Orotic Aciduria via the UMPS Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
1430 UMPS$750.00 81479 Add to Order
Targeted Testing

For ordering targeted known variants, please proceed to our Targeted Variants landing page.

Turnaround Time

The great majority of tests are completed within 18 days.

Clinical Sensitivity

The sensitivity of this test is currently unknown, as comprehensive assessments of sensitivity using direct sequencing methods have not been cited in the published literature for this extremely rare disorder.

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 UMPS$690.00 81479 Add to Order
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Turnaround Time

The great majority of tests are completed within 28 days.

Clinical Sensitivity

The sensitivity of duplication/deletion testing for this extremely rare disorder is currently unknown. However, it should be noted that no gross duplications or deletions in the UMPS gene have been published to date (Human Gene Mutation Database).

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Clinical Features

Hereditary orotic aciduria (MIM #258900) is a rare disorder of pyrimidine metabolism characterized by increased excretion of orotic acid in the urine, failure to thrive, and megaloblastic anemia. Hemoglobin levels often are in the 7-8 g/dL range, with hematocrit around 25% (Nyhan et al., 2012). This anemia is unresponsive to supplementation with iron, folate, or vitamin B12 (Huguley et al., 1959). Neutropenia is also present in most patients, with associated increased risk for infections. In the classical presentation, hair is sparse, fine, and very short; nail growth may also be poor. Some patients have been reported to have congenital anomalies, including cardiac malformations and strabismus (Van Kuilenburg et al., 2012). 

Orotic acid crystals may be visualized in the urine via microscopy, and crystalluria may lead to gross or microscopic hematuria (Nyhan et al., 2012). The amount of orotic acid excreted by affected infants may be as high as 1000 times the normal adult mean, while orotidine excretion may also be elevated, but markedly less so (Sumi et al., 1997). Activities of aspartate transcarbamylase and dihydroorotase, two enzymes which occur earlier in the biochemical pathway, are also usually elevated. 

Orotic aciduria represents pyrimidine nucleotide starvation in man. Impaired intellectual development has been observed in some patients. However, treatment in the form of oral uridine supplementation allows for remission (Nyhan et al., 2012; Van Kuilenburg et al., 2012). Dietary therapy leads to hematologic response, weight gain, increased activity levels, and improvement in overall well-being.


Hereditary orotic aciduria is caused by deficiency of uridine monophosphate (UMP) synthase. This enzyme is bifunctional in nature and catalyzes the last two steps in the de novo pyrimidine biosynthetic pathway. The enzyme’s two independent catalytic activities include orotate phosphoribosyltransferase (OPRT), which converts orotic acid to orotidine-5’-monophospate (OMP), and orotidine-5’-monophospate decarboxylase (ODC), which decraboxylates OMP to uridine monophosphate (UMP).

Hereditary orotic aciduria is extremely rare, with approximately 20 reported cases to date. The disorder shows autosomal recessive inheritance and is not confined to any particular ethnic group. The vast majority of affected patients have deficiency of both OPRT and ODC catalytic activities and were formerly classified as having Type I hereditary orotic aciduria (OMIM #258900). However, there is at least one reported individual who was found to have deficiency of ODC catalytic activity with normal to increased expression of OPRT. This individual was categorized as having Type II hereditary orotic aciduria (formerly reported under OMIM #258920). At present, all cases of hereditary orotic aciduria, regardless of type, are reported under OMIM #258900.

Mutations within the UMPS gene (OMIM 613891) are the only known cause of orotic aciduria.  The gene is located on chromosome 3q13, consists of 6 exons, and encodes a protein that is 480 amino acids in length (Suchi et al., 1997).  While the first 214 amino acids found in the N-terminus contain OPRT, the last 258 amino acids at the C-terminus contain OMP decarboxylase (Suttle et al., 1988). Missense mutations which lead to amino acid substitutions are a common cause of disease; such mutations are known to decrease steady-state levels of the enzyme, impair substrate binding, and reduce catalytic efficiency (Perry et al., 1989; Winkler et al, 1988; Suchi et al., 1997).

Testing Strategy

Bidirectional Sanger sequencing of all six UMPS coding exons plus ~ 20 bp of flanking non-coding intronic DNA on either side of each exon is performed using genomic DNA. We will also sequence any single exon (Test #100) or pair of exons (Test #200) in family members of patients with known mutations or to confirm research results.

