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GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select
for the most up-to-date Resources information.—ED.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Disease characteristics. Ataxia-telangiectasia (A-T) is characterized by progressive cerebellar ataxia beginning between one and four years of age, oculomotor apraxia, frequent infections, choreoathetosis, telangiectasias of the conjunctivae, immunodeficiency, and an increased risk for malignancy, particularly leukemia and lymphoma. Individuals with A-T are unusually sensitive to ionizing radiation.
Diagnosis/testing. Diagnosis of A-T relies upon clinical findings, including slurred speech, truncal ataxia, oculomotor apraxia, family history, and neuroimaging. Testing that supports the diagnosis includes serum alphafetoprotein concentration, which is elevated in more than 95% of individuals with A-T; identification of a 7;14 chromosome translocation on routine karyotype of peripheral blood; the presence of immunodeficiency; and in vitro radiosensitivity assay. Molecular genetic testing of the ATM gene is available on a clinical basis. If the clinical diagnosis can be established with certainty, linkage analysis may be used for genetic counseling of at-risk family members if the specific disease-causing mutations cannot be identified in an affected family member.
Genetic counseling. A-T is inherited in an autosomal recessive manner. Parents of an affected child are obligate carriers of an ATM gene mutation. At conception, the sibs of an affected individual have a 25% chance of being affected, a 50% chance of being asymptomatic carriers, and a 25% chance of being unaffected and not carriers. ATM heterogyzotes (carriers) may have an increased risk of developing cancer. Prenatal testing is available.
A-T is suspected in young children who have signs of progressive cerebellar dysfunction including gait and truncal ataxia, slurred speech, and oculomotor apraxia; the onset of cerebellar dysfunction is usually between one and four years of age. A small cerebellum is often observed on MRI examination but may not be obvious in very young individuals.
Serum concentration of alphafetoprotein (AFP). Serum AFP concentration is elevated above 10 ng/ml in more than 95% of individuals with A-T. Of note, serum AFP concentration may remain above normal in some unaffected children until 24 months of age.
Immunoblotting for ATM protein. To date, the most definitive clinical test for establishing a diagnosis of A-T is immunoblotting to determine whether ATM protein is present in cells. About 90% of individuals with A-T have no detectable ATM protein, approximately 10% have trace amounts, and about 1% have normal amounts that lack ATM protein kinase activity ("kinase-dead"). The results of immunoblotting are not easily quantified, as they depend upon 1) the amount of cell lysate loaded, 2) the titer of the developing antibody to ATM, 3) the time and method of exposure of the autoradiogram, 4) the technique used to compare the densitometry of bands, and 5) the range of sensitivity of the radiographic film. For these reasons, "trace amounts" and "undetectable" ATM protein often overlap. The amount of cell lysate determines the sensitivity of immunoblotting; optimal results are obtained by loading nuclear lysate prepared from at least five million cells, or 25 micrograms of lysate protein [Chun et al 2003]. This is most reliably achieved by first establishing a lymphoblastoid cell line (LCL) on each test sample [personal observation], a procedure requiring four to six weeks and thus prolonging turnaround time. A more efficient procedure should be available in the near future: Butch et al (2004) report the development of a rapid immunoassay to measure ATM protein and determine its sensitivity/specificity for the diagnosis of A-T. Having an LCL also allows for radiosensitivity testing and assessment of kinase activity, and provides a renewable source of RNA and DNA for subsequent identification of ATM mutations — the ultimate confirmation of a molecular diagnosis of A-T.
Either a radiosensitivity assay or a kinase assay can be performed in parallel with immunoblotting. Radiosensitivity testing is somewhat more informative than the kinase assay for identifying those individuals who do not have A-T but may have another DNA repair disorder.
If the ATM protein level is greater than trace amounts and the radiosensitivity is normal, a diagnosis of A-T is excluded.
If the ATM protein level is normal and the radiosensitivity is abnormal, the kinase activity of ATM protein is tested.
Radiosensitivity assay. The colony survival assay (CSA) is an in vitro assay that determines the survival of lymphoblastoid cells following irradiation with 1 Gy [Huo et al 1994, Sun et al 2002]. The test takes approximately three months to complete. The CSA was abnormal in 103 of 104 individuals (99%) who had at least one identifiable ATM mutation. Seven of 104 individuals scored in an intermediate radiosensitivity range that overlaps with the normal range. For such individuals, several radiation exposure doses (1.0, 1.5, and 2.0 Gy) can be administered to obtain a dose-response curve.
