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Blueprint Genetics Hyperammonemia and Urea Cycle Disorder Panel

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Blueprint Genetics Hyperammonemia and Urea Cycle Disorder Panel Hyperammonemia and Urea Cycle Disorder Panel Test code: ME1601 Is a 49 gene panel that includes assessment of non-coding variants. Is ideal for patients with hyperammonemia or a clinical suspicion of a disorder of urea cycle metabolism. The genes on this panel are included in the Comprehensive Metabolism Panel. About Hyperammonemia and Urea Cycle Disorder Congenital urea cycle disorders are the result of defects in the metabolism of nitrogen waste. Deficiency of any of the enzymes in the urea cycle results in an excess of ammonia or other precursor metabolites in the blood. Normally, urea production lowers the ammonia levels in the blood but in the case of defective enzymes, the urea cycle is disturbed. Infants with urea cycle disorders (UCDs) develop cerebral edema, lethargy, hypothermia, neurologic signs and coma, often shortly after birth. Partial, or milder, UCDs are possible if the affected enzyme is positioned in a later phase of the urea cycle. Patients with UCDs may present with hyperammonemia often triggered by stress or illness. The most common primary hyperammonemia is X-linked recessive ornithine transcarbamylase deficiency caused by mutations in the OTC gene. The estimated prevalence is 1:56,000. Prevalence estimates for the other specific urea cycle disorders are 1:200,000 for ASL- and ASS1-related deficiencies and <1:1,000,000 for ARG1, CPS1 and NAGS-related deficiencies. The diagnostic yield ranges from 50% to 80% for different primary urea cycle disorders. In addition to congenital UCDs, this panel has the ability to diagnose other diseases of early phase hyperammonemia and other inborn errors of metabolism showing similar and overlapping symptoms. These include organic acidemias and fatty acid oxidation disorders. In addition, rare syndromes, such as hyperornithinemia-hyperammonemia-homocitrullinuria syndrome and citrin deficiency with hyperammonia symptoms are diagnosed with this panel. Availability 4 weeks Gene Set Description Genes in the Hyperammonemia and Urea Cycle Disorder Panel and their clinical significance Gene Associated phenotypes Inheritance ClinVar HGMD ACADM Acyl-CoA dehydrogenase, medium chain, deficiency AR 104 169 ACADS Acyl-CoA dehydrogenase, short-chain, deficiency AR 43 81 ACADVL Acyl-CoA dehydrogenase, very long chain, deficiency AR 119 282 ARG1 Hyperargininemia AR 28 54 ASL Argininosuccinic aciduria AR 56 162 ASS1 Citrullinemia AR 70 153 BCKDHA Maple syrup urine disease AR 57 98 BCKDHB Maple syrup urine disease AR 87 103 CA5A Carbonic anhydrase VA deficiency AR 6 7 CPS1 Carbamoylphosphate synthetase I deficiency AR 61 269 https://blueprintgenetics.com/ CPT1A Carnitine palmitoyltransferase deficiency AR 60 51 CPT2 Carnitine palmitoyltransferase II deficiency AR 72 111 DBT Maple syrup urine disease AR 39 75 DLD Dihydrolipoyl dehydrogenase deficiency AR 36 21 ETFA Glutaric aciduria, Multiple acyl-CoA dehydrogenase deficiency AR 8 29 ETFB Glutaric aciduria, Multiple acyl-CoA dehydrogenase deficiency AR 6 15 ETFDH Glutaric aciduria, Multiple acyl-CoA dehydrogenase deficiency AR 43 190 GLUD1* Hyperammonemia-hyperinsulinism, Hyperinsulinemic hypoglycemia AD/AR 14 38 GLUL Glutamine deficiency, congenital AR 4 3 HADHA Trifunctional protein deficiency, Long-chain 3-hydroxyacyl-CoA AR 65 71 dehydrogenase deficiency HADHB Trifunctional protein deficiency AR 20 65 HCFC1 Combined methylmalonic acidemia and hyperhomocysteinemia XL 9 17 HLCS Holocarboxylase synthetase deficiency AR 34 47 HMGCL 3-hydroxy-3-methylglutaryl-CoA lyase deficiency AR 24 60 HMGCS2 3-hydroxy-3-methylglutaryl-CoA