PRPS1-Related Disorders

  • 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
1550 PRPS1$680.00 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

Clinical sensitivity cannot be estimated because only a small number of patients for each syndrome have been reported. Analytical sensitivity should be almost 100% because all reported mutations are detectable by sequencing.

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 PRPS1$990.00 81479 Add to Order
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Turnaround Time

The great majority of tests are completed within 20 days.

Clinical Features

Mutations in PRPS1 can result in four syndromes: Phosphoribosylpyrophosphate synthetase (PRPS1) superactivity, Charcot-Marie-Tooth disease-5, Arts syndrome, and X-linked nonsyndromic sensorineural deafness (DFNX1) (de Brouwer et al. 2010).

Gain-of-function missense mutations that cause PRPS1 superactivity can result in gout, uric acid overproduction, neurologic problems, sensorineural hearing loss, and developmental delay (Sperling et al. 1972). Patients may present with a milder phenotype in which uric acid crystalluria and urinary stones are the only findings. In contrast, a severe phenotype seen with infantile or early-childhood onset may present with variable combinations of sensorineural hearing loss, hypotonia, ataxia, and developmental delay (de Brouwer et al. 2013).

Loss-of-function mutations present as Charcot-Marie-Tooth disease-5, Arts syndrome, or DFNX1. Charcot-Marie-Tooth disease-5 presents with optic neuropathy, early-onset sensorineural hearing loss, and peripheral neuropathy (Kim et al. 2007; Kim and Kim 2013). Arts syndrome is characterized by mild to moderate intellectual disability, early-onset hypotonia, ataxia, delayed motor development, hearing impairment, and susceptibility to infections all of which present before two years of age (Arts et al. 1993; de Brouwer et al. 2013). DFNX1 nonsyndromic hearing loss and deafness in males is bilateral, sensorineural, moderate to profound, and prelingual or postlingual (Yuan and Liu 2011). The hearing in female carriers can be normal or abnormal.

Several groups have reported an overlap of symptoms from the described syndromes which is suggestive of a disease spectrum (Moran et al. 2012; Synofzik et al. 2014). The observed phenotypic spectrum results from the specific mutation and degree of residual PRPS1 activity. Males are more severely affected and present at an earlier age, whereas female carriers may be unaffected or have a milder phenotype.

S-adenosylmethionine (SAM) supplementation in patients with Arts syndrome shows promise for alleviating some symptoms of PRPS1 spectrum diseases (de Brouwer et al. 2010).


PRPS1-related syndromes are inherited in an X-linked manner. Female carriers may show isolated and milder manifestations of symptoms which typically become apparent at a later age (García-Pavía et al. 2003; Liu et al. 2010). 100% penetrance in males has been observed. To date, only missense mutations have been reported in PRPS1 (Human Gene Mutation Database).

PRPS1 catalyzes the synthesis of phosphoribosyl pyrophosphate (PRPP) from ATP and ribose-5-phosphate. PRPP is essential for the de novo synthesis of purine, pyrimidine, and pyridine nucleotides. The enzyme activity of PRPS1 is regulated by cofactors, metabolites, and interacting proteins. Gain-of-function mutations alter allosteric sites and disrupt regulation, while loss-of-function mutations are suggested to affect local protein structure or trimer interface. Interestingly, the effect of Val142Leu on protein activity was gain-of-function in proliferating cell types, but loss-of-function in postmitotic cell types (Moran et al. 2012). Missense mutations in PRPS1 can therefore cause a spectrum of clinical features depending on the functional sites that are affected. Mutations have been observed in a variety of ethnic backgrounds.

Testing Strategy

Testing involves PCR amplification from genomic DNA and bidirectional Sanger sequencing of the 7 coding exons in the PRPS1 gene and ~10bp of adjacent noncoding sequences. This testing strategy will reveal coding sequence changes, splice site mutations and small insertions or deletions in the PRPS1 gene, but will not detect large duplications or deletions of the PRPS1 locus. 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

Individuals with clinical symptoms consistent with PRPS1-related disorders are candidates for testing. Testing is also indicated for family members of patients who have known PRPS1 mutations.