ATM kinase activity. The serine/threonine kinase activity of ATM protein can be assessed in various ways, using immunoblotting of cell lysates and commercial antibodies to any phosphorylated ATM target substrate. The most frequently used substrates are p53-serine15, ATM-serine1981, SMC1-serine957, and SMC1-serine966. Cells must first be irradiated to create double-strand DNA breaks; this damage activates ATM kinase activity. Lysates prepared from cell lines established for measuring ATM protein levels or radiosensitivity can be used to evaluate ATM protein serine/threonine kinase activity [Chun et al 2003; Nahas et al, in press]. This activity is difficult to quantify.
If evaluated within 30 minutes after irradiation, ATM kinase activity is undetectable in all situations in which ATM protein levels are undetectable.
ATM kinase activity is markedly reduced in individuals with "kinase-dead" ATM protein (associated with the mutation 7271T→G).
Chromosome analysis. A 7;14 chromosomal translocation is identified in 5-15% of cells in routine chromosomal studies on peripheral blood of individuals with A-T in which lymphocytes are stimulated with phytohemagglutinin (PHA) and harvested at 72 hours. The break points are commonly 14q11 (the T-cell receptor-alpha locus) and 14q32 (the B-cell receptor [IGH] locus). Routine karyotyping may be difficult in individuals with A-T because lymphocytes are decreased in number and do not respond well to PHA, resulting in "no metaphases observed." The difficulty may be partially overcome by adding more PHA and harvesting the cells at 72 hours instead of 48 hours.
Gene. ATM (ataxia-telangiectasia mutated) is the only gene known to be associated with ataxia-telangiectasia.
Molecular genetic testing: Clinical uses
Confirmatory diagnostic testing
Carrier testing
Prenatal diagnosis
Molecular genetic testing: Clinical methods
Sequence analysis. Sequence analysis of the ATM coding region is available on a clinical basis. Sequencing detects about 90% of ATM sequence alterations, but misses intronic mutations and heterozygous deletions. Significant difficulties exist in distinguishing polymorphisms from disease-causing mutations.
Linkage analysis. If two disease-causing mutations have not yet been identified in the index case, linkage studies may sometimes be of value in identifying carriers among family members at risk. Identification of genetic markers linked to the A-T gene in an affected family member and in the individual's parents allows carrier detection in other relatives. The accuracy of linkage testing approaches 100% because at least two of the markers used are intragenic (i.e., lie within the ATM gene).
Molecular genetic testing: Research
Direct DNA. PTT (protein truncation testing) detects approximately 70% of ATM mutations [Telatar et al 1996]. Mutation scanning using DHPLC detects more than 85% of ATM mutations [Bernstein et al 2003].
Ethnic haplotype analysis. In specific well-studied ethnic groups (i.e., Amish, Mennonite, Costa Rican, Spanish, Brazilian, Polish, British, Italian, Turkish, Iranian, Israeli), short-tandem repeat (STR) and single-nucleotide polymorphism (SNP) analysis at 11q22.3 can be used to rapidly identify affected founder haplotypes and the mutations that they carry [Campbell et al 2003, Mitui et al 2003, Coutinho et al 2004].
Table 1 summarizes molecular genetic testing for this disorder.
| Test Method | Mutations Detected | Mutation Detection Rate | Test Availability |
|---|---|---|---|
| Sequence analysis | ATM sequence alterations | >95% | Clinical
 |
| Mutation scanning | 80-85% | Research only | |
| PTT | ATM truncating mutations | ~70% |
Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.
When mutations in a large gene with no "hot spots" are causative, direct sequencing is seldom the most efficient way to establish a diagnosis; therefore, the following assays may be more informative:
Immunoblotting for ATM protein
Radiosensitivity assay
ATM kinase activity
No other phenotypes are associated with mutations in the ATM gene.
