Organic Acidemia/Aciduria & Cobalamin Deficiency Panel

  • bpg-method PLUS
  • bpg-method SEQ
  • bpg-method DEL/DUP

Test code: ME0901

The Blueprint Genetics Organic Acidemia/Aciduria & Cobalamin Deficiency Panel is a 32 gene test for genetic diagnostics of patients with clinical suspicion of cobalamin deficiency, homocystinuria, maple syrup urine disease, methylmalonic acidemia, organic acidemia/aciduria or propionic acidemia.

All disorders of organic acidemia/aciduria and cobalamin metabolism are inherited in an autosomal recessive manner. This Panel is 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 excreated in urine. Usually this is a result of a deficient enzyme activity in amino acid catabolism. The clinical presentation of organic acidemia in young child 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 often result from the accumulation of precursors of the defective pathway. The combined prevalence of organic acidurias is estimated at 1:1000 newborns. Cobalamin is vitamin B12. This vitamin has cobalt in its structure. Humans are not able to synthesize B12 vitamin but it needs to be obtained from a food of animal origin that is the only natural source of cobalamin in 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 mutation 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 alone circa 80% of the cases with intracellular cobalamin deficiency, followed by MMADHC (<5%), MTRR (<5%), LMBRD1 (<5%), MTR (<5%) and ABCD4 (<1%). Clinical manifestation of cobalamin deficiency can have an onset already in perinatal period or later during childhood or adulthood. Symptoms seen also have a wide range, based on the complementation group and defective gene. Perinatal manifestations often include growth retardation, microcephaly, heart diseases and dysmorhic features. Infantile 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 predisposes often to neurological and neuropsychiatric problems. Some specific types of cobalamin deficiencies are extreme rare with only dozens of patients described. The combined prevalence is estimated at >1:100 000.


Results in 3-4 weeks. We do not offer a maternal cell contamination (MCC) test at the moment. We offer prenatal testing only for cases where the maternal cell contamination studies (MCC) are done by a local genetic laboratory. Read more:

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 5 7
ACAT1 Alpha-methylacetoacetic aciduria AR 32 76
ACSF3 Combined malonic and methylmalonic aciduria AR 19 19
BCKDHA Maple syrup urine disease AR 42 91
BCKDHB Maple syrup urine disease AR 65 94
CBS Homocystinuria due to cystathionine beta-synthase deficiency AR 69 187
CD320 Methylmalonic aciduria due to transcobalamin receptor defect AR
DBT Maple syrup urine disease AR 32 71
DLD Dihydrolipoyl dehydrogenase deficiency AR 24 21
ETFA Glutaric aciduria, Multiple acyl-CoA dehydrogenase deficiency AR 8 27
ETFB Glutaric aciduria, Multiple acyl-CoA dehydrogenase deficiency AR 6 14
ETFDH Glutaric aciduria, Multiple acyl-CoA dehydrogenase deficiency AR 37 169
GCDH Glutaric aciduria AR 64 205
GIF Intrinsic factor deficiency AR 7 20
HCFC1 Combined methylmalonic acidemia and hyperhomocysteinemia XL 8 16
HMGCL 3-hydroxy-3-methylglutaryl-CoA lyase deficiency AR 9 58
IVD Isovaleric acidemia AR 33 81
LMBRD1 Methylmalonic aciduria and homocystinuria AR 3 9
MCCC1 3-Methylcrotonyl-CoA carboxylase 1 deficiency AR 25 103
MCCC2 3-Methylcrotonyl-CoA carboxylase 2 deficiency AR 19 113
MCEE Methylmalonyl-CoA epimerase deficiency AR 2 4
MMAA Methylmalonic acidemia AR 41 53
MMAB Methylmalonic acidemia AR 22 39
MMACHC Methylmalonic aciduria and homocystinuria AR 26 91
MMADHC Methylmalonic aciduria and homocystinuria AR 15 13
MTHFR Homocystinuria due to MTHFR deficiency AR 57 119
MTR Methylmalonic acidemia AR 12 40
MTRR Homocystinuria-megaloblastic anemia, cobalamin E AR 8 30
MUT Methylmalonic acidemia due to methylmalonyl-CoA mutase deficiency AR 101 339
PCCA Propionic acidemia AR 43 120
PCCB Propionic acidemia AR 40 111
TCN2 Transcobalamin II deficiency AR 8 33

*Some regions of the gene are duplicated in the genome leading to limited sensitivity within the regions. Thus, low-quality variants are filtered out from the duplicated regions and only high-quality variants confirmed by other methods are reported out. Read more.

