Ectodermal Dysplasia Panel Test code: DE0401 Is a 25 gene panel that includes assessment of non-coding variants. Is ideal for patients with a clinical suspicion of ectodermal dysplasia (hidrotic or hypohidrotic) or Ellis-van Creveld syndrome. About Ectodermal Dysplasia Ectodermal Dysplasia (ED) is a group of closely related conditions of which more than 150 different syndromes have been identified. EDs affects the development or function of teeth, hair, nails and sweat glands. ED may present as isolated or as part of a syndromic disease and is commonly subtyped according to sweating ability. The clinical features of the X-linked and autosomal forms of hypohidrotic ectodermal dysplasia (HED) can be indistinguishable and many of the involved genes may lead to phenotypically distinct outcomes depending on number of defective alleles. The most common EDs are hypohidrotic ED and hydrotic ED. X-linked hypohidrotic ectodermal dysplasia (HED) is caused by EDA mutations and explain 75%-95% of familial HED and 50% of sporadic cases. HED is characterized by three cardinal features: hypotrichosis (sparse, slow-growing hair and sparse/missing eyebrows), reduced sweating and hypodontia (absence or small teeth). Reduced sweating poses risk for episodes of hyperthermia. Female carriers may have some degree of hypodontia and mild hypotrichosis. Isolated dental phenotypes have also been described. Mutations in WNT10A have been reported in up to 9% of individuals with HED and in 25% of individuals with HED who do not have defective EDA. Approximately 50% of individuals with heterozygous WNT10A mutation have HED and the most consistent clinical feature is severe oligodontia of permanent teeth. Mutations in EDAR explain 7% of HED and are associated with both autosomal dominant and recessive ED. This panel provide differential diagnostic power as it covers many syndromes that may present with ED. Several syndromes characterized by ED and hearing loss are associated with GJB2 mutations including KID syndrome, Vohwinkel syndrome, Bart-Pumphrey syndrome. Hidrotic ED type 2 is caused by autosomal dominant GJB6 mutations and characterized by hypotrichosis, dysplastic nails and palmoplantar hyperkeratosis. Unlike other ectodermal dysplasias, sweating and tooth development are normal. Recessive EVC and EVC2 mutations cause Ellis-van Creveld syndrome characterized by ED, dwarfism, polydactyly and heart defects, however, dominant mutations in the same genes cause the less severe Weyers acrofacial dysostosis. Expression of DSP- related ED is variable including woolly hair, alopecia, hyperkeratotic plaques, failure to thrive, dilated and arrhythmogenic right ventricular cardiomyopathy. The most severe presentation is lethal acantholytic epidermolysis bullosa. The prevalence of HED is estimated to be 1:5,000-10,000 newborns while that of Ellis-van Creveld syndrome is 1:60,000 – 200,000. Availability 4 weeks Gene Set Description Genes in the Ectodermal Dysplasia Panel and their clinical significance Gene Associated phenotypes Inheritance ClinVar HGMD BCS1L Bjornstad syndrome, GRACILE syndrome, Leigh syndrome, AR 42 37 Mitochondrial complex III deficiency, nuclear type 1 CDH3 Hypotrichosis, congenital, with juvenile macular dystrophy, AR 7 30 Ectodermal dysplasia, ectrodactyly, and macular dystrophy syndrome DSP Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth AD/AR 177 296 agenesis, Arrhythmogenic right ventricular dysplasia, familial, Cardiomyopathy, dilated, with wooly hair and keratoderma, Keratosis palmoplantaris striata II, Epidermolysis bullosa, lethal acantholytic EDA Ectodermal dysplasia, hypohidrotic, Tooth agenesis, selective XL 115 326 https://blueprintgenetics.com/ EDAR Ectodermal dysplasia, anhidrotic, Hair morphology AD/AR 38 61 EDARADD Ectodermal dysplasia, anhidrotic, autosomal recessive, Ectodermal AD/AR 8 10 dysplasia, anhidrotic, autosomal dominant, Ectodermal dysplasia, hypohidrotic, autosomal dominant, Ectodermal