The primary features of A-T include progressive gait and truncal ataxia with onset between one and four years of age; progressively slurred speech; oculomotor apraxia, i.e., inability to follow an object across visual fields; choreoathetosis (writhing movements); oculocutaneous telangiectasia, usually by six years of age; frequent infections, with accompanying evidence of serum and cellular immunodeficiencies; susceptibility to cancer, usually leukemia or lymphoma; and hypersensitivity to ionizing radiation. Other features include premature aging with graying of the hair. Endocrine abnormalities, such as insulin-resistant diabetes mellitus, have also been observed. The A-T syndrome varies little from family to family in its late stages. (For clinical reviews, see Boder 1985, Gatti 2002, Perlman et al 2003, Chun & Gatti 2004.)
Cerebellar ataxia. The most obvious and troubling characteristic of A-T is the progressive cerebellar ataxia. Shortly after learning to walk, children with A-T begin to stagger. The neurologic status of some individuals appears to improve from two to four years of age, then ataxia begins to progress again; the transient improvement is probably attributable to the rapid learning curve of young children. The ataxia begins as purely truncal but within several years involves peripheral coordination as well. Slurred speech and oculomotor apraxia are noted early. Both horizontal and vertical saccadic eye movements are affected [Lewis et al 1999, Farr et al 2002]. Choreoathetosis is found in almost all individuals with A-T. Myoclonic jerking and intention tremors are present in about 25% of individuals. Writing is affected by seven or eight years of age. By ten years of age, most individuals become confined to a wheelchair for the remainder of their lives. Deep tendon reflexes are decreased or absent in older individuals; plantar reflexes are upgoing or absent. Drooling is frequent. All teenagers with A-T need help with dressing, eating, washing, and using the toilet. Muscle strength is normal at first but wanes with disuse, especially in the legs. Contractures in fingers and toes are common in older individuals but are preventable through rigorous exercise.
The typical individual with A-T is of normal intelligence, although slow motor and verbal responses make it difficult for individuals to complete IQ tests that are time limited. Many American and British individuals with A-T have finished high school with good grades; some have finished college or university. Occasionally, learning difficulties or mild mental retardation occurs.
Cancer risk. The risk for malignancy in individuals with A-T is 38%. Leukemia and lymphoma account for about 85% of malignancies. Younger children tend to have acute lymphocytic leukemia of T-cell origin and older children are likely to have an aggressive T-cell leukemia. Lymphomas are usually B-cell types. As individuals with A-T begin to live longer, other cancers and tumors, including ovarian cancer, breast cancer, gastric cancer, melanoma, leiomyomas, and sarcomas, have been observed.
Immunodeficiency. Immunodeficiencies are present in 60-80% of individuals with A-T; they are variable and do not correlate well with the frequency, severity or spectrum of infections [Boder 1985, Ersoy et al 1991, Woods & Taylor 1992, Gatti 2002, Nowak-Wegrzyn et al 2004]. The immunodeficiency is seldom progressive. The most consistent immunodeficiency reported is poor antibody response to pneumococcal polysaccharide vaccines [Sanal et al 1999, Nowak-Wegrzyn et al 2004]. Serum concentration of the immunoglobulins IgA, IgE, and IgG2 may be reduced. Approximately 30% of individuals with A-T who have immunodeficiency have T-cell deficiencies. At autopsy, virtually all individuals have a small embryonic-like thymus.
Infection. Unlike most immunodeficiency disorders, the spectrum of infection in individuals with A-T does not comprise opportunistic infections. Some individuals develop chronic bronchiectasis. The frequency and severity of infections correlates more with general nutritional status than with the immune status. Individuals with frequent and severe infections appear to benefit from intravenous immunoglobulin (IVIG) replacement therapy [Nowak-Wegrzyn et al 2004]; however, longevity has increased substantially even in individuals not receiving IVIG.
Lifespan. Over the past twenty years, the expected lifespan of individuals with A-T has increased considerably; most individuals now live beyond 25 years of age. Some have survived into their 40s and 50s [Dork et al 2004]. In older individuals, pulmonary failure, with or without identifiable infections, is a major cause of failing health and death. Life-threatening lymphocytic infiltrations of the lung have been reported [Tangsinmankong et al 2001].
Neuropathology. The cerebellum atrophies early in the disease, being visibly smaller on MRI examination by seven or eight years of age, with concomitant loss of Purkinje cells and depletion of granule cells. Microscopic nucleomegaly also occurs in the cells of tissues throughout the body.
