Test Catalog

Test ID: EDSGP    
Ehlers-Danlos Syndrome Panel (12 Genes), Next-Generation Sequencing and Deletion/Duplication Analysis, Varies

Useful For Suggests clinical disorders or settings where the test may be helpful

Confirmation of a clinical diagnosis of Ehlers-Danlos Syndrome (EDS)

 

Differentiating between the different subtypes of EDS for diagnosis and management purposes

 

Ascertaining carrier status of family members of individuals diagnosed with EDS for genetic counseling purposes

Genetics Test Information Provides information that may help with selection of the correct genetic test or proper submission of the test request

This test includes next generation sequencing with deletion/duplication (copy number variation) analysis and supplemental Sanger sequencing to evaluate for variants in the ADAMTS2, ATP7A, CHST14, COL1A1, COL1A2, COL3A1, COL5A1, COL5A2, FKBP14, FLNA, PLOD1, and SLC39A13 genes.

Identification of a pathogenic variant may assist with prognosis, clinical management, familial screening, and genetic counseling.

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

The Ehlers Danlos syndromes (EDS) are a clinically and genetically diverse group of heritable connective tissue disorders. An EDS classification system proposed by the International EDS Consortium identifies 13 subtypes of EDS, with an overall estimated prevalence of EDS between 1:5,000 and 1:25,000. Over 90% of cases are either classic or hypermobile EDS (cEDS or hEDS), while less than 5% of cases are vascular EDS (vEDS). Other, rarer, subtypes of EDS also exist and are listed in the table below.

 

The clinical hallmarks of EDS are joint hypermobility, skin hyperextensibility, and tissue fragility. However, a variety of skin, ligament, joint, and cardiovascular features are seen across the spectrum of EDS. A clinical diagnosis of a specific subtype of EDS may be suspected based on a combination of major (a symptom present in the majority of affected individuals) and minor (a symptom of lesser diagnostic specificity that supports the diagnosis) clinical criteria. However, due to the clinical overlap between EDS subtypes and other heritable connective tissue disorders (eg, Marfan syndrome and Loeys-Dietz syndrome), a definitive diagnosis of all EDS subtypes (except EDS hypermobility type) relies on the identification of a causative variant in the appropriate gene.

 

Genetic variants in collagen-encoding or collagen-modifying genes have been identified as the cause of EDS in the majority of subtypes. These variants result in defects in collagen structure, processing, folding and cross-linking. One notable exception to this is hypermobile EDS (hEDS). Hypermobile EDS is inherited in an autosomal dominant inheritance pattern, similar to cEDS and vEDS, however, the molecular basis of this condition is unknown and a diagnosis is based on clinical criteria.

 

This panel also tests for variants in the ATP7A and FLNA genes, which result in X-linked conditions. Some patients with these conditions have clinical overlap with EDS.

Table1. Genes included in the EDS Gene Panel

GENE SYMBOL (ALIAS)

PROTEIN

INHERITANCE*

EDS CLASSIFICATION

ADAMTS2

Procollagen I N-proteinase (NPI)

AR

Dermatosparaxis EDS (dEDS) / human dermatosparaxis EDS VIIC

ATP7A

Copper-transporting ATPase 1

XL

Occipital horn syndrome

CHST14

Dermatan-4-sulfotransferase-1 (D4ST1)

AR

Musculocontractural EDS (mcEDS-CHST14)

COL1A1

Collagen alpha-1(I) chain

AD

AD

AD

Classical EDS (cEDS)

Vascular EDS (vEDS)

Arthrochalasia EDS (aEDS)

COL1A2

Collagen alpha-2(I) chain

AD

AR

Arthrochalasia EDS (aEDS)

Cardiac valvular EDS (cvEDS)

COL3A1

Collagen alpha-1(III) chain

AD

Vascular EDS (vEDS)

COL5A1

Collagen alpha-1(V) chain

AD

Classical EDS (cEDS)

COL5A2

Collagen alpha-2(V) chain

AD

Classical EDS (cEDS)

FKBP14

Peptidyl-prolyl cis-trans isomerase FKBP14 (FK506 binding protein 14)

AR

Kyphoscoliotic EDS (kEDS-FKBP14)

FLNA

Filamin A

XL

Filamin A related EDS with periventricular nodular heterotopia

PLOD1

Procollagen-lysine 5-dioxygenase

 

AR

Kyphoscoliotic EDS (kEDS – PLOD1)

SLC39A13

Zinc transporter ZIP13

AR

Spondylodysplastic EDS (spEDS-SLC39A13)

*Abbreviations: Autosomal dominant (AD), autosomal recessive (AR), X-linked (XL), Ehlers-Danlos syndrome (EDS)

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

An interpretive report will be provided.

