Ehlers-Danlos Syndrome Panel

  • bpg-method PLUS
  • bpg-method SEQ
  • bpg-method DEL/DUP

Test code: CA0101

The Blueprint Genetics Ehlers-Danlos Syndrome Panel is a 33-gene test for genetic diagnostics of patients with clinical suspicion of Ehlers-Danlos syndrome.

Both autosomal dominant and recessive inheritance patterns are found among different forms of Ehlers-Danlos Syndrome (EDS). These inheritance patterns are also common in other disorders that overlap clinical features with EDS. Genetic diagnosis should be considered in all cases with suspicion of EDS or other disorder with similarities to EDS. Genetic diagnosis can confirm or modify the clinical diagnosis and also confirm the subtype of the disorder. Accurate diagnosis is essential when evaluating prognosis and making decisions on treatment and management strategies. Genetic diagnosis assists also genetic counseling, and risk stratification among family members.

About Ehlers-Danlos Syndrome

Ehlers–Danlos syndrome (EDS) is an inherited connective tissue disorder that has been classified into several primary types. EDS is caused by a defect in the structure, production, or processing of collagen or proteins that interact with collagen. The collagen in connective tissue helps tissues resist deformation. Collagen is an important contributor to the physical strength of skin, joints, ligaments, muscles, visceral organs and blood vessels. Defective collagen changes these structures more elastic. In some cases, the severity of the mutation can be life threatening. EDS can also have neuromuscular complications including ocular and ophthalmic complications. There is no cure for EDS, and treatment is supportive, including close monitoring of the digestive, excretory, and particularly the cardiovascular systems. Occupational and physical therapy, bracing, and corrective surgery may help with the frequent injuries and pain that tend to develop in certain types of EDS. There are several disorders that share some characteristics with EDS, such as cutis laxa where the skin is loose, hanging, and wrinkled. In EDS, the skin can be pulled away from the body but is elastic and returns to normal when let go. In Marfan syndrome, the joints are very mobile and similar cardiovascular complications occur. People with EDS tend to have a "Marfanoid" appearance (skinny, tall, long arms and legs, "spidery" fingers). However, physical appearance and features in several types of Ehlers-Danlos Syndrome also have characteristics including short stature, large eyes, and the appearance of a small mouth and chin, due to a small palate. Blood vessels can sometimes be easily seen through translucent skin, especially on the chest. Because of these similar disorders and complications that can arise from an unmonitored case of EDS, a correct diagnosis is very important. It is difficult to estimate the overall frequency of Ehlers-Danlos syndrome, however, the combined prevalence of all types of this condition may be about 1 in 5,000 individuals worldwide.

Availability

Results in 3-4 weeks. We do not offer a maternal cell contamination (MCC) test at the moment. We offer prenatal testing only for cases where the maternal cell contamination studies (MCC) are done by a local genetic laboratory. Read more: http://blueprintgenetics.com/faqs/#prenatal

Genes in the Ehlers-Danlos Syndrome Panel and their clinical significance
Gene Associated phenotypes Inheritance ClinVar HGMD
ABCC6* Pseudoxanthoma elasticum AR 374 297
ADAMTS2 Ehlers-Danlos syndrome AR 4 11
ALDH18A1 Spastic paraplegia, Cutis laxa AD/AR 19 28
ATP6V0A2 Cutis laxa, Wrinkly skin syndrome AR 16 53
ATP7A Menkes disease XL 109 353
CBS Homocystinuria due to cystathionine beta-synthase deficiency AR 69 187
CHST14 Ehlers-Danlos syndrome, musculocontractural AR 13 21
COL1A1 Ehlers-Danlos syndrome, Caffey disease, Osteogenesis imperfecta type 1, Osteogenesis imperfecta type 2, Osteogenesis imperfecta type 3, Osteogenesis imperfecta type 4 AD 212 929
COL1A2 Ehlers-Danlos syndrome, cardiac valvular form, Osteogenesis imperfecta type 1, Osteogenesis imperfecta type 2, Osteogenesis imperfecta type 3, Osteogenesis imperfecta type 4 AD/AR 118 490
COL2A1 Avascular necrosis of femoral head, Rhegmatogenous retinal detachment, Epiphyseal dysplasia, with myopia and deafness, Czech dysplasia, Achondrogenesis type 2, Platyspondylic dysplasia Torrance type, Hypochondrogenesis, Spondyloepiphyseal dysplasia congenital (SEDC), Spondyloepimetaphyseal dysplasia (SEMD) Strudwick type, Kniest dysplasia, Spondyloperipheral dysplasia, Mild SED with premature onset arthrosis, SED with metatarsal shortening, Stickler syndrome type 1 AD 138 541
COL3A1 Ehlers-Danlos syndrome AD 476 620
COL5A1 Ehlers-Danlos syndrome AD 62 136
COL5A2 Ehlers-Danlos syndrome AD 15 23
COL9A1 Stickler syndrome recessive type, Multiple epiphyseal dysplasia type 6 (EDM6) AR 7 5
COL9A2 Stickler syndrome, Multiple epiphyseal dysplasia type 2 (EDM2) AD/AR 7 12
COL11A1 Marshall syndrome, Fibrochondrogenesis, Stickler syndrome type 2 AD/AR 22 81
COL18A1 Knobloch syndrome AR 23 27
EFEMP2 Cutis laxa AR 12 15
ELN Cutis laxa, Supravalvular aortic stenosis AD 64 104
FBLN5 Cutis laxa, Macular degeneration, age-related AD/AR 13 21
FBN1 MASS syndrome, Shprintzen-Goldberg syndrome, Marfan syndrome, Acromicric dysplasia, Geleophysic dysplasia, Weill-Marchesani syndrome AD 711 2070
FBN2 Congenital contractural arachnodactyly (Beals syndrome) AD 35 87
FKBP14 Ehlers-Danlos syndrome with progressive kyphoscoliosis, myopathy, and hearing loss AR 4 4
FLNA Frontometaphyseal dysplasia, Osteodysplasty Melnick-Needles, Otopalatodigital syndrome type 1, Otopalatodigital syndrome type 2, Terminal osseous dysplasia with pigmentary defects XL 102 220
PLOD1 Ehlers-Danlos syndrome AR 19 37
PYCR1 Cutis laxa AR type 2B AR 14 36
SLC39A13 Spondylodysplastic Ehlers-Danlos syndrome AR 2 8
SMAD3 Aneurysms-osteoarthritis syndrome, Loeys-Dietz syndrome AD 35 53
TGFB2 Loeys-Dietz syndrome AD 25 27
TGFBR1 Loeys-Dietz syndrome AD 28 68
TGFBR2 Loeys-Dietz syndrome AD 57 132
TNXB* Ehlers-Danlos syndrome AR 9 30
ZNF469 Brittle cornea syndrome AR 33 44