Heterozygotes. The cancer risk of individuals heterozygous for A-T disease-causing mutations is approximately four times that of the general population, primarily because of breast cancer [Swift et al 1991, Easton 1994, Athma et al 1996, FitzGerald et al 1997, Stankovic et al 1998, Geoffroy-Perez et al 2001, Olsen et al 2001, Teraoka et al 2001, Chenevix-Trench et al 2002, Sommer et al 2002, Bernstein et al 2003, Bretsky et al 2003, Thorstenson et al 2003]. Risk for cancer probably depends on multiple factors, such as tumor type, age at cancer onset, and whether the heterozygote carries a missense or a truncating mutation [Gatti et al 2001, Concannon 2002, Scott et al 2002, Spring et al 2002].
ATM mutations have been reported in several forms of leukemia and lymphoma, including acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), T-cell prolymphocytic leukemia (T-PLL), and mantle zone lymphoma [Stankovic et al 1998, Stilgenbauer et al 2000, Fang et al 2003, Yamaguchi et al 2003, Eclache et al 2004]. In general, the spectrum of ATM mutations differs for each of these; breast cancer mutations tend to be different from those seen in individuals with A-T of the host population [Bernstein et al 2003], while ATM mutations of T-ALL cases are similar to those seen in individuals with A-T [Liberzon et al 2004].
Epidemiological studies suggest that A-T carriers are also at an increased risk for heart disease [Swift 1985, Swift et al 1991].
In vitro studies indicate that carriers have intermediate levels of radiosensitivity [Paterson et al 1985]. Heterozygotes appear to have intermediate levels of serine-protein kinase ATM protein; however, accurate measurement of serine-protein kinase ATM is still unavailable for clinical testing [Chun et al 2003, Butch et al 2004].
A mutation at 5762ins137nt is associated with a somewhat slower rate of neurologic deterioration, later onset of symptoms, intermediate radiosensitivity, and little or no cancer risk [Woods & Taylor 1992, McConville et al 1996].
The mutations 7271T→G and 8494C→T have been associated with a milder phenotype and longer lifespan. However, the number of individuals with these mutations and the lack of individuals homozygous for these mutations preclude making statistically significant correlations.
A-T is the most common cause of progressive cerebellar ataxia in childhood in most countries; however, ataxia with oculomotor apraxia (AOA) may be more prevalent in Portugal and perhaps Japan [Nemeth et al 2000, Date et al 2001, Moreira et al 2001]. (See Ataxia with Oculomotor Apraxia Type 1 and Ataxia with Oculomotor Apraxia Type 2.) The prevalence of A-T is one in 40,000-100,000 live births in the US. Prevalence varies with the degree of consanguinity in a country.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Establishing the diagnosis of ataxia-telangiectasia is most difficult in very young children, primarily because the full-blown syndrome is not yet apparent. The most common misdiagnosis is cerebral palsy. Diagnosis of A-T is questionable when accompanied by severe mental retardation, seizures, nonprogressive ataxia, or microcephaly. Other disorders with childhood-onset ataxia are discussed in the Ataxia Overview. Lymphoblastoid cells from individuals with Friedreich ataxia and ataxia with oculomotor apraxia type 1 (AOA1) are not radiosensitive by CSA [Nemeth et al 2000, Moreira et al 2001]. The radiosensitivity of cells from individuals with AOA2 has not yet been documented by CSA but is likely to be normal. See AOA1 and AOA2.
Although radiosensitivity, as measured by CSA, is often used in the diagnosis of A-T, radiosensitivity is also seen in individuals with Nijmegen breakage syndrome, X-linked agammaglobulinemia, Fanconi anemia syndrome [Sun et al 2002; Nahas et al, in press], ligase IV deficiency [O'Driscoll et al 2001], Seckle syndrome [O'Driscoll et al 2001], common variable immunodeficiency, and severe combined immunodeficiency. However, none of these disorders is characterized by ataxia or elevated serum concentration of AFP.