Indications for Test

Candidates for this test are patients with hereditary orotic aciduria and family members of patients who have known UMPS mutations. In addition, patients with orotic aciduria and megaloblastic anemia who are suspected to have UMP synthase deficiency also are candidates.


Official Gene Symbol OMIM ID
UMPS 613891
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
Orotic Aciduria 258900


Genetic Counselors
  • Huguley, CM Jr, Bain,  JA, Rivers, SL, Scoggins, al. 1959. Refractory megaloblastic anemia associated with excretion of orotic acid.  Blood. 14:615-634. PubMed ID: 13651334
  • Human Gene Mutation Database (Bio-base).
  • Nyhan, WL et al. 2012. Orotic aciduria. In: Atlas of Inherited Metabolic Disease (3rd Edition). London:  Hodder Arnold Co. Chapter 69:518-521. 
  • Perry, ME, Jones, M.E. 1989. Orotic aciduria fibroblasts express a labile form of UMP synthase. J. Biol. Chem. 264:15522-15528 PubMed ID: 2475503
  • Suchi, M, Mizuno, H, Kawai, Y, Tsuboi, T, Sumi, S, Okajima, K, Hodgson, ME, Ogawa, H, Wada, Y. 1997. Molecular cloning of the human UMP synthase gene and characterization of point mutations in two hereditary orotic aciduria families. Am. J. Hum. Genet. 60:525-539. PubMed ID: 9042911
  • Sumi, S, Suchi, M, Kidouchi, K, Morishita, H, Ohba, S, Wada, Y. et al. 1997. Pyrimidine metabolism in hereditary orotic aciduria. J. Inherit. Metab. Dis. 20: 104-105. PubMed ID: 9061575
  • Suttle, DP, Bugg, BY, Winkler, JK, Kanalas, JJ.. 1988. Molecular cloning and nucleotide sequence for the complete coding region of human UMP synthase. Proc. Natl. Acad. Sci. U. S. A. 85:1754-1758. PubMed ID: 3279416
  • Van Kuilenburg, A.B.P. et al. 2012. Hereditary Orotic Aciduria and Other Disorders of Pyrimidine Metabolism.  In: The Online Metabolic and Molecular Bases of Inherited Disease. Part 11, Chapter 113.
  • Winkler, JK, Suttle, DP. 1988. Analysis of UMP synthase gene and mRNA structure in hereditary orotic aciduria fibroblasts. Am. J. Hum. Genet. 43:86-94. PubMed ID: 2837086
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Bi-Directional Sanger Sequencing

Test Procedure

Nomenclature for sequence variants was from the Human Genome Variation Society (  As required, DNA is extracted from the patient specimen.  PCR is used to amplify the indicated exons plus additional flanking non-coding sequence.  After cleaning of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit.  Products are resolved by electrophoresis on an ABI 3730xl capillary sequencer.  In most cases, sequencing is performed in both forward and reverse directions; in some cases, sequencing is performed twice in either the forward or reverse directions.  In nearly all cases, the full coding region of each exon as well as 20 bases of non-coding DNA flanking the exon are sequenced.

Analytical Validity

As of March 2016, we compared 17.37 Mb of Sanger DNA sequence generated at PreventionGenetics to NextGen sequence generated in other labs. We detected only 4 errors in our Sanger sequences, and these were all due to allele dropout during PCR. For Proficiency Testing, both external and internal, in the 12 years of our lab operation we have Sanger sequenced roughly 8,800 PCR amplicons. Only one error has been identified, and this was due to sequence analysis error.

Our Sanger sequencing is capable of detecting virtually all nucleotide substitutions within the PCR amplicons. Similarly, we detect essentially all heterozygous or homozygous deletions within the amplicons. Homozygous deletions which overlap one or more PCR primer annealing sites are detectable as PCR failure. Heterozygous deletions which overlap one or more PCR primer annealing sites are usually not detected (see Analytical Limitations). All heterozygous insertions within the amplicons up to about 100 nucleotides in length appear to be detectable. Larger heterozygous insertions may not be detected. All homozygous insertions within the amplicons up to about 300 nucleotides in length appear to be detectable. Larger homozygous insertions may masquerade as homozygous deletions (PCR failure).

Analytical Limitations

In exons where our sequencing did not reveal any variation between the two alleles, we cannot be certain that we were able to PCR amplify both of the patient’s alleles. Occasionally, a patient may carry an allele which does not amplify, due for example to a deletion or a large insertion. In these cases, the report contains no information about the second allele.

