Dihydropyrimidinase deficiency via the DPYS Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
8469 DPYS 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
8469DPYS81479 81479 $890 Order Options and Pricing

Pricing Comments

Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information.

A 25% additional charge will be applied to STAT orders. View STAT turnaround times here.

For Reflex to PGxome pricing click here.

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing click here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

Turnaround Time

18 days on average

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

Dihydropyrimidinase (DHP) deficiency is an inherited error in pyrimidine metabolism that results in dihydropyrimidinuria. Dihydropyrimidinase is the second enzyme in the 3-step catabolic pathway of uracil and thymine. It catalyzes the hydrolytic cleavages of dihydropyrimidines (5,6-dihydrouracil and 5,6-dihydrothymine) which creates intermediate metabolites that are processed further to β-alanine and β-aminoisobutyric acid. Patients may have elevated uracil, thymine, dihydrouracil, and dihydrothymine while β-alanine and β-aminoisobutyric acid will be low or undetectable. Most patients with complete DHP deficiency have neurological symptoms ranging from developmental delay, intellectual disability, seizures, hypotonia, and autism (van Kuilenburg et al. 2007; van Kuilenburg et al. 2010; Yeung et al. 2013). Other clinical features include dysmorphic features, failure to thrive, and gastrointestinal problems. Phenotypic variability is common, and some patients with DHP deficiency may even by asymptomatic (van Kuilenburg et al. 2010).

Irrespective of manifestation of symptoms, DHP-deficient patients are vulnerable to a potentially life-threatening toxic reaction to the fluoropyrimidine type of anti-cancer agents such as 5-fluorouracil (5-FU). Dihydropyrimidinase (DHP) is the second enzyme in the catabolism of 5-fluorouracil (5FU). Symptoms included stomatitis, leukopenia, thrombocytopenia, hair loss, diarrhea, fever, marked weight loss, cerebellar ataxia, and neurologic symptoms (Fidlerova et al. 2012). Although DHP deficiency is inherited in an autosomal recessive manner, 5-FU toxicity has been widely found in individuals with one mutated allele of the DPYS gene (Fidlerova et al. 2010; van Kuilenburg et al. 2003; Thomas et al. 2007). Since genotype-phenotype correlations are yet unclear, routine DPH testing to anticipate 5-FU associated toxicities is still lacking in consensus (Ciccolini et al. 2010; van Kuilenburg 2006; Yen and McLeod 2007). Therefore, this testing is NOT for complete risk evaluation of DPYS-associated fluoropyrimidine toxicities.

Genetics

DHP deficiency is an autosomal recessive disorder caused by pathogenic variants in the DPYS gene, which has 9 coding exons that encode the dihydropyrimidinase protein. The native enzyme is a tetramer with molecular weight of 217 kDa consisting of four subunits of 54 kDa each (Webster et al. 2014). DPH is a metalloenzyme containing one zinc atom in each subunit. In the largest study of DHP deficient patients, ~70% of pathogenic variants were located in exons 5-8 (van Kuilenburg et al. 2010). The majority of pathogenic variants are missense; however, nonsense and small deletions/insertions have also been reported (Human Gene Mutation Database).

Testing Strategy

This test provides full coverage of all coding exons of the DPYS gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).

Clinical Sensitivity - Sequencing with CNV PGxome

In the largest studied cohort of patients suspected of dihydropyrimidinase deficiency (metabolic profile and clinical features of DHP deficiency), all 17 (100%) patients were found to be homozygous or compound heterozygous for pathogenic variants (van Kuilenburg et al. 2010). Analytical sensitivity should be close to 100% because all reported pathogenic variants are detectable by sequencing.

Indications for Test

Candidates for this test are patients with elevated levels of dihydropyrimidines in urine, plasma, and CSF. Testing is also indicated for family members of patients who have known DPYS pathogenic variants. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in DPYS.

Gene

Official Gene Symbol OMIM ID
DPYS 613326
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Dihydropyrimidinase Deficiency AR 222748

Citations

  • Ciccolini J, Gross E, Dahan L, Lacarelle B, Mercier C. 2010. Routine dihydropyrimidine dehydrogenase testing for anticipating 5-fluorouracil-related severe toxicities: hype or hope? Clin Colorectal Cancer 9: 224–228. PubMed ID: 20920994
  • Fidlerova J, Kleiblova P, Bilek M, Kormunda S, Formankova Z, Novotny J, Kleibl Z. 2010. Contribution of dihydropyrimidinase gene alterations to the development of serious toxicity in fluoropyrimidine-treated cancer patients. Cancer Chemother. Pharmacol. 65: 661–669. PubMed ID: 19649633
  • Fidlerova J, Kleiblova P, Kormunda S, Novotny J, Kleibl Z. 2012. Contribution of the β-ureidopropionase (UPB1) gene alterations to the development of fluoropyrimidine-related toxicity. Pharmacol Rep 64: 1234–1242. PubMed ID: 23238479
  • Human Gene Mutation Database (Bio-base).
  • Thomas HR, Ezzeldin HH, Guarcello V, Mattison LK, Fridley BL, Diasio RB. 2007. Genetic regulation of dihydropyrimidinase and its possible implication in altered uracil catabolism. Pharmacogenet. Genomics 17: 973–987. PubMed ID: 18075467
  • van Kuilenburg ABP, Dobritzsch D, Meijer J, Meinsma R, Benoist J-F, Assmann B, Schubert S, Hoffmann GF, Duran M, Vries van MC de, Kurlemann G, Eyskens FJM, Greed L, Sass JO, Schwab KO, Sewell AC, Walter J, Hahn A, Zoetekouw L, Ribes A, Lind S, Hennekam RC. 2010. Dihydropyrimidinase deficiency: Phenotype, genotype and structural consequences in 17 patients. Biochim. Biophys. Acta 1802: 639–648. PubMed ID: 20362666
  • van Kuilenburg ABP, Meijer J, Dobritzsch D, Meinsma R, Duran M, Lohkamp B, Zoetekouw L, Abeling NGGM, Tinteren HLG van, Bosch AM. 2007. Clinical, biochemical and genetic findings in two siblings with a dihydropyrimidinase deficiency. Mol. Genet. Metab. 91: 157–164. PubMed ID: 17383919
  • van Kuilenburg ABP, Meinsma R, Zonnenberg BA, Zoetekouw L, Baas F, Matsuda K, Tamaki N, Gennip AH van. 2003. Dihydropyrimidinase Deficiency and Severe 5-Fluorouracil Toxicity. Clin Cancer Res 9: 4363–4367. PubMed ID: 14555507
  • van Kuilenburg ABP. 2006. Screening for dihydropyrimidine dehydrogenase deficiency: to do or not to do, that’s the question. Cancer Invest. 24: 215–217. PubMed ID: 16537192
  • Webster, Dianne R., et al. "Hereditary Orotic Aciduria and Other Disorders of Pyrimidine Metabolism." . Eds. David Valle, et al. New York, NY: McGraw-Hill, 2014. n. pag. OMMBID. Web. 26 May 2015
  • Yen JL, McLeod HL. 2007. Should DPD analysis be required prior to prescribing fluoropyrimidines? Eur. J. Cancer 43: 1011-1016. PubMed ID: 17350823
  • Yeung CW, Yau MM, Ma CK, Siu TS, Tam S, Lam CW. 2013. Diagnosis of dihydropyrimidinase deficiency in a Chinese boy with dihydropyrimidinuria. Hong Kong Med J 19: 272–275. PubMed ID: 23732435

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

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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.

For Requisition Forms, visit our Forms page


Specimen Types

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