A-T variants. Some individuals have A-T-like findings but do not meet all the diagnostic criteria for A-T, e.g., individuals with progressive ataxia who do not have telangiectasias, and who have normal serum AFP concentration and normal immune function. Screening for ATM serine-protein kinase activity and ATM mutations indicates that most individuals with a variant phenotype do not have A-T. Other A-T-like disorders to consider: Mre11 deficiency (aka ATLD) [Stewart et al 1999, Pitts et al 2001], ataxia with oculomotor apraxia type 1 (AOA1 or aprataxin deficiency) [Moreira et al 2001, Date et al 2001], A-T Fresno, [Curry et al 1989], AOA2 (or senataxin deficiency) [Moreira et al 2004], and Nijmegen breakage syndrome (NBS). Mre11 deficiency, which includes normal serum AFP concentration, radiosensitivity, and ataxia, is very rare (only three families reported to date) [Hernandez et al 1993, Stewart et al 1999, Pitts et al 2001].
No proven treatment is available for delaying the progressive ataxia, dysarthria, and reading problems that result from poor ocular tracking.
Antioxidant (e.g., vitamin E or alpha-lipoic acid) is recommended, although there has been no formal testing for efficacy in individuals with A-T. Alpha-lipoic acid has the theoretical advantage of crossing the blood-brain barrier.
IVIG replacement therapy appears to reduce the number of infections and should be considered for individuals with frequent and severe infections [Nowak-Wegrzyn et al 2004].
Early and continued physical therapy minimizes contractures, which appear in almost all individuals with time and lead to other physical problems.
A wheelchair is usually necessary by ten years of age.
Supportive therapy is available to minimize drooling, choreoathetosis, and ataxia; however, individual responses to specific medications vary.
Individuals with chronic bronchiectasis require aggressive pulmonary hygiene.
It is important to monitor individuals for early signs of malignancy with periodic medical visits.
Immune status does not have to be followed routinely from year to year unless severe recurrent infections occur or immunomodulatory therapy is in progress.
Because cells from individuals with A-T are 30% more sensitive to ionizing radiation than cells from normal individuals, the use of radiotherapy and some radiomimetic chemotherapeutic agents should be monitored carefully; conventional doses are potentially lethal.
New research suggests that: 1) iron chelators, such as the antioxidant epigallocatechin-3-gallate (EGCG), improve genomic stability of Atm-deficient mice [Shackelford et al 2004]; and 2) aminoglycoside antibiotics can induce full-length ATM protein and return of ATM functions to A-T cells in culture carrying certain types of ATM mutations [Lai et al 2004]. Clinical studies are planned.
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Ataxia-telangiectasia is inherited an autosomal recessive manner.
Parents of a proband
The parents are both obligate carriers of an ATM gene mutation.
Heterozygotes (carriers) appear to be at increased risk for cancer and coronary artery disease [Swift 1985, Concannon 2002, Spring et al 2002]. (See Heterozygotes.)
Sibs of a proband
At conception, the sibs of an affected individual have a 25% risk of being affected, a 50% risk of being asymptomatic carriers, and a 25% risk of being unaffected and not carriers.
The unaffected sibs of an affected individual have a 2/3 risk of being heterozygous.
Offspring of a proband. Most individuals with A-T do not reproduce.
Other family members of a proband. Sibs of the proband's parents are at 50% risk of also being carriers.
Carrier testing is available on a clinical basis once the mutation(s) has/have been identified in the proband.
DNA banking. DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA particularly when molecular genetic testing is not available. See DNA Banking for a list of laboratories offering this service.
Prenatal diagnosis for pregnancies at 25% risk is possible. This testing should only be performed if a prior affected family member has a diagnosis of A-T confirmed by molecular studies. DNA extracted from fetal cells usually obtained by amniocentesis at about 15-18 weeks' gestation or chorionic villus sampling (CVS) at about 10-12 weeks' gestation is analyzed. Both disease-causing alleles of an affected family member must be identified or linkage established in the family [Gatti et al 1993] before prenatal testing can be performed.
Prenatal diagnosis by chromosomal breakage studies or by radioresistant DNA synthesis (RDS) has proven unreliable in at least three instances (unpublished) and should be avoided in favor of recent molecular approaches.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
| Gene Symbol | Chromosomal Locus | Protein Name |
|---|---|---|
| ATM | 11q22.3 | Serine-protein kinase ATM |
Data are compiled from the following standard references: Gene symbol from HUGO; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot.
| Gene Symbol | Locus Specific | Entrez Gene | HGMD |
|---|---|---|---|
| ATM | ATM | 472 (MIM No. 607585) | ATM |
For a description of the genomic databases listed, click here.
