Brachydactyly / Syndactyly Panel Test code: MA1201 Is a 21 gene panel that includes assessment of non-coding variants. Is ideal for patients with brachydactyly and / or syndactyly. The genes on this panel are included in the Comprehensive Growth Disorders / Skeletal Dysplasias and Disorders Panel. About Brachydactyly / Syndactyly The brachydactyly / syndactyly panel includes genes associated with isolated forms of brachydactyly and syndactyly as well as some syndromic forms, such as the brachydactyly-syndactyly syndrome caused by mutations in the HOXD13 gene and hand-foot-genital syndrome (HFGS) caused by mutations in the HOXA13 gene. Brachydactyly ("short digits") refers to disproportionately short fingers and toes, and forms part of the group of limb malformations characterized by bone dysostosis. The various types of isolated brachydactyly are rare, except for types D and A3 (where the underlying genetic cause is unknown). To date, many different forms of brachydactyly have been identified. Some forms also result in short stature. In isolated brachydactyly, subtle changes may be present elsewhere. Brachydactyly can be accompanied by other hand malformations, such as syndactyly, polydactyly, reduction defects, or symphalangism. Syndactyly is one of the most common hereditary limb malformations resulting in the fusion of certain fingers and/or toes. It can occur as an isolated trait or as part of a syndrome. Both brachydactylies and syndactylies exhibit great inter- and intra-familial clinical variability with reduced penetrance. Roberts syndrome (RBS), caused by mutations in the ESCO2 gene, is characterized by pre- and postnatal growth restriction, severe symmetric limb reduction defects, craniofacial anomalies and severe intellectual deficit. SC phocomelia is a milder form of RBS. RECQL4 mutations are associated with RAPADILINO, Rothmund-Thomson syndrome (RTS) and Baller-Gerold syndrome. TP63 mutations are responsible for Split-hand/split-foot malformation disorder, a syndrome involving the central rays of the autopod and presenting with syndactyly, median clefts of the hands and feet, and aplasia and/or hypoplasia of the phalanges, metacarpals and metatarsals. Availability 4 weeks Gene Set Description Genes in the Brachydactyly / Syndactyly Panel and their clinical significance Gene Associated phenotypes Inheritance ClinVar HGMD BMP2 Brachydactyly type A2 AD 5 28 BMPR1B Acromesomelic dysplasia, Demirhan, Brachydactyly C/Symphalangism-like AD/AR 12 23 pheno, Brachydactyly type A2, Pulmonary arterial hypertension (PAH) CHSY1 Temtamy preaxial brachydactyly syndrome AR 6 16 DHCR7 Smith-Lemli-Opitz syndrome AR 88 217 ESCO2 SC phocomelia syndrome, Roberts syndrome AR 30 31 FAM58A Toe syndactyly, telecanthus, and anogenital and renal malformations (STAR XL 8 11 syndrome) GDF5 Multiple synostoses syndrome, Fibular hypoplasia and complex AD/AR 23 53 brachydactyly, Acromesomelic dysplasia, Hunter-Thompson, Symphalangism, proximal, Chondrodysplasia, Brachydactyly type A2, Brachydactyly type C, Grebe dysplasia https://blueprintgenetics.com/ GNAS McCune-Albright syndrome, Progressive osseous heteroplasia, AD 64 274 Pseudohypoparathyroidism, Albright hereditary osteodystrophy HOXA13 Hand-foot-uterus syndrome, Hand-foot-genital syndrome, Guttmacher AD 8 27 syndrome HOXD13 Brachydactyly-syndactyly syndrome, Synopolydactyly, Syndactyly, AD/AR 18 41 Synopolydactyly with clefting, Brachydactyly type D IHH Acrocapitofemoral dysplasia, Brachydactyly, Syndactyly type Lueken AD/AR 12 32 MYCN Feingold syndrome AD 27 41 NOG Tarsal-carpal coalition syndrome, Multiple synostosis syndrome, Stapes AD 20 63 ankylosis with broad thumb and toes (Teunissen-Cremers syndrome), Symphalangism, proximal, Brachydactyly type B2 PDE3A Hypertension with brachydactyly AD 7 10 PDE4D Acrodysostosis 2, with or without hormone resistance AD 15 38 PTDSS1 Lenz-Majewski hyperostotic dwarfism AD 5 7 PTHLH Brachydactyly, type E2 AD 5 18 RECQL4 Baller-Gerold syndrome, RAPADILINO syndrome, Rothmund-Thomson AR 82 114 syndrome ROR2 Robinow syndrome recessive type, Brachydactyly type B AD/AR 21 40 SOX9 Campomelic dysplasia, 46,XY sex reversal, Brachydactyly with anonychia AD 47 144 (Cooks syndrome) TP63 Rapp-Hodgkin syndrome, Orofacial cleft, ADULT syndrome, Ectrodactyly, AD 59 122 ectodermal dysplasia, and cleft lip/palate syndrome, Ankyloblepharon- ectodermal defects-cleft lip/palate, Split-hand/foot malformation, Limb- mammary 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 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 BMPR1B Chr4:95797053 c.-113+2T>G NM_001203.2 https://blueprintgenetics.com/ ESCO2 Chr8:27650167 c.1354-18G>A NM_001017420.2 rs80359865 GNAS Chr20:57478716 c.2242-11A>G NM_080425.2 SOX9 Chr17:70117348 c.-185G>A NM_000346.3 Test Strengths 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 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 suboptimal coverage in our assay are marked with number sign (#). Gene is considered to have suboptimal coverage when >90% of the gene's target nucleotides are not covered at >20x with mapping quality score (MQ>20) reads. 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 mentioned Non-coding variants deeper than ±20 base pairs from exon-intron boundary unless otherwise indicated (please see above Panel Content / non-coding variants covered by the panel). This test may not reliably detect the following: Low level mosaicism in nuclear genes (variant with a minor allele fraction of 14.6% is detected with 90% probability) Stretches of mononucleotide repeats Low level heteroplasmy in mtDNA (>90% are detected at 5% level) Indels larger than 50bp Single exon deletions or duplications Variants within pseudogene regions/duplicated segments Some disease causing variants present in mtDNA are not detectable from blood, thus post-mitotic tissue such as skeletal muscle may be required for establishing molecular diagnosis. 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. https://blueprintgenetics.com/ Test Performance The genes on the panel have been carefully selected based on scientific literature, mutation databases and our experience. Our panels are sectioned from our high-quality, clinical grade NGS assay. Please see our sequencing and detection performance table for details regarding our ability to detect different types of alterations (Table). Assays have been validated for various sample types including EDTA-blood, isolated DNA (excluding from formalin fixed paraffin embedded tissue), saliva and dry blood spots (filter cards). These sample types were selected in order to maximize the likelihood for high-quality DNA yield. The diagnostic yield varies depending on the assay used, referring healthcare professional, hospital and country. Plus analysis increases the likelihood of finding a genetic diagnosis for your patient, as large deletions and duplications cannot be detected using sequence