Adenosine Deaminase Deficiency via the ADA 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 | |
|---|---|---|---|---|---|
| 7563 | ADA | 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
Adenosine deaminase (ADA) deficiency is a systemic purine metabolic disorder. The clinical severity is variable and dictated by the degree of ADA dysfunction (Arredondo-Vega et al. 1998). Severe ADA deficiency is the most common form with disease onset by six months. Patients have loss of lymphoid tissues (tonsils, lymph nodes), severe combined immunodeficiency (SCID), persistent infections and fail to thrive. Symptom onset typically coincides with decreases in material immunoglobulin levels within the affected infant. About 15% of children with ADA deficiency have delayed onset with symptoms occurring after six months but during the first few years of life. Undiagnosed individuals may survive into the first decade of life but recurrent respiratory infections become more prevalent as affected individuals age. Partial ADA deficiency is a benign form of the disease with patients retaining between 2-50% of normal protein function (Hershfield et al. 2011).
Genetic testing is helpful in differential diagnosis of various SCID disease subtypes. Symptoms of ADA deficiency are also similar to purine nucleoside phosphorylase deficiency. Therefore, an accurate diagnosis is critical for employing the appropriate therapeutics. Enzyme replacement therapy, gene therapy and hematopoietic stem cell transplant have been used to restore T-cell and B-cell function in patients with ADA deficiency (Gaspar et al. 2009; Candotti et al. 2012).
Genetics
ADA deficiency is inherited in an autosomal recessive manner through causative mutations in the ADA gene. ADA deficiency affects an estimated one in 200,000 individuals. To date, mutations in the ADA gene are the lone cause for ADA deficiency (Hershfield et al. 2011). However, mutations in several other genes including RAG1, RAG2, IL2RG, JAK3, DLRE1C, IL7R, CD3D, CD3E, and ZAP70 cause SCID (Piirilä et al. 2006). The distribution of pathogenic variants is about 60% missense, 20% splicing, 9% small indels, 7% nonsense, and 3% large deletions (Santisteban et al. 1993; Santisteban et al. 1995; Arredondo-Vega et al. 1998). Null mutations include non-sense and frame-shift mutations. Deletions are indicative of severe forms of ADA deficiency. Somatic mosaicism has been reported leading to monoallelic reversion of pathogenic mutations and gradual improvements in ADA activity with age (Moncada-Vélez et al. 2011; Arredondo-Vega et al. 2002). Adenosine deaminase is a purine salvage enzyme that catalyzes deoxydenosine and adenosine to deoxyinosin and inosine respectively. Loss of ADA activity results in the accumulation of both deoxyinosine and deoxyadenosinetriphosphate which have deleterious effects in lymphocytes at elevated levels (Hershfield et al. 2011).
Clinical Sensitivity - Sequencing with CNV PG-Select
Mutations in the ADA gene are the only known causes of ADA deficiency. Sequencing is able to detect >95% of mutations (Piirilä et al. 2006). ADA deficiency is responsible for about 15% of all SCID cases.
Testing Strategy
This test provides full coverage of all coding exons of the ADA gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.
Indications for Test
Ideal candidates have biochemical testing showing absence of ADA enzymatic activity in red blood cells. Flow cytometric analysis demonstrating depletion of T-, B-, and natural killer cell lineages differentiates ADA-SCID from other SCID subtypes (Hershfield et al. 2011). Testing is especially recommended for any newborns identified in T-cell receptor excision circles (TRECs) screening (La Marca et al. 2013). Carrier testing is available for individuals with a family history of the disease. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in ADA.
Ideal candidates have biochemical testing showing absence of ADA enzymatic activity in red blood cells. Flow cytometric analysis demonstrating depletion of T-, B-, and natural killer cell lineages differentiates ADA-SCID from other SCID subtypes (Hershfield et al. 2011). Testing is especially recommended for any newborns identified in T-cell receptor excision circles (TRECs) screening (La Marca et al. 2013). Carrier testing is available for individuals with a family history of the disease. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in ADA.
Gene
| Official Gene Symbol | OMIM ID |
|---|---|
| ADA | 608958 |
| Inheritance | Abbreviation |
|---|---|
| Autosomal Dominant | AD |
| Autosomal Recessive | AR |
| X-Linked | XL |
| Mitochondrial | MT |
Disease
| Name | Inheritance | OMIM ID |
|---|---|---|
| Severe Combined Immunodeficiency Due To Ada Deficiency | AR | 102700 |
Related Test
| Name |
|---|
| Familial Hemophagocytic Lymphohistiocytosis (FHL) Panel |
Citations
- Arredondo-Vega FX, Santisteban I, Daniels S, Toutain S, Hershfield MS. 1998. Adenosine deaminase deficiency: genotype-phenotype correlations based on expressed activity of 29 mutant alleles. Am. J. Hum. Genet. 63: 1049–1059. PubMed ID: 9758612
- Candotti F, Shaw KL, Muul L, Carbonaro D, Sokolic R, Choi C, Schurman SH, Garabedian E, Kesserwan C, Jagadeesh GJ, Fu P-Y, Gschweng E, et al. 2012. Gene therapy for adenosine deaminase-deficient severe combined immune deficiency: clinical comparison of retroviral vectors and treatment plans. Blood 120: 3635–3646. PubMed ID: 22968453
- Gaspar HB, Aiuti A, Porta F, Candotti F, Hershfield MS, Notarangelo LD. 2009. How I treat ADA deficiency. Blood 114: 3524–3532. PubMed ID: 19638621
- Hershfield M. 2011. Adenosine Deaminase Deficiency. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews™, Seattle (WA): University of Washington, Seattle. PubMed ID: 20301656
- La Marca G, Canessa C, Giocaliere E, Romano F, Duse M, Malvagia S, Lippi F, Funghini S, Bianchi L, Della Bona ML, Valleriani C, Ombrone D, et al. 2013. Tandem mass spectrometry, but not T-cell receptor excision circle analysis, identifies newborns with late-onset adenosine deaminase deficiency. J. Allergy Clin. Immunol. 131: 1604–1610. PubMed ID: 23280131
- Moncada-Vélez M, Vélez-Ortega A, Orrego J, Santisteban I, Jagadeesh J, Olivares M, Olaya N, Hershfield M, Candotti F, Franco J. 2011. Somatic mosaicism caused by monoallelic reversion of a mutation in T cells of a patient with ADA-SCID and the effects of enzyme replacement therapy on the revertant phenotype. Scand. J. Immunol. 74: 471–481. PubMed ID: 21671975
- Piirilä H, Väliaho J, Vihinen M. 2006. Immunodeficiency mutation databases (IDbases). Hum. Mutat. 27: 1200–1208. PubMed ID: 17004234
- Santisteban I, Arredondo-Vega FX, Kelly S, Debre M, Fischer A, Pérignon JL, Hilman B, elDahr J, Dreyfus DH, Gelfand EW. 1995. Four new adenosine deaminase mutations, altering a zinc-binding histidine, two conserved alanines, and a 5’ splice site. Hum. Mutat. 5: 243–250. PubMed ID: 7599635
- Santisteban I, Arredondo-Vega FX, Kelly S, Mary A, Fischer A, Hummell DS, Lawton A, Sorensen RU, Stiehm ER, Uribe L. 1993. Novel splicing, missense, and deletion mutations in seven adenosine deaminase-deficient patients with late/delayed onset of combined immunodeficiency disease. Contribution of genotype to phenotype. J. Clin. Invest. 92: 2291–2302. PubMed ID: 8227344
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.
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.
- PGnome sequencing panels can be ordered via the myPrevent portal only at this time.
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
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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