Normal allelic variants: The normal gene has 3056 amino acids containing 66 (62 coding) exons and 13-kb cDNA.
| Ethnicity | Mutation | Frequency | Rapid Assay |
|---|---|---|---|
| Costa Rican | |||
| [A] [B] [C] [D] [E] [F] [J] | 5908C→T IVS63del17kb 7449G→A(del70) 4507C→T 8264del5 1120C→T 10744A→C | 56 7 12 12 4 2 - | Yes Yes Yes Yes Yes Yes No |
| Polish | |||
| [A] [B] [C] [D] [E] | IVS53-2A→C(del159) 6095G→A(del89) 7010delGT 5932G→T(del88) 5546gelT | 9 7 4.5 4.5 1 4.5 | Yes Yes Yes Yes - |
| Italian | |||
| [A] [B] [S1] [S2] | 751del4 3576G→A 389insT - | 20 7 Sardinia (>95%); Sardinia (<5%) | Yes - Yes - |
| United Kingdom | |||
| [FM1-11] [FM7] [FM10] | - 5762ins137 7637del9 | 73 18 2 15 3 | - Yes Yes |
| N AfricanJews | 103C→T | >99 | Yes |
| Amish | 1563delAG | >99 | Yes |
| Utah Mormon | |||
| [1] [2] [3] | IVS32-12A→G 8494C→T IVS62+1G→A | - - - | - - - |
| African American | |||
| [1] [2] [3] [4] | IVS16-10T→G 2810insCTAG 7327C→T 7926A→C | - - - - | - - - - |
| Japanese | |||
| [A] [B] | 7883del5 IVS33+2T→C | 25 25 | Yes - |
| Norwegian | |||
| [A] | 3245ATC→TGAT | 55 | Yes |
| Turkish | 5 mutations | 31 | - |
| Iranian | 4 mutations | 55 | - |
1. Also found in Mennonites
2. Milder phenotype?
3. Widely disseminated
Normal gene product:
Domains for: PI3 kinase, FAT, leucine zipper, FATC, p53 binding
Binding sites for: c-abl
Other homologies: DNA-PK, ATR/MEC1, MEI41, Rad3, TEL1, FRAP
Substrates for phosphorylation: p53, Chk2, MDM2, 53BP1, SMC1, BRCA1, FANCD2, H2AX, c-abl, nibrin, Mre11, PHAS-1
Functions: senses double-stranded DNA breaks and coordinates cell cycle checkpoints prior to repair
Abnormal gene product:
Serine-protein kinase ATM is absent on immunoblotting in 95% of individuals.
ATM mRNA is present in more than 99% of individuals.
Some mutations, especially missense mutations, produce a "dominant negative" effect.
"Kinase-dead" ATM protein is present in normal amounts in rare (~1%) individuals with A-T.
GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select
for the most up-to-date Resources information.—ED.
A-T Children's Project
668 S Military Trail
Deerfield Beach, FL 33442
Phone: 800-5-HELP-AT (800-543-5728); 954-481-6611
Fax: 954-725-1153
Email: info@atcp.org
www.atcp.org
A-T Medical Research Foundation
5241 Round Meadow Road
Hidden Hills, CA 91302
Phone: 818-704-8146
The A-T Project
3002 Enfield Road
Austin, Texas 78703-3605
Phone: 512-472-4892
Fax: 512-472-4892
Email: A-Tproject@austin.rr.com
www.atproject.org
Genetics of Breast and Ovarian Cancer (PDQ)
Ataxia-Telangiectasia
National Library of Medicine Genetics Home Reference
Ataxia-telangiectasia
NCBI Genes and Disease
Ataxia-telangiectasia
National Ataxia Foundation
2600 Fernbrook Lane; Suite 119
Minneapolis, MN 55447
Phone: 763-553-0020
Fax: 763-553-0167
Email: naf@ataxia.org
www.ataxia.org
Medical Genetics Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
No specific guidelines regarding genetic testing for this disorder have been developed.
