Version May 2024
INTRODUCTION — This monograph summarizes the interpretation of genetic testing for ATM, the gene associated with ataxia-telangiectasia. It does not discuss indications for testing and is not intended to replace clinical judgment in the decision to test or in the care of the tested person. These subjects are discussed separately [1].
OVERVIEW
How to read the report — The checklist provides important caveats for genetic testing (table 1). Any result obtained for research or by direct-to-consumer testing that has clinical implications for the tested individual or their relatives should be repeated in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory or comparable accreditation body in other jurisdictions, with verified patient identification.
Genetics — Ataxia-telangiectasia (AT) is an autosomal recessive disorder characterized by progressive cerebellar degeneration, oculocutaneous telangiectasias, immunodeficiency, susceptibility to cancer, and radiation sensitivity. The disorder is caused by biallelic (homozygous or compound heterozygous) pathogenic variants in the ataxia-telangiectasia mutated (ATM) gene on chromosome 11q22, which lead to defective DNA repair mechanisms and genome instability.
The ATM gene product, ATM kinase, is involved in the detection of DNA damage and plays an important role in cell cycle progression.
Biallelic, pathogenic (disease-causing) variants affecting both ATM alleles are required to develop ataxia-telangiectasia. Typically, one pathogenic variant is inherited from each parent.
Heterozygosity for a disease variant affecting one ATM allele increases susceptibility to breast, pancreatic, and possibly other cancers. Therefore, at-risk relatives should be offered genetic counseling so that they can be counseled appropriately about their risks. (See "Overview of hereditary breast and ovarian cancer syndromes", section on 'ATM'.)
CLINICAL FEATURES
Biallelic disease variants — The ataxia-telangiectasia (AT) phenotype results from biallelic loss-of-function variants leading to absent or defective ATM kinase. Individuals may be homozygotes or compound heterozygotes for these disease variants. Symptom severity depends on residual ATM activity, which can be gauged by the type of variant. The following phenotypes are generally recognized (see "Ataxia-telangiectasia", section on 'Clinical manifestations'):
Classic AT — The classic and most severe form of AT usually presents either at birth, with partial combined immunodeficiency, or in early childhood, when progressive cerebellar dysfunction and ocular signs become apparent. Young children develop progressive cerebellar ataxia, abnormal eye movements, extrapyramidal motor dysfunction, and oculocutaneous telangiectasias. Progressive pulmonary disease and lymphoid malignancies are major causes of morbidity and mortality.
Variant AT — Variant AT presents slightly later, by the age of 10 years in most cases, with milder cerebellar dysfunction and extrapyramidal movement disorders (eg, tremor, dystonia). Compared with classic AT, cancer tends to occur later in life and may include a higher proportion of solid tumors.
Disease associations
Neurologic manifestations — Ataxia is often the earliest neurologic manifestation of AT. Mild to moderate cognitive impairment is frequently present early in the course of AT, and cognitive deficits may become more widespread and severe in the later stages of AT [2]. Visual performance progressively deteriorates and patients may have extrapyramidal motor difficulties. (See "Ataxia-telangiectasia", section on 'Neurologic manifestations'.)
Telangiectasias — Telangiectasias of blood vessels are seen primarily in the eyes (on the bulbar conjunctivae) and on exposed areas of the skin, typically the pinnae, nose, face, and neck. Additional skin lesions include café-au-lait macules, hypopigmented macules, melanocytic nevi, and facial papulosquamous rash. (See "Ataxia-telangiectasia", section on 'Telangiectasias and skin findings'.)
Immune deficiency — Immune deficiency, affecting both cellular and humoral immunity, occurs in approximately 70 percent of patients with AT. The most common complication is recurrent sinopulmonary infections. (See "Ataxia-telangiectasia", section on 'Immune deficiency'.)
Pulmonary disease — Progressive pulmonary disease is a major cause of morbidity and mortality in patients with AT. Three major types of pulmonary involvement are seen (see "Ataxia-telangiectasia", section on 'Pulmonary disease'):
●Recurrent sinopulmonary infections and bronchiectasis
●Interstitial lung disease/pulmonary fibrosis
●Neuromuscular abnormalities, including dysphagia, aspiration, and respiratory muscle weakness
Cancer — Above age 10 years, the incidence of cancer in patients with AT is 1 percent per year; overall, approximately 10 to 25 percent of patients will develop malignancy [3-5]. The majority (85 percent) are lymphomas and acute leukemias. Among patients who survive to adulthood (>20 years), there also appears to be an increase in the risk of solid tumors as compared with the general population, including breast, liver, gastric, and esophageal cancers. (See "Ataxia-telangiectasia", section on 'Malignancy'.)
Monoallelic ATM disease variant (AT carrier) — Heterozygotes for a single pathogenic AT variant have none of the classic manifestations of AT, but they are at increased risk for some cancers. It is important to note whether the specific variant identified is associated with a unique profile of cancer risks. However, most ATM pathogenic or likely pathogenic variants are associated with an increased risk for female breast cancer and pancreatic cancer, which can occur at younger ages compared with the general population [6]. The risk for ovarian cancer may also be slightly increased in AT carriers. The risk of other solid cancers (eg, gastric, male breast, colorectal, and melanoma) may also be elevated, but there are insufficient data to provide absolute risks [7]. (See "Ataxia-telangiectasia", section on 'Heterozygotes'.)
MANAGEMENT
Patients with ataxia-telangiectasia
General measures for AT — Management of patients with AT is supportive and symptomatic, as there are no disease-modifying treatments available (algorithm 1) [2,8].
●All patients should undergo at least one comprehensive immunologic evaluation to measure both humoral and cellular immune function. Patients with immunodeficiency require additional preventive measures and should be followed by an immunologist whenever possible.
