Alpha-Thalassemia X-linked Intellectual Disability Syndrome via the ATRX Gene

  • 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
1695 ATRX$2270.00 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 have been reported (Stevenson et al. 2010). Analytical sensitivity for detection of known ATRX mutations is ~95% as gross duplications are present in a minority of cases and would not be detected by this sequencing method. Our sequencing will also detect the deep intron variant designated c.6218-12574G>A.

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Deletion/Duplication Testing via aCGH

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

The great majority of tests are completed within 20 days.

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).


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).

Testing Strategy

Our DNA sequencing test involves bidirectional Sanger sequencing of the entire ATRX gene plus ~10 bp of flanking non-coding DNA on either side of each exon. We will also sequence any single exon (Test #100) or pair of exons (Test #200) in patients and relatives of patients or to confirm research results. Our sequencing will also detect the deep intronic variant (c.6218-12574G>A) which is known to cause ATRX syndrome (Mitson et al. 2011; Picketts et al. 1996).

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).


Official Gene Symbol OMIM ID
ATRX 300032
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Genetic Counselors
  • 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
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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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