Gene, refers to HGNC approved gene symbol; Inheritance to inheritance patterns such as autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL); ClinVar, refers to a number of variants in the gene classified as pathogenic or likely pathogenic in ClinVar (; HGMD, refers to a 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 CDG ( or Orphanet ( databases.

Gene Genomic location HG19 HGVS RefSeq RS-number
DBT Chr1:100672742 c.1018-550A>G NM_001918.3 rs796052135
HCFC1 ChrX:153237261 c.-970T>C NM_005334.2 rs398122908
MTHFR Chr1:11863212 c.-13-28_-13-27delCT NM_005957.4 rs786204005
MTHFR Chr1:11850973 c.1753-18G>A NM_005957.4 rs777661576
MUT Chr6:49427219 c.-39-1G>A NM_000255.3
TCN2 Chr22:31011112 c.581-176A>G NM_000355.3 rs372866837

The strengths of this test include:

  • Blueprint Genetics is one of the few laboratories worldwide with CAP and ISO-15189 accreditation for NGS panels and CLIA certification
  • Superior sequencing quality
  • Careful selection of genes based on current literature, our experience and the most current mutation databases
  • Transparent and easy access to quality and performance data at the patient level that are accessible via our Nucleus portal
  • Transparent and reproducible analytical validation for each panel (see Test performance section; for complete details, see our Analytic Validation)
  • Sequencing and high resolution del/dup analysis available in one test
  • Inclusion of non-coding disease causing variants where clinically indicated (please see individual Panel descriptions)
  • Interpretation of variants following ACMG variant classification guidelines
  • Comprehensive clinical statement co-written by a PhD geneticist and a clinician specialist


This test does not detect the following:

  • Complex inversions
  • Gene conversions
  • Balanced translocations
  • Mitochondrial DNA variants
  • Variants in regulatory or non-coding regions of the gene unless otherwise indicated (please see Non-coding disease causing variants covered by the panel). This mean for instance intronic variants locating deeper than 15 nucleotides from the exon-intron boundary.


This test may not reliably detect the following:

  • Low level mosaicism
  • Stretches of mononucleotide repeats
  • Indels larger than 50bp
  • Single exon deletions or duplications
  • Variants within pseudogene regions/duplicated segments
  • Disorders caused by long repetitive sequences (e.g. trinucleotide repeat expansions)


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.

Blueprint Genetics offers a comprehensive Organic Acidemia/Aciduria & Cobalamin Deficiency Panel that covers classical genes associated with cobalamin deficiency, DLD deficiency, homocystinuria, isovaleric acidemia, maple syrup urine disease, methylmalonic acidemia, multiple acyl-CoA dehydrogenase deficiency, organic acidemia/aciduria, propionic acidemia and transcobalamin receptor defect. The genes are carefully selected based on the existing scientific evidence, our experience and most current mutation databases. Candidate genes are excluded from this first-line diagnostic test. The test does not recognise balanced translocations or complex inversions, and it may not detect low-level mosaicism. The test should not be used for analysis of sequence repeats or for diagnosis of disorders caused by mutations in the mitochondrial DNA.

Analytical validation is a continuous process at Blueprint Genetics. Our mission is to improve the quality of the sequencing process and each modification is followed by our standardized validation process. Average sensitivity and specificity in Blueprint NGS Panels is 99.3% and 99.9% for detecting SNPs. Sensitivity to for indels vary depending on the size of the alteration: 1-10bps (96.0%), 11-20 bps (88.4%) and 21-30 bps (66.7%). The longest detected indel was 46 bps by sequence analysis. Detection limit for Del/Dup (CNV) analysis varies through the genome depending on exon size, sequencing coverage and sequence content. The sensitivity is 71.5% for single exon deletions and duplications and 99% for three exons’ deletions and duplications. We have validated the assays for different starting materials including EDTA-blood, isolated DNA (no FFPE) and saliva that all provide high-quality results. The diagnostic yield varies substantially depending on the used assay, referring healthcare professional, hospital and country. Blueprint Genetics’ Plus Analysis (Seq+Del/Dup) maximizes the chance to find molecular genetic diagnosis for your patient although Sequence Analysis or Del/Dup Analysis may be cost-effective first line test if your patient’s phenotype is suggestive for a specific mutation profile.

