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Blueprint Genetics Epidermolysis Bullosa Panel

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Epidermolysis Bullosa Panel Test code: DE0301 Is a 26 gene panel that includes assessment of non-coding variants. Is ideal for patients with a clinical suspicion of congenital epidermolysis bullosa. About Epidermolysis Bullosa Epidermolysis bullosa (EB) is a group of inherited diseases that are characterised by blistering lesions on the skin and mucous membranes, most commonly appearing at sites of friction and minor trauma such as the feet and hands. In some subtypes, blisters may also occur on internal organs, such as the oesophagus, stomach and respiratory tract, without any apparent friction. There are 4 major types of EB based on different sites of blister formation within the skin structure: Epidermolysis bullosa simplex (EBS), Junctional epidermolysis bullosa (JEB), Dystrophic epidermolysis bullosa (DEB), and Kindler syndrome (KS). EBS is usually characterized by skin fragility and rarely mucosal epithelia that results in non-scarring blisters caused by mild or no trauma. 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, 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. JEB is characterized by fragility of the skin and mucous membranes, manifest by blistering with little or no trauma. Blistering may be severe and granulation tissue can form on the skin around the oral and nasal cavities, fingers and toes, and internally around the upper airway. JEB is caused by mutations in LAMB3 (70% of all JEB), COL17A1 (12%), LAMC2 (9%), and LAMA3 (9%). DEB is caused by COL7A1 mutations and can be either dominantly (DDEB) or recessively (RDEB). DDEB is usually mild. Blistering may be localized to the hands, feet, elbows and knees or it may be generalized. RDEB is typically more generalized and severe than DDEB. KS is very rare and involves all layers of the skin with extreme fragility. Availability 4 weeks Gene Set Description Genes in the Epidermolysis Bullosa Panel and their clinical significance Gene Associated phenotypes Inheritance ClinVar HGMD ATP2C1 Benign chronic pemphigus AD 17 185 CDSN Peeling skin syndrome, Hypotrichosis AD/AR 6 14 COL17A1 Epithelial recurrent erosion dystrophy (ERED), Epidermolysis bullosa, AD/AR 32 112 junctional, non-Herlitz COL7A1 Nail disorder, nonsyndromic congenital, Transient bullous dermolysis of the AD/AR 159 816 newborn, Epidermolysis bullosa dystrophica, Epidermolysis bullosa, pretibial, Epidermolysis bullosa pruriginosa CSTA Peeling skin syndrome 4 AR 5 6 DSG1 Severe dermatitis, multiple allergies, and metabolic wasting syndrome (SAM AD/AR 13 31 syndrome), Keratosis palmoplantaris striata I DSG2 Arrhythmogenic right ventricular dysplasia, Dilated cardiomyopathy (DCM) AD 44 129 https://blueprintgenetics.com/ DSG4 Hypotrichosis AR 8 18 DSP Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis, AD/AR 177 296 Arrhythmogenic right ventricular dysplasia, familial, Cardiomyopathy, dilated, with wooly hair and keratoderma, Keratosis palmoplantaris striata II, Epidermolysis bullosa, lethal acantholytic DST Neuropathy, hereditary sensory and autonomic AR 13 7 EXPH5 Epidermolysis bullosa AR 2 10 FERMT1 Kindler syndrome AR 32 83 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, AD/AR 24 99 junctional, with pyloric atresia, Epidermolysis bullosa, junctional, non-Herlitz KLHL24 Epidermolysis bullosa simplex, generalized, with scarring and hair loss, AD/AR 5 5 Dilated cardiomyopathy (DCM), Hypertrophic cardiomyopathy (HCM) KRT1 Palmoplantar keratoderma, nonepidermolytic, Ichthyosis, cyclic, with AD 24 63 epidermolytic hyperkeratosis, Epidermolytic hyperkeratosis, Ichthyosis histrix, Curth-Macklin, Keratosis palmoplantaris striata, Palmoplantar keratoderma, epidermolytic KRT14* Epidermolysis bullosa simplex, Dowling-Meara, Epidermolysis bullosa AD/AR 30 116 simplex, Dermatopathia pigmentosa reticularis, Epidermolysis bullosa simplex, Weber-Cockayne, Epidermolysis bullosa simplex, Koebner, Naegeli- Franceschetti-Jadassohn syndrome KRT5 Epidermolysis bullosa simplex, Dowling-Meara, Dowling-Degos disease, AD 38 152 Epidermolysis bullosa simplex with migratory circinate erythema, Epidermolysis bullosa simplex with mottled pigmentation, Epidermolysis bullosa simplex, Weber-Cockayne, Epidermolysis bullosa simplex, Koebner LAMA3 Epidermolysis bullosa, junctional, Herlitz, Epidermolysis bullosa, generalized AR 88 55 atrophic benign, Laryngoonychocutaneous syndrome LAMB3 Amelogenesis imperfecta, Epidermolysis bullosa, junctional, Herlitz, AD/AR 84 118 Epidermolysis bullosa, junctional, non-Herlitz LAMC2 Epidermolysis bullosa, junctional, Herlitz, Epidermolysis bullosa, junctional, AR 55 41 non-Herlitz PKP1 Ectodermal dysplasia/skin fragility syndrome AR 5 18 PLEC Muscular dystrophy, limb-girdle, Epidermolysis bullosa AD/AR 36 103 TGM5 Peeling skin syndrome AR 10 25 *Some regions of the gene are duplicated in the genome. Read more. # The gene has suboptimal coverage (means <90% of the gene’s target nucleotides are covered at >20x with mapping quality score (MQ>20) reads), and/or the gene has exons listed under Test limitations section that are not included in the panel as they are not sufficiently covered with high quality sequence reads. The sensitivity to detect variants may be limited in genes marked with an asterisk (*) or number sign (#). Due to possible https://blueprintgenetics.com/ limitations these genes may not be available as single gene tests. Gene refers to the HGNC approved gene symbol; Inheritance refers to inheritance patterns such as autosomal dominant (AD), autosomal recessive (AR), mitochondrial (mi), X-linked (XL), X-linked dominant (XLD) and X-linked recessive (XLR); ClinVar refers to the number of variants in the gene classified as pathogenic or likely pathogenic in this database (ClinVar); HGMD refers to the number of variants with possible disease association in the gene listed in Human Gene Mutation Database (HGMD). The list of associated, gene specific phenotypes are generated from CGD or Mitomap databases. Non-coding disease causing variants covered by the panel Gene Genomic location HG19 HGVS RefSeq RS-number COL17A1 Chr10:105840444 c.-11-2A>G NM_000494.3 COL7A1 Chr3:48602516 c.8620+26G>A NM_000094.3 COL7A1 Chr3:48604008 c.8305-12T>A NM_000094.3 COL7A1 Chr3:48605244 c.7929+11_7929+26delGATGGGGGCTGGGGGG NM_000094.3 rs773394779 COL7A1 Chr3:48605981 c.7759-18_7759-14delCATCTinsTTCA NM_000094.3 COL7A1 Chr3:48613354 c.5821-19A>G NM_000094.3 COL7A1 Chr3:48616971 c.5236-23A>G NM_000094.3 COL7A1 Chr3:48626035 c.2587+40G>A NM_000094.3 COL7A1 Chr3:48629915 c.977-15G>A NM_000094.3 COL7A1 Chr3:48632779 c.-187C>T NM_000094.3 COL7A1 Chr3:48632780 c.-188C>T NM_000094.3 FERMT1 Chr20:6074846 c.1139+740G>A NM_017671.4 rs869312728 FERMT1 Chr20:6103422 c.-20A>G NM_017671.4 rs869312722 ITGA3 Chr17:48151801 c.1383-11T>A NM_005501.2 ITGB4 Chr17:73732344 c.1762-25T>A NM_000213.3 ITGB4 Chr17:73748496 c.3977-30_3977-17delAGGGCCCTGGCTCA NM_000213.3 ITGB4 Chr17:73748508 c.3977-19T>A NM_000213.3 LAMA3 Chr18:21441788 c.4584+22_4584+24delTCT NM_198129.1 rs1421336257 LAMB3 Chr1:209801557 c.1133-22G>A NM_000228.2 rs767847211 LAMB3 Chr1:209825713 c.-38+1G>A NM_000228.2 Test Strengths The strengths of this test include: CAP accredited laboratory CLIA-certified personnel performing clinical testing in a CLIA-certified laboratory https://blueprintgenetics.com/ Powerful sequencing technologies, advanced target enrichment methods and precision bioinformatics pipelines ensure superior analytical performance Careful construction of clinically effective and scientifically justified gene panels Some of the panels include the whole mitochondrial genome (please see the Panel Content section) Our Nucleus online portal providing transparent and easy access to quality and performance data at the patient level Our publicly available analytic validation demonstrating complete details of test performance ~2,000 non-coding disease causing variants in our clinical grade NGS assay for panels (please see ‘Non-coding disease causing variants covered by this panel’ in the Panel Content section) Our rigorous variant classification scheme Our systematic clinical interpretation workflow using proprietary software enabling accurate and traceable processing of NGS data Our comprehensive clinical statements Test Limitations Genes with partial, or whole gene, segmental duplications in the human genome are marked with an asterisk (*) if they overlap with the UCSC pseudogene regions. The technology may have limited sensitivity to detect variants in genes marked with these symbols (please see the Panel content table above). This test does not d etect the following: Complex inversions Gene conversions Balanced translocations Some of the panels include the whole mitochondrial genome (please see the Panel Content section) Repeat expansion disorders unless specifically
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  • Hereditary Hearing Impairment with Cutaneous Abnormalities