*Some regions of the gene are duplicated in the genome leading to limited sensitivity within the regions. Thus, low-quality variants are filtered out from the duplicated regions and only high-quality variants confirmed by other methods are reported out. Read more.

Gene, refers to HGNC approved gene symbol; Inheritance to inheritance patterns such as autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL); ClinVar, refers to a number of variants in the gene classified as pathogenic or likely pathogenic in ClinVar (http://www.ncbi.nlm.nih.gov/clinvar/); HGMD, refers to a number of variants with possible disease association in the gene listed in Human Gene Mutation Database (HGMD, http://www.hgmd.cf.ac.uk/ac/). The list of associated (gene specific) phenotypes are generated from CDG (http://research.nhgri.nih.gov/CGD/) or Orphanet (http://www.orpha.net/) databases.

Gene Genomic location HG19 HGVS RefSeq RS-number
COL11A1 Chr1:103491958 c.781-450T>G NM_080629.2 rs587782990
COL1A2 Chr7:94025130 c.70+717A>G NM_000089.3 rs72656354
COL3A1 Chr2:189872183 c.3256-43T>G NM_000090.3 rs587779667
COL5A1 Chr9:137686903 c.2701-25T>G NM_000093.4 rs765079080

The strengths of this test include:

  • Blueprint Genetics is one of the few laboratories worldwide with CAP and ISO-15189 accreditation for NGS panels and CLIA certification
  • Superior sequencing quality
  • Careful selection of genes based on current literature, our experience and the most current mutation databases
  • Transparent and easy access to quality and performance data at the patient level that are accessible via our Nucleus portal
  • Transparent and reproducible analytical validation for each panel (see Test performance section; for complete details, see our Analytic Validation)
  • Sequencing and high resolution del/dup analysis available in one test
  • Inclusion of non-coding disease causing variants where clinically indicated (please see individual Panel descriptions)
  • Interpretation of variants following ACMG variant classification guidelines
  • Comprehensive clinical statement co-written by a PhD geneticist and a clinician specialist

 

This test does not detect the following:

  • Complex inversions
  • Gene conversions
  • Balanced translocations
  • Mitochondrial DNA variants
  • Variants in regulatory or non-coding regions of the gene unless otherwise indicated (please see Non-coding disease causing variants covered by the panel). This mean for instance intronic variants locating deeper than 15 nucleotides from the exon-intron boundary.

 

This test may not reliably detect the following:

  • Low level mosaicism
  • Stretches of mononucleotide repeats
  • Indels larger than 50bp
  • Single exon deletions or duplications
  • Variants within pseudogene regions/duplicated segments
  • Disorders caused by long repetitive sequences (e.g. trinucleotide repeat expansions)

 

The sensitivity of this test may be reduced if DNA is extracted by a laboratory other than Blueprint Genetics.

For additional information, please refer to the Test performance section and see our Analytic Validation.

Blueprint Genetics offers a comprehensive Ehlers-Danlos Syndrome Panel that covers classical genes associated with congenital contractural arachnodactyly, cutis laxa, Ehlers-Danlos syndrome, Loeys-Dietz syndrome and Marfan syndrome. The genes are carefully selected based on the existing scientific evidence, our experience and most current mutation databases. Candidate genes are excluded from this first-line diagnostic test. The test does not recognise balanced translocations or complex inversions, and it may not detect low-level mosaicism. The test should not be used for analysis of sequence repeats or for diagnosis of disorders caused by mutations in the mitochondrial DNA.