●Vaccinations that are safe and especially important in patients with AT include pneumococcus, inactivated influenza, human papillomavirus (HPV), and coronavirus disease 2019 (COVID-19). Live vaccines are contraindicated in most patients with AT due to partial combined immunodeficiency.
●Physical and occupational therapy are critical for maintaining the maximum possible level of function. Swallowing function should be evaluated by an experienced team while minimizing radiation exposure.
●Patients require routine chest therapy for secretion clearance, regular monitoring of pulmonary function, and antibiotics for acute infection.
●Diagnostic tests involving radiation exposure, including radiographs and computed tomography (CT), should be avoided when possible.
Cancer screening
●Patients with AT are at increased risk of lymphoid and other malignancies, but protocols for early detection of hematologic malignancies have not been established. Clinicians should maintain heightened awareness for easy bruising, persistently swollen lymph nodes, weight loss, or unexplained fevers.
●Due to the risk of breast cancer in females with AT who survive into adulthood, some experts suggest beginning yearly breast magnetic resonance imaging (MRI) at age 25 years and avoiding mammography in order to limit radiation exposure. (See "Ataxia-telangiectasia", section on 'Cancer surveillance'.)
Use of chemoradiation therapy — Conventional doses of radiotherapy can cause severe reactions and are potentially lethal in patients with AT. Radiotherapy should be performed only in rare circumstances in patients with AT and only with reduced doses and careful monitoring. Patients are also particularly sensitive to chemotherapeutic agents that cause double-stranded breaks in DNA. (See "Ataxia-telangiectasia", section on 'Cancer management'.)
Monoallelic ATM disease variants (AT carriers)
●We typically initiate annual mammography with tomography and annual MRI with contrast, starting at age 40 years [9]. Screening recommendations may be modified based on genotype and family history (algorithm 1). In light of the higher risk of breast cancer associated with the c.7271T>G variant, surveillance may begin at age 25 years with breast MRI and the addition of annual mammography beginning at age 30 [6]. There is insufficient evidence to uniformly recommend risk-reducing mastectomy, although for those with a personal or family history of breast cancer (eg, conferring >20 percent lifetime risk of breast cancer by a model in women without cancer), it may be reasonable for carriers to consider this option. (See "Overview of hereditary breast and ovarian cancer syndromes", section on 'ATM'.)
●For those with a family history of pancreatic cancer, pancreatic cancer screening with endoscopic ultrasound (EUS) and/or contrast-enhanced MRI/magnetic resonance cholangiopancreatography (MRCP) is offered starting at 45 to 50 years of age or 10 years earlier than the earliest exocrine pancreatic cancer diagnosis in the family [9,10]. (See "Familial risk factors for pancreatic cancer and screening of high-risk patients", section on 'Ataxia-telangiectasia' and "Familial risk factors for pancreatic cancer and screening of high-risk patients", section on 'Screening modalities'.)
●Discussion of screening for prostate cancer with annual prostate-specific antigen (PSA) screening beginning at age 40 years, especially in those with a family history of prostate cancer, and after discussing the potential benefits, risks, and limitations with their provider [11]. (See "Genetic risk factors for prostate cancer", section on 'Guidelines from expert groups'.)
●For those who have a family history of ovarian cancer, we discuss the potential risks and benefits of risk-reducing bilateral salpingo-oophorectomy. However, pathogenic variants in ATM do not appear to confer a significantly increased risk for ovarian cancer. (See "Overview of hereditary breast and ovarian cancer syndromes", section on 'ATM'.)
Other important considerations
Reproductive counseling — Preconception counseling is appropriate for individuals with AT and AT carriers who are considering childbearing. Partners of individuals with AT and partners of carriers may elect to undergo genetic testing to determine if any pathogenic or likely pathogenic variants in ATM are present that would confer a risk of AT in offspring. If there is a risk for AT, some may elect to conceive using donor gametes or in vitro fertilization (IVF) with preimplantation genetic testing (PGT). Testing is also available during a pregnancy or after birth.
Genetic testing of at-risk relatives — Full siblings of the index patient with biallelic germline ATM variants have a 25 percent chance of inheriting both ATM variants (and having AT), a 50 percent chance of being a carrier (heterozygote) of a single ATM variant, and a 25 percent chance of being unaffected and not being a carrier. (See 'Genetics' above.)
Genetic counseling and testing should be offered to all at-risk relatives (siblings, parents, children, aunts, and uncles) through a genetics provider or a provider with expertise in genetic evaluation and counseling. (See 'Resources' below.)
IMPLICATIONS OF VARIANTS OF UNCERTAIN SIGNIFICANCE — Individuals with a variant of uncertain significance (VUS) should be managed based on their personal and family history (algorithm 1). For a VUS, new information may become available, and the testing laboratory or other resource should be consulted periodically for updates in classification (eg, annually).
IMPLICATIONS OF A NEGATIVE TEST — Negative testing means no pathogenic or likely pathogenic variants were identified. However, some tests only query a subset of variants; pathogenic variants might still be present. Additional testing for other variants in ATM or in other genes may be needed (algorithm 1). Referral for genetic counseling may be helpful to determine optimal testing.
RESOURCES
UpToDate topics
●Ataxia-telangiectasia (see "Ataxia-telangiectasia")
●Breast cancer (see "Overview of hereditary breast and ovarian cancer syndromes", section on 'ATM')
●Pancreatic cancer (see "Familial risk factors for pancreatic cancer and screening of high-risk patients", section on 'Ataxia-telangiectasia')
Locating a genetics expert
●Genetic counselor – The National Society of Genetic Counselors (NSGC)
●Clinical geneticist – The American College of Medical Genetics and Genomics (ACMG)
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