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Blueprint Genetics Organic Acidemia/Aciduria &Amp

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Blueprint Genetics Organic Acidemia/Aciduria &Amp Organic Acidemia/Aciduria & Cobalamin Deficiency Panel Test code: ME0901 Is a 54 gene panel that includes assessment of non-coding variants. Is ideal for patients with a clinical suspicion of cobalamin deficiency, homocystinuria, maple syrup urine disease, methylmalonic acidemia, organic acidemia/aciduria or propionic acidemia. The genes on this panel are included in the Comprehensive Metabolism Panel. About Organic Acidemia/Aciduria & Cobalamin Deficiency Organic acidemia and aciduria refer to many disorders, where non-amino organic acids are excreted in urine. This is usually a result of deficient enzyme activity in amino acid catabolism. The clinical presentation of organic acidemia in young children includes neurologic symptoms, poor feeding and lethargy progressing to coma. Older persons with this disorder often also have neurological signs, recurrent ketoacidosis and loss of intellectual function. The symptoms result from the damaging accumulation of precursors of the defective pathway. The combined prevalence of organic acidurias is estimated at 1:1,000 newborns. Cobalamin, also known as vitamin B12, has cobalt in its structure. Humans are not able to synthesize B12. It must therefore be obtained from a food of animal origin (the only natural source of cobalamin in the human diet). Intracellular cobalamin deficiencies can be subgrouped based on the cellular complementation groups and defective genes. Mutations in genes MMAA, MMAB and MMADHC cause deficient synthesis of the coenzyme adenosylcobalamin (AdoCbl), while mutations in genes MMADHC, MTRR and MTR cause defective methylcobalamin (MeCbl) synthesis. Mutation in genes MMACHC, MMADHC, LMBRD1 and ABCD4 result in combined AdoCbl and MeCbl deficiency. Mutations in MMACHC explain approximately 80% of the cases with intracellular cobalamin deficiency, followed by MMADHC (<5%), TRR (<5%), LMBRD1 (<5%), MTR (<5%) and ABCD4 (<1%). The presentation of cobalamin deficiency can be perinatal in onset or during childhood or adulthood. The symptoms are wide ranging based on the complementation group and gene affected. Perinatal onset is characterized by growth restriction, microcephaly, heart disease and dysmorphic features. This presentation is often severe and may be lethal. Babies with cobalamin deficiency often have poor feeding, hypotonia, seizures and multiorgan involvement. Cobalamin deficiency in adulthood often presents with neurological and neuropsychiatric problems. Some specific types of cobalamin deficiencies are extremely rare with only dozens of patients described. The combined prevalence is estimated at >1:100,000. Availability 4 weeks Gene Set Description Genes in the Organic Acidemia/Aciduria & Cobalamin Deficiency Panel and their clinical significance Gene Associated phenotypes Inheritance ClinVar HGMD ABCD4 Methylmalonic aciduria and homocystinuria AR 6 7 ACADSB 2-methylbutyryl-CoA dehydrogenase deficiency AR 8 12 ACAT1 Alpha-methylacetoacetic aciduria AR 31 95 ACSF3 Combined malonic and methylmalonic aciduria AR 18 22 ADK Hypermethioninemia due to adenosine kinase deficiency AR 6 14 AHCY Hypermethioninemia with S-adenosylhomocysteine hydrolase deficiency AR 3 9 AMN Megaloblastic anemia-1, Norwegian AR 29 34 https://blueprintgenetics.com/ BCKDHA Maple syrup urine disease AR 57 98 BCKDHB Maple syrup urine disease AR 87 103 BCS1L Bjornstad syndrome, GRACILE syndrome, Leigh syndrome, Mitochondrial AR 42 37 complex III deficiency, nuclear type 1 CBS Homocystinuria due to cystathionine beta-synthase deficiency AR 88 205 CD320 Methylmalonic aciduria due to transcobalamin receptor