Official Gene Symbol OMIM ID
PRPS1 311850
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Genetic Counselors
  • Arts WF, Loonen MC, Sengers RC, Slooff JL. 1993. X-linked ataxia, weakness, deafness, and loss of vision in early childhood with a fatal course. Ann. Neurol. 33: 535–539. PubMed ID: 8498830
  • de Brouwer AP, Duley JA, Christodoulou J. 2013. Arts Syndrome. In: Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews(®), Seattle (WA): University of Washington, Seattle. PubMed ID: 20301738
  • de Brouwer APM, Bokhoven H van, Nabuurs SB, Arts WF, Christodoulou J, Duley J. 2010. PRPS1 Mutations: Four Distinct Syndromes and Potential Treatment. Am J Hum Genet 86: 506–518. PubMed ID: 20380929
  • García-Pavía P, Torres RJ, Rivero M, Ahmed M, García-Puig J, Becker MA. 2003. Phosphoribosylpyrophosphate synthetase overactivity as a cause of uric acid overproduction in a young woman. Arthritis & Rheumatism 48: 2036–2041. PubMed ID: 12847698
  • Human Gene Mutation Database (Bio-base).
  • Kim H-J, Sohn K-M, Shy ME, Krajewski KM, Hwang M, Park J-H, Jang S-Y, Won H-H, Choi B-O, Hong SH, Kim B-J, Suh Y-L, et al. 2007. Mutations in PRPS1, Which Encodes the Phosphoribosyl Pyrophosphate Synthetase Enzyme Critical for Nucleotide Biosynthesis, Cause Hereditary Peripheral Neuropathy with Hearing Loss and Optic Neuropathy (CMTX5). Am J Hum Genet 81: 552–558. PubMed ID: 17701900
  • Kim J-W, Kim H-J. 2013. Charcot-Marie-Tooth Neuropathy X Type 5. PubMed ID: 20301731
  • Liu X, Han D, Li J, Han B, Ouyang X, Cheng J, Li X, Jin Z, Wang Y, Bitner-Glindzicz M, Kong X, Xu H, et al. 2010. Loss-of-Function Mutations in the PRPS1 Gene Cause a Type of Nonsyndromic X-linked Sensorineural Deafness, DFN2. Am J Hum Genet 86: 65–71. PubMed ID: 20021999
  • Moran R, Kuilenburg ABP, Duley J, Nabuurs SB, Retno-Fitri A, Christodoulou J, Roelofsen J, Yntema HG, Friedman NR, Bokhoven H van, Brouwer APM de. 2012. Phosphoribosylpyrophosphate synthetase superactivity and recurrent infections is caused by a p.Val142Leu mutation in PRS-I. Am. J. Med. Genet. 158A: 455–460. PubMed ID: 22246954
  • Sperling O, Eilam G, Sara-Persky-Brosh, De Vries A. 1972. Accelerated erythrocyte 5-phosphoribosyl-1-pyrophosphate synthesis. A familial abnormality associated with excessive uric acid production and gout. Biochem Med 6: 310–316. PubMed ID: 4340256
  • Synofzik M, Muller vom Hagen J, Haack TB, Wilhelm C, Lindig T, Beck-Wodl S, Nabuurs SB, Kuilenburg AB van, Brouwer AP de, Schols L. 2014. X-linked Charcot-Marie-Tooth disease, Arts syndrome, and prelingual non-syndromic deafness form a disease continuum: evidence from a family with a novel PRPS1 mutation. Orphanet J Rare Dis 9: 24. PubMed ID: 24528855
  • Yuan H, Liu XZ. 2011. DFNX1 Nonsyndromic Hearing Loss and Deafness. PubMed ID: 21834172
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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 10 bases of non-coding DNA flanking the exon are sequenced.

Analytical Validity

As of February 2018, we compared 26.8 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 14 years of our lab operation we have Sanger sequenced roughly 14,300 PCR amplicons. Only one error has been identified, and this was an error in analysis of sequence data.

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 10 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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