Analytical validation is a continuous process at Blueprint Genetics. Our mission is to improve the quality of the sequencing process and each modification is followed by our standardized validation process. Average sensitivity and specificity in Blueprint NGS Panels is 99.3% and 99.9% for detecting SNPs. Sensitivity to for indels vary depending on the size of the alteration: 1-10bps (96.0%), 11-20 bps (88.4%) and 21-30 bps (66.7%). The longest detected indel was 46 bps by sequence analysis. Detection limit for Del/Dup (CNV) analysis varies through the genome depending on exon size, sequencing coverage and sequence content. The sensitivity is 71.5% for single exon deletions and duplications and 99% for three exons’ deletions and duplications. We have validated the assays for different starting materials including EDTA-blood, isolated DNA (no FFPE) and saliva that all provide high-quality results. The diagnostic yield varies substantially depending on the used assay, referring healthcare professional, hospital and country. Blueprint Genetics’ Plus Analysis (Seq+Del/Dup) maximizes the chance to find molecular genetic diagnosis for your patient although Sequence Analysis or Del/Dup Analysis may be cost-effective first line test if your patient’s phenotype is suggestive for a specific mutation profile.

The sequencing data generated in our laboratory is analyzed with our proprietary data analysis and annotation pipeline, integrating state-of-the art algorithms and industry-standard software solutions. Incorporation of rigorous quality control steps throughout the workflow of the pipeline ensures the consistency, validity and accuracy of results. The highest relevance in the reported variants is achieved through elimination of false positive findings based on variability data for thousands of publicly available human reference sequences and validation against our in-house curated mutation database as well as the most current and relevant human mutation databases. Reference databases currently used are the 1000 Genomes Project (http://www.1000genomes.org), the NHLBI GO Exome Sequencing Project (ESP; http://evs.gs.washington.edu/EVS), the Exome Aggregation Consortium (ExAC; http://exac.broadinstitute.org), ClinVar database of genotype-phenotype associations (http://www.ncbi.nlm.nih.gov/clinvar) and the Human Gene Mutation Database (http://www.hgmd.cf.ac.uk). The consequence of variants in coding and splice regions are estimated using the following in silico variant prediction tools: SIFT (http://sift.jcvi.org), Polyphen (http://genetics.bwh.harvard.edu/pph2/), and Mutation Taster (http://www.mutationtaster.org).

Through our online ordering and statement reporting system, Nucleus, the customer can access specific details of the analysis of the patient. This includes coverage and quality specifications and other relevant information on the analysis. This represents our mission to build fully transparent diagnostics where the customer gains easy access to crucial details of the analysis process.

In addition to our cutting-edge patented sequencing technology and proprietary bioinformatics pipeline, we also provide the customers with the best-informed clinical report on the market. Clinical interpretation requires fundamental clinical and genetic understanding. At Blueprint Genetics our geneticists and clinicians, who together evaluate the results from the sequence analysis pipeline in the context of phenotype information provided in the requisition form, prepare the clinical statement. Our goal is to provide clinically meaningful statements that are understandable for all medical professionals, even without training in genetics.

Variants reported in the statement are always classified using the Blueprint Genetics Variant Classification Scheme modified from the ACMG guidelines (Richards et al. 2015), which has been developed by evaluating existing literature, databases and with thousands of clinical cases analyzed in our laboratory. Variant classification forms the corner stone of clinical interpretation and following patient management decisions. Our statement also includes allele frequencies in reference populations and in silico predictions. We also provide PubMed IDs to the articles or submission numbers to public databases that have been used in the interpretation of the detected variants. In our conclusion, we summarize all the existing information and provide our rationale for the classification of the variant.

A final component of the analysis is the Sanger confirmation of the variants classified as likely pathogenic or pathogenic. This does not only bring confidence to the results obtained by our NGS solution but establishes the mutation specific test for family members. Sanger sequencing is also used occasionally with other variants reported in the statement. In the case of variant of uncertain significance (VUS) we do not recommend risk stratification based on the genetic finding. Furthermore, in the case VUS we do not recommend use of genetic information in patient management or genetic counseling. For some cases Blueprint Genetics offers a special free of charge service to investigate the role of identified VUS.

We constantly follow genetic literature adapting new relevant information and findings to our diagnostics. Relevant novel discoveries can be rapidly translated and adopted into our diagnostics without delay. These processes ensure that our diagnostic panels and clinical statements remain the most up-to-date on the market.

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Extra services

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ICD & CPT codes

CPT codes

SEQ 81479
DEL/DUP 81479


ICD codes

Commonly used ICD-10 codes when ordering the Ehlers-Danlos Syndrome Panel

ICD-10 Disease
Q79.6 Ehlers-Danlos syndrome

Accepted sample types

  • EDTA blood, min. 1 ml
  • Purified DNA, min. 5μg
  • Saliva (Oragene DNA OG-500 kit)

Label the sample tube with your patient’s name, date of birth and the date of sample collection.

Note that we do not accept DNA samples isolated from formalin-fixed paraffin-embedded (FFPE) tissue.

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