Similarly, our sequencing tests have almost no power to detect duplications, triplications, etc. of the gene sequences.

In most cases, only the indicated exons and roughly 20 bp of flanking non-coding sequence on each side are analyzed. Test reports contain little or no information about other portions of the gene, including many regulatory regions.

In nearly all cases, we are unable to determine the phase of sequence variants. In particular, when we find two likely causative mutations for recessive disorders, we cannot be certain that the mutations are on different alleles.

Our ability to detect minor sequence variants, due for example to somatic mosaicism is limited. Sequence variants that are present in less than 50% of the patient’s nucleated cells may not be detected.

Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during PCR and cycle sequencing.

Unless otherwise indicated, the sequence data that we report are based on DNA isolated from a specific tissue (usually leukocytes). Test reports contain no information about gene sequences in other tissues.

Deletion/Duplication Testing via Array Comparative Genomic Hybridization

Test Procedure

Equal amounts of genomic DNA from the patient and a gender matched reference sample are amplified and labeled with Cy3 and Cy5 dyes, respectively. To prevent any sample cross contamination, a unique sample tracking control is added into each patient sample. Each labeled patient product is then purified, quantified, and combined with the same amount of reference product. The combined sample is loaded onto the designed array and hybridized for at least 22-42 hours at 65°C. Arrays are then washed and scanned immediately with 2.5 µM resolution. Only data for the gene(s) of interest for each patient are extracted and analyzed.

Analytical Validity

PreventionGenetics' high density gene-centric custom designed aCGH enables the detection of relatively small deletions and duplications within a single exon of a given gene or deletions and duplications encompassing the entire gene. PreventionGenetics has established and verified this test's accuracy and precision.

Analytical Limitations

Our dense probe coverage may allow detection of deletions/duplications down to 100 bp; however due to limitations and probe spacing this cannot be guaranteed across all exons of all genes. Therefore, some copy number changes smaller than 100-300 bp within a targeted large exon may not be detected by our array.

This array may not detect deletions and duplications present at low levels of mosaicism or those present in genes that have pseudogene copies or repeats elsewhere in the genome.

aCGH will not detect balanced translocations, inversions, or point mutations that may be responsible for the clinical phenotype.

Breakpoints, if occurring outside the targeted gene, may be hard to define.

The sensitivity of this assay may be reduced when DNA is extracted by an outside laboratory.

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Ordering Options

myPrevent - Online Ordering
  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.


(Delivery accepted Monday - Saturday)

  • Collect 3 ml -5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10 ml -20 ml of whole blood.
  • For small babies, we require a minimum of 1 ml of blood.
  • Only one blood tube is required for multiple tests.
  • Ship blood tubes at room temperature in an insulated container. Do not freeze blood.
  • During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube.
  • In cold weather, include an unfrozen ice pack in the shipping container as insulation.
  • At room temperature, blood specimen is stable for up to 48 hours.
  • If refrigerated, blood specimen is stable for up to one week.
  • Label the tube with the patient name, date of birth and/or ID number.


(Delivery accepted Monday - Saturday)

  • Send in screw cap tube at least 5 µg -10 µg of purified DNA at a concentration of at least 20 µg/ml for NGS and Sanger tests and at least 5 µg of purified DNA at a concentration of at least 100 µg/ml for gene-centric aCGH, MLPA, and CMA tests, minimum 2 µg for limited specimens.
  • For requests requiring more than one test, send an additional 5 µg DNA per test ordered when possible.
  • DNA may be shipped at room temperature.
  • Label the tube with the composition of the solute, DNA concentration as well as the patient’s name, date of birth, and/or ID number.
  • We only accept genomic DNA for testing. We do NOT accept products of whole genome amplification reactions or other amplification reactions.


(Delivery preferred Monday - Thursday)

  • PreventionGenetics should be notified in advance of arrival of a cell culture.
  • Culture and send at least two T25 flasks of confluent cells.
  • Some panels may require additional flasks (dependent on size of genes, amount of Sanger sequencing required, etc.). Multiple test requests may also require additional flasks. Please contact us for details.
  • Send specimens in insulated, shatterproof container overnight.
  • Cell cultures may be shipped at room temperature or refrigerated.
  • Label the flasks with the patient name, date of birth, and/or ID number.
  • We strongly recommend maintaining a local back-up culture. We do not culture cells.
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