Spinal Muscular Atrophy Panel Test code: NE1801 Is a 30 gene panel that includes assessment of non-coding variants. Is ideal for patients with a clinical suspicion of distal hereditary motor neuropathy or spinal muscular atrophy. About Spinal Muscular Atrophy Spinal muscular atrophies (SMAs) are a genetically and clinically heterogeneous group of rare debilitating disorders characterized by the degeneration of lower motor neurons and subsequent atrophy of various muscle groups in the body. While some SMAs lead to death in infancy, other types can present with mild weakness in an otherwise healthy adult. Based on the type of muscles affected, spinal muscular atrophies can be divided into proximal and distal SMAs. The distal SMAs significantly overlap with distal hereditary motor neuropathies and this has been taken into account in the panel design. While the presence of several symptoms may point towards a particular genetic disorder, an accurate diagnosis can only be established with certainty by genetic testing. Availability 4 weeks Gene Set Description Genes in the Spinal Muscular Atrophy Panel and their clinical significance Gene Associated phenotypes Inheritance ClinVar HGMD AARS Epileptic encephalopathy, early infantile, Charcot-Marie-Tooth disease AD/AR 9 16 ASAH1 Spinal muscular atrophy with progressive myoclonic epilepsy, Farber AR 16 71 lipogranulomatosis ATP7A Menkes disease, Occipital horn syndrome, Spinal muscular atrophy, distal, XL 116 354 X-linked 3 BICD2 Childhood-onset proximal spinal muscular atrophy with contractures AD 12 28 BSCL2 Lipodystrophy, congenital generalized, Encephalopathy, progressive, AD/AR 34 50 Neuropathy, distal hereditary motor, type VA, Charcot-Marie-Tooth disease type 2, Silver syndrome, Silver spastic paraplegia syndrome, Spastic paraplegia 17 CHCHD10 Myopathy, isolated mitochondrial, Frontotemporal dementia and/or AD 4 26 amyotrophic lateral sclerosis 2, Spinal muscular atrophy, Jokela type DCTN1 Perry syndrome, Neuropathy, distal hereditary motor AD 10 52 DNAJB2 Spinal muscular atrophy, distal, Charcot-Marie-Tooth disease AR 9 5 DYNC1H1 Spinal muscular atrophy, Charcot-Marie-Tooth disease, Mental retardation AD 60 71 EXOSC3 Pontocerebellar hypoplasia AR 11 19 EXOSC8 Pontocerebellar hypoplasia AR 1 3 FBXO38 Neuronopathy, distal hereditary motor AD 1 5 https://blueprintgenetics.com/ GARS Neuropathy, distal hereditary motor, Charcot-Marie-Tooth disease AD 19 38 HEXA Tay-Sachs disease, GM2-gangliosidosis, Hexosaminidase A deficiency AR 128 194 HSPB1 Neuropathy, distal hereditary motor, Charcot-Marie-Tooth disease AD 27 44 HSPB3 Neuronopathy, distal hereditary motor AD 2 HSPB8 Charcot-Marie-Tooth disease, Distal hereditary motor neuronopathy AD 6 9 IGHMBP2 Spinal muscular atrophy, distal, Charcot-Marie-Tooth disease AR 52 128 LAS1L* Spinal muscular atrophy with respiratory distress XL 5 4 PLEKHG5 Spinal muscular atrophy, Charcot-Marie-Tooth disease AR 16 8 REEP1 Spastic paraplegia, Distal hereditary motor neuronopathy AD 16 60 SCO2 Leigh syndrome, Hypertrophic cardiomyopathy (HCM), AR 42 37 Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency, Myopia SLC5A7 Neuronopathy, distal hereditary motor, Myasthenic syndrome, congenital, AD/AR 5 17 Neuronopathy, distal hereditary motor, type VIIA SMN1*,# Spinal muscular atrophy AR 29 111 SMN2*,# Spinal muscular atrophy AD 1 9 TBCE Progressive encephalopathy with amyotrophy and optic atrophy (PEAMO) AR 12 8 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 UBA1 Spinal muscular atrophy, infantile XL 3 5 VAPB Amyotrophic lateral sclerosis, Spinal muscular atrophy, late-onset, Finkel AD 2 9 VRK1 Pontocerebellar hypoplasia AR 9 9 *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 ATP7A ChrX:77279056 c.2916+2480T>G NM_000052.5 ATP7A ChrX:77287843 c.3294+763C>G NM_000052.5 BSCL2 Chr11:62470032 c.405-11A>G NM_001122955.3 EXOSC3 Chr9:37782146 c.475-12A>G NM_016042.3 rs370087266 HEXA Chr15:72640009 c.1146+18A>G NM_000520.4 HSPB1 Chr7:75931813 c.-217T>C NM_001540.3 rs545738637 IGHMBP2 Chr11:68697719 c.1235+894C>A NM_002180.2 Test Strengths Deletion / duplication analysis (either in isolation or as part of Plus analysis including sequencing) testing can detect the copy number of SMN1 exon 7, which is commonly used as a marker for copy number of the SMN1 gene. In individuals identified to have homozygous SMN1 deletions, we include reporting of SMN2 copy number. 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 Due to high sequence homology between SMN1 and SMN2, this panel has not been validated to detect single nucleotide variants or small insertions and deletions in SMN1 which are associated with spinal muscular atrophy in a small number of patients (<5%). 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: https://blueprintgenetics.com/ 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 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),