ATAXIA-TELANGIECTASIA

Ataxia-telangiectasia is an autosomal recessive neurogenetic condition characterized by progressive cerebellar ataxia, telangiectasias, and an increased risk for a variety of cancers in childhood. Carriers have an increased risk to develop cancer in adulthood.

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Ataxia-telangiectasia is an autosomal recessive neurogenetic condition characterized by progressive cerebellar ataxia, telangiectasias, and an increased risk for a variety of cancers in childhood. Carriers have an increased risk to develop cancer in adulthood.

Disease Name 
Ataxia-telangiectasia
Louis-Barr syndrome
Disease Information 

Ataxia-telangiectasia (AT) is an autosomal recessive neurodegenerative disease characterized by progressive cerebellar ataxia, chromosome instability, telangiectasia, sensitivity to ionizing radiation, and a predisposition to cancer, most notably leukemias and lymphomas in childhood.1-3 In addition to the hallmark AT symptoms, other clinical findings can include immunodeficiency, diabetes, choreoathetosis, oculomotoric apraxia, elevated AFP, hypogonadism and accelerated aging.4-6

ATM is the gene responsible for AT. The clinical findings are linked to the gene’s active involvement in numerous critical pathways. Most notably, its role in the cellular response to DNA double-strand breaks, In addition, ATM has an important role in T and B lymphocyte maturation. As such, AT patients can be more susceptible to infections due to immunodeficiency.

Women who are carriers of one ATM mutation can have between a 2-4 fold risk increase for breast cancer.7,8 Some specific mutations (rare missense mutations in the 3’ ATM functional domains) may cause an even higher female breast cancer risk (up to 52-69%).9,10 Mutations in the ATM gene have also been found in patients with hereditary pancreatic cancer; however, the risk for pancreatic cancer is difficult to estimate, and there may be other cancer risks that are not yet well defined.11 Cancer risk estimates for male ATM carriers are not currently available.

Testing Benefits & Indication 

Genetic testing is useful for diagnostic confirmation in symptomatic individuals, and for testing of at-risk asymptomatic family members (including prenatal diagnosis). Molecular confirmation of a diagnosis may help avoid unnecessary testing and procedures, as well as guide recommendations for medical treatment and screening. Genetic testing to identify individuals who have only one ATM mutation may also guide appropriate cancer screening recommendations. 

The American Academy of Pediatrics recommends ATM genetic testing for any of the following:12

  • Any individual who expresses characteristic neurologic features of AT, such as gait ataxia in the first 2-3 years of life, oculomotor signs and dysarthria by school years, and subsequent movement disorders
  • Any individual with one of the following: ocular telangiectasias, elevated α-fetoprotein serum levels after 1 year of age, or spontaneous or x-irradiation-induced chromosomal breakage

ATM analysis may also benefit:

  • Any patient meeting clinical diagnostic criteria for AT for whom genetic confirmation would assist with enrollment on clinical trials, family planning, or other management decisions
  • Any individual with suspected AT who does not yet meet the clinical diagnostic criteria
  • Any individual with a family history of AT
  • Any individual with a personal and/or family history suggestive of hereditary breast and/or pancreatic cancer. These individuals may have previously tested negative for BRCA1/2 mutations or may be considering BRCA genetic testing
Test Description 

ATM coding exons 1-62 and well into the 5’ and 3’ ends of all the introns and untranslated regions are analyzed by sequencing. Gross deletion/duplication analysis determines gene copy number for coding exons 1-62. Clinically significant intronic findings beyond 5 base pairs are always reported. Intronic variants of unknown or unlikely clinical significance are not reported beyond 5 base pairs from the splice junction. Genomic deoxyribonucleic acid (gDNA) is isolated from the patient’s specimen using standardized methodology and quantified. Sequence enrichment of the targeted coding exons and adjacent intronic nucleotides is carried out by a bait-capture methodology, using long biotinylated oligonucleotide probes followed by polymerase chain reaction (PCR) and next generation sequencing (NGS). Sanger sequencing is performed for any regions missing or with insufficient read depth coverage for reliable heterozygous variant detection. Reportable small insertions and deletions, potentially homozygous variants, variants in regions complicated by pseudogene interference, and single nucleotide variant calls not satisfying 100x depth of coverage and 40% het ratio thresholds are verified by Sanger sequencing.13  Gross deletion/duplication analysis of ATM using read-depth from NGS data is also performed. Any copy number changes detected by NGS are confirmed by targeted chromosomal microarray and/or multiplex ligation-dependent probe amplification (MLPA).

Mutation Detection Rate 

Gene sequence analysis of ATM can detect at least one mutation in about 90% of individuals with AT (clinical sensitivity). Our AT test detects >99.9% of sequencing mutations, when present.

Specimen Requirements 

Complete specimen requirements are available here or by downloading the PDF found above in the Quick Links section at the top of this page.

Prenatal testing is available. 

Turnaround Time 
TEST CODE TEST NAME TURNAROUND TIME (weeks)
9014 ATM gene sequence and deletion/duplication analysis 2-3
5600 ATM specific site analysis 1-2

 

Specialty 
Genes 
ATM
References 
  1. Stracker T, et al. The ATM signaling network in development and disease. Frontiers in Genet. 2013; 4:1-19.
  2. Becker-Catania S, et al. Ataxia-telangiectasia: phenotype/genotype studies of ATM protein expression, mutations and radiosensitivity. Mol Gen and Met. 2000; 70:122-133.
  3. Demuth I, et al. New mutations in the ATM gene and clinical data of 25 AT patients. Neurogenetics. 2001; 12:273-282.
  4. Lanvin MF. Ataxia-telangiectasia: from a rare disorder to a paradigm for cell signalling and cancer. Nat Rev Mol Cell Biol. 2008; 9:759-69.
  5. Shafman T, et al. Prevalence of germline truncating mutations in ATM in women with a second breast cancer after radiation therapy for a contralateral tumor. Genes, Chrom and Can. 2000; 27:124-129.
  6. Perry JJ, Tainer JA. All stressed out without ATM kinase. Sci Signal. 2011; 4(167):18.
  7. Easton DF. Cancer risks in A-T heterozygotes. Int J Radiat Biol. 1994; 66(6 Suppl):S177-82.
  8. Thompson D, et al. Cancer risks and mortality in heterozygous ATM mutation carriers. J Natl Cancer Inst. 2005; 97(11):813-22.
  9. Goldgar D, et al. Rare variants in the ATM gene and risk of breast cancer. Breast Cancer Res. 2011; 13(4):R73.
  10. Tavtigian S, et al. Rare, evolutionarily unlikely missense substitutions in ATM confer increased risk of breast cancer. Am J Hum Genet. 2009; 85(4):427-46.
  11. Roberts NJ, et al. ATM mutations in patients with hereditary pancreatic cancer. Cancer Discov. 2012;2(1):41-46.
  12. Cabana M, et al. Consequences of the delayed diagnosis of ataxia-telangiectasia. Pediatrics. 1998; 102(1 Pt 1):98-100.
  13. Mu W, et al. Sanger confirmation is required to achieve optimal sensitivity and specificity in next-generation sequencing panel testing. J Mol Diagn. 2016. 18(6):923-932.