Hyperammonemia and Urea Cycle Disorder Panel

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

Test code: ME1601

The Blueprint Genetics Hyperammonemia and Urea Cycle Disorder Panel is a 45 gene test for genetic diagnostics of patients with clinical suspicion of disorder of urea cycle metabolism or ornithine transcarbamylase deficiency.

The most common urea cycle disorder, ornithine transcarbamylase OTC deficiency, is inherited in X-linked recessive manner. Deficiencies of CPS1, ASS1, ASL, NAGS and ARG are inherited in autosomal recessive manner. The diagnostic yield ranges from 50% to 80% for different primary urea cycle disorders. In addition to congenital urea cycle disorders, this Panel has good differential diagnostics power to other diseases of early phase hyperammonemia and other inborn errors of metabolism showing similar and overlapping symptoms. These include deficiencies such as organic acidemias and fatty acid oxidation disorders. In addition, rare syndroms, such as hyperornithinemia-hyperammonemia-homocitrullinuria syndrome and citrin deficiency with hyperammonia symptoms are diagnosed with this Panel. This Panel is included in the Comprehensive Metabolism Panel.

About Hyperammonemia and Urea Cycle Disorder

Congenital urea cycle disorders are medical defects in the metabolism of nitrogen waste. Deficiency of any of the enzymes in the urea cycle results in 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, urea cycle is distrubed. Infants with defects in the urea cycle develop cerebral edema, lethargy, hypothermia, neurologic sings and coma, usually rapidly after birth. Also partial, or milder, deficiencies are possible, if defective enzyme is positioned in a later phase of the urea cycle. Patients with these kind of diseases face hyperammonium later in life, triggered often 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 other specific urea cycle disorders are 1:200 000 for ASL and ASS1 deficiencies and <1:1 000 000 for ARG1, CPS1 and NAGS deficiencies.


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: http://blueprintgenetics.com/faqs/#prenatal

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 84 166
ACADS Acyl-CoA dehydrogenase, short-chain, deficiency AR 50 81
ACADVL Acyl-CoA dehydrogenase, very long chain, deficiency AR 94 260
ARG1 Hyperargininemia AR 16 54
ASL Argininosuccinic aciduria AR 35 153
ASS1 Citrullinemia AR 52 153
BCKDHA Maple syrup urine disease AR 42 91
BCKDHB Maple syrup urine disease AR 65 94
CPS1 Carbamoylphosphate synthetase I deficiency AR 19 261
CPT1A Carnitine palmitoyltransferase deficiency AR 49 46
CPT2 Carnitine palmitoyltransferase II deficiency AR 47 104
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
GLUD1* Hyperammonemia-hyperinsulinism, Hyperinsulinemic hypoglycemia AD/AR 13 38
HADHA Trifunctional protein deficiency, Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency AR 42 68
HADHB Trifunctional protein deficiency AR 17 57
HCFC1 Combined methylmalonic acidemia and hyperhomocysteinemia XL 8 16
HLCS Holocarboxylase synthetase deficiency AR 21 47
HMGCL 3-hydroxy-3-methylglutaryl-CoA lyase deficiency AR 9 58
HMGCS2 3-hydroxy-3-methylglutaryl-CoA synthase 2 deficiency AR 8 27
IVD Isovaleric acidemia AR 33 81
MCCC1 3-Methylcrotonyl-CoA carboxylase 1 deficiency AR 25 103
MCCC2 3-Methylcrotonyl-CoA carboxylase 2 deficiency AR 19 113
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
MUT Methylmalonic acidemia due to methylmalonyl-CoA mutase deficiency AR 101 339
NAGS N-acetylglutamate synthase deficiency AR 11 45
OAT Gyrate atrophy of choroid and retina AR 63 70
OTC Ornithine transcarbamylase deficiency XL 331 502
PC Pyruvate carboxylase deficiency AR 29 39
PCCA Propionic acidemia AR 43 120
PCCB Propionic acidemia AR 40 111
SLC7A7 Lysinuric protein intolerance AR 52 66
SLC22A5 Carnitine deficiency, systemic primary AR 76 117
SLC25A13 Citrin deficiency AR 23 109
SLC25A15* Hyperornithinemia-hyperammonemia-homocitrullinemia syndrome AR 21 36
SLC25A20 Carnitine-acylcarnitine translocase deficiency AR 11 41
SUCLA2 Mitochondrial DNA depletion syndrome AR 8 27
SUCLG1 Mitochondrial DNA depletion syndrome AR 11 28
TMEM70 Mitochondrial complex V (ATP synthase) deficiency AR 10 18

*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 (http://www.ncbi.nlm.nih.gov/clinvar/); HGMD, refers to a number of variants with possible disease association in the gene listed in Human Gene Mutation Database (HGMD, http://www.hgmd.cf.ac.uk/ac/). The list of associated (gene specific) phenotypes are generated from CDG (http://research.nhgri.nih.gov/CGD/) or Orphanet (http://www.orpha.net/) databases.

Gene Genomic location HG19 HGVS RefSeq RS-number
ACADM Chr1:76211473 c.600-18G>A NM_000016.4 rs370523609
ASS1 Chr9:133355236 c.773+49C>T NM_000050.4 rs763389916
DBT Chr1:100672742 c.1018-550A>G NM_001918.3 rs796052135
HCFC1 ChrX:153237261 c.-970T>C NM_005334.2 rs398122908
MUT Chr6:49427219 c.-39-1G>A NM_000255.3

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 Hyperammonemia and Urea Cycle Disorder Panel that covers classical genes associated with citrin deficiency, disorder of urea cycle metabolism, fatty acid oxidation disorder, hyperornithinemia-hyperammonemia-homocitrullinuria syndrome, organic acidemias and ornithine transcarbamylase deficiency. 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 (http://www.1000genomes.org), the NHLBI GO Exome Sequencing Project (ESP; http://evs.gs.washington.edu/EVS), the Exome Aggregation Consortium (ExAC; http://exac.broadinstitute.org), ClinVar database of genotype-phenotype associations (http://www.ncbi.nlm.nih.gov/clinvar) and the Human Gene Mutation Database (http://www.hgmd.cf.ac.uk). The consequence of variants in coding and splice regions are estimated using the following in silico variant prediction tools: SIFT (http://sift.jcvi.org), Polyphen (http://genetics.bwh.harvard.edu/pph2/), and Mutation Taster (http://www.mutationtaster.org).

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 Hyperammonemia and Urea Cycle Disorder Panel

ICD-10 Disease
E72.20 Disorder of urea cycle metabolism
E72.4 Ornithine transcarbamylase deficiency

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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