Ordering
  • Test code: 02313
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit
Billing
 

Invitae Ehlers-Danlos Syndrome Panel

Test description

This test analyzes genes associated with Ehlers-Danlos syndrome (EDS) and other multi-system disorders that may present with features similar to EDS or have connective tissue disease as one feature. Given the clinical overlap between Ehlers-Danlos syndrome and related connective tissue disorders, this panel enables a more efficient evaluation of multiple disorders based on a single indication.

Order test

Primary panel (15 genes)

ADAMTS2 ATP7A CHST14 COL12A1 COL1A1 COL1A2 COL3A1 COL5A1 COL5A2 CRTAP FKBP14 FLNA P3H1 PLOD1 SLC39A13

  • Ehlers-Danlos syndrome
    • classic type (types I/II)
    • vascular type (type IV)
    • kyphoscoliotic form (type VI)
    • arthrochalasia type (types VIIA/B)
    • dermatosparaxis type (type VIIC)
    • musculocontractural type 1
    • with progressive kyphoscoliosis, myopathy and hearing loss
  • genes on this panel are also associated with other disorders

Ehlers-Danlos syndrome (EDS) is a clinically heterogeneous connective tissue disorder that can affect the integrity of the skin, joints, blood vessels and internal organs. Clinical features include joint hypermobility or recurrent dislocation, abnormal bruising or bleeding, hyperextensible skin, unexplained vessel aneurysm or dissection, or unexplained rupture of an internal organ. The clinical presentation and severity of EDS, classic and vascular types, can be highly variable, even among family members. The clinical features of the rare forms of EDS may also include joint contractures, generalized hypotonia, scoliosis, blue or fragile sclera, or hearing loss. EDS can exhibit clinically overlapping features with osteogenesis imperfecta (OI). OI is characterized by bone fragility specifically, however additional features can include blue sclerae, progressive skeletal changes and hearing loss. Some individuals may demonstrate features of both EDS and OI. COL12A1-related myopathy can present with joint laxity similar to EDS and clinical features may be consistent with a mixed myopathy and connective tissue phenotype.

The clinical sensitivity of this test is 52-93% for EDS, classic type and 90-95% for EDS, vascular type for individuals with a clinical diagnosis. The other types of EDS included in this test panel are rare causes of EDS. The clinical sensitivity is unknown for individuals with borderline or non-specific connective tissue disease.

The classic, vascular and arthrochalasia types of EDS due to COL5A1, COL5A2, COL3A1, COL1A1, COL1A2 and COL12A1 are inherited in an autosomal dominant manner. Pathogenic COL1A2 and COL12A1 variants may also exhibit autosomal recessive inheritance. EDS or EDS-like clinical features due to ADAMTS2, FKBP14, PLOD1 and SLC39A13 are inherited in an autosomal recessive manner. CRTAP-related and P3H1-related osteogenesis imperfecta is inherited in an autosomal recessive manner. The ATP7A and FLNA genes are associated with X-linked conditions.

The classic and vascular types of EDS exhibit high penetrance but highly variable clinical presentations, ranging from severe, multi-system features of connective tissue disease to mild features that may go unrecognized. The autosomal recessive types of EDS typically demonstrate high penetrance with early-onset of connective tissue disease features.

The prevalence of EDS, classic type is estimated to be 1 in 20,000, while the prevalence of the vascular type is approximately 1 in 200,000.

This test may be considered for individuals with:

  • clinical diagnosis of EDS, classic or vascular type
  • early-onset connective tissue disease
  • features of EDS and osteogenesis imperfecta (OI)

  1. Sobey, G. Ehlers-Danlos syndrome: how to diagnose and when to perform genetic tests. Arch. Dis. Child. 2015; 100(1):57-61. PMID: 24994860
  2. Malfait, F, De, Paepe, A. The Ehlers-Danlos syndrome. Adv. Exp. Med. Biol. 2014; 802:129-43. PMID: 24443025
  3. Byers, PH, Murray, ML. Heritable collagen disorders: the paradigm of the Ehlers-Danlos syndrome. J. Invest. Dermatol. 2012; 132(E1):E6-11. PMID: 23154631
  4. Vanakker, O, et al. The Genetics of Soft Connective Tissue Disorders. Annu Rev Genomics Hum Genet. 2015; 16:229-55. PMID: 26002060
  5. Malfait, F, et al. Ehlers-Danlos Syndrome, Classic Type. 2007 May 29. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301422
  6. Leistritz, DF, et al. COL3A1 haploinsufficiency results in a variety of Ehlers-Danlos syndrome type IV with delayed onset of complications and longer life expectancy. Genet. Med. 2011; 13(8):717-22. PMID: 21637106
  7. Pepin, MG, et al. Vascular Ehlers-Danlos Syndrome. 1999 Sep 02. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301667
  8. De, Paepe, A, Malfait, F. The Ehlers-Danlos syndrome, a disorder with many faces. Clin. Genet. 2012; 82(1):1-11. PMID: 22353005
  9. Malfait, F, et al. The molecular basis of classic Ehlers-Danlos syndrome: a comprehensive study of biochemical and molecular findings in 48 unrelated patients. Hum. Mutat. 2005; 25(1):28-37. PMID: 15580559
  10. Ritelli, M, et al. Clinical and molecular characterization of 40 patients with classic Ehlers-Danlos syndrome: identification of 18 COL5A1 and 2 COL5A2 novel mutations. Orphanet J Rare Dis. 2013; 8:58. doi: 10.1186/1750-1172-8-58. PMID: 23587214
  11. Yeowell, HN, et al. Mutational analysis of the lysyl hydroxylase 1 gene (PLOD) in six unrelated patients with Ehlers-Danlos syndrome type VI: prenatal exclusion of this disorder in one family. Hum. Mutat. 2000; 16(1):90. PMID: 10874315
  12. Zou, Y, et al. Recessive and dominant mutations in COL12A1 cause a novel EDS/myopathy overlap syndrome in humans and mice. Hum. Mol. Genet. 2014; 23(9):2339-52. PMID: 24334604
  13. Punetha, J, et al. A novel COL12A1 variant expands the clinical picture of congenital myopathies with extracellular matrix defects. Muscle Nerve. 2016; :None. PMID: 27348394

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
ADAMTS2 NM_014244.4
ATP7A NM_000052.6
CHST14 NM_130468.3
COL12A1 NM_004370.5
COL1A1 NM_000088.3
COL1A2 NM_000089.3
COL3A1 NM_000090.3
COL5A1 NM_000093.4
COL5A2 NM_000393.3
CRTAP NM_006371.4
FKBP14 NM_017946.3
FLNA NM_001456.3
P3H1 NM_022356.3
PLOD1 NM_000302.3
SLC39A13 NM_152264.4