defect AR 2 CLPB 3-methylglutaconic aciduria with cataracts, neurologic involvement, and AR 26 25 neutropenia (MEGCANN) CTH Cystathioninuria AR 5 9 CUBN* Megaloblastic anemia-1, Finnish AR 42 53 D2HGDH D-2-hydroxyglutaric aciduria 1 AR 13 33 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 FLAD1 Lipid storage myopathy due to FLAD1 deficiency (LSMFLAD) AR 9 10 GCDH Glutaric aciduria AR 90 241 GIF Intrinsic factor deficiency AR 7 22 GNMT Glycine N-methyltransferase deficiency AR 3 5 HCFC1 Combined methylmalonic acidemia and hyperhomocysteinemia XL 9 17 HIBCH 3-hydroxyisobutryl-CoA hydrolase deficiency AR 18 16 HMGCL 3-hydroxy-3-methylglutaryl-CoA lyase deficiency AR 24 60 IDH2 D-2-hydroxyglutaric aciduria 2 AD 10 4 IVD Isovaleric acidemia AR 51 90 L2HGDH L-2-hydroxyglutaric aciduria AR 15 79 LMBRD1 Methylmalonic aciduria and homocystinuria AR 4 9 MCCC1 3-Methylcrotonyl-CoA carboxylase 1 deficiency AR 40 105 MCCC2 3-Methylcrotonyl-CoA carboxylase 2 deficiency AR 24 114 MCEE Methylmalonyl-CoA epimerase deficiency AR 1 4 MLYCD Malonyl-CoA decarboxylase deficiency AR 14 38 MMAA Methylmalonic acidemia AR 61 75 https://blueprintgenetics.com/ MMAB Methylmalonic acidemia AR 31 40 MMACHC Methylmalonic aciduria and homocystinuria AR 59 93 MMADHC Methylmalonic aciduria and homocystinuria AR 16 13 MTHFR Homocystinuria due to MTHFR deficiency AR 65 122 MTR Methylmalonic acidemia AR 13 43 MTRR Homocystinuria-megaloblastic anemia, cobalamin E AR 10 31 MUT Methylmalonic acidemia due to methylmalonyl-CoA mutase deficiency AR 159 366 PCCA Propionic acidemia AR 66 125 PCCB Propionic acidemia AR 68 115 PEPD Prolidase deficiency AR 12 31 SERAC1 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like AR 22 52 syndrome SLC25A1 Combined D-2- and L-2-hydroxyglutaric aciduria AR 8 24 SUCLA2 Mitochondrial DNA depletion syndrome AR 9 29 SUCLG1 Mitochondrial DNA depletion syndrome AR 12 28 SUGCT Glutaric aciduria III AR 6 7 TCN2 Transcobalamin II deficiency AR 9 35 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 ACAT1 Chr11:108004534 c.121-13T>A NM_000019.3 AMN Chr14:103395424 c.514-34G>A NM_030943.3 rs144077391 https://blueprintgenetics.com/ AMN Chr14:103396444 c.1007-31_1006+34delCCTCGCCCCGCCGCG NM_030943.3 rs386834161 AMN Chr14:103396458 c.1007-29_1006+36delTCGCCCCGCCGCGGG NM_030943.3 rs386834162 BCKDHA Chr19:41930736 c.*223T>A NM_000709.3 rs373164531 BCS1L Chr2:219524871 c.-147A>G NM_004328.4 BCS1L Chr2:219525123 c.-50+155T>A NM_004328.4 rs386833855 CBS Chr21:44496326 c.-86_-85+8delAGGTAGAAGA NM_001178008.1 CUBN Chr10:17088532 c.3330-439C>G NM_001081.3 rs386833782 D2HGDH Chr2:242680425 c.293-23A>G NM_152783.3 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 GCDH Chr19:13010271 c.1244-11A>G NM_000159.3 HCFC1 ChrX:153237261 c.-970T>C NM_005334.2 rs398122908 L2HGDH Chr14:50735527 c.906+354G>A NM_024884.2 MCCC2 Chr5:70898313 c.384-20A>G NM_022132.4 rs770917710 MCCC2 Chr5:70939634 c.1073-12C>G NM_022132.4 rs1280511914 MCEE Chr2:71337896 c.379-644A>G NM_032601.3 MLYCD Chr16:83948547 c.949-14A>G NM_012213.2 rs761146008 MTHFR Chr1:11850973 c.1753-18G>A NM_005957.4 rs777661576 MTHFR Chr1:11863212 c.-13-28_-13-27delCT NM_005957.4 rs786204005 MTR Chr1:236971838 c.340-166A>G NM_000254.2 MTR Chr1:236977232 c.609+1088G>A NM_000254.2 rs752526782 MTR Chr1:237057461 c.3205-196A>G NM_000254.2 rs544410324 MTRR Chr5:7883859 c.984+469T>C NM_024010.2 MUT Chr6:49427219 c.-39-1G>A NM_000255.3 PCCA Chr13:100958030 c.1285-1416A>G NM_000282.3 PCCB Chr3:136003251 c.714+462A>G NM_001178014.1 SERAC1 Chr6:158576548 c.92-165C>T NM_032861.3 SERAC1 Chr6:158576622 c.92-239G>C NM_032861.3 TCN2 Chr22:31011112 c.581-176A>G NM_000355.3 rs372866837 TCN2 Chr22:31011112 c.581-176A>T NM_000355.3 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
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