Alpha-Thalassemia X-linked Intellectual Disability Syndrome via the ATRX 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 | |
|---|---|---|---|---|---|
| 9835 | ATRX | 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
Alpha-Thalassemia X-linked Intellectual Disability (ATRX) syndrome is characterized by severe mental retardation, craniofacial abnormalities, genital abnormalities and alpha thalassemia due to mutation in the ATRX gene. Global development delays are common at infancy and in severe cases, cognitive function is profoundly impaired with patients being unable to walk independently or develop significant speech. Craniofacial abnormalities may include upswept frontal hair line, hypertelorism, epicanthic folds, hypotonic facies, and a small triangular upturned nose. Genital abnormalities range from hypospadia to ambiguous genitalia. About 85% of ATRX individuals have lowered Hemoglobin H levels but near normal red blood cell indicies. Mutations in the ATRX gene have been found in phenotypically similar X-linked intellectual disorders, including Carpenter-Waziri syndrome, Holmes-Gang syndrome, and Chudley-Lowre syndrome (Stevenson et al. 2010). Acquired mutations in ATRX have also been found in patients with alpha thalassemia myelodysplastic syndrome (ATMDS), a pre-leukemic condition typically found in elderly men (Steensma et al. 2004), and in low grade glioma (Kannan et al. 2012). Genetic testing is helpful in differential diagnosis of ATRX from other similar X-linked intellectual disorders including Coffin-Lowry Syndrome, MECP2 duplication syndrome and from classical alpha-thalassemia (Stevenson et al. 2010).
Genetics
ATRX is an X-linked recessive disorder with complete penetrance due to mutations in the ATRX gene. Female carriers have been reported to have ATRX syndrome in rare cases due to skewed X-chromosome inactivation (Stevenson et al. 2010). Mutations in the zinc finger domain (exons 7-9) and helicase domain (exons 17-20), with missense being most predominant, occur in more than 80% of individuals with ATRX (Gibbons et al. 2008; Picketts et al. 1996). However, mutations have been found throughout the coding region with nonsense, small insertions, small deletions, and splice site alterations being found in the minority of cases. A deep intronic variant denoted as c.6218-12574G>A has also been reported to cause ATRX syndrome through altered splicing (Picketts et al. 1996). Duplications in the ATRX gene have been reported to be causative for ATRX syndrome and represent <5% of cases (Thienpont et al. 2007). The ATRX protein is a member of the SWI/SNF chromatin remodeling protein family and functions to control telomere stability and chromatin cohesion (Mitson et al. 2011). The ATRX protein forms a complex with the histone chaperone DAXX to regulate gene expression of several genes including HBA1 and HBA2 leading the presence of alpha thalassemia in affected patients (Mitson et al. 2011).
Clinical Sensitivity - Sequencing with CNV PG-Select
Clinical sensitivity cannot be estimated because only a small number of patients have been reported (Stevenson et al. 2010). Analytical sensitivity for detection of known ATRX mutations is >95% (Stevenson et al. 2010. PubMed ID: 14592816).
Testing Strategy
This test provides full coverage of all coding exons of the ATRX gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.
Indications for Test
Patients with clinical features consistent with ATRX syndrome and hemoglobin electrophoresis indicating HbH are candidates for testing. In ~25% cases, female carriers for a pathogenic variant in the ATRX gene exhibit HbH inclusions following brilliant cresyl blue staining. Ideal candidates have a family history of ATRX syndrome. Genetic testing is often helpful in confirming diagnosis of ATRX (Stevenson et al. 2010).
Patients with clinical features consistent with ATRX syndrome and hemoglobin electrophoresis indicating HbH are candidates for testing. In ~25% cases, female carriers for a pathogenic variant in the ATRX gene exhibit HbH inclusions following brilliant cresyl blue staining. Ideal candidates have a family history of ATRX syndrome. Genetic testing is often helpful in confirming diagnosis of ATRX (Stevenson et al. 2010).
Gene
| Official Gene Symbol | OMIM ID |
|---|---|
| ATRX | 300032 |
| Inheritance | Abbreviation |
|---|---|
| Autosomal Dominant | AD |
| Autosomal Recessive | AR |
| X-Linked | XL |
| Mitochondrial | MT |
Diseases
| Name | Inheritance | OMIM ID |
|---|---|---|
| Alpha-Thalassemia Myelodysplasia Syndrome | 300448 | |
| ATR-X Syndrome | XL | 301040 |
Citations
- Gibbons RJ, Wada T, Fisher CA, Malik N, Mitson MJ, Steensma DP, Fryer A, Goudie DR, Krantz ID, Traeger-Synodinos J. 2008. Mutations in the chromatin-associated protein ATRX. Human Mutation 29: 796–802. PubMed ID: 18409179
- Kannan K, Inagaki A, Silber J, Gorovets D, Zhang J, Kastenhuber ER, Heguy A, Petrini JH, Chan TA, Huse JT. 2012. Whole-exome sequencing identifies ATRX mutation as a key molecular determinant in lower-grade glioma. Oncotarget 3: 1194–1203. PubMed ID: 23104868
- Mitson M, Kelley LA, Sternberg MJE, Higgs DR, Gibbons RJ. 2011. Functional significance of mutations in the Snf2 domain of ATRX. Human Molecular Genetics 20: 2603–2610. PubMed ID: 21505078
- Picketts DJ, Higgs DR, Bachoo S, Blake DJ, Quarrell OW, Gibbons RJ. 1996. ATRX encodes a novel member of the SNF2 family of proteins: mutations point to a common mechanism underlying the ATR-X syndrome. Human molecular genetics 5: 1899–1907. PubMed ID: 8968741
- Steensma DP, Higgs DR, Fisher CA, Gibbons RJ. 2004. Acquired somatic ATRX mutations in myelodysplastic syndrome associated with thalassemia (ATMDS) convey a more severe hematologic phenotype than germline ATRX mutations. Blood 103: 2019–2026. PubMed ID: 14592816
- Stevenson RE. 2010. Alpha-Thalassemia X-Linked Intellectual Disability 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: 20301622
- Thienpont B, Ravel T de, Esch H Van, Schoubroeck D Van, Moerman P, Vermeesch JR, Fryns J-P, Froyen G, Lacoste C, Badens C, others. 2007. Partial duplications of the ATRX gene cause the ATR-X syndrome. European Journal of Human Genetics 15: 1094–1097. PubMed ID: 17579672
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
Specimen Requirements and Shipping Details
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