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Blueprint Genetics Metaphyseal Dysplasia Panel Metaphyseal Dysplasia Panel Test code: MA2501 Is a 12 gene panel that includes assessment of non-coding variants. Is ideal for patients with a clinical suspicion of craniometaphyseal dysplasia, metaphyseal anadysplasia, metaphyseal chondrodysplasia or metaphyseal dysplasia. The genes on this panel are included in the Comprehensive Growth Disorders / Skeletal Dysplasias and Disorders Panel. About Metaphyseal Dysplasia Metaphyseal dysplasia, also known as Pyle's disease, is a rare recessive bone dysplasia characterised by genu valgum, metaphyseal anomalies with broadening of the long bones extending into the diaphyses, widening of the ribs and clavicles, platyspondyly and cortical thinning. The differential diagnosis includes Braun-Tinschert type of metaphyseal dysplasia. Schmid type metaphyseal chondrodysplasia is a type of chondrodysplasia associated with a deficiency of COL10A1. It is characterized by short stature with short legs, bowing of the long bones, coxa vara, and waddling gait. Jansen type metaphyseal chondrodysplasia is a disease that results from ligand-independent activation of the type 1 of the parathyroid hormone receptor (PTHR1). It is a rare autosomal dominant form of short limb dwarfism characterized by asymptomatic hypercalcemia and skeletal deformities. Metaphyseal anadysplasia is a very rare form of metaphyseal dysplasia that is characterized by short stature, rhizomelic micromelia and a mild varus deformity of the legs evident from the first months of life. It is associated with radiological features of severe metaphyseal changes in the long bones, and generalized osteopenia that typically resolves spontaneously by the age of three years. Severe autosomal dominant and milder recessive variants have been observed in either MMP9 or MMP13. Craniometaphyseal dysplasia is an osteochondrodysplasia characterized by hyperostosis and sclerosis of the craniofacial bones associated with abnormal modeling of the metaphyses. Sclerosis of the skull may lead to asymmetry of the mandible, as well as to cranial nerve compression, that may finally result in hearing loss and facial palsy. Autosomal dominant and autosomal recessive forms exist, with causative gene ANKH. Achondroplasia is characterized by rhizomelia, exaggerated lumbar lordosis, brachydactyly, and macrocephaly with frontal bossing and midface hypoplasia. The estimated incidence is at about 1/25,000 live births worldwide. Achondroplasia is due to mutations in the FGFR3 gene. Inheritance is autosomal dominant so genetic counseling is warranted. Achondroplasia has overlapping features with conditions such as multiple epiphyseal dysplasia tarda, achondrogenesis, osteopetrosis, and thanatophoric dysplasia. Availability 4 weeks Gene Set Description Genes in the Metaphyseal Dysplasia Panel and their clinical significance Gene Associated phenotypes Inheritance ClinVar HGMD ANKH Calcium pyrophosphate deposition disease (familial chondrocalcinosis type AD 13 20 2), Craniometaphyseal dysplasia autosomal dominant type CDKN1C Beckwith-Wiedemann syndrome, IMAGE syndrome AD 35 81 COL10A1 Metaphyseal chondrodysplasia, Schmid AD 21 53 FGFR3 Lacrimoauriculodentodigital syndrome, Muenke syndrome, Crouzon AD/AR 54 77 syndrome with acanthosis nigricans, Camptodactyly, tall stature, and hearing loss (CATSHL) syndrome, Achondroplasia, Hypochondroplasia, Thanatophoric dysplasia type 1, Thanatophoric dysplasia type 2, SADDAN https://blueprintgenetics.com/ FLNA Frontometaphyseal dysplasia, Osteodysplasty Melnick-Needles, XL 133 257 Otopalatodigital syndrome type 1, Otopalatodigital syndrome type 2, Terminal osseous dysplasia with pigmentary defects MMP13 Metaphyseal anadysplasia 1, Metaphyseal dysplasia, Spahr type, AD/AR 7 7 Spondyloepimetaphyseal dysplasia, Missouri type MMP9 Metaphyseal anadysplasia AR 1 7 PISD AR PTH1R Metaphyseal chondrodysplasia Jansen type, Failure of tooth eruption, Eiken AD/AR 13 43 dysplasia, Blomstrand dysplasia RMRP Cartilage-hair hypoplasia, Metaphyseal dysplasia without hypotrichosis, AR 87 123 Anauxetic dysplasia RUNX2 Cleidocranial dysplasia, Metaphyseal dysplasia with maxillary hypoplasia AD 21 216 SBDS* Aplastic anemia, Shwachman-Diamond syndrome, Severe AR 19 90 spondylometaphyseal dysplasia *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 ANKH Chr5:14871567 c.-11C>T NM_054027.4 CDKN1C Chr11:2905209 c.*5+20G>T NM_000076.2 rs760540648 FLNA ChrX:153581587 c.6023-27_6023-16delTGACTGACAGCC NM_001110556.1 PTH1R Chr3:46939842 c.544-25_544-23delCTG NM_000316.2 PTH1R Chr3:46942604 c.1049+29C>T NM_000316.2 RMRP Chr9:35658026 NR_003051.3 rs781730798 RMRP Chr9:35658026 NR_003051.3 RMRP Chr9:35658026 NR_003051.3 RMRP Chr9:35658026 NR_003051.3 https://blueprintgenetics.com/ 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 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 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: https://blueprintgenetics.com/ 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 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
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