndrome, Cutis Laxa, Marfan syndrome, Osteogenesis imperfecta, Ullrich congenital muscular dystrophy, and Brittle cornea syndrome (Sobey. 2015. PubMed ID: 24994860; Vanakker et al. 2015. PubMed ID: 26002060).

This test includes genes identified through literature, OMIM, and HGMD searches that have a reported association with EDS or may be considered a differential diagnosis of EDS.

EDS is a genetically heterogeneous group of disorders. Disorders may be inherited in an autosomal dominant (AD), autosomal recessive (AR), and X-linked (XL) manner, or may arise de novo. Causative variants may include missense, nonsense, splicing, regulatory, or copy number alterations.

See individual gene summaries for information about molecular biology of gene products and spectra of pathogenic variants.

Due to the genetic heterogeneity of the disorders tested in this panel, the clinical sensitivity of this specific grouping of genes is difficult to estimate. Clinical sensitivity varies depending on the disorder.

The underlying genetic etiology for hypermobile EDS remains elusive, therefore the clinical sensitivity is unknown (Levy and Levy. 1993. PubMed ID: 20301456; Forghani. 2019. PubMed ID: 30063214). Three studies have analyzed the clinical efficacy of classic EDS and identified a causative variant in the COL5A1 or COL5A2 gene in 52-93% of their cohort members (Malfait et al. 2005. PubMed ID: 15580559; Symoens et al. 2012. PubMed ID: 22696272; Ritelli et al. 2013. PubMed ID: 23587214). Another study analyzed individuals with a clinical presentation of vascular EDS and identified a causative variant in COL3A1 in ~90% of the cohort (Pepin et al. 2014. PubMed ID: 24922459). The other types of EDS included in this panel are rare causes of EDS with unknown clinical sensitivity. In addition, the clinical sensitivity is unknown for individuals with borderline or non-specific connective tissue disease.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 96.98% coverage of all coding exons of the genes listed, plus ~10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Of note, TNXB exons 32-44 are not analyzed due to multiple close copies of these sequences in the genome. If full coverage of TNXB is desired, we can offer an enhancement of the gene for an additional $530.

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).