    Hereditary Hearing Impairment with Cutaneous Abnormalities

    G C A T T A C G G C A T genes Review Hereditary Hearing Impairment with Cutaneous Abnormalities Tung-Lin Lee 1 , Pei-Hsuan Lin 2,3, Pei-Lung Chen 3,4,5,6 , Jin-Bon Hong 4,7,* and Chen-Chi Wu 2,3,5,8,* 1 Department of Medical Education, National Taiwan University Hospital, Taipei City 100, Taiwan; [email protected] 2 Department of Otolaryngology, National Taiwan University Hospital, Taipei 11556, Taiwan; [email protected] 3 Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei City 100, Taiwan; [email protected] 4 Graduate Institute of Medical Genomics and Proteomics, National Taiwan University College of Medicine, Taipei City 100, Taiwan 5 Department of Medical Genetics, National Taiwan University Hospital, Taipei 10041, Taiwan 6 Department of Internal Medicine, National Taiwan University Hospital, Taipei 10041, Taiwan 7 Department of Dermatology, National Taiwan University Hospital, Taipei City 100, Taiwan 8 Department of Medical Research, National Taiwan University Biomedical Park Hospital, Hsinchu City 300, Taiwan * Correspondence: [email protected] (J.-B.H.); [email protected] (C.-C.W.) Abstract: Syndromic hereditary hearing impairment (HHI) is a clinically and etiologically diverse condition that has a profound influence on affected individuals and their families. As cutaneous findings are more apparent than hearing-related symptoms to clinicians and, more importantly, to caregivers of affected infants and young individuals, establishing a correlation map of skin manifestations and their underlying genetic causes is key to early identification and diagnosis of syndromic HHI. In this article, we performed a comprehensive PubMed database search on syndromic HHI with cutaneous abnormalities, and reviewed a total of 260 relevant publications.