PRPS1-Related Disorders via the PRPS1 Gene
Summary and Pricing 
Test Method
Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes| Test Code | Test Copy Genes | Test CPT Code | Gene CPT Codes Copy CPT Code | Base Price | |
|---|---|---|---|---|---|
| 7791 | PRPS1 | 81479 | 81479,81479 | $990 | Order Options and Pricing |
Pricing Comments
Testing run on PG-select capture probes includes CNV analysis for the gene(s) on the panel but does not permit the optional add on of exome-wide CNV analysis. Any of the NGS platforms allow reflex to other clinically relevant genes, up to whole exome or whole genome sequencing depending upon the base platform selected for the initial test.
An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.
This test is also offered via a custom panel (click here) on our exome or genome backbone which permits the optional add on of exome-wide CNV or genome-wide SV analysis.
Turnaround Time
3 weeks on average for standard orders or 2 weeks on average for STAT orders.
Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.
Targeted Testing
For ordering sequencing of targeted known variants, go to our Targeted Variants page.
Clinical Features and Genetics
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).
Genetics
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.
Clinical Sensitivity - Sequencing with CNV PG-Select
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.
Testing Strategy
This test provides full coverage of all coding exons of the PRPS1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.
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.
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.
Gene
| Official Gene Symbol | OMIM ID |
|---|---|
| PRPS1 | 311850 |
| Inheritance | Abbreviation |
|---|---|
| Autosomal Dominant | AD |
| Autosomal Recessive | AR |
| X-Linked | XL |
| Mitochondrial | MT |
Diseases
| Name | Inheritance | OMIM ID |
|---|---|---|
| Arts Syndrome | XL | 301835 |
| Charcot-Marie-Tooth Disease, X-Linked Recessive, Type 5 | XL | 311070 |
| Deafness, X-Linked 1 | XL | 304500 |
| Phosphoribosylpyrophosphate Synthetase Superactivity | XL | 300661 |
Related Tests
| Name |
|---|
| Charcot-Marie-Tooth (CMT) - Axonal Neuropathy Panel |
| Charcot-Marie-Tooth (CMT) - Comprehensive Panel |
Citations
- 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
Ordering/Specimens
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Requisition Form
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- 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
If ordering a Duo or Trio test, the proband and all comparator samples are required to initiate testing. If we do not receive all required samples for the test ordered within 21 days, we will convert the order to the most effective testing strategy with the samples available. Prior authorization and/or billing in place may be impacted by a change in test code.
Specimen Types
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