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Blueprint Genetics Osteopetrosis and Dense Bone Dysplasia Panel

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Blueprint Genetics Osteopetrosis and Dense Bone Dysplasia Panel Osteopetrosis and Dense Bone Dysplasia Panel Test code: MA2001 Is a 25 gene panel that includes assessment of non-coding variants. Is ideal for patients with a clinical suspicion of osteopetrosis. The genes on this panel are included in the Comprehensive Growth Disorders / Skeletal Dysplasias and Disorders Panel. About Osteopetrosis and Dense Bone Dysplasia Autosomal dominant osteopetrosis (ADO, also known as Albers-Schönberg disease) is typically an adult-onset, more benign form whereas autosomal recessive osteopetrosis (ARO), also termed malignant infantile osteopetrosis, presents soon after birth, is often severe and leads to death if left untreated. Autosomal recessive osteopetrosis (ARO) is a genetically and phenotypically heterogeneous disease; most forms result from late endosomal trafficking defects that prevent osteoclast ruffled‐border formation. Hematopoietic stem cell transplantation (HSCT) can cure ARO if given in early life to patients with osteoclast‐intrinsic disease without neurodegenerative complications. New treatments that target RANKL/RANK signaling offer promise in ARO subtypes that currently cannot be cured by HSCT and to prevent hypercalcemia after HSCT. Paget’s disease is a common metabolic bone disease characterized by focal abnormalities of increased bone turnover affecting one or more sites throughout the skeleton, primarily the axial skeleton. Bone lesions in this disorder show evidence of increased osteoclastic bone resorption and disorganized bone structure. Genetic factors play an important role in the disease. In some cases, Paget’s disease is inherited in an autosomal dominant manner and the most common cause for this is a mutation in the SQSTM1 gene. Mutations in TNFRSF11A, TNFRSF11B and VCP have been identified in rare syndromes with Paget’s disease- like features. Availability 4 weeks Gene Set Description Genes in the Osteopetrosis and Dense Bone Dysplasia Panel and their clinical significance Gene Associated phenotypes Inheritance ClinVar HGMD AMER1 Osteopathia striata with cranial sclerosis XL 14 40 ANKH Calcium pyrophosphate deposition disease (familial chondrocalcinosis AD 13 20 type 2), Craniometaphyseal dysplasia autosomal dominant type CA2 Osteopetrosis, with renal tubular acidosis AR 9 31 CLCN7 Osteopetrosis AD/AR 15 98 COL1A1 Ehlers-Danlos syndrome, Caffey disease, Osteogenesis imperfecta AD 352 962 type 1, Osteogenesis imperfecta type 2, Osteogenesis imperfecta type 3, Osteogenesis imperfecta type 4 CTSK Pycnodysostosis AR 35 58 DLX3 Amelogenesis imperfecta, Trichodontoosseous syndrome AD 5 11 FAM20C Hypophosphatemia, hyperphosphaturia, dental anomalies, AR 13 25 intracerebral calcifications and osteosclerosis (Raine syndrome) https://blueprintgenetics.com/ GJA1* Oculodentodigital dysplasia mild type, Oculodentodigital dysplasia AD/AR 31 107 severe type, Syndactyly type 3 LEMD3 Buschke-Ollendorff syndrome, Osteopoikilosis AD 13 32 LRP4 Cenani-Lenz syndactyly syndrome, Sclerosteosis, Myasthenic AD/AR 14 28 syndrome, congenital LRP5* Van Buchem disease, Osteoporosis-pseudoglioma syndrome, AD/AR/Digenic 57 196 Hyperostosis, endosteal, Osteosclerosis, Exudative vitreoretinopathy, Osteopetrosis late-onset form type 1, LRP5 primary osteoporosis OSTM1 Osteopetrosis, autosomal recessive 5 AR 5 9 PTDSS1 Lenz-Majewski hyperostotic dwarfism AD 5 7 PTH1R Metaphyseal chondrodysplasia Jansen type, Failure of tooth eruption, AD/AR 13 43 Eiken dysplasia, Blomstrand dysplasia SLC29A3 Histiocytosis-lymphadenopathy plus syndrome, Dysosteosclerosis AR 17 25 SLCO2A1 Hypertrophic osteoarthropathy AD/AR 13 72 SNX10 Osteopetrosis, autosomal recessive 8 AR 3 13 SOST Craniodiaphyseal dysplasia, autosomal dominant, Sclerosteosis 1, van AD/AR 6 14 Buchem disease TCIRG1 Osteopetrosis, severe neonatal or infantile forms (OPTB1) AD/AR 48 130 TGFB1 Diaphyseal dysplasia Camurati-Engelmann AD 15 23 TNFRSF11A Familial expansile osteolysis, Paget disease of bone, Osteopetrosis, AD/AR 8 24 severe neonatal or infantile forms (OPTB1) TNFRSF11B Paget disease of bone, juvenile AR 8 18 TNFSF11 Osteopetrosis, autosomal recessive 2 AR 3 5 TYROBP Nasu-Hakola disease, Polycystic lipomembranous osteodysplasia with AR 8 14 sclerosing leukoencephalopathy *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. https://blueprintgenetics.com/ Non-coding disease causing variants covered by the panel Gene Genomic location HG19 HGVS RefSeq RS-number ANKH Chr5:14871567 c.-11C>T NM_054027.4 CLCN7 Chr16:1506057 c.916+57A>T NM_001287.5 CLCN7 Chr16:1507356 c.739-18G>A NM_001287.5 rs371893553 COL1A1 Chr17:48266910 c.2668-11T>G NM_000088.3 rs786205505 COL1A1 Chr17:48267594 c.2451+94G>T NM_000088.3 COL1A1 Chr17:48267611 c.2451+77C>T NM_000088.3 rs72651665 COL1A1 Chr17:48268147 c.2343+31T>A NM_000088.3 COL1A1 Chr17:48272201 c.1354-12G>A NM_000088.3 rs72648337 COL1A1 Chr17:48273368 c.1003-43_1003-32delTGCCATCTCTTC NM_000088.3 rs72645359 COL1A1 Chr17:48273574 c.958-18_958-15delTTCC NM_000088.3 rs72645351 COL1A1 Chr17:48273742 c.904-14G>A NM_000088.3 COL1A1 Chr17:48273743 c.904-15T>A NM_000088.3 CTSK Chr1:150778521 c.244-29A>G NM_000396.3 PTH1R Chr3:46939842 c.544-25_544-23delCTG NM_000316.2 PTH1R Chr3:46942604 c.1049+29C>T NM_000316.2 SLC29A3 Chr10:73122778 c.*413G>A NM_018344.5 TCIRG1 Chr11:67806587 c.-5+1G>C/T NM_006019.3 TCIRG1 Chr11:67806587 c.-5+1G>C NM_006019.3 TCIRG1 Chr11:67806587 c.-5+1G>T NM_006019.3 TCIRG1 Chr11:67816893 c.1887+132T>C NM_006019.3 TCIRG1 Chr11:67816903 c.1887+142T>A NM_006019.3 TCIRG1 Chr11:67816907 c.1887+146G>A NM_006019.3 TCIRG1 Chr11:67816910 c.1887+149C>T NM_006019.3 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 https://blueprintgenetics.com/ 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 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. 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
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