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Blueprint Genetics Spondylometaphyseal Spondylometaphyseal / Spondyloepi-(meta)-physeal Dysplasia Panel Test code: MA1701 Is a 30 gene panel that includes assessment of non-coding variants. Is ideal for patients with a clinical suspicion of spondylometaphyseal dysplasia or spondyloepi-(meta)-physeal dysplasia. The genes on this panel are included in the Comprehensive Growth Disorders / Skeletal Dysplasias and Disorders Panel. About Spondylometaphyseal / Spondyloepi-(meta)-physeal Dysplasia The spondylometaphyseal dysplasias constitute a very complex heterogeneous group of disorders. The disorders are characterized by the association of spondular dysplasia and metaphyseal abnormalities of the tubular bones and are associated with walking and growth disturbances that become evident in early childhood. The disorders involve platyspondyly (flattened vertebrae) and marked hip and knee metaphyseal lesions. The different forms of spondylometaphyseal dysplasia are distinguished by the localization and severity of involvement of the affected metaphyses. In addition to the Kozlowski type, which is the most common form, three subgroups can be distinguished by the appearance of the femoral neck. In the first group the changes are severe with absent ossification of the femoral neck and coxa vara. In the second group the changes of the femoral neck are moderate and in the third mild metaphyseal irregularities are only visible. Spondylometaphyseal dysplasia may also occur in association with other clinical manifestations such as facial dysmorphism and dentinogenesis imperfecta. The Kozlowski type of spondylometaphyseal dysplasia results in severe kyphoscoliosis and is caused by mutations in the TRPV4 gene. It is transmitted in an autosomal dominant manner, as well as the form of spondylometaphyseal dysplasia (‘corner fracture’ or Sutcliffe type), the Algerian (or Schmidt) type and some moderate forms. Several autosomal recessive forms have also been identified, including type A4 and an axial type associated with retinitis pigmentosa and optic atrophy. A form of spondylometaphyseal dysplasia with X-linked transmission has also been reported. Availability 4 weeks Gene Set Description Genes in the Spondylometaphyseal / Spondyloepi-(meta)-physeal Dysplasia Panel and their clinical significance Gene Associated phenotypes Inheritance ClinVar HGMD ACAN# Spondyloepimetaphyseal dysplasia, aggrecan type, Spondyloepiphyseal AD/AR 20 56 dysplasia, Kimberley type, Osteochondritis dissecans, short stature, and early-onset osteoarthritis ACP5 Spondyloenchondrodysplasia with immune dysregulation AR 12 26 B3GALT6 Spondyloepimetaphyseal dysplasia with joint laxity, Ehlers-Danlos AR 17 27 syndrome BGN Spondyloepimetaphyseal dysplasia, X-linked, Meester-Loeys syndrome XL 8 7 CANT1 Desbuquois dysplasia AR 20 28 CHST3 Spondyloepiphyseal dysplasia with congenital joint dislocations (recessive AR 18 37 Larsen syndrome) COL11A1 Marshall syndrome, Fibrochondrogenesis, Stickler syndrome type 2 AD/AR 34 94 https://blueprintgenetics.com/ COL11A2 Weissenbacher-Zweymuller syndrome, Deafness, AD/AR 29 57 Otospondylomegaepiphyseal dysplasia, Fibrochondrogenesis, Stickler syndrome type 3 (non-ocular) COL2A1 Avascular necrosis of femoral head, Rhegmatogenous retinal detachment, AD 180 561 Epiphyseal dysplasia, with myopia and deafness, Czech dysplasia, Achondrogenesis type 2, Platyspondylic dysplasia Torrance type, Hypochondrogenesis, Spondyloepiphyseal dysplasia congenital (SEDC), Spondyloepimetaphyseal dysplasia (SEMD) Strudwick type, Kniest dysplasia, Spondyloperipheral dysplasia, Mild SED with premature onset arthrosis, SED with metatarsal shortening, Stickler syndrome type 1 DDR2 Spondylometaepiphyseal dysplasia, short limb-hand type AR 11 9 DYM Dyggve-Melchior-Clausen dysplasia, Smith-McCort dysplasia AR 22 34 EIF2AK3 SED, Wolcott-Rallison type AR 9 80 HSPG2 Schwartz-Jampel syndrome, Dyssegmental dysplasia Silverman- AD/AR 16 60 Handmaker type, Dyssegmental dysplasia Rolland-Desbuquis type INPPL1 Opsismodysplasia AR 16 32 KIF22 Spondyloepimetaphyseal dysplasia with joint laxity, type 2 AD 4 4 LONP1 Cerebral, Ocular, Dental, Auricular, and Skeletal anomalies (CODAS) AR 9 18 syndrome MATN3 Spondyloepimetaphyseal dysplasia Matrilin type, Multiple epiphyseal AD/AR 8 25 dysplasia type 5 (EDM5) MMP13 Metaphyseal anadysplasia 1, Metaphyseal dysplasia, Spahr type, AD/AR 7 7 Spondyloepimetaphyseal dysplasia, Missouri type NKX3-2 Spondylo-megaepiphyseal-metaphyseal dysplasia AR 4 4 PAPSS2 Brachyolmia 4 with mild epiphyseal and metaphyseal changes, SEMD AR 13 20 PAPPS2 type PCYT1A Spondylometaphyseal dysplasia with cone-rod dystrophy AR 12 20 PISD AR RAB33B Dyggve-Melchior-Clausen syndrome, Smith-McCort dysplasia 2 AR 6 7 RMRP Cartilage-hair hypoplasia, Metaphyseal dysplasia without hypotrichosis, AR 87 123 Anauxetic dysplasia RSPRY1 Spondyloepimetaphyseal dysplasia, Faden-Alkuraya type AR 2 2 SLC39A13 Spondylodysplastic Ehlers-Danlos syndrome AR 2 9 SMARCAL1 Schimke immunoosseous dysplasia AR 20 88 TRAPPC2* Spondyloepiphyseal dysplasia tarda XL 12 55 TRPV4 Metatropic dysplasia, Spondyloepiphyseal dysplasia Maroteaux type, AD 61 78 Parastremmatic dwarfism, Hereditary motor and sensory neuropathy, Spondylometaphyseal dysplasia Kozlowski type, Spinal muscular atrophy, Charcot-Marie-Tooth disease, Brachyolmia (autosomal dominant type), Familial Digital arthropathy with brachydactyly https://blueprintgenetics.com/ WISP3 Arthropathy, progressive pseudorheumatoid, of childhood, AR 16 69 Spondyloepiphyseal dysplasia tarda with progressive arthropathy *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 CANT1 Chr17:77005745 c.-342+1G>A NM_138793.3 COL11A1 Chr1:103386637 c.3744+437T>G NM_080629.2 COL11A1 Chr1:103488576 c.1027-24A>G NM_080629.2 COL11A1 Chr1:103491958 c.781-450T>G NM_080629.2 rs587782990 COL2A1 Chr12:48379984 c.1527+135G>A NM_001844.4 HSPG2 Chr1:22211006 c.1654+15G>A NM_005529.5 HSPG2 Chr1:22215993 c.574+481C>T NM_005529.5 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 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 https://blueprintgenetics.com/ RMRP Chr9:35658029 NR_003051.3 RMRP Chr9:35658029 NR_003051.3 RMRP Chr9:35658032 NR_003051.3 WISP3 Chr6:112381431 c.103-763G>T NM_198239.1 WISP3 Chr6:112386227 c.643+27C>G NM_198239.1 rs200472841 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 (#) and 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. 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)
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