Alnylam Act^® Primary Hyperoxaluria Type 1 Sponsored Testing Program

Primary hyperoxaluria type 1 is a progressive genetic disease that is potentially life-threatening and often presents with calcium oxalate kidney stones. Calcium oxalate crystals are insoluble and toxic and can lead to serious disease manifestations, including recurrent kidney stones, nephrocalcinosis, progressive renal failure, and multiorgan damage from systemic oxalosis once the disease advances. One study estimated that 57% of diagnosed PH1 patients had ESKD by age 40.(1-3)

References:

1. Hoppe B. Nat Rev Nephrol. 2012;8(8):467-475.
2. Milliner DS, Harris PC, Cogal AG, Lieske JC. https://www.ncbi.nlm.nih.gov/books/NBK1283. Updated November 30, 2017. Accessed January 3, 2022.
3. Cochat P, Rumsby G. N Engl J Med. 2013;369(7):649-658.

Primary hyperoxaluria is an autosomal recessive disorder, which comprises three types depending on the causative genes: type 1 (AGXT), type 2 (GRHPR) and type 3 (HOGA1) (Hopp et al. 2015).

AGXT has 11 coding exons that encode the liver peroxisomal enzyme alanine:glyoxylate-aminotransferase (AGT), which catalyzes the conversion of glyoxylate to glycine. Genetic defects of AGXT throughout the whole coding region include missense, nonsense, splicing site pathogenic variants, and small deletion/insertions (Human Gene Mutation Database). Exon-level large deletions involving AGXT have also been reported, but are relatively uncommon.

GRHPR has 9 coding exons that encode the glyoxylate reductase/hydroxypyruvate reductase, which catalyzes the reduction of hydroxypyruvate to D-glycerate, the reduction of glyoxylate to glycolate and the oxidation of D-glycerate to hydroxypyruvate. Genetic defects of GRHPR throughout the whole coding region include missense, nonsense, splicing site pathogenic variants and small deletion/insertions (Human Gene Mutation Database). Exon-level large deletions and duplications involving GRHPR have not been reported.

HOGA1 (formerly DHDPSL) has 7 coding exons that encode the 4-hydroxy-2-oxoglutarate aldolase, which catalyzes the final step in the metabolic pathway of hydroxyproline. Genetic defects of HOGA1 throughout the whole coding region include missense, nonsense, splicing site pathogenic variants and small deletion/insertions (Human Gene Mutation Database). Exon-level large deletions and duplications involving HOGA1 have not been reported.

The Alnylam Act^® program offers testing with either of the following panels.

Primary Hyperoxaluria Panel (3 genes) | Nephrolithiasis Panel (45 genes)

Please note that this program does not offer the ability to reflex to another panel. Please select the panel that is most appropriate for your patient.

This panel provides 100% coverage of all coding exons of the genes listed, plus ~10 bases of flanking noncoding DNA. We define coverage as ≥20X NGS reads or Sanger sequencing.

To learn more about our test methods and limitations, please CLICK HERE.

To be eligible for the Alnylam Act^® PH1 program, patients must have a family history or suspected diagnosis of primary hyperoxaluria with one or more of the following symptoms:

Family history of primary hyperoxaluria

• Or, adult (18 years or older) with either elevated urinary oxalate OR elevated plasma oxalate
• Or, child (less than 18 years old) with one of the following:
  • Failure to thrive and impaired kidney function
  • Nephrolithiasis
  • Nephrocalcinosis
  • Elevated urinary oxalate OR elevated plasma oxalate

Individuals in the US and Canada tested through the Alnylam Act^® program are eligible for optional pre- and post-test genetic counseling to help them understand their test results. This service is provided through GenomeMedical, a third-party genetic counseling service, and is made available by Alnylam at no charge as part of the program.

Pre-test genetic counseling is intended to help the patient learn more about what to expect during the genetic testing process. If the patient receives a negative test result, Genome Medical will provide an educational video explaining the results.

Patients can access genetic counseling by having their healthcare provider complete the pre- and/or post-test genetic counseling section of the PreventionGenetics test requisition form.

Patients will be contacted by GenomeMedical to schedule an appointment, generally within 24-48 hours of receipt of the faxed referral form.

SPECIMEN REQUIREMENTS

Whole Blood

Collect 3 ml - 5 ml of whole blood in EDTA (purple top tube) or ACD (yellow top tube).

Saliva

Oragene™ or GeneFiX™ Saliva Collection kit used according to manufacturer instructions. DNA from saliva specimens is invariably contaminated with microbial and food DNA, which can impact specimen quality and may result in delayed testing and/or the need for a second specimen.

OCD-100 Swab

OCD-100 Buccal Swab used according to manufacturer instructions.

Buccal

Specimens may be shipped at room temperature.

Specimen collection kits: Buccal specimen collection kits, which contain the TRF and the shipping label, may be requested through the kit order form or via the online order form.

SHIPPING AND HANDLING INSTRUCTIONS

Label all specimen containers with the patient's name, date of birth, and/or ID number. At least two identifiers should be listed on specimen containers. Specimen deliveries are accepted Monday-Saturday for all specimen types. Holiday schedules will be posted on our website at least one week prior to major holidays.