The sequencing data generated in our laboratory is analyzed with our proprietary data analysis and annotation pipeline, integrating state-of-the art algorithms and industry-standard software solutions. Incorporation of rigorous quality control steps throughout the workflow of the pipeline ensures the consistency, validity and accuracy of results. The highest relevance in the reported variants is achieved through elimination of false positive findings based on variability data for thousands of publicly available human reference sequences and validation against our in-house curated mutation database as well as the most current and relevant human mutation databases. Reference databases currently used are the 1000 Genomes Project (, the NHLBI GO Exome Sequencing Project (ESP;, the Exome Aggregation Consortium (ExAC;, ClinVar database of genotype-phenotype associations ( and the Human Gene Mutation Database ( The consequence of variants in coding and splice regions are estimated using the following in silico variant prediction tools: SIFT (, Polyphen (, and Mutation Taster (

Through our online ordering and statement reporting system, Nucleus, the customer can access specific details of the analysis of the patient. This includes coverage and quality specifications and other relevant information on the analysis. This represents our mission to build fully transparent diagnostics where the customer gains easy access to crucial details of the analysis process.

In addition to our cutting-edge patented sequencing technology and proprietary bioinformatics pipeline, we also provide the customers with the best-informed clinical report on the market. Clinical interpretation requires fundamental clinical and genetic understanding. At Blueprint Genetics our geneticists and clinicians, who together evaluate the results from the sequence analysis pipeline in the context of phenotype information provided in the requisition form, prepare the clinical statement. Our goal is to provide clinically meaningful statements that are understandable for all medical professionals, even without training in genetics.

Variants reported in the statement are always classified using the Blueprint Genetics Variant Classification Scheme modified from the ACMG guidelines (Richards et al. 2015), which has been developed by evaluating existing literature, databases and with thousands of clinical cases analyzed in our laboratory. Variant classification forms the corner stone of clinical interpretation and following patient management decisions. Our statement also includes allele frequencies in reference populations and in silico predictions. We also provide PubMed IDs to the articles or submission numbers to public databases that have been used in the interpretation of the detected variants. In our conclusion, we summarize all the existing information and provide our rationale for the classification of the variant.

A final component of the analysis is the Sanger confirmation of the variants classified as likely pathogenic or pathogenic. This does not only bring confidence to the results obtained by our NGS solution but establishes the mutation specific test for family members. Sanger sequencing is also used occasionally with other variants reported in the statement. In the case of variant of uncertain significance (VUS) we do not recommend risk stratification based on the genetic finding. Furthermore, in the case VUS we do not recommend use of genetic information in patient management or genetic counseling. For some cases Blueprint Genetics offers a special free of charge service to investigate the role of identified VUS.

We constantly follow genetic literature adapting new relevant information and findings to our diagnostics. Relevant novel discoveries can be rapidly translated and adopted into our diagnostics without delay. These processes ensure that our diagnostic panels and clinical statements remain the most up-to-date on the market.

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ICD & CPT codes

CPT codes

SEQ 81479
DEL/DUP 81479

ICD codes

Commonly used ICD-10 codes when ordering the Organic Acidemia/Aciduria & Cobalamin Deficiency Panel

ICD-10 Disease
E71.0 Maple syrup urine disease
E71.121 Propionic acidemia
E72.10 Methylmalonic acidemia
E72.10 Cobalamin deficiency
E72.10 Homocystinuria

Accepted sample types

  • EDTA blood, min. 1 ml
  • Purified DNA, min. 5μg
  • Saliva (Oragene DNA OG-500 kit)

Label the sample tube with your patient’s name, date of birth and the date of sample collection.

Note that we do not accept DNA samples isolated from formalin-fixed paraffin-embedded (FFPE) tissue.

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