Interpretation Provides information to assist in interpretation of the test results

Evaluation and categorization of variants is performed using the most recent published American College of Medical Genetics and Genomics (ACMG) recommendations as a guideline. Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.

 

Multiple in silico evaluation tools may be used to assist in the interpretation of these results. The accuracy of predictions made by in silico evaluation tools is highly dependent upon the data available for a given gene, and predictions made by these tools may change over time. Results from in silico evaluation tools should be interpreted with caution and professional clinical judgment.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

Clinical Correlations:

Some individuals who have involvement of 1 or more of the genes on the panel may have a variation that is not identified by the methods performed (eg, promoter variants, deep intronic variants). The absence of a variant, therefore, does not eliminate the possibility of disease.

 

Test results should be interpreted in context of clinical findings, family history, and other laboratory data. Misinterpretation of results may occur if the information provided is inaccurate or incomplete.

 

For predictive testing of asymptomatic individuals, it is often useful to first test an affected family member. Identification of a pathogenic variant in an affected individual allows for more informative testing of at-risk individuals.

 

Technical Limitations:

Next generation sequencing (NGS) may not detect all types of genetic variants. Additionally, rare polymorphisms may be present that could lead to false negative or positive results. If results do not match clinical findings, consider alternative methods for analyzing these genes, such as Sanger sequencing.

 

If the patient has had an allogeneic blood or bone marrow transplant or a recent (ie, <6 weeks from time of sample collection) heterologous blood transfusion, results may be inaccurate due to the presence of donor DNA. Call 800-533-1710 for instructions for testing patients who have received a bone marrow transplant.

 

Reclassification of Variants Policy:

At this time, it is not standard practice for the laboratory to systematically review likely pathogenic variants or variants of uncertain significance that are detected and reported. The laboratory encourages health care providers to contact the laboratory at any time to learn how the status of a particular variant may have changed over time. Consultation with a genetics professional should be considered for interpretation of this result.

 

A list of benign and likely benign variants detected for this patient is available from the laboratory upon request.

 

Contact the laboratory if additional information is required regarding the transcript or human genome assembly used for the analysis of the patient's results.

Clinical Reference Recommendations for in-depth reading of a clinical nature

1. Malfait F, Francomano C, Byers P, et al: The 2017 international classification of the Ehlers-Danlos syndromes. Am J Med Genet C Semin Med Genet. 2017;175(1):8-26. doi: 10.1002/ajmg.c.31552

2. Meester JAN, Verstraeten A, Schepers D, et al: Differences in manifestations of Marfan syndrome, Ehlers-Danlos syndrome, and Loeys-Dietz syndrome. Ann Cardiothorac Surg. 2017;6(6):582-594. doi: 10.21037/acs.2017.11.03

3. Brady AF, Demirdas S, Fournel-Gigleux S, et al: The Ehlers-Danlos syndromes, rare types. Am J Med Genet C Semin Med Genet. 2017;175(1):70-115. doi: 10.1002/ajmg.c.31550

4. Bowen JM, Sobey GJ, Burrows NP, et al: Ehlers-Danlos syndrome, classical type. Am J Med Genet C Semin Med Genet. 2017;175(1):27-39. doi: 10.1002/ajmg.c.31548

5. Bursztejn AC, Baumann M, Lipsker D: Ehlers-Danlos syndrome related to FKBP14 mutations: detailed cutaneous phenotype. Clin Exp Dermatol 2017;42(1):64-67. doi: 10.1111/ced.12983

Special Instructions Library of PDFs including pertinent information and forms related to the test