synthase 2 deficiency AR 9 30 IVD Isovaleric acidemia AR 51 90 MCCC1 3-Methylcrotonyl-CoA carboxylase 1 deficiency AR 40 105 MCCC2 3-Methylcrotonyl-CoA carboxylase 2 deficiency AR 24 114 MMAA Methylmalonic acidemia AR 61 75 MMAB Methylmalonic acidemia AR 31 40 MMACHC Methylmalonic aciduria and homocystinuria AR 59 93 MMADHC Methylmalonic aciduria and homocystinuria AR 16 13 MUT Methylmalonic acidemia due to methylmalonyl-CoA mutase deficiency AR 159 366 NAGS N-acetylglutamate synthase deficiency AR 12 48 NBAS Infantile liver failure syndrome 2, Short stature, optic nerve atrophy, and AR 23 43 Pelger-Huet anomaly (SOPH syndrome) OAT Gyrate atrophy of choroid and retina AR 67 71 OTC Ornithine transcarbamylase deficiency XL 343 513 PC Pyruvate carboxylase deficiency AR 32 41 PCCA Propionic acidemia AR 66 125 PCCB Propionic acidemia AR 68 115 https://blueprintgenetics.com/ SLC22A5 Carnitine deficiency, systemic primary AR 98 151 SLC25A13 Citrin deficiency AR 24 113 SLC25A15* Hyperornithinemia-hyperammonemia-homocitrullinemia syndrome AR 24 36 SLC25A20 Carnitine-acylcarnitine translocase deficiency AR 15 42 SLC7A7 Lysinuric protein intolerance AR 55 67 SUCLA2 Mitochondrial DNA depletion syndrome AR 9 29 SUCLG1 Mitochondrial DNA depletion syndrome AR 12 28 TMEM70 Mitochondrial complex V (ATP synthase) deficiency AR 12 18 UMPS Orotic aciduria AR 3 12 *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 ACADM Chr1:76200457 c.388-19T>A NM_000016.4 ACADM Chr1:76211473 c.600-18G>A NM_000016.4 rs370523609 ACADVL Chr17:7123160 c.-144_-132delCCCAGCATGCCCCinsT NM_000018.3 ACADVL Chr17:7125469 c.822-27C>T NM_001270447.1 rs374911841 ACADVL Chr17:7125485 c.822-11T>G NM_001270447.1 ACADVL Chr17:7126199 c.1146+15C>T NM_001270447.1 rs202237278 ACADVL Chr17:7126948 c.1252-15A>G NM_001270447.1 rs765390290 ACADVL Chr17:7127894 c.1747+23C>T NM_001270447.1 rs147546456 ARG1 Chr6:131901748 c.306-611T>C NM_000045.3 ASS1 Chr9:133327601 c.-5-10C>G NM_000050.4 rs375136377 ASS1 Chr9:133332669 c.175-1119G>A NM_000050.4 https://blueprintgenetics.com/ ASS1 Chr9:133355236 c.773+49C>T NM_000050.4 rs763389916 BCKDHA Chr19:41930736 c.*223T>A NM_000709.3 rs373164531 CPS1 Chr2:211539387 c.4102-239A>G NM_001875.4 DBT Chr1:100672742 c.1018-550A>G NM_001918.3 rs796052135 ETFDH Chr4:159593534 c.-75A>G NM_004453.2 ETFDH Chr4:159602711 c.176-636C>G NM_004453.2 HADHB Chr2:26500642 c.442+614A>G NM_000183.2 HADHB Chr2:26500691 c.442+663A>G NM_000183.2 HCFC1 ChrX:153237261 c.-970T>C NM_005334.2 rs398122908 MCCC2 Chr5:70898313 c.384-20A>G NM_022132.4 rs770917710 MCCC2 Chr5:70939634 c.1073-12C>G NM_022132.4 rs1280511914 MUT Chr6:49427219 c.-39-1G>A NM_000255.3 NAGS Chr17:42078968 c.-3063C>A NM_153006.2 NBAS Chr2:15567431 c.2423+404G>C NM_015909.3 OTC ChrX:38202566 c.-9384G>T NM_000531.5 OTC ChrX:38211584 NM_000531.5 rs191615506 OTC ChrX:38211793 c.-157T>G NM_000531.5 OTC ChrX:38211808 c.-142G>A NM_000531.5 OTC ChrX:38211811 c.-139A>G NM_000531.5 OTC ChrX:38211834 c.-116C>T NM_000531.5 OTC ChrX:38211835 c.-115C>T NM_000531.5 OTC ChrX:38211844 c.-106C>A NM_000531.5 rs749748052 OTC ChrX:38260946 c.540+265G>A NM_000531.5 OTC ChrX:38269404 c.867+1126A>G NM_000531.5 OTC ChrX:38272343 c.1005+1091C>G NM_000531.5 PC Chr11:66620883 c.1369-29A>G NM_000920.3 PCCA Chr13:100958030 c.1285-1416A>G NM_000282.3 PCCB Chr3:136003251 c.714+462A>G NM_001178014.1 SLC22A5 Chr5:131714054 c.394-16T>A NM_003060.3 rs775097754 SLC22A5 Chr5:131722665 c.825-52G>A NM_003060.3 https://blueprintgenetics.com/ 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 The following exons are not included in the panel as they are not sufficiently covered with high quality sequence reads: PCCB (NM_001178014:4). Genes with suboptimal coverage in our assay are marked with number
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