Epidermolysis Bullosa Panel

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

Test code: DE0301

The Blueprint Genetics Epidermolysis Bullosa Panel is a 25 gene test for genetic diagnostics of patients with clinical suspicion of congenital epidermolysis bullosa.

Epidermolysis Bullosa is usually an autosomal dominant condition when the major disease genes, KRT5 or KRT14, are defective.

About Epidermolysis Bullosa

Epidermolysis bullosa simplex (EBS) is usually characterized by skin fragility and rarely mucosal epithelia that results in non-scarring blisters caused by mild or no trauma. The current classification of epidermolysis bullosa includes two major types and 12 minor subtypes. They all share the common feature of blistering above the dermal-epidermal junction at the ultrastructural level. The four most common subtypes of EBS are: 1) localized EBS (EBS-loc; also known as Weber-Cockayne type), 2) Dowling-Meara type EBS (EBS-DM), 3) other generalized EBS(EBS, gen-nonDM; also known as Koebner type) and 4) EBS-with mottled pigmentation (EBS-MP). Skin biopsy from fresh blister is considered mandatory for diagnostics of generalized forms of EBS. The prevalence of EBS is is estimated to be 1:30,000 – 50,000. EBS-loc is the most prevalent as it does not result in neonatal death. EBS-DM and EBS-gen-nonDM are rare, and EBS-MP is even rarer. Penetrance is 100% for known KRT5 and KRT14 mutations. Location of the mutations within functional domains of KRT5and KRT14 has shown to predict EBS phenotype.

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 Epidermolysis Bullosa Panel and their clinical significance
Gene Associated phenotypes Inheritance ClinVar HGMD
ATP2C1 Benign chronic pemphigus AD 15 181
CDSN Peeling skin syndrome, Hypotrichosis AD/AR 6 13
COL7A1 Nail disorder, nonsyndromic congenital, Transient bullous dermolysis of the newborn, Epidermolysis bullosa dystrophica, Epidermolysis bullosa, pretibial, Epidermolysis bullosa pruriginosa AD/AR 136 773
COL17A1 Epithelial recurrent erosion dystrophy (ERED), Epidermolysis bullosa, junctional, non-Herlitz AD/AR 27 97
DSG1 Severe dermatitis, multiple allergies, and metabolic wasting syndrome (SAM syndrome) AR 12 29
DSG2 Arrhythmogenic right ventricular dysplasia, Dilated cardiomyopathy (DCM) AD 37 117
DSG4 Hypotrichosis AR 8 17
DSP Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis, Arrhythmogenic right ventricular dysplasia, familial, Cardiomyopathy, dilated, with wooly hair and keratoderma AD/AR 128 262
DST Neuropathy, hereditary sensory and autonomic AR 5 6
EXPH5 Epidermolysis bullosa AR 2 8
FERMT1 Kindler syndrome AR 31 78
GRIP1 Fraser syndrome AR 5 17
ITGA3 Interstitial lung disease with nephrotic syndrome and epidermolysis bullosa AR 6 11
ITGA6 Epidermolysis bullosa, junctional, with pyloric stenosis AR 2 8
ITGB4 Epidermolysis bullosa simplex, Weber-Cockayne, Epidermolysis bullosa, junctional, with pyloric atresia, Epidermolysis bullosa, junctional, non-Herlitz AD/AR 22 95
KRT1 Palmoplantar keratoderma, nonepidermolytic, Ichthyosis, cyclic, with epidermolytic hyperkeratosis, Epidermolytic hyperkeratosis, Ichthyosis histrix, Curth-Macklin, Keratosis palmoplantaris striata, Palmoplantar keratoderma, epidermolytic AD 22 61
KRT5 Epidermolysis bullosa simplex, Dowling-Meara, Dowling-Degos disease, Epidermolysis bullosa simplex with migratory circinate erythema, Epidermolysis bullosa simplex with mottled pigmentation, Epidermolysis bullosa simplex, Weber-Cockayne, Epidermolysis bullosa simplex, Koebner AD 35 150
KRT14* Epidermolysis bullosa simplex, Dowling-Meara, Epidermolysis bullosa simplex, Dermatopathia pigmentosa reticularis, Epidermolysis bullosa simplex, Weber-Cockayne, Epidermolysis bullosa simplex, Koebner, Naegeli-Franceschetti-Jadassohn syndrome AD/AR 27 112
LAMA3 Epidermolysis bullosa, junctional, Herlitz, Epidermolysis bullosa, generalized atrophic benign, Laryngoonychocutaneous syndrome AR 31 48
LAMB3 Amelogenesis imperfecta, Epidermolysis bullosa, junctional, Herlitz, Epidermolysis bullosa, junctional, non-Herlitz AD/AR 59 110
LAMC2 Epidermolysis bullosa, junctional, Herlitz, Epidermolysis bullosa, junctional, non-Herlitz AR 30 39
MMP1 Severe generalized recessive dystrophic epidermolysis bullosa AD/AR 1 2
PKP1 Ectodermal dysplasia/skin fragility syndrome AR 4 16
PLEC Muscular dystrophy, limb-girdle, Epidermolysis bullosa AR 26 91
TGM5 Peeling skin syndrome AR 8 25

*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
FERMT1 Chr20:6103422 c.-20A>G NM_017671.4 rs869312722
FERMT1 Chr20:6074846 c.1139+740G>A NM_017671.4 rs869312728

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 Epidermolysis Bullosa Panel that covers classical genes associated with congenital epidermolysis bullosa. 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 Epidermolysis Bullosa Panel

ICD-10 Disease
Q81.8 Congenital epidermolysis bullosa

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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