dysplasia, hypohidrotic, autosomal recessive ERCC2 Xeroderma pigmentosum, Trichothiodystrophy, photosensitive, AR 26 98 Cerebrooculofacioskeletal syndrome 2 EVC Weyers acrofacial dysostosis, Ellis-van Creveld syndrome AD/AR 58 83 EVC2 Ellis-van Creveld syndrome, Weyers acrodental dysostosis AD/AR 78 75 GJB2 Deafness, Bart-Pumphrey syndrome, Keratoderma, palmoplantar, with AD/AR/Digenic 133 405 deafness, Vohwinkel syndrome, Hystrix-like ichthyosis with deafness, Keratitis-icthyosis-deafness syndrome GJB6 Deafness, Deafness, autosomal dominant 3B, Ectodermal dysplasia, AD/AR 10 33 hidrotic (Clouston syndrome) HOXC13 Ectodermal dysplasia 9 AR 3 10 HR Hypotrichosis 4, Atrichia with papular lesions, Alopecia universalis AD/AR 15 52 congenita IFT122* Sensenbrenner syndrome, Cranioectodermal dysplasia (Levin- AR 13 23 Sensenbrenner) type 1, Cranioectodermal dysplasia (Levin- Sensenbrenner) type 2 JUP Arrhythmogenic right ventricular dysplasia, Naxos disease AD/AR 8 46 LRP6 Tooth agenesis, selective, 7 AD 19 37 MPLKIP Trichothiodystrophy 4, nonphotosensitive AR 8 19 PAX9 Tooth agenesis, selective, 3 AD 19 57 PORCN Focal dermal hypoplasia XL 16 121 PRKD1 Congenital heart defects and ectodermal dysplasia AD 2 7 PVRL4 Ectodermal dysplasia-syndactyly syndrome 1 AR 6 10 RMRP Cartilage-hair hypoplasia, Metaphyseal dysplasia without AR 87 123 hypotrichosis, Anauxetic dysplasia TP63 Rapp-Hodgkin syndrome, Orofacial cleft, ADULT syndrome, AD 59 122 Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome, Ankyloblepharon-ectodermal defects-cleft lip/palate, Split-hand/foot malformation, Limb-mammary syndrome WDR35 Cranioectodermal dysplasia (Levin-Sensenbrenner) type 1, AR 28 31 Cranioectodermal dysplasia (Levin-Sensenbrenner) type 2, Short rib- polydactyly syndrome type 5 WNT10A Odontoonychodermal dysplasia, Tooth agenesis, selective, Schopf- AD/AR 23 81 Schulz-Passarge syndrome *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 https://blueprintgenetics.com/ 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 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 BCS1L Chr2:219524871 c.-147A>G NM_004328.4 BCS1L Chr2:219525123 c.-50+155T>A NM_004328.4 rs386833855 EDA ChrX:69249341 c.707-13T>C/G NM_001399.4 EDA ChrX:69249341 c.707-13T>C NM_001399.4 EDA ChrX:69249341 c.707-13T>G NM_001399.4 EVC Chr4:5749725 c.940-150T>G NM_153717.2 GJB2 Chr13:20763744 c.-22-2A>C NM_004004.5 rs201895089 GJB2 Chr13:20766920 c.-23+2T>A NM_004004.5 GJB2 Chr13:20766921 c.-23+1G>A NM_004004.5 rs80338940 GJB2 Chr13:20766922 c.-23G>T NM_004004.5 rs786204734 GJB2 Chr13:20767158 c.-259C>T NM_004004.5 GJB2 Chr13:20767159 c.-260C>T NM_004004.5 HR Chr8:21988118 c.-218A>G NM_005144.4 rs267606869 HR Chr8:21988149 c.-249C>G NM_005144.4 rs267606868 HR Chr8:21988215 c.-315C>T NM_005144.4 rs267606867 HR Chr8:21988220 c.-320T>C NM_005144.4 rs387906382 IFT122 Chr3:129207087 c.2005-13T>A NM_052985.3 PAX9 Chr14:37130036 c.-393-866G>A NM_006194.3 PORCN ChrX:48370668 c.374-46T>A NM_203475.1 PORCN ChrX:48370699 c.374-15G>A NM_203475.1 RMRP Chr9:35658026 NR_003051.3 rs781730798 RMRP Chr9:35658026 NR_003051.3 https://blueprintgenetics.com/ RMRP Chr9:35658026 NR_003051.3 RMRP Chr9:35658026 NR_003051.3 RMRP Chr9:35658027 NR_003051.3 RMRP Chr9:35658027 NR_003051.3 RMRP Chr9:35658027 NR_003051.3 RMRP Chr9:35658027 NR_003051.3 rs727502775 RMRP Chr9:35658027 NR_003051.3 RMRP Chr9:35658028 NR_003051.3 RMRP Chr9:35658028 NR_003051.3 RMRP Chr9:35658029 NR_003051.3 RMRP Chr9:35658029 NR_003051.3 RMRP Chr9:35658032 NR_003051.3 WDR35 Chr2:20151929 c.1434-684G>T NM_001006657.1 WDR35 Chr2:20182313 c.143-18T>A NM_001006657.1 Test Strengths Our panel assay enables the detection of common deletions in GJB6 such as ((~309 kb del (GJB6-D13S1830) and ~232 kb del (GJB6-D13S1854)). The strengths of this test include: CAP accredited laboratory CLIA-certified personnel performing clinical testing in a CLIA-certified laboratory 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